Interleukin-11 variants and uses thereof

Abstract

The present disclosure relates generally to non-human interleukin 11 (IL-11) variants, methods of producing said non-human IL-11 variants, and methods of using said non-human IL-11 variants for the treatment of an inflammatory or fibrotic disease, disorder, or condition, or a cancer.

Description

Attorney Docket No: 2019493-0008INTERLEUKIN-11 VARIANTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to United States Provisional Application No. 63 / 681,672, filed August 9, 2024, the entirety of which is incorporated herein by reference.SEQUENCE LISTING

[0002] The present application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML file copy, created on August 8, 2025, is named 2019493-0008_SL.xml and is 51,376 bytes in size.BACKGROUND

[0003] Interleukin- 11 (IL-11) is a 19 kDa protein belonging to the interleukin-6 (IL-6) family. IL- 11 is a type-I protein composed of a bundle of four a-helices. IL- 11 forms a hexameric signaling complex including two molecules of IL-11, two molecules of IL-ll’s cognate receptor (IL-llRa), and two molecules of the common gpl30 signaling receptor. Whereas the common gpl30 signaling receptor is ubiquitously expressed and is shared by other members of the IL-6 family, the IL-Ra receptors is expressed only on certain cell types (e.g., macrophages, T cells, megakaryocytes, osteoblasts, epithelial cells, fibroblasts, and endothelia cells).

[0004] Upon binding of IL-11 to IL-llRa and formation of the hexameric signaling complex, Janus kinases (e.g., JAK1 and TYK2) are recruited to the cytoplasmic region of the gpl30 receptor and phosphorylate tyrosine residues on the cytoplasmic region of the gpl30 receptor. These phosphorylated tyrosine residues serve as docking sites for STAT1 and / or STAT3 which are phosphorylated and form homo or heterodimers that translocate to the nucleus to regulate gene transcription. Aberrant IL-11 signaling has been associated with various inflammatory diseases, hematologic diseases, and cancers.

[0005] Studies have identified structural regions of human and murine IL- 11 that are important for IL-11 binding to IL-1 IRa and the gpl30 receptor. Variants including one or more amino acid substitutions have been produced that modify the binding affinities of human IL- 11 and murine IL-11 to IL-1 IRa and / or gpl30 receptor. Such human and murine IL-11 variants can be used as IL-11 antagonists.Page 1 of 8312916101V1Attorney Docket No: 2019493-0008

[0006] However, the structural regions of IL- 11 responsible for mediating IL-llRa or common gpl30 receptor interactions and binding in non-human and non-murine species have not been well characterized. Moreover, studies have shown that administration of recombinant human IL-11 to rodents elicits different, sometimes opposite, biological effects as compared to those observed when administered to humans. Therefore, despite significant sequence conservation across species, the consequence of modifying one or more amino residues in an IL- 11 protein cannot be directly translated between IL- 11 proteins of different species.SUMMARY OF THE INVENTION

[0007] The present disclosure provides IL-11 variants (e.g., muteins) of non-human and non-murine species having one or more amino acid substitutions that modify the binding affinity to the IL-11 receptor (e.g., IL-llRa and / or gpl30) as compared to a reference IL-11 that is a wild-type IL-11 protein from the same non-human and non-murine species.

[0008] In some embodiments, the present disclosure provides a non-human IL-11 variant comprising one or more amino acid substitutions relative to a reference non-human IL- 11, wherein the variant has: at least a 2-fold increased binding affinity to a non-human IL-11 receptor alpha as compared to the reference; and / or at least a 2-fold decreased binding affinity to a non-human gpl30 relative to the reference.

[0009] In some embodiments, a non-human IL-11 variant comprises one or more amino acid substitutions at positions corresponding to positions 58, 59, 60, 61, 62, and / or 147 of SEQ ID NO: 1. In some embodiments, an amino acid substitution at position 58 is from an alanine to a proline (A58P). In some embodiments, an amino acid substitution at position 59 is from a methionine to an alanine (M59A). In some embodiments, an amino acid substitution at position 60 is from a serine to an isoleucine (S60I). In some embodiments, an amino acid substitution at position 61 is from an alanine to aspartic acid (A61D). In some embodiments, an amino acid substitution at position 62 is from a glycine to a tyrosine (G62Y). In some embodiments, an amino substitution at position 147 is from a tryptophan to an alanine (W147A). In some embodiments a non-human IL-11 variant of the present disclosure comprises a combination of any or all of A58P, M59A, S60I, A61D, G62Y, and W147A substitutions.

[0010] In some embodiments, a non-human IL- 11 variant of the present disclosure comprises an A58P substitution, an M59A substitution, an S60I substitution, an A61D substitution, a G62Y substitution, and a W147A substitution.Page 2 of 8312916101V1Attorney Docket No: 2019493-0008

[0011] In some embodiments, a non-human IL-11 variant of the present disclosure is a variant of feline IL-11. In some embodiments, a feline IL-11 variant of the present disclosure further comprises a signal peptide at its N-terminus. In some embodiments, a non-human IL- 11 variant comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 21 or SEQ ID NO: 28.

[0012] In some embodiments, a non-human IL-11 variant of the present disclosure is a variant of canine IL-11. In some embodiments, a canine IL-11 variant of the present disclosure further comprises a signal peptide at its N-terminus. In some embodiments, a non-human IL- 11 variant comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 22 or SEQ ID NO: 29.

[0013] In some embodiments, a non-human IL-11 variant of the present disclosure is a variant of porcine IL-11. In some embodiments, a porcine IL-11 variant of the present disclosure further comprises a signal peptide at its N-terminus. In some embodiments, a non- human IL-11 variant comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 24 or SEQ ID NO: 31.

[0014] In some embodiments, a non-human IL-11 variant of the present disclosure is a variant of camelid IL-11. In some embodiments, a cam elid IL- 11 variant of the present disclosure further comprises a signal peptide at its N-terminus. In some embodiments, a non- human IL-11 variant comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 27.

[0015] In some embodiments, a non-human IL-11 variant of the present disclosure is a variant of caprine IL-11. In some embodiments, a caprine IL- 11 variant of the present disclosure further comprises a signal peptide at its N-terminus. In some embodiments, a non- human IL-11 variant comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 25.Page 3 of 8312916101V1Attorney Docket No: 2019493-0008

[0016] In some embodiments, a non-human IL-11 variant of the present disclosure is a variant of bovine IL-11. In some embodiments, a bovine IL-11 variant of the present disclosure further comprises a signal peptide at its N-terminus. In some embodiments, a non-human IL- 11 variant comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 26 or SEQ ID NO: 32.

[0017] In some embodiments, a non-human IL-11 variant of the present disclosure is a variant of equine IL-11. In some embodiments, an equine IL-11 variant of the present disclosure further comprises a signal peptide at its N-terminus. In some embodiments, a non- human IL-11 variant comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 23 or SEQ ID NO: 30.

[0018] In some embodiments, increased binding affinity to the IL-11 receptor alpha is quantified in vitro using surface plasmon resonance. In some embodiments, decreased binding affinity to gpl30 is quantified in vitro using a competitive enzyme-linked immunosorbent assay.

[0019] In some embodiments, a non-human IL-11 variant of the present disclosure competitively inhibits non-human wild-type IL- 11 -induced STAT3 phosphorylation in non- human macrophages.

[0020] In some embodiments, a non-human IL-11 variant of the present disclosure is PEGylated.

[0021] In some embodiments, the present disclosure also provides a nucleic acid encoding a non-human IL-11 variant described herein and a vector comprising a nucleic acid encoding a non-human IL-11 variant described herein. In some embodiments, the present disclosure provides a cell comprising a nucleic acid encoding a non-human IL-11 variant described herein.

[0022] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a non-human IL-11 variant as described herein and one or more pharmaceutically acceptable carriers, diluents, and / or excipients.Page 4 of 8312916101V1Attorney Docket No: 2019493-0008

[0023] The present disclosure also provides a method of treating an inflammatory disease or condition in a non-human animal, the method comprising administering to said nonhuman animal, an effective amount of a non-human IL-11 variant described herein. In some embodiments, the inflammatory disease or condition is rheumatoid arthritis, multiple sclerosis, or inflammatory bowel disease.

[0024] In some embodiments, the present disclosure provides a method of treating a hematologic disease or condition in a non-human animal, the method comprising administering to said non-human animal, an effective amount of a non-human IL- 11 variant described herein. In some embodiments, a hematologic disease is thrombocytopenia.

[0025] In some embodiments, the present disclosure provides a method of treating a cancer in a non-human animal, the method comprising administering to said non-human animal, an effective amount of a non-human IL- 11 variant described herein.

[0026] In some embodiments, the present disclosure provides a method of manufacturing a medicament comprising combining a non-human IL-11 variant described herein and one or more pharmaceutically acceptable carriers, diluents, and / or excipients.BRIEF DESCRIPTION OF THE DRAWING

[0027] FIG. 1 is a Clustal Omega (1.2.4) multiple sequence alignment of IL-11 from various species including rat, mouse, cynomolgus monkey (cyno monkey), human, horse, bovine, goat, alpaca, pig, canine and feline. indicates that residues in a given position are identical in all sequences in the alignment. indicates conservation between groups of strongly similar properties according to a scoring matrix like Gonnet PAM 250 (score >0.5).Indicates conservation between groups of weaky similar properties (score < 0.5 and > 0). Blank spaces indicate residues at a given position are not conserved.

[0028] FIG. 2 is a schematic illustration of an exemplary Biacore™ assay that captures IL-11 variants on FLAG-tagged IL-llRa (1 pg / ml or 10 pg / ml) immobilized on a Biacore™ CM5 chip. Wild-type IL-11 (IL-11), IL-11 variant, or IL-4 negative control were titrated to quantify binding affinity.

[0029] FIG. 3A is a Biacore™ sensorgram showing binding of feline IL-11 to surface- immobilized feline IL-llRa (1 pg / ml).

[0030] FIG. 3B is a Biacore™ sensorgram showing binding of an exemplary feline IL- 11 variant to surface-immobilized feline IL-llRa (1 pg / ml).Page 5 of 8312916101V1Attorney Docket No: 2019493-0008

[0031] FIG. 3C is a Biacore™ sensorgram showing binding of feline IL-4 (negative control) to surface-immobilized feline IL-llRa (1 pg / ml).

[0032] FIG. 4A is a Biacore™ sensorgram showing binding of feline IL-11 to surface- immobilized feline IL-llRa (10 pg / ml).

[0033] FIG. 4B is a Biacore™ sensorgram showing binding of an exemplary feline IL- 11 variant to surface-immobilized feline IL-llRa (10 pg / ml).

[0034] FIG. 4C is a Biacore™ sensorgram showing binding of feline IL-4 (negative control) to surface-immobilized feline IL-llRa (10 pg / ml).

[0035] FIG. 5A is a Biacore™ sensorgram showing binding of canine IL-11 to surface- immobilized canine IL-llRa (1 pg / ml).

[0036] FIG. 5B is a Biacore™ sensorgram showing binding of an exemplary canine IL-11 variant to surface-immobilized canine IL-llRa (1 pg / ml).

[0037] FIG. 5C is a Biacore™ sensorgram showing binding of canine IL-4 (negative control) to surface-immobilized canine IL-llRa (1 pg / ml).

[0038] FIG. 6A is a Biacore™ sensorgram showing binding of canine IL-11 to surface- immobilized canine IL-llRa (10 pg / ml).

[0039] FIG. 6B is a Biacore™ sensorgram showing binding of an exemplary canine IL-11 variant to surface-immobilized canine IL-llRa (10 pg / ml).

[0040] FIG. 6C is a Biacore™ sensorgram showing binding of canine IL-4 (negative control) to surface-immobilized canine IL-llRa (10 pg / ml).

[0041] FIG. 7 is a schematic illustration of an exemplary ELISA competition assay, whereby, in the presence of gpl30 (Strep-tagged for purification), IL-11 variant (Strep-tagged for purification) competitively blocks binding of IL-11 (His6-tagged) to plate-immobilized IL- llRa.

[0042] FIG. 8A is a line graph showing dose-dependent binding of feline IL-11 in the presence of gpl30 to feline IL-llRa (0 pg / ml or 2 pg / ml) in an ELISA competition assay as depicted in FIG. 7 with various concentrations of anti-His detection antibody (1 :3000, 1 :2000, or 1 : 1000).

[0043] FIG. 8B is a line graph showing dose-dependent binding of feline IL-11 in the presence of gpl30 to feline IL-llRa (0 pg / ml or 4 pg / ml) in an ELISA competition assay as Page 6 of 8312916101V1Attorney Docket No: 2019493-0008 depicted in FIG. 7 with various concentrations of anti-His detection antibody (1 :3000, 1 :2000, or 1 : 1000).

[0044] FIG. 9 is a line graph showing dose-dependent binding of feline IL-11 in the presence or absence of gpl30 to feline IL-llRa (2 pg / ml) in an ELISA competition assay as depicted in FIG. 7.

[0045] FIG. 10 is a line graph showing dose-dependent competitive binding of exemplary feline IL- 11 variant (or feline IL-4, negative control) with wild-type feline IL-4 in the presence of gpl30 to feline IL-llRa (2 pg / ml) in an ELISA competition assay as depicted in FIG. 7

[0046] FIG. 11A is a line graph showing dose-dependent binding of canine IL-11 in the presence of gpl30 to canine IL-llRa (0 pg / ml or 2 pg / ml) in an ELISA competition assay as depicted in FIG. 7 with various concentrations of anti-His detection antibody (1 :3000, 1 :2000, or 1 : 1000).

[0047] FIG. 11B is a line graph showing dose-dependent binding of canine IL-11 in the presence of gpl30 to canine IL-llRa (0 pg / ml or 4 pg / ml) in an ELISA competition assay as depicted in FIG. 7 with various concentrations of anti-His detection antibody (1 :3000, 1 :2000, or 1 : 1000).

[0048] FIG. 12 is a line graph showing dose-dependent competitive binding of exemplary canine IL- 11 variant (or canine IL-4, negative control) with wild-type canine IL-4 in the presence of gpl30 to canine IL-llRa (2 pg / ml) in an ELISA competition assay as depicted in FIG. 7.

[0049] FIG. 13 is a line graph showing STAT3 phosphorylation in Fcwf-4 feline macrophages treated with various concentrations of feline IL-11 for 15 minutes.

[0050] FIG. 14 is a line graph showing STAT3 phosphorylation in Fcwf-4 feline macrophages pre-treated for 30 minutes with various concentrations of exemplary feline IL-11 variant, feline IL-4 (negative control), or buffer (no competitor), then stimulated with 4.34 nM (EC80) of wild-type feline IL- 11 for 15 minutes.DEFINITIONS

[0051] In order for various embodiments described herein to be more readily understood, certain terms are defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference Page 7 of 8312916101V1Attorney Docket No: 2019493-0008 materials referenced herein describe the background of various aspects described herein and provide additional detail regarding its practice are hereby incorporated by reference.

[0052] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “a variant” means one variant or more than one variant.

[0053] About'. As used herein, the term “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In some embodiments, the term “about” refers to a range of values that fall within about 25%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less, in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed about 100% of a possible value).

[0054] Amino acid. In its broadest sense, as used herein, the term “amino acid” refers to a compound and / or substance that can be, is, or has been incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a non-natural amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. “Nonstandard amino acid” refers to any amino acid, other than the standard amino acids, regardless of whether it is prepared synthetically or obtained from a natural source. In some embodiments, an amino acid, including a carboxy- and / or amino-terminal amino acid in a polypeptide, can contain a structural modification as compared with the general structure above. For example, in some embodiments, an amino acid may be modified by methylation, amidation, acetylation, pegylation, glycosylation, phosphorylation, and / or substitution (e.g., of the amino group, the carboxylic acid group, one or more protons, and / or the hydroxyl group) as compared with the general structure. In some embodiments, such modification may, for example, alter the circulating half-life of a polypeptide containing the modified amino acid as compared with one containing an otherwise identical unmodified amino acid. In some embodiments, such modification does not significantly alter a relevant activity of a polypeptide containing the modified amino acid, as compared with one containing an otherwise identical unmodified Page 8 of 8312916101V1Attorney Docket No: 2019493-0008 amino acid. As will be clear from context, in some embodiments, the term “amino acid” may be used to refer to a free amino acid; in some embodiments it may be used to refer to an amino acid residue of a polypeptide.

[0055] Antibody. As used herein, the term “antibody” refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen.

[0056] Associated. Two events or entities are “associated” with one another, as that term is used herein, if the presence, level, degree, type and / or form of one is correlated with that of the other. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of, susceptibility to, severity of, stage of, etc. the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and / or remain in physical proximity with one another. In some embodiments, two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non- covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.

[0057] Binding'. As used herein, the term “binding” refers to a non-covalent association between or among two or more entities, for example a protein (e.g., a cytokine or variant thereof) and its receptor. “Direct” binding involves physical contact between entities or moieties. Indirect binding involves physical interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts - including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0058] Comparable. As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable sets of conditions, circumstances, individuals, orPage 9 of 8312916101V1Attorney Docket No: 2019493-0008 populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.

[0059] Composition'. Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., liquid, solid, gas, or gel.

[0060] Comprising'. A composition or method described herein as “comprising” one or more named elements or steps is open-ended, meaning that the named elements or steps are essential, but other elements or steps may be added within the scope of the composition or method. To avoid prolixity, it is also understood that any composition or method described as “comprising” (or which “comprises”) one or more named elements or steps also describes the corresponding, more limited composition or method “consisting essentially of’ (or which “consists essentially of’) the same named elements or steps, meaning that the composition or method includes the named essential elements or steps and may also include additional elements or steps that do not materially affect the basic and novel characteristic(s) of the composition or method. It is also understood that any composition or method described herein as “comprising” or “consisting essentially of’ one or more named elements or steps also describes the corresponding, more limited, and closed-ended composition or method “consisting of’ (or “consists of’) the named elements or steps to the exclusion of any other unnamed element or step. In any composition or method described herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.

[0061] “Corresponding to”: As used herein, the term “corresponding to” refers to a relationship between two or more entities. For example, the term “corresponding to” may be used to designate the position / identity of a structural element in a compound or composition relative to another compound or composition (e.g., to an appropriate reference compound or composition). For example, in some embodiments, a monomeric residue in a polymer (e.g., an Page 10 of 8312916101V1Attorney Docket No: 2019493-0008 amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as “corresponding to” a residue in an appropriate reference polymer. For example, those of ordinary skill will appreciate that, for purposes of simplicity, residues in a polypeptide are often designated using a canonical numbering system based on a reference related polypeptide, so that an amino acid “corresponding to” a residue at position 190, for example, need not actually be the 190th amino acid in a particular amino acid chain but rather corresponds to the residue found at 190 in the reference polypeptide; those of ordinary skill in the art readily appreciate how to identify “corresponding” amino acids. For example, those skilled in the art will be aware of various sequence alignment strategies, including software programs such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GL SEARCH, Genoogle, HMMER, HHpred / HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE that can be utilized, for example, to identify “corresponding” residues in polypeptides and / or nucleic acids in accordance with the present disclosure. Those of skill in the art will also appreciate that, in some instances, the term “corresponding to” may be used to describe an event or entity that shares a relevant similarity with another event or entity (e.g., an appropriate reference event or entity). To give but one example, a gene or protein in one organism may be described as “corresponding to” a gene or protein from another organism in order to indicate, in some embodiments, that it plays an analogous role or performs an analogous function and / or that it shows a particular degree of sequence identity or homology, or shares a particular characteristic sequence element.

[0062] Derived. In the context of an amino acid sequence (peptide or polypeptide), one amino acid sequence can be “derived from” a designated or reference amino acid sequence (peptide or polypeptide) if it is a structural analogue of the designated or reference amino acid sequence. In some embodiments, an amino acid sequence which is derived from a particular amino acid sequence has an amino acid sequence that is identical, essentially identical or homologous to that particular sequence or a fragment thereof. Amino acid sequences derived from a designated or reference amino acid sequence may be variants of that designated or reference sequence or a fragment thereof.

[0063] Detecting'. The term “detecting” is used broadly herein to include appropriate means of determining the presence or absence of an entity of interest (e.g., an antigen or antigenic fragment) or any form of measurement of an entity of interest in a sample. Thus, “detecting” may include determining, measuring, assessing, or assaying the presence orPage 11 of 8312916101V1Attorney Docket No: 2019493-0008 absence, level, amount, and / or location of an entity of interest. Quantitative and qualitative determinations, measurements or assessments are included, including semi-quantitative. Such determinations, measurements or assessments may be relative, for example when an entity of interest is being detected relative to a control reference, or absolute. As such, the term “quantifying” when used in the context of quantifying an entity of interest can refer to absolute or to relative quantification. Absolute quantification may be accomplished by correlating a detected level of an entity of interest to known control standards (e.g., through generation of a standard curve). Alternatively, relative quantification can be accomplished by comparison of detected levels or amounts between two or more different entities of interest to provide a relative quantification of each of the two or more different entities of interest, i.e., relative to each other.

[0064] Encode'. As used herein, the term “encode” or “encoding” refers to sequence information of a first molecule that guides production of a second molecule having a defined sequence of nucleotides (e.g., a polyribonucleotide) or a defined sequence of amino acids. For example, a DNA molecule can encode an RNA molecule (e.g., by a transcription process that includes a DNA-dependent RNA polymerase enzyme). An RNA molecule can encode a polypeptide (e.g., by a translation process). Thus, a gene, a cDNA, a DNA molecule, or an RNA molecule encodes a polypeptide if transcription and / or translation of said gene, cDNA, DNA molecule, or RNA molecule produces the polypeptide in a cell or other biological system. In some embodiments, a coding region of a polyribonucleotide encoding a target antigen or antigenic fragment refers to a coding strand, the nucleotide sequence of which is identical to the polyribonucleotide sequence of such a target antigen. In some embodiments, a coding region of a polyribonucleotide encoding a target antigen refers to a non-coding strand of such a target antigen, which may be used as a template for transcription of a gene or cDNA.

[0065] Fragment'. As used herein, “fragment” refers to a molecule that is or includes a discrete portion of a reference molecule (sometimes referred to as the “parent” molecule). In some embodiments, a fragment lacks one or more moieties found in the reference molecule. In some embodiments, a fragment is or includes one or more moieties found in the reference agent. In some embodiments, the reference molecule is a polymer such as a polynucleotide or polypeptide. In some embodiments, a fragment of a polymer is or includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more monomeric units (e.g., amino acid Page 12 of 8312916101V1Attorney Docket No: 2019493-0008 residues) of the reference polymer. In some embodiments, a fragment of a polymer is or includes at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more of the monomeric units (e.g., residues) found in the reference polymer. A fragment of a reference polymer is not necessarily identical to a corresponding portion of the reference polymer. For example, a fragment of a reference polymer can be a polymer having a sequence of residues having at least about 5%, 10%, 15%, 20%, 25%, 30%, 25%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity to the reference polymer. A fragment may, or may not, be generated by physical fragmentation of a reference agent. In some instances, a fragment is generated by physical fragmentation of a reference agent. In some instances, a fragment is not generated by physical fragmentation of a reference molecule and can be instead, for example, produced by de novo synthesis or other means.

[0066] Homology. As used herein, the term “homology” or “homolog” refers to the overall relatedness between polypeptide molecules and / or between polynucleotide molecules (e.g., DNA molecules and / or RNA molecules). In some embodiments, polypeptide and / or polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) are considered to be “homologous” to one another if their sequences are at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% identical. In some embodiments, polypeptide molecules and / or polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) are considered to be “homologous” to one another if their sequences are at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% similar (e.g., containing residues with related chemical properties at corresponding positions). For example, as is well known by those of ordinary skill in the art, certain amino acids are typically classified as similar to one another as “hydrophobic” or “hydrophilic” amino acids, and / or as having “polar” or “non-polar” side chains. Substitution of one amino acid for another of the same type may often be considered a “homologous” substitution.

[0067] Increase'. As used herein, the terms “increase,” “enhance,” or “exceed” relate to an overall increase or the ability to cause an overall increase, preferably at least about 5%, Page 13 of 8312916101V1Attorney Docket No: 2019493-0008 at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 150%, at least about 200%, or more as compared to a reference level.

[0068] Linker: As used herein, the term “linker” refers to a portion of a polypeptide that connects different regions, portions, or antigens to one another.

[0069] Mutation: As used herein, the term “mutation” refers to an amino acid substitution, insertion, inversion, or truncation, as compared to a reference polypeptide. Additional mutations, e.g., fusions and indels, are known to those of skill in the art. For example, a mutation refers to a substitution of an amino acid residue, in which one amino acid residue is replaced with another amino acid residue.

[0070] In some embodiments, a mutation may be a conservative amino acid mutation, which refers to a mutation in which one amino acid residue is replaced with another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been generally defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), betabranched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, mutation of a phenylalanine for a tyrosine is considered to be a conservative mutation. Generally, conservative mutations in the sequences of polypeptides and / or antibodies do not abrogate the binding of the polypeptide or antibody to the target binding site. Methods of identifying nucleotide and amino acid conservative substitutions that do not eliminate binding are well-known in the art.

[0071] In some embodiments, a mutation may be a non-conversative amino acid mutation.

[0072] Nucleic acid / Polynucleotide'. As used herein, the terms “nucleic acid” or “polynucleotide” refers to a polymer of at least 10 nucleotides or more. In some embodiments, a nucleic acid is or comprises DNA. In some embodiments, a nucleic acid is or comprises RNA. In some embodiments, a nucleic acid is or comprises peptide nucleic acid (PNA). In some embodiments, a nucleic acid is or comprises a single stranded nucleic acid. In somePage 14 of 8312916101V1Attorney Docket No: 2019493-0008 embodiments, a nucleic acid is or comprises a double-stranded nucleic acid. In some embodiments, a nucleic acid comprises both single and double-stranded portions. In some embodiments, a nucleic acid comprises a backbone that comprises one or more phosphodiester linkages. In some embodiments, a nucleic acid comprises a backbone that comprises both phosphodiester and non-phosphodiester linkages. For example, in some embodiments, a nucleic acid may comprise a backbone that comprises one or more phosphorothioate or 5'-N- phosphoramidite linkages and / or one or more peptide bonds, e.g., as in a “peptide nucleic acid”. In some embodiments, a nucleic acid comprises one or more, or all, natural residues (e.g., adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, a nucleic acid comprises one or more, or all, nonnatural residues. In some embodiments, a non-natural residue comprises a nucleoside analog (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5- methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5- bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, 6-O-methylguanine, 2-thiocytidine, methylated bases, intercalated bases, and combinations thereof). In some embodiments, a non-natural residue comprises one or more modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose) as compared to those in natural residues. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or polypeptide. In some embodiments, a nucleic acid has a nucleotide sequence that comprises one or more introns. In some embodiments, a nucleic acid may be prepared by isolation from a natural source, enzymatic synthesis (e.g., by polymerization based on a complementary template, e.g., in vivo or in vitro), reproduction in a recombinant cell or system, or chemical synthesis. In some embodiments, a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, or 20,000 or more residues or nucleotides long.

[0073] Peptide-. As used herein, the term “peptide refers to oligo- and polypeptides and refers to molecules comprising about two or more, about 3 or more, about 4 or more, about 6Page 15 of 8312916101V1Attorney Docket No: 2019493-0008 or more, about 7 or more, about 8 or more, about 9 or more, about 10 or more, about 12 or more, about 15 or more, or about 20 or more consecutive amino acids linked to one another via peptide bonds.

[0074] Pharmaceutically acceptable'. As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0075] Prevent'. As used herein, the term “prevent” when used in connection with the occurrence of a disease, disorder, or condition described herein (e.g., an inflammatory disease, disorder, or condition; a fibrotic disease, disorder, or condition; or a cancer) refers to reducing the risk of developing a disease, disorder, or condition described herein and / or to delaying onset of one or more characteristics or symptoms of a disease, disorder, or condition described herein

[0076] Polypeptide'. The terms "polypeptide" or protein, as used herein, refer to a polymeric chain of amino acids. In some embodiments, a polypeptide has an amino acid sequence that occurs in nature. In some embodiments, a polypeptide has an amino acid sequence that does not occur in nature. In some embodiments, a polypeptide has an amino acid sequence that is engineered in that it is designed and / or produced through action of the hand of man. In some embodiments, a polypeptide may comprise or consist of natural amino acids, non-natural amino acids, or both. In some embodiments, a polypeptide may comprise or consist of only natural amino acids or only non-natural amino acids. In some embodiments, a polypeptide may comprise D-amino acids, L-amino acids, or both. In some embodiments, a polypeptide may comprise only D-amino acids. In some embodiments, a polypeptide may comprise only L-amino acids. In some embodiments, a polypeptide may include one or more pendant groups or other modifications, e.g., modifying or attached to one or more amino acid side chains, at the polypeptide’s N-terminus, at the polypeptide’s C-terminus, or any combination thereof. In some embodiments, such pendant groups or modifications comprise acetylation, amidation, lipidation, methylation, pegylation, etc., including combinations thereof. In some embodiments, a polypeptide may be cyclic, and / or may comprise a cyclic portion. In some embodiments, a polypeptide is not cyclic and / or does not comprise any cyclic portion. In some embodiments, a polypeptide is linear. In some embodiments, a polypeptide may be or comprise a stapled polypeptide. In some embodiments, the term “polypeptide” may be appended to a name of a reference polypeptide, activity, or structure; in such instances it isPage 16 of 8312916101V1Attorney Docket No: 2019493-0008 used herein to refer to polypeptides that share the relevant activity or structure and thus can be considered to be members of the same class or family of polypeptides. For each such class, the present specification provides and / or those skilled in the art will be aware of exemplary polypeptides within the class whose amino acid sequences and / or functions are known; in some embodiments, such exemplary polypeptides are reference polypeptides for the polypeptide class or family. In some embodiments, a member of a polypeptide class or family shows significant sequence homology or identity with, shares a common sequence motif (e.g., a characteristic sequence element) with, and / or shares a common activity (in some embodiments at a comparable level or within a designated range) with a reference polypeptide of the class; in some embodiments with all polypeptides within the class). For example, in some embodiments, a member polypeptide shows an overall degree of sequence homology or identity with a reference polypeptide that is at least about 30-40%, and is often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in some embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 35 or more amino acids; in some embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or more contiguous amino acids. In some embodiments, a relevant polypeptide may comprise or consist of a fragment of a parent polypeptide.

[0077] Reduce'. As used herein, the terms “reduce,” “decrease,” “inhibit,” or “impair” relate to an overall reduction or the ability to cause an overall reduction, preferably at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% as compared to a reference level. These terms include a complete or essentially complete inhibition, i.e.., a reduction to zero or a reduction to essentially zero.

[0078] Reference'. As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value. In some Page 17 of 8312916101V1Attorney Docket No: 2019493-0008 embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0079] Sequence Identity: As used herein, the term “sequence identity” refers to the overall relatedness between the sequences of polypeptide molecules and / or polynucleotide molecules (e.g., DNA molecules and / or RNA molecules). In some embodiments, polypeptide and / or polynucleotide molecules (e.g., DNA molecules and / or RNA molecules) are considered to be “substantially identical” to one another if their sequences are at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical. Calculation of the percent identity of two polypeptide or nucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In some embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or substantially 100% of the length of a reference sequence. The amino acids (for polypeptides) or nucleotides (for nucleic acids) at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., amino acid or nucleotide) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller, 1989, which has been incorporated into the ALIGN program (version 2.0). In some embodiments, nucleic acid sequence comparisons made with the ALIGN program use a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percentPage 18 of 8312916101V1Attorney Docket No: 2019493-0008 identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix.

[0080] Signal Peptide -. As used herein, the term “signal peptide” (also referred to as a “secretory signal” or “signal sequence”) refers to an amino acid sequence motif that targets associated polypeptides for translocation to a secretory pathway.

[0081] Subject'. As used herein, the term “subject” refers to an organism, for example, a mammal (e.g., a non-human mammal, a cat, a dog, a horse, a cow, a pig, an alpaca, a goat, etc.). In some embodiments, a subject is an adult, adolescent, or pediatric subject. In some embodiments, a subject is suffering from a disease, disorder, or condition described herein (e.g., an inflammatory disease, disorder, or condition; a hematologic disease, disorder, or condition; a fibrotic disease, disorder, or condition; or a cancer). In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a susceptible subject is predisposed to and / or shows an increased risk (as compared to the average risk observed in a reference subject or population) of developing a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms of a disease, disorder, or condition. In some embodiments, a subject does not display a particular symptom (e.g., clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a patient (e.g., a veterinary patient). In some embodiments, a subject is an individual to whom a clinical diagnosis has been made. In some embodiments, a subject is an individual to whom a therapy has been administered.

[0082] Substantially. As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0083] Tag'. As used herein, the term “tag” refers to a peptide or short polypeptide fused to a polypeptide. In some embodiments, a tag is fused to a polypeptide to facilitate purification and / or facilitate detection.

[0084] Treat'. As used herein, the terms “treat,” “treatment,” or “treating” refer to partial or complete alleviation, amelioration, delay of onset of, inhibition, prevention, relief, and / orPage 19 of 8312916101V1Attorney Docket No: 2019493-0008 reduction in incidence and / or severity of one or more symptoms or features of a disease, disorder, and / or condition described herein (e.g., an inflammatory disease, disorder, or condition; a hematologic disease, disorder, or condition; a fibrotic disease, disorder, or condition; or a cancer). In some embodiments, treatment is administered to a subject who does not exhibit signs or features of a disease, disorder, and / or condition (e.g., may be prophylactic). In some embodiments, treatment is administered to a subject who exhibits only early or mild signs or features of a disease, disorder, and / or condition, such as for the purpose of decreasing the risk of developing pathology associated with a disease, disorder, or condition. In some embodiments, treatment is administered to a subject who exhibits established, severe, and / or late-stage signs of a disease, disorder, or condition. In some embodiments, treating comprises administering an IL- 11 variant protein described herein to a subject.

[0085] Wild-type'. As used herein, the term “wild-type,” “wt,” or “native” refers to an amino acid sequence found in nature, including allelic variations. A wild-type amino acid sequence, peptide, or protein, has an amino acid sequence that has not been intentionally modified.

[0086] Variant'. As used herein, the terms “variant” and “mutein” refer to a polypeptide amino acid sequence that differs from a reference amino acid sequence by one or more amino acid substitutions, insertions, deletions, or combination thereof. In some embodiments, a reference amino acid sequence may be a naturally occurring or wild-type (WT) amino acid sequence. In some embodiments, a reference amino acid sequence may be a modified version of a WT amino acid sequence. In some embodiments, a variant has 1 to 25, 5 to 25, 10 to 25, 15 to 25, 20 to 25, 1 to 20, 5 to 20, 10 to 20, 15 to 20, 1 to 15, 5 to 15, 10 to 15, 1 to 10, 5 to 10, or 1 to 5 amino acid substitutions as compared to a reference amino acid sequence. In some embodiments, a variant has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions as compared to a reference amino acid sequence.

[0087] Amino acid substitution variants are characterized by at least one residue in the sequence being removed and another residue being inserted in its place. In some embodiments, amino acid substitutions in a peptide or protein variant are conservative amino acid substitutions, e.g., substitutions of similarly charged or uncharged amino acids. In some embodiments, a conservative amino acid substitution comprises a substitution of one amino acid of a family of related by their side chains with another amino acid in the same family. Naturally occurring amino acids are generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, Page 20 of 8312916101V1Attorney Docket No: 2019493-0008 proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. In some embodiments, conservative amino acid substitutions include substitutions within the following groups: (i) glycine, alanine; (ii) valine, isoleucine, leucine; (iii) aspartic acid, glutamic acid; (iv) asparagine, glutamine; (v) serine, threonine; (vi) lysine, arginine; and (vii) phenylalanine, tyrosine. In some embodiments, amino acid substitutions in a peptide or protein variant are conservative amino acid substitutions

[0088] In some embodiments, the percent sequence identity between a reference amino acid sequence and a variant amino acid sequence will be at least about 60%, at least about 70%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. The degree of percent sequence identity for an amino acid variant region may be at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the entire length of the reference amino acid sequence. In some embodiments, the degree of sequence identity is given for the entire length of a reference amino acid sequence. In some embodiments, alignment for determining sequence identity may be determined using the best sequence alignment, for example, using Align, using standard settings, e.g., EMBOSS: rneedle, Matrix: Blosum62, Gap Open 10.0, Gap Extend 0.5.

[0089] Throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 2, from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 3, from 2 to 4, from 2 to 5, from 2 to 6, from 3 to 4, from 3 to 5, from 3 to 6, from 4 to 5, from 4 to 6, and from 5 to 6; individual numbers within that range, for example, 1, 2, 3, 4, 5 and 6; and fractional numbers within that range, for example, 1.1, 2.22, 3.333, 4.444, 5.9999, etc. This applies regardless of the breadth of the range.Page 21 of 8312916101V1Attorney Docket No: 2019493-0008DETAILED DESCRIPTION

[0090] The present disclosure provides non-human IL- 11 variants for use in treating diseases, disorders, and / or conditions in a non-human animal from which the non-human IL- 11 was derived. Further provided are methods of treating non-human animals comprising administering non-human IL- 11 variants described herein and methods of manufacturing said non-human IL- 11 variants.A. IL-11

[0091] IL-11 is a 19 kDa member of the IL-6 cytokine family. IL-11 is a Type-I protein whose structure is comprised of bundle of four a helices. IL- 11 forms a hexameric signaling complex comprising of the IL-11 protein, IL-llRa, and the common gpl30 receptor in a 2:2:2 stoichiometry. While the gpl30 is ubiquitously expressed and shared amongst the receptors of the IL-6 family cytokines, the cognate IL-Ra is cell type specific (e.g., macrophages, T cells, megakaryocytes, osteoblasts, epithelial cells, fibroblasts, and endothelia cells).

[0092] Canonical IL-11 signaling begins with binding of IL-11 to its cognate receptor, IL-llRa, and formation of the hexameric IL- 11 signaling complex. Complex formation recruits Janus kinases (e.g., JAK1, JAK2, and TYK2) to the cytoplasmic regions of the common gpl30 receptor. JAK recruitment results in phosphorylation of tyrosine residues that serve as docking sites for STAT1 and STAT3 molecules which themselves become phosphorylated and homodimerize or heterodimerize before translocating to the nucleus to regulate gene expression.

[0093] In addition to the classical JAK / STAT signaling pathway, IL- 11 binding to IL- HRa / gpl30 has been reported to activate other pathways including ERK, MAPK, and PI3K pathways. The differential balance of activation of these various signaling pathways in different cell types may contribute to the varying biological responses elicited by IL-11.

[0094] One of IL-ll’s first described biological functions was as a thrombopoietic factor and recombinant human IL-11 was approved by the U.S. Food and Drug Administration for the treatment of platelet level reconstitution post-chemotherapy. However, similar thrombopoietic activities of IL-11 have not been observed in mice. Indeed, the biological activities of human IL-11 and murine IL-11 have been reported to antagonize each other. These observations suggest that there are species-specific structural and biophysical differences in IL- 11 molecules that elicit the activation of differential signaling pathways downstream of the IL- 11 receptor complex.Page 22 of 8312916101V1Attorney Docket No: 2019493-0008

[0095] Among other insights, the present disclosure characterizes the homology of IL- 11 across a number of non-human animal species (see TABLE 2). Despite significant sequence homology between species (see FIG. 1), even small differences between IL-11 derived from different species may result in dramatic differences in biological activity.

[0096] TABLE 1 provides the wild-type amino acid sequences of IL-11 from various mammalian species.TABLE 1: Wild-type IL-11 amino acid sequences from various speciesPage 23 of 8312916101V1Attorney Docket No: 2019493-0008Page 24 of 8312916101V1Attorney Docket No: 2019493-0008TABLE 2: Comparison of Percent Sequence Identities of Various Mammalian IL-111. IL-11 variants

[0097] Structure-function studies have characterized regions of human and murine IL- 11 that appear to be important for receptor binding (e.g., IL-Ra and / or gpl30 binding). For example, substitution of the tryptophan residue at position 147 of human and murine IL-11 has been shown to significantly reduce binding to gpl30 while maintaining binding affinity to IL-Page 25 of 8312916101V1Attorney Docket No: 2019493-0008HRa (see Underhill-Day etal. (2003) Endocrinology 144: 3406-3414, the disclosure of which is herein incorporated by reference in its entirety).

[0098] Studies have also identified residues in the C-terminal end of the D-helix (Asp at position 165; Trp at position 166, Arg at position 169, Leu at position 172, and Leu at position 173) and A-B loop (Met at position 58, Leu at position 64, and Leu at position 67) of human IL-11 that appear to participate in interaction with IL-llRa (see Czypryn et al. (1995) J Biol Chem. 270(2): 978-985; Czypryn et al. (1995) Ann NY Acad Sci. 762: 152-164; Miyadai et al. (1996) Biosci Biotechnol Biochem. 60(3): 541-542; Tacken etal. (1999) Awry Biochem. 265(2): 645-655; and Harmegnies et al. (2003) Biochem J. 375(1): 23-32, the disclosures of each of which are herein incorporated by reference in their entireties).

[0099] W02005014643 describes human IL-11 variants comprising amino acid substitutions at the His at position 182 and the Asp at position 186 resulting in IL- 11 superagonists.

[0100] W02009052588 describes human, murine, and macaques IL-11 variants comprising amino acid substitutions of the sequence AMSAG (SEQ ID NO: 49) at positions 58 to 62 to PAIDY (SEQ ID NO: 36) or FMQIQ (SEQ ID NO: 37), having enhanced binding to IL-llRa, and an amino acid substitution of the Trp at position 147 to Ala (W147A).

[0101] Among the insights provided by the present disclosure is the identification that, despite the significant biological impact of relatively small differences in IL- 11 sequence homology across species, certain amino acid substitutions can modulate the activity of nonhuman IL-11 to enhance non-human IL-llRa binding and / or reduce non-human gpl30 binding.

[0102] In some embodiments, a non-human IL- 11 variant of the present disclosure comprises a non-human IL-11 sequence comprising one or more amino acid substitutions, deletions, insertions, additions, or a combination thereof. In some embodiments, an IL-11 variant of the present disclosure comprises a non-human IL-11 sequence comprising one or more amino acid substitutions. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 1 to 25, 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6 to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 11 to 25, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 24 to 25, 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20, 16 to 20, 17 to 20, 18 to 20, 19 to 20, 1 to 15, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to 15,Page 26 of 8312916101V1Attorney Docket No: 2019493-00088 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, 14 to 15, 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 5, 2 to 5, 3 to 5, or 4 to 5 amino acid substitutions as compared to a reference sequence. In some embodiments, a reference sequence is a wild-type non-human IL-11 amino acid sequence from which the non-human IL-11 variant was derived.

[0103] In some embodiments, a non-human IL-11 variant of the present disclosure comprises 1 amino acid substitution as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 2 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure comprises 3 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 4 amino acid substitutions as compared to a wild-type non- human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 5 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 6 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure comprises 7 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 8 amino acid substitutions as compared to a wild-type non- human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 9 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 10 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non- human IL-11 variant of the present disclosure comprises 11 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 12 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 13 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 14 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure comprises 15 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 16 amino acid substitutions as compared to a wild-typePage 27 of 8312916101V1Attorney Docket No: 2019493-0008 non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 17 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 18 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non- human IL-11 variant of the present disclosure comprises 19 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 20 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 21 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 22 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non- human IL-11 variant of the present disclosure comprises 23 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 24 amino acid substitutions as compared to a wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure comprises 25 amino acid substitutions as compared to a wild-type non-human IL-11.

[0104] In some embodiments, a non-human IL-11 variant of the present disclosure comprises one or more amino acid substitutions that increases binding affinity to a non-human IL-llRa as compared to a reference wild-type non-human IL-11. In some embodiments, a non-human IL- 11 variant of the present disclosure comprises one or more amino acid substitutions that decreases binding affinity to a non-human gpl30 receptor as compared to a reference wild-type non-human IL-11.

[0105] In some embodiments, as compared to a wild-type non-human IL-11, a non- human IL- 11 variant of the present disclosure comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, or a combination thereof. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL-11 variant comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, and an amino acid substitution at position 62. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution a serine at position 60, an amino acid Page 28 of 8312916101V1Attorney Docket No: 2019493-0008 substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, or a combination thereof. In some embodiments, as compared to a wild-type non-human IL- 11, a non-human IL- 11 variant comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution of a serine at position 60, an amino acid substitution of an alanine at position 61, and an amino acid substitution of a glycine at position 62. In some embodiments, as compared to a wild-type non- human IL-11, a non-human IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, or a combination thereof. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL- 11 variant comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution of a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, and an amino acid substitution of a glycine at position 62 to tyrosine. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, or a combination thereof. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL-11 variant comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution of a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, and an amino acid substitution of a glycine at position 62 to glutamine.

[0106] In some embodiments, as compared to a wild-type non-human IL-11, a non- human IL- 11 variant of the present disclosure comprises an amino acid substitution at position 147. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL- 11 variant of the present disclosure comprises an amino acid substitution of a tryptophan at position 147. In some embodiments, as compared to a wild-type non-human IL-11, a non- human IL- 11 variant of the present disclosure comprises an amino acid substitution of a tryptophan at position 147 to alanine.Page 29 of 8312916101V1Attorney Docket No: 2019493-0008

[0107] In some embodiments, as compared to a wild-type non-human IL-11, a nonhuman IL- 11 variant of the present disclosure comprises an amino acid substitution at position58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, an amino acid substitution at position 147, or a combination thereof. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL-11 variant comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, and an amino acid substation at position 147. In some embodiments, as compared to a wild-type non- human IL-11, a non-human IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position59, an amino acid substitution a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, amino acid substitution of a tryptophan at position 147, or a combination thereof. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL-11 variant comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution of a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, and an amino acid substitution of a tryptophan at position 147. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, an amino acid substitution of a tryptophan at position 147 to alanine, or a combination thereof. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL- 11 variant comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution of a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, and an amino acid substitution of a tryptophan at position 147 to alanine. In some embodiments, as compared to a wild-type non- human IL-11, a non-human IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of aPage 30 of 8312916101V1Attorney Docket No: 2019493-0008 methionine at position 59 to methionine, an amino acid substitution a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, an amino acid substitution of a tryptophan at position 147 to alanine, or a combination thereof. In some embodiments, as compared to a wild-type non-human IL-11, a non-human IL-11 variant comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution of a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, and an amino acid substation of a tryptophan at position 147 to alanine.

[0108] In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL- 11 variant comprising 1 to 25, 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6 to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 11 to 25, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 24 to 25, 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20, 16 to 20, 17 to 20, 18 to 20, 19 to 20, 1 to 15, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, 14 to 15, 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 5, 2 to 5, 3 to 5, or 4 to 5 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5.

[0109] In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 1 amino acid substitution as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non- human IL- 11 variant of the present disclosure is a feline IL- 11 variant comprising 2 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 3 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 4 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 5 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some Page 31 of 8312916101V1Attorney Docket No: 2019493-0008 embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 6 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 7 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL- 11 variant comprising 8 amino acid substitutions as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non- human IL- 11 variant of the present disclosure is a feline IL- 11 variant comprising 9 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 10 amino acid substitutions as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 11 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 12 amino acid substitutions as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 13 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non- human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 14 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL- 11 variant comprising 15 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 16 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 17 amino acid substitutions as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 18 amino acid substitutions as compared to a wild-type feline IL-11Page 32 of 8312916101V1Attorney Docket No: 2019493-0008 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a nonhuman IL-11 variant of the present disclosure is a feline IL-11 variant comprising 19 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 20 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 21 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 22 amino acid substitutions as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 23 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non- human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 24 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL-11 variant comprising 25 amino acid substitutions as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5.

[0110] In some embodiments, a feline IL-11 variant of the present disclosure comprises one or more amino acid substitutions that increases binding affinity to a feline IL-llRa as compared to a reference wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5. In some embodiments, a feline IL-11 variant of the present disclosure comprises one or more amino acid substitutions that decreases binding affinity to a feline gpl30 receptor as compared to a reference wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5.[oni] In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant of the present disclosure comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, or a combination thereof. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant comprises an amino acid substitution at position 58, an amino acid substitution Page 33 of 8312916101V1Attorney Docket No: 2019493-0008 at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, and an amino acid substitution at position 62. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL- 11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, or a combination thereof. In some embodiments, as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution of a serine at position 60, an amino acid substitution of an alanine at position 61, and an amino acid substitution of a glycine at position 62. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL- 11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, or a combination thereof. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution of a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, and an amino acid substitution of a glycine at position 62 to tyrosine. In some embodiments, as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, or a combination thereof. In some embodiments, as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution of a serine at position 60 to glutamine, an aminoPage 34 of 8312916101V1Attorney Docket No: 2019493-0008 acid substitution of an alanine at position 61 to isoleucine, and an amino acid substitution of a glycine at position 62 to glutamine.

[0112] In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant of the present disclosure comprises an amino acid substitution at position 147. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL- 11 variant of the present disclosure comprises an amino acid substitution of a tryptophan at position 147. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant of the present disclosure comprises an amino acid substitution of a tryptophan at position 147 to alanine.

[0113] In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant of the present disclosure comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, an amino acid substitution at position 147, or a combination thereof. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, and an amino acid substation at position 147. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL- 11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, amino acid substitution of a tryptophan at position 147, or a combination thereof. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution of a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, and an amino acid substitution of a tryptophan at position 147. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant of the present disclosure comprises an amino acid substitution of an Page 35 of 8312916101V1Attorney Docket No: 2019493-0008 alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, an amino acid substitution of a tryptophan at position 147 to alanine, or a combination thereof. In some embodiments, as compared to a wild-type feline IL- 11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution of a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, and an amino acid substitution of a tryptophan at position 147 to alanine. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, an amino acid substitution of a tryptophan at position 147 to alanine, or a combination thereof. In some embodiments, as compared to a wild-type feline IL-11 having an amino acid sequence according to SEQ ID NO: 5, a feline IL-11 variant comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution of a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, and an amino acid substation of a tryptophan at position 147 to alanine.

[0114] In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL- 11 variant comprising 1 to 25, 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6 to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 11 to 25, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 24 to 25, 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20, 16 to 20, 17 to 20, 18 to 20, 19 to 20, 1 to 15, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, 14 to 15, 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 5, 2 to 5, 3 to 5, or 4 to 5 amino acidPage 36 of 8312916101V1Attorney Docket No: 2019493-0008 substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6.

[0115] In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL- 11 variant comprising 1 amino acid substitution as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 2 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 3 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 4 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 5 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL- 11 variant comprising 6 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non- human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 7 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 8 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 9 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 10 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 11 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 12 amino acid substitutions as compared to a wild-type canine IL-11 having anPage 37 of 8312916101V1Attorney Docket No: 2019493-0008 amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 13 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 14 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 15 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 16 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 17 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 18 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 19 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 20 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 21 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 22 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 23 amino acid substitutions as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11 variant of the present disclosure is a canine IL-11 variant comprising 24 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a non-human IL-11Page 38 of 8312916101V1Attorney Docket No: 2019493-0008 variant of the present disclosure is a canine IL-11 variant comprising 25 amino acid substitutions as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6.

[0116] In some embodiments, a canine IL-11 variant of the present disclosure comprises one or more amino acid substitutions that increases binding affinity to a canine IL- HRa as compared to a reference wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6. In some embodiments, a canine IL-11 variant of the present disclosure comprises one or more amino acid substitutions that decreases binding affinity to a canine gpl30 receptor as compared to a reference wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6.

[0117] In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, or a combination thereof. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, and an amino acid substitution at position 62. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, or a combination thereof. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution of a serine at position 60, an amino acid substitution of an alanine at position 61, and an amino acid substitution of a glycine at position 62. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution a serine at position 60 to Page 39 of 8312916101V1Attorney Docket No: 2019493-0008 isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, or a combination thereof. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution of a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, and an amino acid substitution of a glycine at position 62 to tyrosine. In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, or a combination thereof. In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution of a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, and an amino acid substitution of a glycine at position 62 to glutamine.

[0118] In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution at position 147. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution of a tryptophan at position 147. In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution of a tryptophan at position 147 to alanine.

[0119] In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, an amino acid substitution at position 147, or a Page 40 of 8312916101V1Attorney Docket No: 2019493-0008 combination thereof. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, and an amino acid substation at position 147. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, amino acid substitution of a tryptophan at position 147, or a combination thereof. In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution of a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, and an amino acid substitution of a tryptophan at position 147. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, an amino acid substitution of a tryptophan at position 147 to alanine, or a combination thereof. In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution of a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, and an amino acid substitution of a tryptophan at position 147 to alanine. In some embodiments, as compared to a wild-type canine IL-11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution a serine at position 60 to glutamine, an amino acid substitution of anPage 41 of 8312916101V1Attorney Docket No: 2019493-0008 alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, an amino acid substitution of a tryptophan at position 147 to alanine, or a combination thereof. In some embodiments, as compared to a wild-type canine IL- 11 having an amino acid sequence according to SEQ ID NO: 6, a canine IL-11 variant comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution of a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, and an amino acid substation of a tryptophan at position 147 to alanine.

[0120] In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 1 to 25, 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6 to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 11 to 25, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 24 to 25, 1 to 20, 2 to 20, 3 to 20, 4 to 20, 5 to 20, 6 to 20, 7 to 20, 8 to 20, 9 to 20, 10 to 20, 11 to 20, 12 to 20, 13 to 20, 14 to 20, 15 to 20, 16 to 20, 17 to 20, 18 to 20, 19 to 20, 1 to 15, 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, 14 to 15, 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 1 to 5, 2 to 5, 3 to 5, or 4 to 5 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7.

[0121] In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 1 amino acid substitution as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 2 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 3 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 4 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 5 amino acid substitutions as compared to a wild-type equine (e.g., Page 42 of 8312916101V1Attorney Docket No: 2019493-0008 horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 6 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 7 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 8 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 9 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 10 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 11 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 12 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 13 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 14 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 15 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 16 amino acid substitutions as compared to a wild-type equine (e.g.,Page 43 of 8312916101V1Attorney Docket No: 2019493-0008 horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 17 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 18 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 19 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 20 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 21 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 22 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 23 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 24 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, a non-human IL-11 variant of the present disclosure is an equine (e.g., horse) IL-11 variant comprising 25 amino acid substitutions as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7.

[0122] In some embodiments, an equine IL-11 variant of the present disclosure comprises one or more amino acid substitutions that increases binding affinity to an equine IL- HRa as compared to a reference wild-type equine IL- 11 having an amino acid sequence according to SEQ ID NO: 7. In some embodiments, an equine IL-11 variant of the present disclosure comprises one or more amino acid substitutions that decreases binding affinity to anPage 44 of 8312916101V1Attorney Docket No: 2019493-0008 equine gpl30 receptor as compared to a reference wild-type equine IL-11 having an amino acid sequence according to SEQ ID NO: 7.

[0123] In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant of the present disclosure comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, or a combination thereof. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, and an amino acid substitution at position 62. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL- 11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, or a combination thereof. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution of a serine at position 60, an amino acid substitution of an alanine at position 61, and an amino acid substitution of a glycine at position 62. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, or a combination thereof. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution of a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to asparticPage 45 of 8312916101V1Attorney Docket No: 2019493-0008 acid, and an amino acid substitution of a glycine at position 62 to tyrosine. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, or a combination thereof. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution of a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, and an amino acid substitution of a glycine at position 62 to glutamine.

[0124] In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant of the present disclosure comprises an amino acid substitution at position 147. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant of the present disclosure comprises an amino acid substitution of a tryptophan at position 147. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant of the present disclosure comprises an amino acid substitution of a tryptophan at position 147 to alanine.

[0125] In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant of the present disclosure comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, an amino acid substitution at position 147, or a combination thereof. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant comprises an amino acid substitution at position 58, an amino acid substitution at position 59, an amino acid substitution at position 60, an amino acid substitution at position 61, an amino acid substitution at position 62, and an amino acidPage 46 of 8312916101V1Attorney Docket No: 2019493-0008 substation at position 147. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL- 11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, amino acid substitution of a tryptophan at position 147, or a combination thereof. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant comprises an amino acid substitution of an alanine at position 58, an amino acid substitution of a methionine at position 59, an amino acid substitution of a serine at position 60, an amino acid substitution of an alanine at position 61, an amino acid substitution of a glycine at position 62, and an amino acid substitution of a tryptophan at position 147. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant of the present disclosure comprises an amino acid substitution of an alanine at position58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, an amino acid substitution of a tryptophan at position 147 to alanine, or a combination thereof. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant comprises an amino acid substitution of an alanine at position 58 to proline, an amino acid substitution of a methionine at position 59 to alanine, an amino acid substitution of a serine at position 60 to isoleucine, an amino acid substitution of an alanine at position 61 to aspartic acid, an amino acid substitution of a glycine at position 62 to tyrosine, and an amino acid substitution of a tryptophan at position 147 to alanine. In some embodiments, as compared to a wild-type equine (e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL- 11 variant of the present disclosure comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position59 to methionine, an amino acid substitution a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, an amino acid substitution of a tryptophan at position 147 to alanine, or a combination thereof. In some embodiments, as compared to a wild-type equinePage 47 of 8312916101V1Attorney Docket No: 2019493-0008(e.g., horse) IL-11 having an amino acid sequence according to SEQ ID NO: 7, an equine (e.g., horse) IL-11 variant comprises an amino acid substitution of an alanine at position 58 to phenylalanine, an amino acid substitution of a methionine at position 59 to methionine, an amino acid substitution of a serine at position 60 to glutamine, an amino acid substitution of an alanine at position 61 to isoleucine, an amino acid substitution of a glycine at position 62 to glutamine, and an amino acid substation of a tryptophan at position 147 to alanine.

[0126] In some embodiments, a non-human IL-11 variant of the present disclosure comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity (across its entire length) to any exemplary non-human IL- 11 variant listed in TABLE 3.TABLE 3: Exemplary non-human IL-11 variant amino acid sequencesPage 48 of 8312916101V1Attorney Docket No: 2019493-0008

[0127] In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL- 11 variant comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity (across its entire length) to SEQ ID NO: 21.Page 49 of 8312916101V1Attorney Docket No: 2019493-0008

[0128] In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL- 11 variant comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity (across its entire length) to SEQ ID NO: 22.

[0129] In some embodiments, a non-human IL-11 variant of the present disclosure is a feline IL- 11 variant comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity (across its entire length) to SEQ ID NO: 23.

[0130] In some embodiments, a non-human IL-11 variant of the present disclosure is fused to a peptide tag. In some embodiments, a peptide tag is fused to the C-terminus of a non- human IL-11 variant of the present disclosure. In some embodiments, a peptide tag is fused to the N-terminus of a non-human IL-11 variant of the present disclosure. In some embodiments, a peptide tag is fused to a non-human IL-11 variant of the present disclosure to facilitate purification of the non-human IL- 11 variant using standard protein purification methods. In some embodiments, a peptide tag is fused to a non-human IL-11 variant of the present disclosure to facilitate detection of the non-human IL-11 variant. In some embodiments, a non- human IL-11 variant is fused to a His tag (e.g., 6xHis tag; SEQ ID NO: 33). In some embodiments, a non-human IL-11 variant is fused to a FLAG tag (SEQ ID NO: 34). In some embodiments, a non-human IL-11 variant is fused to a STREP tag (SEQ ID NO: 35). In some embodiments, a peptide tag is fused to a nonOhuman IL-11 variant of the present disclosure via a peptide linker. In some embodiments, a peptide tag is fused to a non-human IL-11 variant of the present disclosure via a GSSG peptide linker (SEQ ID NO: 38).TABLE 4: Exemplary Tags

[0131] In some embodiments, a non-human IL-11 variant of the present disclosure is glycosylated. In some embodiments, a non-human IL-11 variant of the present disclosure comprises one or more substitutions that introduces one or more glycosylation sites as compared to a reference wild-type non-human IL-11. In some embodiments, a non-human IL-Page 50 of 8312916101V1Attorney Docket No: 2019493-000811 variant of the present disclosure comprises one or more substitutions that removes one or more glycosylation sites as compared to a reference wild-type non-human IL-11.

[0132] In some embodiments, a non-human IL-11 variant of the present disclosure is PEGylated.

[0133] In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to IL-llRa that is at least about 1.5 times greater than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to IL-1 IRa that is at least about 1.75 times greater than the binding affinity of a reference wildtype non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to IL-1 IRa that is at least about 2 times greater than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL- 11 variant of the present disclosure is characterized as having a binding affinity to IL-llRa that is at least about 2.25 times greater than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL- 11 variant of the present disclosure is characterized as having a binding affinity to IL-1 IRa that is at least about 2.5 times greater than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to IL-llRa that is at least about 2.75 times greater than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to IL-1 IRa that is at least about 3 times greater than the binding affinity of a reference wild-type non-human IL- 11. In some embodiments, a non-human IL- 11 variant of the present disclosure is characterized as having a binding affinity to IL-llRa that is at least about 4 times greater than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to IL-1 IRa that is at least about 5 times greater than the binding affinity of a reference wild-type non-human IL- 11. In some embodiments, a non-human IL- 11 variant of the present disclosure is characterized as having a binding affinity to IL-llRa that is at least about 7.5 times greater than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to IL-1 IRa that is at least about 10 times greater than the binding affinity of a reference wild-type non-human IL- 11. In some embodiments, a non-human IL- 11 variant of the present disclosure is characterized Page 51 of 8312916101V1Attorney Docket No: 2019493-0008 as having a binding affinity to IL-llRa that is at least about 15 times greater than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to IL-1 IRa that is at least about 20 times greater than the binding affinity of a reference wild-type non-human IL- 11. In some embodiments, the binding affinity of a non-human IL- 11 variant of the present disclosure is quantified using surface plasmon resonance (SPR). In some embodiments, the binding affinity of a non-human IL- 11 variant of the present disclosure is quantified using a competitive binding assay.

[0134] In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 1.5 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 1.75 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 2 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 2.25 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 2.5 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 2.75 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 3 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 4 times lower than the binding affinity of a reference wild-type non- human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 5 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure is characterized as having a binding affinity to gp!30 that is at least about 7.5 times lower than the binding affinity of a reference wild-typePage 52 of 8312916101V1Attorney Docket No: 2019493-0008 non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 10 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non- human IL- 11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 15 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, a non-human IL-11 variant of the present disclosure is characterized as having a binding affinity to gpl30 that is at least about 20 times lower than the binding affinity of a reference wild-type non-human IL-11. In some embodiments, the binding affinity of a non-human IL-11 variant of the present disclosure is quantified using surface plasmon resonance (SPR). In some embodiments, the binding affinity of a non-human IL-11 variant of the present disclosure is quantified using a competitive binding assay.

[0135] In some embodiments, a non-human IL-11 variant of the present disclosure competes with a reference wild-type non-human IL- 11 for binding to a non-human IL-Ra on the surface of a non-human cell. In some embodiments, competitive binding of a non-human IL- 11 variant of the present disclosure reduces non-human wild-type IL- 11 -induced STAT3 phosphorylation in a cell. In some embodiments, competitive binding of a non-human IL- 11 variant of the present disclosure reduces non-human wild-type IL- 11 induced STAT3 phosphorylation by at least 1.25 fold. In some embodiments, competitive binding of a non- human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 1.5 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 1.75 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 2 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 2.25 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 2.5 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 2.75 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 3 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 inducedPage 53 of 8312916101V1Attorney Docket No: 2019493-0008STAT3 phosphorylation by at least 4 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 5 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 7.5 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 10 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 15 fold. In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation by at least 20 fold. In some embodiments, a non-human cell is a macrophage, T cell, megakaryocyte, osteoblast, epithelial cell, fibroblast, or endothelial cell.

[0136] In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation in a non-human cell by about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 40% to about 70%, about 50% to about 70%, about 60% to about 70%, about 5% to about 60%, about 10% to about 60%, about 15% to about 60%, about 20% to about 60%, about 25% to about 60%, about 30% to about 60%, about 40% to about 60%, about 50% to about 60%, about 5% to about 50%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 25% to about 50%, about 30% to about 50%, about 40% to about 50%, about 50% to about 50%, about 60% to about 50%, about 70% to about 50%, about 5% to about 40%, about 10% to about 40%, about 15% to about 40%, about 20% to about 40%, about 25% to about 40%, about 30% to about 40%, about 5% to about 30%, about 10% toPage 54 of 8312916101V1Attorney Docket No: 2019493-0008 about 30%, about 15% to about 30%, about 20% to about 30%, about 25% to about 30%, about 5% to about 20%, about 10% to about 20%, about 15% to about 20%, or about 5% to about 10%. In some embodiments, competitive binding of a non-human IL- 11 variant of the present disclosure reduces non-human wild-type IL-11 induced STAT3 phosphorylation in a non- human cell by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, a non-human cell is a macrophage, T cell, megakaryocyte, osteoblast, epithelial cell, fibroblast, or endothelial cell.

[0137] In some embodiments, competitive binding of a non-human IL-11 variant of the present disclosure reduces non-human wild-type IL-11 induced cytokine production in a non- human immune cell by about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 90% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 80% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, about 60% to about 80%, about 70% to about 80%, about 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 40% to about 70%, about 50% to about 70%, about 60% to about 70%, about 5% to about 60%, about 10% to about 60%, about 15% to about 60%, about 20% to about 60%, about 25% to about 60%, about 30% to about 60%, about 40% to about 60%, about 50% to about 60%, about 5% to about 50%, about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 25% to about 50%, about 30% to about 50%, about 40% to about 50%, about 50% to about 50%, about 60% to about 50%, about 70% to about 50%, about 5% to about 40%, about 10% to about 40%, about 15% to about 40%, about 20% to about 40%, about 25% to about 40%, about 30% to about 40%, about 5% to about 30%, about 10% to about 30%, about 15% to about 30%, about 20% to about 30%, about 25% to about 30%, about 5% to about 20%, about 10% to about 20%, about 15% to about 20%, or about 5% to about 10%. In some embodiments, competitive binding of a non-human IL- 11 variant of the presentPage 55 of 8312916101V1Attorney Docket No: 2019493-0008 disclosure reduces non-human wild-type IL- 11 induced cytokine production in a non-human immune cell by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, a non-human immune cell is a macrophage or T cell. In some embodiments, a non-human wild-type IL-11 induced cytokine is TNFa, IL-ip, or IL-12.B. POLYNUCLEOTIDES

[0138] Provided herein, among other things, are polynucleotides encoding non-human IL-11 variants described herein. In some embodiments, a polynucleotide encodes a non-human IL- 11 variant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity (across the entire length) to an amino sequence according to any non-human IL-11 variant described in TABLE 3. In some embodiments, a polynucleotide encodes a non-human IL-11 variant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity (across the entire length) to an amino sequence according to SEQ ID NO: 21. In some embodiments, a polynucleotide encodes a non-human IL-11 variant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity (across the entire length) to an amino sequence according to SEQ ID NO: 22. In some embodiments, a polynucleotide encodes a non-human IL-11 variant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity (across the entire length) to an amino sequence according to SEQ ID NO: 23. Such polynucleotides may be present in a vector. Such polynucleotides may be present in the genome of a cell, e.g., a cell of a non-human subject in need of treatment or a cell for production of a non-human IL- 11 variant described herein.

[0139] Polynucleotides encoding non-human IL-11 variants described herein may be modified to include codons that are optimized for expression in a particular cell type or organism. Codon optimized sequences are synthetic sequences, and preferably encode an identical polypeptide encoded by a non-codon optimized parent polynucleotide. In some embodiments, a coding region of a polynucleotide encoding a non-human IL-11 variant Page 56 of 8312916101V1Attorney Docket No: 2019493-0008 described herein, in whole or in part, may include an altered sequence to optimize codon usage for a particular cell type (e.g., a eukaryotic or prokaryotic cell). For example, a coding sequence for a feline, canine, or equine IL-11 variant as described herein may be optimized for expression in a bacterial cell. Alternatively, the coding sequence may be optimized for expression in a mammalian cell. Such a sequence may be described as a codon-optimized sequence.

[0140] Polynucleotides described herein may be inserted into an expression vector or viral vector by methods known to the art, and polynucleotides may be operably linked to an expression control sequence. In some embodiments, the present disclosure provides a vector comprising a nucleic acid encoding a non-human IL-11 variant described herein. Nucleic acids or fragments thereof described herein can be cloned into any suitable vector and can be used to transform or transfect any suitable host. Selection of vectors and methods to construct them may be known to one of skill in the art (see, e.g., “Recombinant DNA Part D,” Methods in Enzymology, Vol. 153, Wu and Grossman, eds., Academic Press (1987)).

[0141] Conventional techniques including, for example, electrophoresis, calcium phosphate precipitation, DEAE-dextran transfection, or lipofection, may be used to introduce a foreign nucleic acid (e.g., DNA or RNA) into a prokaryotic or eukaryotic host cell. Desirably, a vector may include regulatory sequences, such as transcription and / or translation initiation and / or termination codons, which are specific to the type of host (e.g., bacterium, fungus, plant, or animal) into which a vector is to be introduced, as appropriate and taking into consideration whether a vector is DNA or RNA. In some embodiments, a vector comprises regulatory sequences that are specific to a genus of a host cell. In some embodiments, a vector comprises regulatory sequences that are specific to a species of a host.

[0142] An expression vector can comprise a native or non-native promoter operably linked to an isolated or purified polynucleotide described herein. Promoters may be considered relatively strong, relatively weak, inducible, tissue-specific, and / or developmental-specific. A polynucleotide described herein may be combined with a promoter described herein.

[0143] Suitable vectors include those designed for propagation and expansion and / or for expression. For example, a cloning vector may be selected from the pUC series, the pBluescript series (Stratagene, LaJolla, Calif.), the pET series (Novagen, Madison, Wis.), the pGEX series (Pharmacia Biotech, Uppsala, Sweden), or the pEX series (Clontech, Palo Alto, Calif.). Bacteriophage vectors, such as ZGT10, ZGT11, XZapII (Stratagene), ZEMBL4, andPage 57 of 8312916101V1Attorney Docket No: 2019493-0008XNM1149, may be used. Examples of plant expression vectors that can be used include pBIHO, pBI101.2, pBI101.3, pBI121, or pBIN19 (Clontech). Examples of animal expression vectors that can be used include pEUK-Cl, pMAM, or pMAMneo (Clontech). The TOPO cloning system (Invitrogen, Carlsbad, Calif.) also can be used in accordance with the manufacturer's recommendations.

[0144] Additional nucleic acid sequences can be added to such cloning and / or expression nucleic acid sequences to optimize their function in cloning and / or expression, to aid in isolation of a polynucleotide encoding a non-human IL-11 variant described herein, or to improve introduction of a nucleic acid into a cell. Use of cloning vectors, expression vectors, adapters, and linkers have been described (see, e.g., Sambrook et al., 1989, “Molecular Cloning, a Laboratory Manual,” 2ndedition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y.; and Ausubel et al., 1994, “Current Protocols in Molecular Biology,” Greene Publishing Associates and John Wiley & Sons, New York, N.Y, each of which is hereby incorporated by reference in its entirety).

[0145] In some embodiments, polynucleotides and vectors described herein are isolated and / or purified. Provided herein, among other things, is a composition comprising an isolated or purified polynucleotide, optionally in the form of a vector. Isolated polynucleotide and vectors may be prepared using standard techniques including, for example, alkali / SDS treatment, CsCl binding, column chromatography, agarose gel electrophoresis, and / or other techniques. The composition can comprise other components as described further herein.

[0146] Methods known to one skilled in the art for the insertion of nucleic acids into a vector may be used to construct expression vectors encoding a non-human IL- 11 variant described herein under control of transcriptional and / or translational control signals. These methods may include in vitro recombinant DNA and synthetic techniques and in vivo recombination (see, e.g., Ausubel, supra or Sambrook, supra).C. PHARMACEUTICAL COMPOSITION

[0147] In some embodiments, the present disclosure provides compositions, e.g., pharmaceutical compositions, comprising a non-human IL-11 variant described herein. A pharmaceutical composition may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suitedPage 58 of 8312916101V1Attorney Docket No: 2019493-0008 to the particular dosage form desired. Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure.

[0148] In some embodiments, an excipient is approved for veterinary use. In some embodiments, an excipient is approved by the United States Food and Drug Administration. In some embodiments, an excipient is pharmaceutical grade. In some embodiments, an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia.

[0149] Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Such excipients may optionally be included in pharmaceutical compositions. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and / or perfuming agents can be present in the composition, according to the judgment of the formulator.

[0150] General considerations in the formulation and / or manufacture of pharmaceutical agents may be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference).

[0151] In some embodiments, pharmaceutical compositions provided herein may be formulated with one or more pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference).

[0152] In some embodiments, a pharmaceutical composition provided herein may be formulated with one or more buffer systems. In some embodiments, a buffer system may include a 2-amino-2-(hydroxymethyl)propate-l, 3-dial (Tris), phosphate, 2-[4-(2- hydroxyethyl)piperazin-l-yl]ethanesulfonic acid (HEPES), acetate, or histidine buffer system.Page 59 of 8312916101V1Attorney Docket No: 2019493-0008In some embodiments, a pharmaceutical composition disclosed herein includes a Tris buffer. In some embodiments, a pharmaceutical composition disclosed herein includes a phosphate buffer (e.g., phosphate buffered saline (PBS)).

[0153] In some embodiments, a pharmaceutical composition of the present disclosure comprises a non-human IL-11 variant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity (across its entire length) to an amino acid sequence according to any non-human IL- 11 variant described in TABLE 3

[0154] In some embodiments, a pharmaceutical composition of the present disclosure comprises a feline IL-11 variant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity (across its entire length) to an amino acid sequence according to SEQ ID NO: 21, and a pharmaceutically acceptable carrier and / or excipient.

[0155] In some embodiments, a pharmaceutical composition of the present disclosure comprises a canine IL-11 variant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity (across its entire length) to an amino acid sequence according to SEQ ID NO: 22, and a pharmaceutically acceptable carrier and / or excipient.

[0156] In some embodiments, a pharmaceutical composition of the present disclosure comprises a equine IL- 11 variant comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity (across its entire length) to an amino acid sequence according to SEQ ID NO: 23, and a pharmaceutically acceptable carrier and / or excipient.

[0157] Pharmaceutical compositions described herein can be administered by appropriate methods known in the art. As will be appreciated by a skilled artisan, the route and / or mode of administration may depend on a number of factors, including, e.g., but not limited to stability and / or pharmacokinetics and / or pharmacodynamics of pharmaceutical compositions described herein.Page 60 of 8312916101V1Attorney Docket No: 2019493-0008

[0158] In some embodiments, pharmaceutical compositions described herein are formulated for parenteral administration, which includes modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, subcuticular, or intraarticular injection and infusion. In preferred embodiments, pharmaceutical compositions described herein are formulated for intravenous, intramuscular, or subcutaneous administration.D. CELLS

[0159] In some embodiments, the present disclosure provides host cell lines transformed with vectors described herein that encode non-human IL- 11 variants. Host cell lines include, but are not limited to, bacterial cells, such as E. coli, insect cells, and mammalian cell lines.

[0160] Mammalian cell lines available as hosts for expression are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC), including: Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells, and various other cell lines. Mammalian host cells include cat, dog, human, mouse, rat, monkey, pig, goat, bovine, horse and hamster cells. Cell lines of particular preference are selected through determining which cell lines have high expression levels. Other cell lines that may be used are insect cell lines, such as Sf9. cells, amphibian cells, bacterial cells, plant cells and fungal cells.E. METHODS OF PRODUCING NON-HUMAN IL-11 VARIANTS

[0161] When recombinant expression vectors encoding non-human IL- 11 variants of the present disclosure are introduced into host cells, the variants are produced by culturing the host cells for a period of time sufficient to allow for expression of the non-human IL-11 variant in the host cells or, more preferably, secretion of the non-human IL-11 variant into the culture medium in which the host cells are grown. Non-human IL- 11 variants may be recovered from culture medium using standard protein purification methods. For example, in some embodiments, non-human IL-11 variants may be recovered from culture medium using an affinity chromatography column that binds to a peptide tag (as described in TABLE 4) that is fused to the non-human IL- 11 variant.Page 61 of 8312916101V1Attorney Docket No: 2019493-0008F. METHODS OF TREATMENT

[0162] In some embodiments, the present disclosure provides methods of treating or preventing an inflammatory disease, disorder, or condition; a fibrotic disease, disorder, or condition; or a cancer in a non-human subject comprising administering a non-human IL-11 variant described herein to the non-human subject. In some embodiments, a non-human IL-11 variant described herein binds specifically to IL- 1 IRa and competitively blocks wild-type non- human IL-11 from binding the same IL-1 IRa. Pharmaceutical compositions comprising a non- human IL-11 variant described herein can be for use in the manufacture of a medicament for treating or preventing an inflammatory disease, disorder, or condition in a non-human subject. Pharmaceutical compositions comprising a non-human IL-11 variant described herein can be for use in the manufacture of a medicament for treating or preventing a fibrotic disease, disorder, or condition in a non-human subject. Pharmaceutical compositions comprising a non- human IL-11 variant described herein can be for use in the manufacture of a medicament for treating or preventing a cancer in a non-human subject.

[0163] In some embodiments, a subject is a non-human mammal. In some embodiments, a subject is a cat, dog, horse, pig, goat, sheep, cow, alpaca, or other non-human mammal. In some embodiments, a subject is a cat. In some embodiments, a subject is a dog. In some embodiments, a subject is a horse.

[0164] In some embodiments, a non-human IL-11 variant described herein is administered parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or intramuscularly). In some embodiments, a non-human IL- 11 variant described herein is administered by injection or infusion. In some embodiments, a non-human IL- 11 variant described herein is administered intravenously, intramuscularly, subcutaneously, or intraperitoneally by infusion or injection. In some embodiments, a non-human IL-11 variant described herein is administered transarterially, subcutaneously, intravenously, intradermally, intratumorally, intranodally, intramedullary, intramuscularly, or intraperitoneally. In some embodiments, a non-human IL- 11 variant described herein is administered intramuscularly. In some embodiments, a non-human IL-11 variant described herein is administered intravenously. In some embodiments, a non-human IL- 11 variant described herein is administered subcutaneously. In some embodiments, a non-human IL- 11 variant described herein is administered by intramuscular injection. In some embodiments, a non-human IL-11 variant described herein is administered by intravenous injection. In some embodiments, a non-human IL- 11 variant described herein is administered by subcutaneous injection.Page 62 of 8312916101V1Attorney Docket No: 2019493-00081. Autoimmune disease, disorder, or condition

[0165] A non-human IL-11 variant described herein can be administered to improve one or more symptoms of or reduce an inflammatory disease, disorder, or condition in a non- human subject, e.g., to treat or prevent an inflammatory disease, disorder, or condition in a subject. Methods can include administering a non-human IL-11 variant described herein to a non-human subject in need thereof, in an amount sufficient to decrease one or more symptoms of or prevent an inflammatory disease, disorder, or condition in a non-human subject. In some embodiments, a non-human IL-11 variant described herein can be administered to reduce, decrease, diminish, or attenuate an immune response. In some embodiments, a non-human IL- 11 variant described herein can be administered to enhance, stimulate, or increase an immune response. In some embodiments, a non-human subject has an inflammatory disease or has been diagnosed with an inflammatory disease, disorder, or condition.

[0166] In some embodiments, a non-human IL- 11 variant described herein is for use as a medicament in treating (e.g., reversing, reducing, or ameliorating) or preventing an inflammatory disease, disorder, or condition in a subject (e.g., a subject with an autoimmune disease, disorder, or condition). In some embodiments, a non-human IL-11 variant described herein is for use in the manufacture of a medicament for treating (e.g., reversing, reducing, or ameliorating) or preventing an inflammatory disease, disorder, or condition in a non-human subject (e.g., a non-human subject with an inflammatory disease, disorder, or condition).

[0167] In some embodiments, a method of treating an inflammatory disease, disorder, or condition in a non-human subject with a non-human IL-11 variant described herein is provided. In some embodiments, a non-human subject has, or is at risk of, developing an inflammatory disease, disorder, or condition (e.g., a chronic or acute inflammatory disease, disorder, or condition). In some embodiments, a subject has, or is at risk, of developing an inflammatory, disorder, or condition.

[0168] Exemplary inflammatory diseases, disorders, or conditions that can be treated or prevented with methods described herein include, but are not limited to, Alzheimer's disease, asthma (e.g., bronchial asthma, eosinophilic asthma, neutrophilic asthma, pauci granulocytic asthma, mixed eosinophilic and neutrophilic asthma), allergy (e.g., an atopic allergy), acquired immunodeficiency syndrome (AIDS), atopic dermatitis, atherosclerosis, vasculitis, ankylosing spondylitis, Anti-IgLON5 disease, anti-phospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, acute disseminated encephalomyelitis, agammaglobulinemia,Page 63 of 8312916101V1Attorney Docket No: 2019493-0008 antiphospholipid syndrome, anti synthetase syndrome, autoimmune enteropathy, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune poly endocrine syndrome, autoimmune progesterone dermatitis, autoimmune urticaria, Addison’s disease, amyotrophic lateral sclerosis, alopecia areata, Bechet’s Disease, blepharitis, bullous pemphigoid, Castleman’s disease, cold agglutinin disease, cardiomyopathy, CASPR2 autoimmune encephalitis, celiac disease, Crohn’s disease, chronic inflammatory demyelinating polyneuropath, chronic obstructive pulmonary disease (COPD), dermatomyositis, diabetes, diabetic retinopathy, dermatomyositis, diabetes, eczema, encephalitis, eosinophilic fasciitis, Goodpasture syndrome, fibromyalgia, fibromyositis, Giant Cell Arteritis, Granulomatosis, Guillain-Barre Syndrome, Graves' disease, graft vs. host disease (GVHD), gastrointestinal pemphigoid, Goodpasture’s syndrome, hemophilia, hemolytic anemia, Hashimoto’s disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, immune-mediated necrotizing myopathy (IMNM), inflammatory bowel disease, inflammatory myositis, immune thrombocytopenic purpura (ITP), keratoconjunctivitis sicca, lupus, Miller Fisher syndrome, mixed connective tissue disease (MCTD), Myelin Oligodendrocyte Glycoprotein (MOG) antibody disease, multiple sclerosis, myasthenia gravis, neuromyelitis optica, narcolepsy, nephritis, nephropathy, anti- histidyl-tRNA synthetase syndrome (Jo-1 ARS), paraneoplastic neurological syndrome (PNS), pemphigus foliaceous, pemphigus vulgaris, pernicious anemia, polymyositis, arthritis, primary biliary cirrhosis, primary biliary cholangitis (PBC), primary membranous nephropathy, primary membranous nephropathy, psoriasis, plaque psoriasis, generalized pustular psoriasis, erythrodermic psoriasis, primary sclerosis cholangitis, psoriatic arthritis, Raynaud's phenomenon, reactive arthritis, Reiter's syndrome, relapsing polychondritis, rheumatoid arthritis, rheumatic fever, scleroderma, Sjogren's syndrome, Stevens-Johnson Syndrome, systemic lupus erythematosus (SLE), sclerodactyly, sarcoidosis, scleroderma, systemic sclerosis, temporal arthritis, transplant rejection, transverse myelitis, Type 1 Diabetes, uveitis, ulcerative colitis (UC), vitiligo, thrombotic thrombocytopenic purpura, Wegener's disease, or a combination thereof.

[0169] Anon-human IL-11 variant described herein can be used to enhance or modulate an immune response in a subject (e.g., a subject having, or at risk of, an autoimmune disease, disorder, or condition described herein). In some embodiments, a non-human IL- 11 variant described herein enhances, stimulates, or increases an immune response in a subject (e.g., a subject having, or at risk of, an inflammatory disease, disorder, or condition described herein).Page 64 of 8312916101V1Attorney Docket No: 2019493-0008In some embodiments, a subject is, or is at risk of being, immunocompromised. For example, a subject can be undergoing or could have has undergone a chemotherapeutic treatment and / or radiation therapy.2. Fibrotic disease, disorder, or condition

[0170] In some embodiments, a non-human IL- 11 variant described herein can be administered to improve one or more symptoms of or reduce fibrosis in a non-human subject, e.g., to treat or prevent a fibrotic disease, disorder, or condition in a non-human subject. In some embodiments, methods can include administering a non-human IL-11 variant described herein to a non-human subject in need thereof, in an amount sufficient to decrease one or more symptoms of or prevent fibrosis in the non-human subject. Non-human IL- 11 variants described herein can be administered to improve tissue repair in a non-human subject with a fibrotic disease, disorder, or condition. In some embodiments, a non-human subject has a fibrotic disease, disorder, or condition or has been diagnosed with a fibrotic disease, disorder, or condition.

[0171] In some embodiments, a non-human IL- 11 variant described herein is for use as a medicament in treating (e.g., reversing, reducing, or ameliorating) or preventing fibrosis in a non-human subject (e.g., a non-human subject with a fibrotic disease, disorder, or condition). In some embodiments, a non-human IL-11 variant described herein is for use in the manufacture of a medicament for treating (e.g., reversing, reducing, or ameliorating) or preventing fibrosis in a non-human subject (e.g., a non-human subject with a fibrotic disease, disorder, or condition).

[0172] In some embodiments, administration of a non-human IL-11 variant described herein to a non-human subject delays onset of or reduces one or more of: formation or deposition of tissue fibrosis; size, cellularity, composition, or cellular content of a fibrotic lesion; collagen and / or hydroxyproline content of a fibrotic lesion; one or both of expression or activity of a fibrogenic protein; fibrosis associated with an inflammatory response; or weight loss associated with fibrosis relative to a non-human subject that did not receive such administration. In some embodiments, reducing fibrosis increases survival of a non-human subject relative to a non-human subject that did not receive such administration of a non-human IL- 11 variant described herein.

[0173] In some embodiments, a fibrotic disease, disorder, or condition includes a systemic disease, disorder, or condition (e.g., systemic sclerosis, multifocal fibrosclerosis,Page 65 of 8312916101V1Attorney Docket No: 2019493-0008 sclerodermatous chronic graft-versus-host disease, nephrogenic systemic fibrosis, or scleroderma) and organ-specific diseases, disorders, or conditions (e.g., liver, lung, heart, kidney, pancreas, skin, and / or nervous system fibrosis). In some embodiments, a fibrotic disease, disorder, or condition comprises or is a hyperproliferative fibrotic disease (e.g., a non- cancerous fibrotic disease). In some embodiments, a fibrotic disease, disorder, or condition is associated with cancer (e.g., colon cancer).

[0174] In some embodiments, a fibrotic disease, disorder, or condition comprises or is a liver, lung, heart, vasculature, kidney, pancreas, skin, gastrointestinal, bone marrow, hematopoietic tissue, nervous system, and / or eye fibrotic disease, disorder, or condition. In some embodiments, a fibrotic disease, disorder, or condition affects tissue comprising tendon, cartilage, skin (e.g., skin epidermis and / or endodermis), cardiac tissue, vascular tissue (e.g., artery and / or vein), pancreatic tissue, lung tissue, kidney tissue, uterine tissue, ovarian tissue, neural tissue, testicular tissue, peritoneal tissue, colon, small intestine, biliary tract, gut, bone marrow, hematopoietic tissue, and / or eye tissue (e.g., retinal tissue).

[0175] In some embodiments, a fibrotic disease, disorder, or condition comprises or is a liver fibrotic disease, disorder, or condition. In some embodiments, a non-human IL-11 variant described herein can be administered to improve liver function, e.g., in a non-human subject with a liver fibrotic disease, disorder, or condition. In some embodiments, a liver fibrotic disease, disorder, or condition comprises or is a fatty liver disease, disorder, or condition. In some embodiments, a fatty liver disease, disorder, or condition comprises or is non-alcoholic fatty liver disease (NAFL) (e.g., non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH)) or alcoholic liver disease (e.g., alcoholic fatty liver disease (AFLD) or alcoholic steatohepatitis (ASH)). In some embodiments, a non-human subject has cirrhosis, primary biliary cirrhosis, liver fibrosis, hepatocarcinoma, an increased risk of liver failure, an increased risk of death, metabolic syndrome, type 2 diabetes, Hepatitis B infection (HBV), mechanical trauma, biliary obstruction, autoimmune hepatitis, iron overload, Hepatitis B infection (HBV), and / or Hepatitis C infection (HCV).

[0176] In some embodiments, a fibrotic disease, disorder, or condition comprises or is a lung fibrotic disease, disorder, or condition. In some embodiments, a non-human IL-11 variant described herein can be administered to improve lung function (e.g., in a non-human subject with a lung fibrotic disease, disorder, or condition). In some embodiments, a lung fibrotic disease, disorder, or condition comprises or is pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lung disease, Page 66 of 8312916101V1Attorney Docket No: 2019493-0008 cryptogenic fibrosing alveolitis (CFA), bronchiectasis, and / or scleroderma lung disease. In some embodiments, lung fibrosis is associated with an occupational hazard, an environmental pollutant, cigarette smoking, an autoimmune connective tissue disorders (e.g., rheumatoid arthritis, scleroderma, or systemic lupus erythematosus (SLE)), a connective tissue disorder (e.g., sarcoidosis), pulmonary inflammation, and / or or an infectious disease.

[0177] In some embodiments, a fibrotic disease, disorder, or condition comprises or is a kidney fibrotic disease, disorder, or condition. In some embodiments, a non-human IL-11 variant described herein can be administered to improve kidney function, e.g., in a non-human subject with a kidney fibrotic disease, disorder, or condition. In some embodiments, a kidney fibrotic disease, disorder, or condition comprises or is renal fibrosis (e.g., chronic kidney fibrosis), nephropathies associated with fibrosis (e.g., diabetic nephropathy), lupus, scleroderma of the kidney, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosis associated with human chronic kidney disease (CKD), chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephrosis (PGN), glomerulonephritis, endothelial / thrombotic microangiopathy injury, HIV-associated nephropathy, or a combination thereof. In some embodiments, kidney fibrosis is associated with exposure to a toxin, an irritant, or a chemotherapeutic agent.

[0178] In some embodiments, a fibrotic disease, disorder, or condition comprises or is a heart fibrotic disease, disorder, or condition. A non-human IL-11 variant described herein can be administered to improve heart function (e.g., in a non-human subject with a heart fibrotic disease, disorder, or condition). In some embodiments, a heart fibrotic disease, disorder, or condition comprises or is myocardial fibrosis. In some embodiments, myocardial fibrosis is associated with radiation myocarditis, surgical procedure complications (e.g., myocardial postoperative fibrosis), infectious diseases (e.g., Chagas disease), granulomatous, metabolic storage disorders (e.g., cardiomyopathy or hemochromatosis), developmental disorders (e.g., endocardial fibroelastosis), arteriosclerotic, and / or exposure to toxins or irritants (e.g., drug- induced cardiomyopathy, drug-induced cardiotoxicity, or alcoholic cardiomyopathy). In some embodiments, myocardial fibrosis is associated with myocardial sarcoidosis, myocardial infarction, and / or congestive heart failure. In some embodiments, a heart fibrotic disease, disorder, or condition comprises atherosclerosis or restenosis.

[0179] In some embodiments, a fibrotic disease, disorder, or condition comprises or is an eye fibrotic disease, disorder, or condition. In some embodiments, a non-human IL-11 Page 67 of 8312916101V1Attorney Docket No: 2019493-0008 variant described herein can be administered to improve eye function (e.g., in a non-human subject with an eye fibrotic disease, disorder, or condition). In some embodiments, an eye fibrotic disease, disorder, or condition comprises or is glaucoma, macular degeneration (e.g., age-related macular degeneration), macular edema (e.g., diabetic macular edema), retinopathy (e.g., diabetic retinopathy), retinal retinopathy, vitreal retinopathy, dry eye disease, or a combination thereof.

[0180] In some embodiments, a fibrotic disease, disorder, or condition comprises or is a skin fibrotic disease, disorder, or condition. In some embodiments, a non-human IL-11 variant described herein can be administered to improve skin function (e.g., in a non-human subject with a skin fibrotic disease, disorder, or condition). In some embodiments, a skin fibrotic disease, disorder, or condition comprises or is skin fibrosis (e.g., hypertrophic scarring and / or keloid scars), scleroderma of the skin, and / or nephrogenic systemic fibrosis.

[0181] In some embodiments, a fibrotic disease, disorder, or condition comprises or is a gastrointestinal tract fibrotic disease, disorder, or condition. In some embodiments, a non- human IL-11 variant described herein can be administered to improve gastrointestinal tract function (e.g., in a non-human subject with a gastrointestinal tract fibrotic disease, disorder, or condition). In some embodiments, a gastrointestinal tract fibrotic disease, disorder, or condition comprises or is radiation-induced gut fibrosis, fibrosis associated with a foregut inflammatory disorder (e.g., Barrett’s esophagus or chronic gastritis), fibrosis associated with a hindgut inflammatory disorder (e.g., inflammatory bowel disease, ulcerative colitis, or Crohn’s disease), or a combination thereof.

[0182] In some embodiments, a fibrotic disease, disorder, or condition comprises or is a chronic fibrotic disease, disorder, or condition. In some embodiments, a fibrotic disease, disorder, or condition is associated with an inflammatory disease, disorder, or condition. In some embodiments, a fibrotic disease, disorder, or condition comprises or is osteomyelitis (e.g., chronic osteomyelitis). In some embodiments, a fibrotic disease, disorder, or condition comprises or is an amyloidosis (e.g., amyloidosis associated with chronic osteomyelitis).3. Cancer

[0183] In some embodiments, a non-human IL- 11 variant described herein can be administered to improve one or more symptoms of or reduce a cancer in a non-human subject, e.g., to treat or prevent a cancer in a non-human subject. In some embodiments, methods can include administering a non-human IL-11 variant described herein to a non-human subject inPage 68 of 8312916101V1Attorney Docket No: 2019493-0008 need thereof, in an amount sufficient to decrease one or more symptoms of or prevent cancer in the non-human subject.

[0184] In some embodiments, a non-human IL- 11 variant described herein is for use as a medicament in treating (e.g., reversing, reducing, or ameliorating) or preventing a cancer in a non-human subject (e.g., a non-human subject with a cancer). In some embodiments, a non- human IL- 11 variant described herein is for use in the manufacture of a medicament for treating (e.g., reversing, reducing, or ameliorating) or preventing a cancer in a non-human subject (e.g., a non-human subject with a cancer).

[0185] Exemplary cancers that can be treated or prevented with methods described herein include, but are not limited to, liver cancer, pancreatic cancer, breast cancer, ovarian cancer, colorectal cancer, lung cancer, non-small cell lung cancer, acute myeloid lymphoid leukemia, multiple myeloma, gastric cancer, gastric adenocarcinoma, pancreatic adenocarcinoma, glioblastoma, neuroblastoma, lung squamous cell carcinoma, hepatocellular carcinoma, and bladder cancer.EXAMPLES

[0186] The following examples are provided to describe to the skilled artisan how to make and use compositions described herein and is not intended to limit the scope of various aspects of the non-human IL- 11 variants described herein.EXAMPLE 1: Binding Affinities of Exemplary Feline and Canine IL-11 Variants

[0187] The present example characterizes the binding affinities of exemplary non- human IL-11 variants (e.g., feline and canine) to IL-llRa.

[0188] Biacore™ surface plasmon resonance (SPR) experiments as depicted in FIG. 2, were performed as follows in a Biacore™ SI 00 instrument. A Biacore™ CM5 sensorchip was activated with a mixture of EDC (N-ethyl-N’-(3-dimethylaminopropyl) carbodiimide) and NHS (N-hydroxysuccinimide). An anti-FLAG tag antibody ligand (Thermo Fisher Scientific MAI -91878, diluted to 17 pg / ml in acetate pH 4.5) was bioconjugated to the activated CM5 chip by flowing over the chip at 10 pl / min. for 420 seconds. The surface was blocked with a bolus of ethanolamine, and equilibrated in Running Buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% Surfactant P20, pH 7.4).

[0189] FLAG-tagged feline IL-llRa (SEQ ID NO: 39) or FLAG-tagged canine IL- llRa (SEQ ID NO: 40) was captured onto a sensorchip by flowing a solution at 1 pg / ml or 10Page 69 of 8312916101V1Attorney Docket No: 2019493-0008 pg / ml for 60 sec at flow rate 10 pl / min. Running buffer was then flowed over the surface of the sensorchip for a 400 second surface stabilization period. 6xHis-tagged feline IL-11 variant (SEQ ID NO: 43), 6xHis- tagged canine IL-11 variant (SEQ ID NO: 44), 6xHis-tagged wildtype feline IL-11 (SEQ ID NO: 41), 6xHis-tagged wild-type canine IL-11 variant (SEQ ID NO: 42), feline IL-4 (feline negative control), or canine IL-4 (canine negative control), were diluted in Running Buffer and injected as analytes over the sensorchip surface at 30 pl / min with a 120 second contact time and a 600 second dissociation time. Surfaces were regenerated with a solution of glycine buffer at pH 2.0, 30 pl / min for 30 seconds.TABLE 5: Sequences of Exemplary Tagged IL-11 Proteins and IL-11 ReceptorsPage 70 of 8312916101V1Attorney Docket No: 2019493-0008

[0190] Biacore™ SPR experiments demonstrated dose-dependent binding of wild-type feline IL-11 (FIG. 3A) and exemplary feline IL-11 variant (FIG. 3B) to feline IL-llRa (immobilized to the sensorchip surface at a concentration of 1 pg / ml) with comparable binding kinetics, whereas feline IL-4 (negative control) did not bind to feline IL-llRa (FIG. 3C). As shown in FIG. 4A and FIG. 4B, increased concentration of feline IL-llRa immobilized onto the sensorchip surface (10 pg / ml) further enhanced capture signal of wild-type feline IL- 11 and exemplary feline IL- 11 variant, respectively. Feline IL-4 (negative control) did not bind to feline IL-llRa (FIG. 4C).

[0191] Similarly, Biacore™ SPR experiments demonstrated dose-dependent binding of wild-type canine IL- 11 (FIG. 5A) and exemplary canine IL- 11 variant (FIG. 5B) to canine IL- llRa (immobilized to the sensorchip surface at a concentration of 1 pg / ml) with comparable binding kinetics, whereas canine IL-4 (negative control) did not bind to canine IL-llRa (FIG. 5C). As shown in FIG. 6A and FIG. 6B, increased concentration of canine IL-llRa immobilized onto the sensorchip surface (10 pg / ml) further enhanced capture signal of wildtype canine IL- 11 and exemplary canine IL- 11 variant, respectively. Canine IL-4 (negative control) did not bind to canine IL-llRa (FIG. 6C).

[0192] These data indicate that exemplary feline and canine IL- 11 variants of the present disclosure bind to IL-llRa with similar binding affinities and kinetics as compared to wild-type feline and canine IL-11, respectively.Page 71 of 8312916101V1Attorney Docket No: 2019493-0008EXAMPLE 2: Competition Assays Characterizing Exemplary Feline and Canine IL-11 variants

[0193] The present example describes competition assays characterizing the ability of exemplary non-human IL-11 variants (e.g., feline and canine) of the present disclosure to block binding of wild-type non-human IL-11 (e.g., feline and canine) to their respective IL-llRa (e.g., feline and canine).

[0194] NUNC Maxisorp™ plates were incubated overnight at 4 °C with 50 pL anti- FLAG antibody (Invitrogen # MAI 91878) at 2 pg / mL in 0.2 M carbonate-bicarbonate buffer (Thermo Scientific Cat# 28382). The following day, plate wells were washed with 3 cycles of 300 pL 0.05% Tween™-20 in phosphate buffered saline (PBS). The plate was then blocked by the addition of 150 pL / well 5% “Blocker A” (Meso Scale Discovery) in PBS and incubated 1 hour at room temperature in a plate shaker at 150-300 RPM. Plates were washed with 3 cycles of 300 pL 0.05% Tween™-20 in PBS. Feline IL-llRa-FLAG (SEQ ID NO: 39) and / or Canine IL-llRa-FLAG (SEQ ID NO: 40) were diluted to 2 pg / mL in Diluent Buffer (2% Blocker A / 0.05% Tween™-20 / PBS) and incubated for 1 hour at room temperature, with shaking at 150-300 RPM. Plates were subsequently washed with 3 cycles of 300 pL 0.05% Tween™-20 in PBS. A standard curve with 1 : 1 molar stoichiometry of IL-11 :gpl30 was generated by making 200 pL of a top concentration solution containing 42 nM of IL-11 and 42 nM gpl30. 100 pl of solution was serially diluted into 100 pl of Diluent Buffer down to 0.656 nM to make the titration series. 50 pl of solution from the titration series was added to the plate containing captured IL-llRa-FLAG and incubated for 1 hour at room temperature with shaking at 150-300 RPM. Plates were washed with 3 cycles of 300 pL 0.05% Tween™-20 in PBS. 50 pL of anti-His antibody (Biolegend # 652504) diluted 1 : 1000, 1 :2000, and 1 :3000 in Diluent Buffer was added to titration curve wells and incubated for 1 hour at room temperature, with shaking at 150-300 RPM. Plates were washed with 3 cycles of 300 pL 0.05% Tween™- 20 in PBS. 50 pL of TMB (BD Bioscience # 555214) premixed reagents A / B were added to each well and incubated for 10-20 minutes, quenched with 50 pL ELISA Stop Solution (Invitrogen # SS04), and absorbance of each well was measured on a Spectramax™ plate reader at wavelength 450nm with plate correction at 540nm. A 4-parameter EC50 equation was used to calculate EC50 values. In some wells, no IL-1 IRa-FLAG was added to determine specificity of IL-ll-His binding. In a separate experiment, gpl30 was omitted from wells to determine the impact of gp 130 on IL- 11 binding to IL-llRa.Page 72 of 8312916101V1Attorney Docket No: 2019493-0008TABLE 6: Sequences of Tagged gp!30

[0195] A competition ELISA was performed by coating NUNC Maxisorp™ plates overnight at 4 °C with Anti -FLAG antibody (Invitrogen # MAI 91878) at 2 pg / mL in 0.2 M carbonate-bicarbonate buffer (Thermo Scientific. Cat# 28382). The following day, plate wells were washed with 3 cycles of 300 pL 0.05% Tween™-20 in PBS. Plates were then blocked by the addition of 150 pL / well of 5% “Blocker A” in PBS and incubated for 1 hour at room temperature on a plate shaker at 150-300 RPM. Plates were washed with 3 cycles of 300 pL 0.05% Tween™-20 in PBS. Feline IL-llRa-FLAG (SEQ ID NO: 39) and canine IL-llRa- FLAG (SEQ ID NO: 40) and / or was diluted to 2 pg / mL in Diluent Buffer and incubated for 1 hour at room temperature, with shaking at 150-300 RPM. Plates were washed with 3 cycles of 300 pL 0.05% Tween™-20 in PBS. A standard curve with 1 : 1 molar stoichiometry of IL- 11 :gpl30 was generated as described above (1 :2 dilution of IL-ll / gpl30 complex starting at 42 nM) for both feline and canine IL-11, with 50 pl of this titration solution added to the IL- HRa-coated plate to ensure assay reproducibility as compared to previous experiments.

[0196] Competitive binding samples were prepared by combining 1 : 1 molar equivalents of His-tagged IL-11 (feline: SEQ ID NO: 42, canine: SEQ ID NO: 42) and STREP -Page 73 of 8312916101V1Attorney Docket No: 2019493-0008 tagged gpl30 (feline: SEQ ID NO: 47, canine: SEQ ID NO: 48) at 29.24 nM each (two times the EC80 determined in a primary titration, i.e., 14.62 nM). Non-human IL-ll-variant titrations were prepared by 1 :2 serial dilutions starting from a highest STREP -tagged non- human IL-11 variant (feline: SEQ ID NO: 45, canine: SEQ ID NO: 46) concentration of 22.14 pM to a lowest concentration of 0.00034 pM. Dilution buffer alone served as a blank control.

[0197] 80 pl of the IL-ll / gpl30 mixture was combined with 80 pl of the STREP - tagged IL-ll-variant titration series (or feline or canine IL-4 negative control), and 50 pl of the combined solution was then added to certain wells of the washed, prepared plates and incubated for 1 hour at room temperature with shaking at 150-300 RPM. After incubation, the plates were washed with 3 cycles of 300 pL of 0.05% Tween™-20 in PBS. 50pL of anti -His antibody (Biolegend # 652504) diluted 1 :2000 in Diluent Buffer was added to each well and incubated for 1 hour at room temperature, with shaking at 150-300 RPM. Plates were washed with 3 cycles of 300 pL of 0.05% Tween™-20 in PBS. 50 pL of pre-mixed TMB Reagent (BD Bioscience # 555214) were added to each well and incubated for 10-20 minutes and quenched with 50 pL of ELISA Stop Solution (Invitrogen # SS04). Plates were read on a Spectramax™ plate reader at 450nm with plate correction at 540nM. A 4-parameter IC50 equation was used to calculate IC50 values.

[0198] As shown in FIG. 8A and FIG. 8B, dose dependent binding of wild-type feline IL- 11 to feline IL-llRa was observed at various concentrations tested and optimal binding required the presence of the common gpl80 receptor (FIG. 9). In the presence of exemplary feline IL-11 variant, binding of wild-type feline IL-11 to feline IL-llRa was competitively blocked (FIG. 10).

[0199] Similarly, as shown in FIG. HA and FIG. 11B, dose dependent binding of canine IL-11 to canine IL-llRa was observed at various concentrations tested and canine IL- 11 variant competitively blocked binding of wild-type canine IL-11 to canine IL-llRa (FIG. 12).

[0200] These data indicate that exemplary feline and canine IL-11 variants described herein block wild-type IL-11 binding to IL-llRa in the presence of the gpl30 co-receptor, which is critical for IL-11 signaling at the cell surface.Page 74 of 8312916101V1Attorney Docket No: 2019493-0008EXAMPLE 3: Exemplary feline IL-11 variant reduces wild-type IL-ll-induced STAT- pathway activation

[0201] The present example characterizes the ability of exemplary feline IL-11 variant to inhibit / antagonize wild-type IL-ll-induced activation of feline macrophages.

[0202] To evaluate the inhibitory activity of exemplary IL-11 variant, a cell-based assay was developed using the feline-specific macrophage cell line Fcwf-4 (ATCC #CRL-2787). Phosphorylated STAT3 was quantitatively measured using the AlphaLISA® SureFire® Ultra™ Human and Mouse Phospho-STAT3 (Tyr705) Detection Kit (Revvity #ALSU-PST3-A500). Although the kit is designed for human and mouse samples, cross-reactivity with feline phospho-STAT3 was confirmed by treating Fcwf-4 cells with a dose titration of wild-type feline IL-11. From this titration, an EC80 concentration of feline IL-11 was determined to be 4.34 nM and this EC80 concentration was used for subsequent antagonist testing.

[0203] Fcwf-4 cells were seeded at 50,000 cells per well in 100 pL of DMEM (Invitrogen # 11995073) supplemented with 10% FBS (Invitrogen # 16140071) in a 96-well tissue culture plate and incubated overnight. Following incubation, media was aspirated and replaced with 45 pL of serum-free DMEM for 1 hour to reduce background activation. Cells were pretreated for 30 minutes with 2.5 pL serial dilutions of exemplary feline IL-11 variant at a highest concentration of 22.14 pM and a lowest concentration of 0.011 pM (or IL-4 negative control). Following pretreatment, cells were stimulated with 2.5 pL of wild-type feline IL-11 at the EC80 concentration (4.34 nM) for 15 minutes. After stimulation, media was removed, and 50 pL of AlphaLISA™ 1* lysis buffer was added to each well. The plate was agitated on a shaker for 10 minutes, and 10 pL of lysate was transferred to a 384-well ProxiPlate™ (Revvity #6008280). 5 pL of AlphaLISA™ acceptor mix was added to each well and incubated for 1 hour in the dark at room temperature. 5 pL of donor mix was added under subdued lighting and the plate was sealed with aluminum foil and incubated for another hour at room temperature in the dark. Plates were read using an EnVision™ plate reader with AlphaLISA™ settings.

[0204] As shown in FIG. 13, wild-type feline IL- 11 was shown to activate STAT3 signaling in the feline macrophage cell line Fcwf-4. This STAT3 pathway activation was competitively blocked in the presence of exemplary feline IL- 11 variant that exhibited an IC50 of 0.26 pM (FIG. 14).Page 75 of 8312916101V1Attorney Docket No: 2019493-0008

[0205] These data indicate that exemplary non-human IL- 11 variants of the present disclosure are capable of inhibiting immune cell activation.EQUIVALENTS

[0206] It is to be appreciated by those skilled in the art that various alterations, modifications, and improvements to various aspects of innovations described herein will readily occur to those skilled in the art. Such alterations, modifications, and improvements are intended to be part of various aspects of innovations described herein and are intended to be within the spirit and scope of such aspects of innovation.

[0207] Those skilled in the art will appreciate typical standards of deviation or error attributable to values obtained in assays or other processes described herein. The publications, websites and other reference materials referenced herein to describe the background of various aspects of innovations described herein and to provide additional detail regarding its practice are hereby incorporated by reference in their entireties.Page 76 of 8312916101V1

Claims

Attorney Docket No: 2019493-0008CLAIMSLISTING OF THE CLAIMS1. A non-human interleukin 11 (IL-11) variant comprising one or more amino acid substitutions relative to a reference non-human IL-11, wherein the variant has: at least a 2-fold increased binding affinity to a non-human IL-11 receptor alpha as compared to the reference; and / or at least a 2-fold decreased binding affinity to a non-human gpl30 relative to the reference.

2. The non-human IL-11 variant of claim 1 wherein the one or more substitutions include amino acid substitutions at positions corresponding to positions 58, 59, 60, 61, 62, and / or 147 of SEQ ID NO: 1.

3. The non-human IL-11 variant of claim 1 or 2, wherein: the amino acid substitution at position 58 is from an alanine to a proline (A58P); the amino acid substitution at position 59 is from a methionine to an alanine (M59A); the amino acid substitution at position 60 is from a serine to an isoleucine (S60I); the amino acid substitution at position 61 is from an alanine to aspartic acid (A61D); the amino acid substitution at position 62 is from a glycine to a tyrosine (G62Y); the amino acid substitution at position 147 is from a tryptophan to an alanine (W147A), or any combination thereof.

4. The non-human IL-11 variant of any one of claims 1 to 3 comprising an A58P substitution, an M59A substitution, an S60I substitution, an A61D substitution, a G62Y substitution, and a W147A substitution.

5. The non-human IL-11 variant of any one of claims 1 to 4, wherein the non-human IL-11 variant is a variant of feline IL-11.Page 77 of 8312916101V1Attorney Docket No: 2019493-00086. The non-human IL-11 variant of any one of claims 1 to 5, comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 21.

7. The non-human IL-11 variant of any one of claims 1 to 6, comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 21.

8. The non-human IL-11 variant of any one of claims 1 to 7, further comprising a signal peptide at its N-terminus.

9. The non-human IL-11 variant of claim 8, wherein the signal peptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 28.

10. The non-human IL-11 variant of any one of claims 1 to 4, wherein the non-human IL-11 variant is a variant of canine IL-11.

11. The non-human IL-11 variant of claim 10, comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 22.

12. The non-human IL-11 variant of claim 10 or 11, comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 22.

13. The non-human IL-11 variant of any one of claims 10 to 12, further comprising a signal peptide at its N-terminus.

14. The non-human IL-11 variant of claim 13, wherein the signal peptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 29.

15. The non-human IL-11 variant of any one of claims 1 to 4, wherein the non-human IL-11 variant is a variant of porcine IL-11.Page 78 of 8312916101V1Attorney Docket No: 2019493-000816. The non-human IL-11 variant of claim 15, comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 24.

17. The non-human IL-11 variant of claim 15 or 16, comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 24.

18. The non-human IL-11 variant of any one of claims 15 to 17, further comprising a signal peptide at its N-terminus.

19. The non-human IL-11 variant of claim 18, wherein the signal peptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 31.

20. The non-human IL-11 variant of any one of claims 1 to 4, wherein the non-human IL-11 variant is a variant of camelid IL-11.

21. The non-human IL-11 variant of claim 20, comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 27.

22. The non-human IL-11 variant of claim 20 or 21, comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 27.

23. The non-human IL-11 variant of any one of claims 20 to 22, further comprising a signal peptide at its N-terminus.

24. The non-human IL-11 variant of any one of claims 1 to 4, wherein the non-human IL-11 variant is a variant of caprine IL-11.

25. The non-human IL-11 variant of claim 24, comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 25.Page 79 of 8312916101V1Attorney Docket No: 2019493-000826. The non-human IL-11 variant of claim 24 or 25, comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 25.

27. The non-human IL-11 variant of any one of claims 24 to 26, further comprising a signal peptide at its N-terminus.

28. The non-human IL-11 variant of any one of claims 1 to 4, wherein the non-human IL-11 variant is a variant of bovine IL-11.

29. The non-human IL-11 variant of claim 28, comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 26.

30. The non-human IL-11 variant of claim 28 or 29, comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 26.

31. The non-human IL-11 variant of any one of claims 28 to 30, further comprising a signal peptide at its N-terminus.

32. The non-human IL-11 variant of claim 31, wherein the signal peptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 32.

33. The non-human IL-11 variant of any one of claims 1 to 4, wherein the non-human IL-11 variant is a variant of equine IL-11.

34. The non-human IL-11 variant of claim 33, comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 23.

35. The non-human IL-11 variant of claim 33 or 34, comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 23.

36. The non-human IL-11 variant of any one of claims 33 to 35, further comprising a signal peptide at its N-terminus.Page 80 of 8312916101V1Attorney Docket No: 2019493-000837. The non-human IL-11 variant of claim 36, wherein the signal peptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to SEQ ID NO: 30.

38. The non-human IL-11 variant of any one of claims 1 to 37, wherein increased binding affinity to the IL- 11 receptor alpha is quantified in vitro using surface plasmon resonance.

39. The non-human IL-11 variant of any one of claims 1 to 38, wherein decreased binding affinity to gpl30 is quantified in vitro using a competitive enzyme-linked immunosorbent assay.

40. The non-human IL-11 variant of any one of claims 1 to 39, wherein the non-human IL- 11 variant competitively inhibits non-human wild-type IL-ll-induced STAT3 phosphorylation in non-human macrophages.

41. The non-human IL-11 variant of any one of claims 1 to 40, wherein the non-human IL- 11 variant is PEGylated.

42. A nucleic acid encoding a non-human IL-11 variant comprising one or more amino acid substitutions relative to a reference non-human IL-11, wherein the variant has: at least a 2-fold increased binding affinity to a non-human IL-11 receptor alpha as compared to the reference; and / or at least a 2-fold decreased binding affinity to a non-human gpl30 relative to the reference.

43. A vector comprising a nucleic acid encoding a non-human IL-11 variant comprising one or more amino acid substitutions relative to a reference non-human IL-11, wherein the variant has: at least a 2-fold increased binding affinity to a non-human IL-11 receptor alpha as compared to the reference; and / or at least a 2-fold decreased binding affinity to a non-human gpl30 relative to the reference.Page 81 of 8312916101V1Attorney Docket No: 2019493-000844. A cell comprising a nucleic acid encoding a non-human IL-11 variant comprising one or more amino acid substitutions relative to a reference non-human IL-11, wherein the variant has: at least a 2-fold increased binding affinity to a non-human IL-11 receptor alpha as compared to the reference; and / or at least a 2-fold decreased binding affinity to a non-human gpl30 relative to the reference.

45. A pharmaceutical composition comprising a non-human IL-11 variant of any one of claims 1 to 41, and one or more pharmaceutically acceptable carriers, diluents, and / or excipients.

46. A method of treating an inflammatory disease or condition in a non-human animal, the method comprising administering to said non-human animal, an effective amount of a non-human IL- 11 variant of any one of claims 1 to 41.

47. The method of claim 46, wherein the inflammatory disease or condition is rheumatoid arthritis, multiple sclerosis, or inflammatory bowel disease.

48. A method of treating a hematologic disease or condition in a non-human animal, the method comprising administering to said non-human animal, an effective amount of a non-human IL- 11 variant of any one of claims 1 to 41.

49. The method of claim 48, wherein the hematologic disease is thrombocytopenia.

50. A method of treating a cancer in a non-human animal, the method comprising administering to said non-human animal, an effective amount of a non-human IL- 11 variant of any one of claims 1 to 41.

51. A method of manufacturing a medicament comprising combining a non-human IL-11 variant of any one of claims 1 to 41, and one or more pharmaceutically acceptable carriers, diluents, and / or excipients.Page 82 of 8312916101V1

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