Immunomodulatory proteins and related methods

Abstract

Provided herein are immunomodulatory proteins and compositions (e.g., pharmaceutical compositions) comprising the same; and methods of making the immunomodulatory proteins and compositions. The immunomodulatory proteins provided herein are useful in pharmaceutical compositions and methods for treating IL-10 responsive diseases.

Description

Cross - Reference to Related Applications

[0001] This application claims priority to U.S. Serial No. 63 / 394,155, filed August 1, 2022; U.S. Serial No. 63 / 483,419, filed February 6, 2023; and U.S. Serial No. 63 / 502,864, filed May 17, 2023, the entire contents of each of which are incorporated herein by reference. 1. Field of the Invention

[0002] This disclosure relates to immunomodulatory polypeptides and proteins that bind to human interleukin - 10 receptor (hIL - 10R), and polynucleotides encoding these immunomodulatory polypeptides and proteins. This disclosure also relates to methods for their manufacture and use. 2. Background Art

[0003] Human IL - 10 (hIL - 10) is a pleiotropic immunomodulatory cytokine that primarily targets antigen - presenting cells such as monocytes and macrophages, inhibiting the release of pro - inflammatory cytokines (e.g., TNFα, IL - 1β, IL - 6, and IL - 8). hIL - 10 also interferes with antigen presentation by reducing the expression of major histocompatibility complex (MHC) - II and co - stimulatory molecules. hIL - 10 further exerts its inhibitory effect on T - cell responses by suppressing the expression of cytokines IL - 12 and IL - 23 required for CD4+ T - cell differentiation. In addition to these anti - inflammatory properties, hIL - 10 also has pro - inflammatory functions. For example, hIL - 10 has been shown to stimulate CD8+ T cells and promote the survival, proliferation, and differentiation of B cells. 3. Summary of the Invention

[0004] Provided herein are, inter alia, immunomodulatory polypeptides and polynucleotides encoding them; fusions and conjugates comprising these immunomodulatory polypeptides; methods of manufacture; pharmaceutical compositions; and methods of use, including, for example, methods of treating pro - inflammatory diseases (e.g., autoimmune diseases), methods of promoting an immune response, methods of treating viral infections, and diagnostic methods.

[0005] Thus, in one aspect, provided herein is an isolated polypeptide or protein comprising an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of the amino acid sequences of SEQ ID NOs: 108 - 454, wherein the polypeptide or protein specifically binds to the human IL - 10 receptor (hIL - 10R) (e.g., hIL - 10Rα).

[0006] In some embodiments, the isolated polypeptide or protein consists of an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the amino acid sequences of SEQ ID NOs: 108 - 454. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 85% identical to any one of the amino acid sequences of SEQ ID NOs: 108 - 454. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 90% identical to any one of the amino acid sequences of SEQ ID NOs: 108 - 454. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 95% identical to any one of the amino acid sequences of SEQ ID NOs: 108 - 454. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NOs: 108 - 454.

[0007] In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 85% identical to any one of the amino acid sequences of SEQ ID NOs: 108, 111 - 119 or 122 - 126. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 90% identical to any one of the amino acid sequences of SEQ ID NOs: 108, 111 - 119 or 122 - 126. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 95% identical to any one of the amino acid sequences of SEQ ID NOs: 108, 111 - 119 or 122 - 126. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NOs: 108, 111 - 119 or 122 - 126.

[0008] In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 85% identical to the amino acid sequence of any one of SEQ ID NOs: 112-115 or 123-126. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 90% identical to the amino acid sequence of any one of SEQ ID NOs: 112-115 or 123-126. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 95% identical to the amino acid sequence of any one of SEQ ID NOs: 112-115 or 123-126. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 112-115 or 123-126.

[0009] In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 85% identical to the amino acid sequence of any one of SEQ ID NO: 114. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 90% identical to the amino acid sequence of any one of SEQ ID NO: 114. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 95% identical to the amino acid sequence of any one of SEQ ID NO: 114. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 114.

[0010] In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 85% identical to the amino acid sequence of any one of SEQ ID NO: 125. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 90% identical to the amino acid sequence of any one of SEQ ID NO: 125. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 95% identical to the amino acid sequence of any one of SEQ ID NO: 125. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 125.

[0011] In one aspect, the present disclosure provides an isolated polypeptide or protein comprising an amino acid sequence that is at least about 85% identical to any one of the amino acid sequences of SEQ ID NOs: 119 - 126 or 291 - 454, wherein the polypeptide or protein specifically binds to hIL-10R (e.g., hIL-10Rα).

[0012] In some embodiments, the isolated polypeptide or protein consists of an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the amino acid sequences of SEQ ID NOs: 119 - 126 or 291 - 454. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 85% identical to any one of the amino acid sequences of SEQ ID NOs: 119 - 126 or 291 - 454. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 90% identical to any one of the amino acid sequences of SEQ ID NOs: 119 - 126 or 291 - 454. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 95% identical to any one of the amino acid sequences of SEQ ID NOs: 119 - 126 or 291 - 454. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NOs: 119 - 126 or 291 - 454.

[0013] In one aspect, the present disclosure provides an isolated polypeptide or protein comprising an amino acid sequence that is at least about 85% identical to any one of the amino acid sequences of SEQ ID NOs: 108 - 118 or 127 - 290, wherein the polypeptide or protein specifically binds to hIL-10R (e.g., hIL-10Rα).

[0014] In some embodiments, the isolated polypeptide or protein consists of an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 118 or 127 - 290. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 118 or 127 - 290. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 118 or 127 - 290. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is at least about 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 118 or 127 - 290. In some embodiments, the isolated polypeptide or protein comprises or consists of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 118 or 127 - 290.

[0015] It should be understood that any one of the following examples applies to any one of the foregoing aspects related to isolated polypeptides and proteins.

[0016] In some embodiments, the isolated polypeptide or protein (a) binds to cells expressing hIL-10R (e.g., hIL-10Rα) on the surface with an EC50 of less than about 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, 0.9 pM, 0.8 pM, 0.7 pM, 0.6 pM, 0.5 pM, 0.4 pM, 0.3 pM, 0.2 pM, or 0.1 pM; or (b) binds to cells expressing hIL-10R (e.g., hIL-10Rα) on the surface with an EC50 of about 500 pM–0.1 pM, 400 pM–0.1 pM, 300 pM–0.1 pM, 200 pM–0.1 pM, 100 pM–0.1 pM, 50 pM–0.1 pM, 25 pM–0.1 pM, 10 pM–0.1 pM, 5 pM–0.1 pM, or 1 pM–0.1 pM, 500 pM–0.5, 400 pM–0.5, 300 pM–0.5, 200 pM–0.5, 100 pM–0.5, 50 pM–0.5, 25 pM–0.5, 10 pM–0.5, 5 pM–0.5, or 1 pM–0.5 pM. In some embodiments, the EC50 is determined by the assay described in Example 3 herein.

[0017] In some embodiments, the isolated polypeptide or protein (a) binds to cells expressing hIL-10R (e.g., hIL-10Rα) on the surface with an EC50 that is at least about 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, or 150-fold higher than the EC50 of a reference hIL-10 polypeptide (e.g., SEQ ID NO:2); or (b) binds to cells expressing hIL-10R (e.g., hIL-10Rα) on the surface with an EC50 that is about 10-150-fold, 20-150-fold, 30-150-fold, 40-150-fold, 50-150-fold, 60-150-fold, 70-150-fold, 80-150-fold, 90-150-fold, 100-150-fold, 110-150-fold, 120-150-fold, 130-150-fold, or 140-150-fold higher than the EC50 of a reference hIL-10 protein or polypeptide (e.g., SEQ ID NO:2). In some embodiments, the EC50 is determined by the assay described in Example 3 herein.

[0018] In some embodiments, the polypeptide or protein specifically binds to hIL-10Rα. In some embodiments, the polypeptide or protein specifically binds to hIL-10Rβ. In some embodiments, the polypeptide or protein specifically binds to both hIL-10Rα and hIL-10Rβ.

[0019] In some embodiments, the polypeptide or protein is an agonist of hIL-10R (such as hIL-10Rα, hIL-10Rβ). In some embodiments, the polypeptide or protein is an antagonist of hIL-10R (such as hIL-10Rα, hIL-10Rβ).

[0020] In some embodiments, the isolated polypeptide or protein further comprises a homologous or heterologous signal peptide operably linked to the N-terminus of the polypeptide or protein.

[0021] In some embodiments, the isolated polypeptide or protein is an isolated protein.

[0022] In one aspect, provided herein is a polypeptide comprising a polypeptide or protein described herein operably linked to a heterologous moiety.

[0023] In one aspect, provided herein is a fusion polypeptide or protein comprising a polypeptide or protein described herein operably linked to a heterologous polypeptide or protein.

[0024] In some embodiments, the heterologous polypeptide or protein comprises a polypeptide or protein with an extended half-life.

[0025] In some embodiments, the heterologous polypeptide or protein comprises an immunoglobulin (Ig) (such as human Ig (hIg), murine Ig (mIg)) Fc region. In some embodiments, the Ig (such as, hIg, mIg) Fc region comprises at least a portion of the hinge region, CH2 region, and CH3 region. In some embodiments, the Ig (such as, hIg, mIg) Fc region comprises the hinge region, CH2 region, and CH3 region.

[0026] In some embodiments, the Ig is hIg. In some embodiments, the hIg is human IgG (hIgG). In some embodiments, the hIgG is hIgG1 or hIgG4.

[0027] In some embodiments, the Ig is mIg. In some embodiments, the mIg is mIgG1. In some embodiments, the mIg is mIgG2a.

[0028] In some embodiments, the Fc region of an Ig (e.g., hIg, mIg) comprises one or more amino acid substitutions relative to a reference Ig (e.g., hIg, mIg) Fc region, and the substitution(s) reduce or eliminate one or more of the following effector functions relative to the reference hIg Fc region: antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and / or affinity for one or more human Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))).

[0029] In some embodiments, the Fc region of an Ig (e.g., hIg, mIg) substantially does not mediate ADCC, substantially does not mediate CDC, and / or does not bind to one or more human Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))).

[0030] In some embodiments, the Ig is hIgG4 and the amino acid sequence of the Fc region comprises an amino acid substitution at amino acid position S228, an amino acid substitution at amino acid position F234, and / or an amino acid substitution at amino acid position L235, according to the Kabat EU index numbering. In some embodiments, the Ig is hIgG4 and the amino acid sequence of the Fc region comprises proline at amino acid position S228, alanine at amino acid position F234, and / or alanine at amino acid position L235, according to the Kabat EU index numbering.

[0031] In some embodiments, the Ig is hIgG1 and the amino acid sequence of the Fc region comprises an amino acid substitution at amino acid position L234, and / or an amino acid substitution at amino acid position L235, according to the Kabat EU index numbering. In some embodiments, the Ig is hIgG1 and the amino acid sequence of the Fc region comprises alanine at amino acid position L234 and / or alanine at amino acid position L235, according to the Kabat EU index numbering. In some embodiments, the Ig is hIgG1 and the amino acid sequence of the Fc region comprises alanine at amino acid position L234, alanine at amino acid position L235, and / or glycine at position P329, according to the Kabat EU index numbering.

[0032] In some embodiments, the Ig is mIgG2a and the amino acid sequence of the Fc region comprises an amino acid substitution at amino acid position L234, and / or an amino acid substitution at amino acid position L235, according to the Kabat EU index numbering. In some embodiments, the Ig is mIgG2a and the amino acid sequence of the Fc region comprises proline (or alanine) at amino acid position L234 and / or proline (or alanine) at amino acid position L235, according to the Kabat EU index numbering. In some embodiments, the Ig is mIgG2a and the amino acid sequence of the Fc region comprises proline (or alanine) at amino acid position L234, proline (or alanine) at amino acid position L235, and / or glycine at position P329, according to the Kabat EU index numbering.

[0033] In some embodiments, the polypeptide or protein described herein is directly operably linked to a heterologous polypeptide or protein by a peptide bond.

[0034] In some embodiments, the polypeptide or protein described herein is indirectly operably linked to a heterologous polypeptide or protein by a peptide linker. In some embodiments, the amino acid sequence of the peptide linker comprises or consists of: glycine or glycine and serine amino acid residues. In some embodiments, the amino acids of the peptide linker comprise or consist of: (a) the amino acid sequence of any one of SEQ ID NOs: 49 - 57; or (b) the amino acid sequence of any one of SEQ ID NOs: 49 - 57, which comprises or consists of: 1, 2, or 3 amino acid substitutions.

[0035] In some embodiments, the fusion polypeptide or protein comprises, from the N-terminus to the C-terminus: the polypeptide or protein described herein and a heterologous polypeptide or protein. In some embodiments, the fusion polypeptide or protein comprises, from the N-terminus to the C-terminus: the polypeptide or protein described herein, a peptide linker, and a heterologous polypeptide or protein. In some embodiments, the fusion polypeptide or protein comprises, from the N-terminus to the C-terminus: a signal peptide, the polypeptide or protein described herein, a peptide linker, and a heterologous polypeptide or protein. In some embodiments, the fusion polypeptide or protein comprises, from the N-terminus to the C-terminus: a heterologous polypeptide or protein and the polypeptide or protein described herein. In some embodiments, the fusion polypeptide or protein comprises, from the N-terminus to the C-terminus: a heterologous polypeptide or protein, a peptide linker, and the polypeptide or protein described herein. In some embodiments, the fusion polypeptide or protein comprises, from the N-terminus to the C-terminus: a signal peptide, a heterologous polypeptide or protein, a peptide linker, and the isolated polypeptide or protein described herein.

[0036] In one aspect, the present disclosure provides a fusion protein comprising a first polypeptide or protein and a second polypeptide or protein, wherein the first polypeptide or protein comprises a first Ig (e.g., hIg, mIg) Fc region operably linked to the first polypeptide or protein described herein (e.g., the first immunomodulatory protein described herein); and wherein the second polypeptide or protein comprises a second Ig (e.g., hIg, mIg) Fc region operably linked to the second polypeptide or protein described herein (e.g., the second immunomodulatory protein described herein).

[0037] In some embodiments, the first Fc region and the second Fc region associate to form a dimer.

[0038] In some embodiments, the first polypeptide or protein comprises an amino acid sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of the second polypeptide or protein.

[0039] In some embodiments, the first Ig (e.g., hIg, mIg) Fc region comprises at least a portion of the hinge region, the CH2 region, and the CH3 region; and the second Ig (e.g., hIg, mIg) Fc region comprises at least a portion of the hinge region, the CH2 region, and the CH3 region. In some embodiments, the first Ig (e.g., hIg, mIg) Fc region comprises the hinge region, the CH2 region, and the CH3 region; and the second Ig (e.g., hIg, mIg) Fc region comprises the hinge region, the CH2 region, and the CH3 region.

[0040] In some embodiments, the Ig of the first Ig Fc region is hIg and the Ig of the second Ig Fc region is hIg. In some embodiments, the hIg of the first hIg Fc region is hIgG and the hIg of the second hIg Fc region is hIgG. In some embodiments, the hIgG of the first hIg Fc region is hIgG4 and the hIgG of the first hIg Fc region is hIgG4. In some embodiments, the hIgG of the first hIg Fc region is hIgG1 and the hIgG of the first hIg Fc region is hIgG1.

[0041] In some embodiments, the Ig of the first Ig Fc region is hIg and the Ig of the second Ig Fc region is mIg. In some embodiments, the mIg of the first mIg Fc region is mIgG and the mIg of the second mIg Fc region is mIgG. In some embodiments, the mIg of the first mIg Fc region is mIgG1 and the mIg of the second mIg Fc region is mIgG1. In some embodiments, the mIg of the first mIg Fc region is mIgG2A and the mIg of the second mIg Fc region is mIgG2a.

[0042] In some embodiments, the first Ig (e.g., hIg, mIg) Fc region and the second Ig (e.g., hIg, mIg) Fc region each comprise one or more amino acid substitutions relative to a reference Ig (e.g., hIg, mIg) Fc region, the substitutions reducing or eliminating one or more of the following effector functions relative to the reference Ig (e.g., hIg, mIg) Fc region: ADCC, CDC, and / or binding affinity for one or more Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))).

[0043] In some embodiments, the fusion protein substantially does not mediate ADCC, substantially does not mediate CDC, and / or does not bind one or more Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))).

[0044] In some embodiments, the Ig of the first Ig Fc region and the second Ig Fc region is hIgG4, and the amino acid sequence of each of the first Fc region and the second Fc region comprises an amino acid substitution at amino acid position S228, an amino acid substitution at amino acid position F234, and / or an amino acid substitution at amino acid position E235, according to the Kabat EU index numbering. In some embodiments, the Ig of the first Ig Fc region and the second Ig Fc region is hIgG4, and the amino acid sequence of each of the first Fc region and the second Fc region comprises a proline at amino acid position S228, an alanine at amino acid position F234, and / or an alanine at amino acid position E235, according to the Kabat EU index numbering.

[0045] In some embodiments, the Ig of the first Ig Fc region and the second Ig Fc region is hIgG1, and the amino acid sequences of the first Fc region and the second Fc region each contain an amino acid substitution at amino acid position L234, and / or an amino acid substitution at amino acid position L235, according to the Kabat EU index numbering. In some embodiments, the Ig of the first Ig Fc region and the second Ig Fc region is hIgG1, and the amino acid sequences of the first Fc region and the second Fc region each contain alanine at amino acid position L234 and / or alanine at amino acid position L235, according to the Kabat EU index numbering. In some embodiments, the Ig of the first Ig Fc region and the second Ig Fc region is hIgG1, and the amino acid sequences of the first Fc region and the second Fc region each contain proline (or alanine) at amino acid position L234 and / or proline (or alanine) at amino acid position L235, according to the Kabat EU index numbering. In some embodiments, the Ig of the first Ig Fc region and the second Ig Fc region is hIgG1, and the amino acid sequences of the first Fc region and the second Fc region each contain proline (or alanine) at amino acid position L234, proline (or alanine) at amino acid position L235, and / or glycine at amino acid position P329, according to the Kabat EU index numbering.

[0046] In some embodiments, the Ig of the first Ig Fc region and the second Ig Fc region is mIgG2a, and the amino acid sequences of the first Fc region and the second Fc region each contain an amino acid substitution at amino acid position L234, and / or an amino acid substitution at amino acid position L235, according to the Kabat EU index numbering.

[0047] In some embodiments, the first Ig (e.g., hIg, mIg) Fc region comprises an amino acid sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of the second Ig (e.g., hIg, mIg) Fc region.

[0048] In some embodiments, the first polypeptide or protein comprises, from the N-terminus to the C-terminus: a first Ig (e.g., hIg, mIg) Fc region and the first polypeptide or protein described herein (e.g., the immunomodulatory protein described herein); and the second polypeptide or protein comprises, from the N-terminus to the C-terminus: a second Ig (e.g., hIg, mIg) Fc region and the second polypeptide or protein described herein (e.g., the immunomodulatory protein described herein).

[0049] In some embodiments, the first polypeptide or protein comprises, from the N-terminus to the C-terminus: a first Ig (e.g., hIg, mIg) Fc region, a first peptide linker, and the first protein or polypeptide described herein (e.g., the immunomodulatory protein described herein); and the second polypeptide or protein comprises, from the N-terminus to the C-terminus: a second Ig (e.g., hIg, mIg) Fc region, a second peptide linker, and the second protein or polypeptide described herein (e.g., the immunomodulatory protein described herein).

[0050] In some embodiments, the first polypeptide or protein comprises, from the N-terminus to the C-terminus: the first polypeptide or protein described herein (e.g., the immunomodulatory protein described herein), and a first Ig (e.g., hIg, mIg) Fc region; and the second polypeptide or protein comprises, from the N-terminus to the C-terminus: the second polypeptide or protein described herein (e.g., the immunomodulatory protein described herein), and a second Ig (e.g., hIg, mIg) Fc region.

[0051] In some embodiments, the first polypeptide or protein comprises, from the N-terminus to the C-terminus: the first polypeptide or protein described herein (e.g., the immunomodulatory protein described herein), a first peptide linker, and a first Ig (e.g., hIg, mIg) Fc region; and the second polypeptide or protein comprises, from the N-terminus to the C-terminus: the second polypeptide or protein described herein (e.g., the immunomodulatory protein described herein), a second peptide linker, and a second Ig (e.g., hIg, mIg) Fc region.

[0052] In some embodiments, the amino acid sequence of each of the first peptide linker and the second peptide linker comprises or consists of the following: glycine or glycine and serine amino acid residues. In some embodiments, the amino acids of each of the first peptide linker and the second peptide linker comprise or consist of the following: (a) the amino acid sequence of any one of SEQ ID NOs: 49-57; or (b) the amino acid sequence of any one of SEQ ID NOs: 49-57, which comprises or consists of 1, 2, or 3 amino acid substitutions.

[0053] In some embodiments, the polypeptide or fusion protein comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO:58, 61-69, or 72-79. In some embodiments, the polypeptide or fusion protein comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO:58, 61-69, or 72-79. In some embodiments, the polypeptide or fusion protein comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO:58, 61-69, or 72-79. In some embodiments, the polypeptide or fusion protein comprises an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO:58, 61-69, or 72-79. In some embodiments, the polypeptide or fusion protein comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO:62-65, or 73-76. In some embodiments, the polypeptide or fusion protein comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO:62-65, or 73-76. In some embodiments, the polypeptide or fusion protein comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO:62-65, or 73-76. In some embodiments, the polypeptide or fusion protein comprises an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO:62-65, or 73-76.

[0054] In one aspect, provided herein are conjugates comprising a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) operably linked to a heterologous moiety.

[0055] In one aspect, provided herein are immunogenic peptides or proteins that comprise (a) at least a portion of a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein); and / or (b) a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) that comprises at least one amino acid variation (e.g., substitution, addition, deletion), and wherein the immunogenic peptide or protein does not specifically bind hIL-10R (e.g., hIL-10Rα) or binds hIL-10R (e.g., hIL-10Rα) with a lower affinity relative to a reference polypeptide or protein.

[0056] In some embodiments, the immunogenic peptide or protein comprises at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, or 250 amino acids. In some embodiments, the immunogenic peptide or protein comprises about 10 - 250, 10 - 200, 10 - 100, 10 - 90, 10 - 80, 10 - 70, 10 - 60, 10 - 50, 10 - 40, 10 - 30, 10 - 20, 10 - 250, 20 - 250, 30 - 250, 40 - 250, 50 - 250, 60 - 250, 70 - 250, 80 - 250, 90 - 250, 100 - 250, 10 - 200, 20 - 200, 30 - 200, 40 - 200, 50 - 200, 60 - 200, 70 - 200, 80 - 200, 90 - 200, or 100 - 200 amino acids.

[0057] In some embodiments, the amino acid sequence of the immunogenic peptide or protein comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid variations (e.g., substitutions, additions, deletions) relative to a reference polypeptide or protein.

[0058] In some embodiments, the immunogenic peptide or protein comprises an amino acid sequence that is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a contiguous segment of at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, or 200 amino acids of any one of SEQ ID NOs: 108 - 454.

[0059] In some embodiments, the immunogenic peptide or protein comprises an amino acid sequence that is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454, except for at least one amino acid variation (e.g., substitution, addition, deletion).

[0060] In some embodiments, the immunogenic polypeptide or protein is formulated with an adjuvant.

[0061] In one aspect, provided herein is an isolated antibody that specifically binds to a protein or polypeptide described herein (e.g., an immunomodulatory protein or polypeptide described herein).

[0062] In one aspect, provided herein are polynucleotides encoding the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, or the antibodies described herein.

[0063] In some embodiments, the polynucleotide is RNA (e.g., mRNA) or DNA.

[0064] In one aspect, provided herein are mRNA polynucleotides encoding the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, or the antibodies described herein.

[0065] In some embodiments, the mRNA comprises a heterologous 5'-untranslated region (UTR), 3'-UTR, or both 5'-UTR and 3'-UTR. In some embodiments, the mRNA comprises a poly(A) sequence. In some embodiments, the mRNA comprises a 5' cap structure.

[0066] In some embodiments, the polynucleotide or mRNA polynucleotide comprises at least one variant nucleotide. In some embodiments, the nucleic acid sequence of the polynucleotide or mRNA polynucleotide is codon-optimized, respectively.

[0067] In one aspect, provided herein are expression vectors comprising the polynucleotides described herein or the mRNA polynucleotides described herein. In some embodiments, the expression vector is a viral vector or a plasmid.

[0068] In one aspect, provided herein are cells (e.g., host cells) that comprise the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNA described herein, the expression vectors described herein, or the carriers described herein.

[0069] In one aspect, provided herein are carriers that comprise the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNA described herein, the expression vectors described herein, or the cells described herein. In some embodiments, the carrier is a lipid nanoparticle, liposome, lipoplex, or nanoliposome.

[0070] In one aspect, the present disclosure provides lipid nanoparticles comprising a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, or a cell described herein.

[0071] In one aspect, the present disclosure provides a vaccine composition comprising an immunogenic peptide or protein described herein (or a nucleic acid molecule encoding the same (or a vector encoding the nucleic acid molecule)).

[0072] In one aspect, the present disclosure provides a pharmaceutical composition comprising a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein; and a pharmaceutically acceptable excipient.

[0073] In one aspect, the present disclosure provides a kit comprising a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein; and optionally instructions for using any one or more of the foregoing.

[0074] In one aspect, provided herein are methods for delivering a polypeptide, protein, fusion protein, conjugate, polynucleotide, mRNA polynucleotide, expression vector, cell, carrier, lipid nanoparticle, immunogenic peptide or protein, antibody, vaccine composition, or pharmaceutical composition to a subject, the methods comprising administering to the subject a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, thereby delivering the polypeptide, protein, fusion polypeptide, fusion protein, conjugate, immunogenic peptide or protein, antibody, mRNA polynucleotide, expression vector, cell, carrier, lipid nanoparticle, vaccine composition, or pharmaceutical composition to the subject.

[0075] In one aspect, provided herein is the use in medicine of a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein.

[0076] In one aspect, provided herein are methods for stimulating the IL-10 pathway in a subject in need thereof, the methods comprising administering to the subject a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, thereby stimulating the IL-10 pathway in the subject.

[0077] In one aspect, provided herein is the use of a polypeptide or protein as described herein (e.g., an immunomodulatory protein or polypeptide as described herein), a fusion polypeptide or protein as described herein, a conjugate as described herein, an immunogenic peptide or protein as described herein, an antibody as described herein, a polynucleotide as described herein, an mRNA as described herein, an expression vector as described herein, a cell as described herein, a carrier as described herein, a lipid nanoparticle as described herein, a vaccine composition as described herein, or a pharmaceutical composition as described herein, in a method for stimulating the IL-10 pathway in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion protein or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby stimulating the IL-10 pathway in the subject.

[0078] In one aspect, provided herein is the use of a polypeptide or protein as described herein (e.g., an immunomodulatory protein or polypeptide as described herein), a fusion polypeptide or protein as described herein, a conjugate as described herein, an immunogenic peptide or protein as described herein, an antibody as described herein, a polynucleotide as described herein, an mRNA as described herein, an expression vector as described herein, a cell as described herein, a carrier as described herein, a lipid nanoparticle as described herein, a vaccine composition as described herein, or a pharmaceutical composition as described herein, in the manufacture of a medicament for stimulating the IL-10 pathway in a subject in need thereof, comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion protein or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby stimulating the IL-10 pathway in the subject.

[0079] In one aspect, the present disclosure provides methods for treating, preventing, or ameliorating IL-10-responsive diseases in a subject in need thereof, the methods comprising administering to the subject a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, thereby treating, preventing, or ameliorating the IL-10-responsive disease. In some embodiments, the IL-10-responsive disease is a pro-inflammatory disease. In some embodiments, the IL-10-responsive disease is an autoimmune disease. In some embodiments, the IL-10-responsive disease is a metabolic inflammatory disease.

[0080] In one aspect, the present disclosure provides a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein for use in a method for treating, preventing, or ameliorating an IL-10-responsive disease in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby treating, preventing, or ameliorating the IL-10-responsive disease. In some embodiments, the IL-10-responsive disease is a pro-inflammatory disease. In some embodiments, the IL-10-responsive disease is an autoimmune disease. In some embodiments, the IL-10-responsive disease is a metabolic inflammatory disease.

[0081] In one aspect, the present disclosure provides the use of a polypeptide or protein as described herein (e.g., an immunomodulatory protein or polypeptide as described herein), a fusion polypeptide or protein as described herein, a conjugate as described herein, an immunogenic peptide or protein as described herein, an antibody as described herein, a polynucleotide as described herein, an mRNA as described herein, an expression vector as described herein, a cell as described herein, a carrier as described herein, a lipid nanoparticle as described herein, a vaccine composition as described herein, or a pharmaceutical composition as described herein in the manufacture of a medicament for treating, preventing, or ameliorating an IL-10 responsive disease in a subject in need thereof, comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby treating, preventing, or ameliorating the IL-10 responsive disease. In some embodiments, the IL-10 responsive disease is a pro-inflammatory disease. In some embodiments, the IL-10 responsive disease is an autoimmune disease. In some embodiments, the IL-10 responsive disease is a metabolic inflammatory disease.

[0082] In one aspect, the present disclosure provides a method of inhibiting or preventing an immune response in a subject in need thereof, the method comprising administering to the subject a polypeptide or protein as described herein (e.g., an immunomodulatory protein or polypeptide as described herein), a fusion polypeptide or protein as described herein, a conjugate as described herein, an immunogenic peptide or protein as described herein, an antibody as described herein, a polynucleotide as described herein, an mRNA as described herein, an expression vector as described herein, a cell as described herein, a carrier as described herein, a lipid nanoparticle as described herein, a vaccine composition as described herein, or a pharmaceutical composition as described herein, thereby inhibiting or preventing an immune response in the subject.

[0083] In one aspect, provided herein are the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNAs described herein, the expression vectors described herein, the cells described herein, the carriers described herein, the lipid nanoparticles described herein, the vaccine compositions described herein, or the pharmaceutical compositions described herein, for use in a method of inhibiting or preventing an immune response in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inhibiting or preventing an immune response in the subject.

[0084] In one aspect, provided herein is the use of the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNAs described herein, the expression vectors described herein, the cells described herein, the carriers described herein, the lipid nanoparticles described herein, the vaccine compositions described herein, or the pharmaceutical compositions described herein in the manufacture of a medicament for inhibiting or preventing an immune response in a subject in need thereof, comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inhibiting or preventing an immune response in the subject.

[0085] In one aspect, provided herein is a method of inducing tolerance to an immunogen in a subject in need thereof, the method comprising administering to the subject the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNAs described herein, the expression vectors described herein, the cells described herein, the carriers described herein, the lipid nanoparticles described herein, the vaccine compositions described herein, or the pharmaceutical compositions described herein, thereby inducing tolerance to the immunogen in the subject.

[0086] In one aspect, provided herein is the use of a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, in a method for inducing tolerance to an immunogen in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inducing tolerance to the immunogen in the subject.

[0087] In one aspect, provided herein is the use of a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, in the manufacture of a medicament for inducing tolerance to an immunogen in a subject in need thereof, comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inducing tolerance to the immunogen in the subject.

[0088] In one aspect, provided herein is a method for inhibiting IgE expression in a subject in need thereof, the method comprising administering to the subject a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, thereby inhibiting IgE expression in the subject.

[0089] In one aspect, provided herein is the use of a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, in a method for inhibiting IgE expression in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inhibiting IgE expression in the subject.

[0090] In one aspect, provided herein is the use of a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, in the manufacture of a medicament for inhibiting IgE expression in a subject in need thereof, comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inhibiting IgE expression in the subject.

[0091] In some embodiments, the levels of one or more pro-inflammatory cytokines (e.g., IFNγ, TNFα, IL-17A) are inhibited (e.g., as measured by the assays described herein).

[0092] In some embodiments, the levels of immunogen-specific immunoglobulins are inhibited (e.g., as measured by the assays described herein).

[0093] In some embodiments, the levels of IgE (e.g., immunogen-specific IgE, e.g., allergen-specific IgE) are inhibited (e.g., as measured by the assays described herein).

[0094] In some embodiments, the subject has an IL-10 responsive disease (e.g., an IL-10 responsive disease as described herein (e.g., an autoimmune disease (e.g., GvHD, allergic disease, etc.))).

[0095] In some embodiments, prior to administering to the subject a polypeptide or protein as described herein (e.g., an immunomodulatory protein or polypeptide as described herein), a fusion polypeptide or protein as described herein, a conjugate as described herein, an immunogenic peptide or protein as described herein, an antibody as described herein, a polynucleotide as described herein, an mRNA as described herein, an expression vector as described herein, a cell as described herein, a carrier as described herein, a lipid nanoparticle as described herein, a vaccine composition as described herein, or a pharmaceutical composition as described herein, the subject has been administered one or more immunosuppressive agents (e.g., one or more steroids (e.g., corticosteroids)).

[0096] In some embodiments, the IL-10 responsive disease is refractory to one or more immunosuppressive agents (e.g., one or more steroids (e.g., corticosteroids)).

[0097] In some embodiments, a polypeptide or protein as described herein (e.g., an immunomodulatory protein or polypeptide as described herein), a fusion polypeptide or protein as described herein, a conjugate as described herein, an immunogenic peptide or protein as described herein, an antibody as described herein, a polynucleotide as described herein, an mRNA as described herein, an expression vector as described herein, a cell as described herein, a carrier as described herein, a lipid nanoparticle as described herein, a vaccine composition as described herein, or a pharmaceutical composition as described herein is administered to the subject in combination with one or more immunosuppressive agents (e.g., one or more steroids (e.g., corticosteroids)).

[0098] In some embodiments, the immunogen is an allergen. In some embodiments, the subject has been administered allergen-specific therapy (e.g., as described herein (e.g., the subject has been administered at least 1 (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses (e.g., escalating doses)) of allergen)). In some embodiments, the allergen-specific therapy induces a degree of tolerance to the immunogen in the subject.

[0099] In some embodiments, administration of the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNAs described herein, the expression vectors described herein, the cells described herein, the carriers described herein, the lipid nanoparticles described herein, the vaccine compositions described herein, or the pharmaceutical compositions described herein enhances the degree of tolerance induced by immunogen-specific therapies.

[0100] In some embodiments, the subject has received an allogeneic or autologous cell, tissue, or organ transplant. In some embodiments, the immunogen is a portion of an allogeneic or autologous cell, tissue, or organ. In some embodiments, the subject has graft-versus-host disease. In some embodiments, the graft-versus-host disease is acute or chronic.

[0101] In one aspect, provided herein is a method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNAs described herein, the expression vectors described herein, the cells described herein, the carriers described herein, the lipid nanoparticles described herein, the vaccine compositions described herein, or the pharmaceutical compositions described herein, thereby inducing an immune response in the subject.

[0102] In one aspect, provided herein are the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNAs described herein, the expression vectors described herein, the cells described herein, the carriers described herein, the lipid nanoparticles described herein, the vaccine compositions described herein, or the pharmaceutical compositions described herein for use in a method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject the polypeptides or proteins, the polypeptides or proteins, the fusion polypeptides or proteins, the fusions, the conjugates, the immunogenic peptides or proteins, the antibodies, the polynucleotides, the mRNA polynucleotides, the expression vectors, the cells, the carriers, the lipid nanoparticles, the vaccine compositions, or the pharmaceutical compositions, thereby inducing an immune response in the subject.

[0103] In one aspect, the present disclosure provides the use of a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein in the manufacture of a medicament for inducing an immune response in a subject in need thereof, comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inducing an immune response in the subject.

[0104] In one aspect, the present disclosure provides a method for preventing, treating, or ameliorating a viral infection in a subject in need thereof, the method comprising administering to the subject a polypeptide or protein described herein (e.g., an immunomodulatory protein or polypeptide described herein), a fusion polypeptide or protein described herein, a conjugate described herein, an immunogenic peptide or protein described herein, an antibody described herein, a polynucleotide described herein, an mRNA described herein, an expression vector described herein, a cell described herein, a carrier described herein, a lipid nanoparticle described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, thereby preventing, treating, or ameliorating the viral infection in the subject. In some embodiments, the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus.

[0105] In one aspect, provided herein are the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNAs described herein, the expression vectors described herein, the cells described herein, the carriers described herein, the lipid nanoparticles described herein, the vaccine compositions described herein, or the pharmaceutical compositions described herein for use in a method of preventing, treating, or ameliorating a viral infection in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby preventing, treating, or ameliorating a viral infection in the subject. In some embodiments, the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus.

[0106] In one aspect, provided herein is the use of the polypeptides or proteins described herein (e.g., the immunomodulatory proteins or polypeptides described herein), the fusion polypeptides or proteins described herein, the conjugates described herein, the immunogenic peptides or proteins described herein, the antibodies described herein, the polynucleotides described herein, the mRNAs described herein, the expression vectors described herein, the cells described herein, the carriers described herein, the lipid nanoparticles described herein, the vaccine compositions described herein, or the pharmaceutical compositions described herein in the manufacture of a medicament for preventing, treating, or ameliorating a viral infection in a subject in need thereof, comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby preventing, treating, or ameliorating a viral infection in the subject. In some embodiments, the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus.

[0107] In one aspect, the present disclosure provides methods for determining the presence of a virus in a subject, the methods comprising (a) obtaining a sample from the subject or providing a sample obtained from the subject, and (b) determining the presence or absence of a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof) or a polynucleotide encoding a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof) in the sample.

[0108] In some embodiments, the sample is blood, cells, tissue, saliva, or a nasal swab. In some embodiments, the subject is a human. In some embodiments, the antibodies described herein are used to determine the presence or absence of a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof). In some embodiments, the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus.

[0109] In one aspect, the present disclosure provides methods for diagnosing a viral infection in a subject, the methods comprising (a) obtaining a sample from the subject or providing a sample that has been obtained from the subject, (b) determining the presence or absence of a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof) or a polynucleotide encoding a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof), and (c) diagnosing the subject as having the viral infection if the polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof) or the polynucleotide encoding a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof) is determined to be present in the sample in step (b). In some embodiments, the method is an in vitro method.

[0110] In some embodiments, the sample is blood, cells, tissue, saliva, or a nasal swab. In some embodiments, the subject is a human. In some embodiments, the antibodies described herein are used to determine the presence or absence of a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof). In some embodiments, the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus.

[0111] In one aspect, the present disclosure provides a method for treating a viral infection in a subject, the method comprising (a) receiving test results that determine the presence of a polypeptide or protein (e.g., an immunomodulatory polypeptide or protein as described herein) (or a fragment or variant thereof) or a polynucleotide encoding a polypeptide or protein (e.g., an immunomodulatory polypeptide or protein as described herein) (or a fragment or variant thereof) in a sample from the subject, (b) diagnosing the subject as having the viral infection, and (c) administering a therapeutic agent to treat the viral infection.

[0112] In some embodiments, the sample is blood, cells, tissue, or saliva, or a nasal swab. In some embodiments, the subject is a human. In some embodiments, the antibodies described herein are used to determine the presence or absence of a polypeptide or protein (e.g., an immunomodulatory polypeptide or protein as described herein) (or a fragment or variant thereof). In some embodiments, the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus.

[0113] In one aspect, the present disclosure provides a therapeutic agent for treating a viral infection, for use in a method for treating a viral infection in a subject, the method comprising (a) receiving test results that determine the presence of a polypeptide or protein (e.g., an immunomodulatory polypeptide or protein as described herein) (or a fragment or variant thereof) or a polynucleotide encoding a polypeptide or protein (e.g., an immunomodulatory polypeptide or protein as described herein) (or a fragment or variant thereof) in a sample from the subject, (b) diagnosing the subject as having the viral infection, and (c) administering the therapeutic agent to treat the viral infection.

[0114] In some embodiments, the sample is blood, cells, tissue, or saliva, or a nasal swab. In some embodiments, the subject is a human. In some embodiments, the antibodies described herein are used to determine the presence or absence of a polypeptide or protein (e.g., an immunomodulatory polypeptide or protein as described herein) (or a fragment or variant thereof). In some embodiments, the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus.

[0115] In one aspect, the present disclosure provides the use of a therapeutic agent for treating a viral infection in the preparation of a medicament for treating a viral infection in a subject, comprising (a) receiving test results determining the presence of a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof) or a polynucleotide encoding a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof) in a sample from the subject, (b) diagnosing the subject with the viral infection, and (c) administering the therapeutic agent to treat the viral infection.

[0116] In some embodiments, the sample is blood, cells, tissue, or saliva, or a nasal swab. In some embodiments, the subject is a human. In some embodiments, the antibodies described herein are used to determine the presence or absence of a polypeptide or protein described herein (e.g., an immunomodulatory polypeptide or protein described herein) (or a fragment or variant thereof). In some embodiments, the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus. 4. BRIEF DESCRIPTION OF THE DRAWINGS

[0117] Figure 1 The bar graph of shows the levels (ng / mL) of each immunomodulatory fusion protein 1-11 (IFP-1-11) and the in vitro expressed reference Fc-hIL-10 fusion protein.

[0118] Figure 2A The line graph of shows the in vitro engagement of IFP-1 and the reference Fc-hIL-10 fusion protein with hIL-10R. Figure 2B The line graph of shows the in vitro engagement of IFP-2 and the reference Fc-hIL-10 fusion protein with hIL-10R. Figure 2C The line graph of shows the in vitro engagement of IFP-3 and the reference Fc-hIL-10 fusion protein with hIL-10R. Figure 2D The line graph of shows the in vitro engagement of IFP-4 and the reference Fc-hIL-10 fusion protein with hIL-10R. Figure 2E The line graph of shows the in vitro engagement of IFP-5 and the reference Fc-hIL-10 fusion protein with hIL-10R. Figure 2F The line graph of shows the in vitro engagement of IFP-6 and the reference Fc-hIL-10 fusion protein with hIL-10R. Figure 2G The line graph of shows the in vitro engagement of IFP-7 and the reference Fc-hIL-10 fusion protein with hIL-10R. Figure 2H The line graph of shows the in vitro engagement of IFP-8 and the reference Fc-hIL-10 fusion protein with hIL-10R. Figure 2IThe line graph shows the in vitro binding of IFP-9 and reference Fc-hIL-10 fusion protein to hIL-10R. Figure 2J The line graph shows the in vitro binding of IFP-10 and reference Fc-hIL-10 fusion protein to hIL-10R. Figure 2K The line graph shows the in vitro binding of IFP-11 and reference Fc-hIL-10 fusion protein to hIL-10R.

[0119] Figure 3A The line graph shows the in vitro binding of reference Fc-hIL-10 fusion protein to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3B The line graph shows the in vitro binding of IFP-1 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3C The line graph shows the in vitro binding of IFP-2 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3D The line graph shows the in vitro binding of IFP-3 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3E The line graph shows the in vitro binding of IFP-4 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3F The line graph shows the in vitro binding of IFP-5 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3G The line graph shows the in vitro binding of IFP-6 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3H The line graph shows the in vitro binding of IFP-7 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3I The line graph shows the in vitro binding of IFP-8 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3J The line graph shows the in vitro binding of IFP-9 to hIL-10R in the presence and absence of anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα.Figure 3K The line graph shows the in vitro conjugation of IFP-10 with hIL-10R in the presence and absence of an anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα. Figure 3L The line graph shows the in vitro conjugation of IFP-11 with hIL-10R in the presence and absence of an anti-IL-10Rα antibody that blocks the binding of hIL-10 to hIL-10Rα.

[0120] Figure 4A The radar graph shows the expression of IFN-γ, IL-1β, IL-8, IL-6, TNFα, and IL-4 from LPS-stimulated human peripheral blood mononuclear cells (hPBMCs) treated with a reference Fc-hIL-10 fusion protein or an Fc-GFP negative control (referred to as "Fc" in Figure 4A . The ratios represent the percentage of cytokines present relative to the levels in the Fc-GFP control group. Figure 4B The radar graph shows the expression of IL-1β, IL-8, IL-6, and TNFα from LPS-stimulated human peripheral blood mononuclear cells (hPBMCs) treated with IFP-2 or an Fc-GFP negative control (referred to as "Fc" in Figure 4B . The ratios represent the percentage of cytokines present relative to the levels in the Fc-GFP control group. Figure 4C The radar graph shows the expression of IFN-γ, IL-1β, IL-8, IL-6, TNFα, and IL-4 from LPS-stimulated human peripheral blood mononuclear cells (hPBMCs) treated with IFP-5 or an Fc-GFP negative control (referred to as "Fc" in Figure 4C . The ratios represent the percentage of cytokines present relative to the levels in the Fc-GFP control group. Figure 4D The radar graph shows the expression of IL-1β, IL-8, IL-6, and TNFα from LPS-stimulated human peripheral blood mononuclear cells (hPBMCs) treated with IFP-6 or an Fc-GFP negative control (referred to as "Fc" in Figure 4D . The ratios represent the percentage of cytokines present relative to the levels in the Fc-GFP control group. Figure 4E The radar graph shows the expression of IFN-γ, IL-1β, IL-8, IL-6, TNFα, and IL-4 from LPS-stimulated human peripheral blood mononuclear cells (hPBMCs) treated with IFP-7 or an Fc-GFP negative control (referred to as "Fc" in Figure 4E . The ratios represent the percentage of cytokines present relative to the levels in the Fc-GFP control group. Figure 4F The radar graph shows the expression of... from LPS-stimulated human peripheral blood mononuclear cells (hPBMCs) treated with IFP-8 or an Fc-GFP negative control (referred to as "Fc" inFigure 4F Expression of IL-1β, IL-8, IL-6, and TNFα in LPS-stimulated human peripheral blood mononuclear cells (hPBMCs) treated with (referred to as "Fc" in the text). The ratio represents the percentage of cytokines present relative to the levels in the Fc-GFP control group.

[0121] Figure 5 A series of line graphs shows the expression of IFNγ, TNFα, and IL-17a in stimulated human peripheral blood mononuclear cells (hPBMCs) treated with IFP-7 alone (bottom row), or a reference hIL-10Fc fusion protein (top row), or in combination with dexamethasone.

[0122] Figure 6 The PCA plot shows clustering of IMP 1-175 (SEQ ID NOs: 108-454) by sequence and structural similarity and visualization by principal component analysis (PCA). "Sampled" indicates 97 IMPs (IMP 1-12, 21, 26-27, 31-32, 36, 38, 41, 49-50, 53, 55, 58, 62, 67-70, 72-73, 75-82, 84, 86-87, 89, 91, 93, 95, 97-100, 102-103, 106-109, 111-112, 115, 117-118, 120-127, 129-130, 132, 134-136, 138-158) generated and analyzed in Examples 1 and 3 herein, for example. "Unsamples" indicates the other 78 IMPs. As shown, the sequences cluster in clusters 0-5. The IMPs in each cluster are shown in Example 2.

[0123] Figure 7 The bar graph shows the in vivo engraftment of human CD45+ immune cells (hCD45) in a xenograft mouse model. Mice were treated with dexamethasone (dexa) and IFP-7, dexamethasone (dexa) and a reference hIL-10Fc fusion protein, dexamethasone (dexa) and human Fc protein, or an untreated control. Data are represented as the ratio of hCD45+ immune cells to murine CD45+ immune cells (mCD45). "*" indicates a P-value of approximately 0.02. "**" indicates a P-value of approximately 0.001 - 0.005.

[0124] Figure 8AThe bar graph shows the percentage of human naive (CD27+ and CD45Ra+) CD4+ FOXP3− T cells in vivo in a xenograft mouse model. Mice were treated with dexamethasone (dexa) and IFP-7, dexamethasone (dexa) and reference hIL-10Fc fusion protein, dexamethasone (dexa) and human Fc protein, or untreated control. “*” indicates a P value of approximately 0.05. “****” indicates a P value less than 0.0001. Figure 8B The bar graph shows the percentage of human effector (CD27− and CD45Ra−) CD4+ FOXP3− T cells in vivo in a GVHD xenograft mouse model. Mice were treated with dexamethasone (dexa) and IFP-7, dexamethasone and reference hIL-10Fc fusion protein, dexamethasone and human Fc, or untreated control. “**” indicates a P value of approximately 0.001. “***” indicates a P value of approximately 0.0009. “****” indicates a P value less than 0.0001.

[0125] Figure 9 The bar graph shows the in vivo expression of IFNγ in a xenograft mouse model. Mice were treated with dexamethasone (dexa) and IFP-7, dexamethasone and reference hIL-10Fc fusion protein, dexamethasone and human Fc, or untreated control. “*” indicates a P value of approximately 0.05.

[0126] Figure 10 The bar graph shows the relative body weight of mice in a xenograft mouse model of graft-versus-host disease (GVHD). Mice were treated with dexamethasone (dexa) and IFP-7, dexamethasone and reference hIL-10Fc fusion protein, untreated control, or control mice not receiving hPBMC.

[0127] Figure 11 The bar graph shows the survival of mice in a GVHD xenograft mouse model. Mice were treated with dexamethasone (dexa) and IFP-7, dexamethasone and reference hIL-10Fc fusion protein, untreated control, or control mice not receiving hPBMC. “*” indicates a P value of approximately 0.02. 5. Specific embodiments

[0128] Although hIL-10 has been evaluated as an agent for treating various autoimmune diseases, it has shown limited efficacy in each case. The biologically active form of hIL-10 is an unstable homodimer that exhibits a short half-life, is easily degraded, and has low potency in vivo. In particular, the present invention has identified immunomodulatory proteins and polypeptides that bind to hIL-10R (e.g., hIL-10Rα), and in particular exhibit one or more improved properties compared to hIL-10, such as increased binding affinity for hIL-10R (e.g., hIL-10Rα), enhanced potency, enhanced inhibition of one or more pro-inflammatory cytokines, etc. Accordingly, the novel immunomodulatory proteins disclosed herein can be used to modulate the immune response and for treating diseases (e.g., IL-10-responsive diseases). Thus, the present disclosure provides novel immunomodulatory proteins for use, in particular, in pharmaceutical compositions for treating diseases (e.g., IL-10-responsive diseases). 5.1 Definitions

[0129] The section headings used herein are for purposes of arrangement only and should not be construed as limiting the subject matter described.

[0130] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit any claimed subject matter.

[0131] Unless otherwise expressly stated, the singular forms used herein include the plural. For example, as used herein, the singular forms "a / an" and "the" include plural referents unless the context clearly dictates otherwise. Further, the use of the term "including" and other forms (e.g., "include," "includes," and "included") is not limiting.

[0132] It should be understood that whenever aspects are described herein in terms of the language "comprising," other similar aspects are also provided described in terms of the terms "consisting of" and "consisting essentially of."

[0133] In addition, as used herein, the term "and / or" shall be taken to mean a specific disclosure of each of two designated features or components with or without the other. Thus, the term "and / or" as used in phrases such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover the following various aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0134] As described herein, unless otherwise indicated, any range of concentrations, percentage ranges, ratio ranges, or integer ranges should be understood to include any integer value within the stated range and, when appropriate, fractions thereof (such as tenths and hundredths of an integer).

[0135] The term "about" refers to a value or a composition within an acceptable error range of a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measuring system. When a particular value or composition is provided herein, unless otherwise stated, the meaning of "about" should be assumed to be within the acceptable error range of the stated particular value or composition.

[0136] When proteins and / or polypeptides are described herein, it should be understood that polynucleotides encoding the proteins or polypeptides (e.g., RNA (e.g., mRNA) or DNA nucleic acid molecules) are also provided herein.

[0137] When proteins, polypeptides, nucleic acid molecules, vectors, carriers, etc. are described herein, it should be understood that isolated forms of the proteins, polypeptides, nucleic acid molecules, vectors, carriers, etc. are also provided herein.

[0138] When proteins, polypeptides, nucleic acid molecules, etc. are described herein, it should be understood that recombinant forms of the proteins, polypeptides, nucleic acid molecules, etc. are also provided herein.

[0139] When polypeptides or groups of polypeptides are described herein, it should be understood that proteins containing the polypeptides or groups of polypeptides folded into their three-dimensional structure (i.e., tertiary or quaternary structure) are also provided herein, and vice versa.

[0140] As used herein, the term "adjuvant" refers to a substance that causes stimulation of the immune system of a subject when administered to the subject.

[0141] As used herein, the term "administer" refers to the physical introduction of an agent, such as a therapeutic agent (or a therapeutic agent precursor that is metabolized or altered in a subject's body to produce a therapeutic agent in vivo), or a vaccine, into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods of time.

[0142] As used herein, the term "affinity" refers to the strength of binding of one protein (such as a ligand) to another protein (such as a receptor). The affinity of a protein is measured by the dissociation constant Kd, defined as [ligand] x [receptor] / [ligand-receptor], where [ligand-receptor] is the molar concentration of the ligand-receptor complex, [ligand] is the molar concentration of unbound ligand, and [receptor] is the molar concentration of unbound receptor. The association constant Ka is defined as 1 / Kd. Standard methods for measuring affinity are known to those of ordinary skill in the art. Exemplary methods for measuring affinity are described herein; see, for example, §5.2.2.

[0143] As used herein, the term "antibody" or "antibodies" is used in the broadest sense and encompasses various immunoglobulin (Ig) (e.g., human Ig (hIg), murine Ig (mIg)) structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific (e.g., bispecific, trispecific) antibodies, and antibody fragments, so long as they exhibit the desired antigen-binding activity (i.e., antigen-binding fragments or variants). Thus, the term antibody includes, for example, full-length antibodies; antigen-binding fragments of full-length antibodies; molecules containing antibody CDRs, VH regions, and / or VL regions; and antibody-like scaffolds (e.g., fibronectin). Examples of antibodies include but are not limited to monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, camelized antibodies, intracellular antibodies, affibodies, diabodies, triabodies, heteroconjugate antibodies, antibody-drug conjugates, single-domain antibodies (e.g., VHH, (VHH) 2 ), single-chain antibodies, single-chain Fv (scFv; (scFv) 2 ), Fab fragments (e.g., Fab, single-chain Fab (scFab), F(ab') 2 fragments, disulfide-linked Fv (sdFv), Fc fusions (e.g., Fab-Fc, scFv-Fc, VHH-Fc, (scFv) 2 -Fc, (VHH) 2 -Fc), and any antigen-binding fragment of any of the above, as well as conjugates or fusion proteins containing any of the above. Antibodies can be of an Ig isotype (e.g., IgG, IgE, IgM, IgD, or IgA), any class (e.g., IgG1, IgG2 , IgG 3 , IgG 4 , IgA 1 or IgA 2 ) or any subclass (e.g., IgG of Ig 2a or IgG 2b ). In certain embodiments, the antibodies described herein are IgG antibodies or their classes (e.g., human IgG 1 or IgG 4 ). In certain embodiments, the antibodies described herein are mIgG antibodies or one of their classes (e.g., mIgG1 or mIgG2a) or subclasses. In some embodiments, the antibodies are human, humanized or chimeric IgG 1 or IgG 4 monoclonal antibodies. In some embodiments, the term antibody refers to a monoclonal or polyclonal antibody population. The antibodies described herein can be produced by any standard method known in the art, e.g., recombinantly produced in a host cell, see, e.g., §5.5; or produced synthetically.

[0144] The terms "CH1" and "CH1 region" are used interchangeably herein and refer to the first constant region of an immunoglobulin heavy chain. An exemplary reference to the amino acid sequence of the hIgG1 CH1 region is shown in SEQ ID NO:531; and an exemplary reference to the amino acid sequence of the hIgG4 CH1 region is shown in SEQ ID NO:534.

[0145] The terms "CH2" and "CH2 region" are used interchangeably herein and refer to the second constant region of an immunoglobulin heavy chain. An exemplary reference to the amino acid sequence of the hIgG1 CH2 region is shown in SEQ ID NO:13; and an exemplary reference to the amino acid sequence of the hIgG4 CH2 region is shown in SEQ ID NO:24.

[0146] The terms "CH3" and "CH3 region" are used interchangeably herein and refer to the third constant region of an immunoglobulin heavy chain. An exemplary reference to the amino acid sequence of the hIgG1 CH3 region is shown in SEQ ID NO:14; and an exemplary reference to the amino acid sequence of the hIgG4 CH3 region is shown in SEQ ID NO:25.

[0147] As used herein, the term "conjugation" refers to the chemical conjugation of a protein or polypeptide with a moiety (e.g., a small molecule, polypeptide, polynucleotide, carbohydrate, lipid, synthetic polymer (e.g., a polymer of polyethylene glycol (PEG)), etc.). The moiety can be directly attached to the protein or polypeptide, or indirectly attached via a linker, e.g., as described herein. Chemical conjugation methods are well known in the art, as are commercially available conjugation reagents and kits, and detailed instructions for their use can be readily obtained from commercial suppliers.

[0148] As used herein, the term "derived from" with respect to a polynucleotide refers to a polynucleotide having at least 70% sequence identity to a reference polynucleotide (e.g., a naturally occurring polynucleotide) or a fragment thereof. The term "derived from" with respect to a polypeptide or protein refers to a polypeptide or protein comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of a reference polypeptide or protein (e.g., a naturally occurring polypeptide or protein). The term "derived from" as used herein does not denote any particular process or method of obtaining the polynucleotide, polypeptide, or protein. For example, the polynucleotide, polypeptide, or protein may be recombinantly produced or chemically synthesized.

[0149] As used herein, the term "diagnosing" or "diagnosis" refers to determining the presence, absence, severity, or course of treatment of a disease (e.g., an infection, e.g., a viral infection). The term "diagnosis" encompasses both an initial determination and subsequent determinations (e.g., monitoring) following the initial determination.

[0150] As used herein, the term "disease" refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, disease, abnormality, pathology, condition, illness, or syndrome in which physiological function is impaired, regardless of the nature of the etiology.

[0151] The terms "DNA" and "polydeoxyribonucleotide" are used interchangeably herein and refer to a macromolecule comprising a plurality of deoxyribonucleotides polymerized by phosphodiester bonds. A deoxyribonucleotide is a nucleotide in which the sugar is deoxyribose.

[0152] The term "EC50" or "half-maximal effective concentration" is a measure of the potency of an agent (e.g., an immunomodulatory protein or polypeptide as described herein) and refers to the concentration of the agent (e.g., an immunomodulatory protein or polypeptide as described herein) required to induce half of the response between the baseline and the maximal response after a specific exposure period. Assays for measuring the EC50 of a protein or polypeptide are standard in the art, see also, e.g., §5.2.2. In some embodiments, the EC50 is measured according to the method described in Example 3 herein.

[0153] When referring to an antibody, the term "effector function" refers to those biological activities attributable to the Fc region of the antibody and thus varies with the antibody isotype. Antibody effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), Fc receptor binding (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa)), and Clq binding.

[0154] As used herein, the term "Fc region" refers to the C-terminal region of an Ig heavy chain that includes at least the CH2 region operably linked to the CH3 region from the N-terminus to the C-terminus. In some embodiments, the Fc region includes an Ig hinge region or at least a portion of the Ig hinge region operably linked to the N-terminus of the CH2 region. In some embodiments, the Fc region is engineered relative to a reference Fc region, see, e.g., §5.3.1.3. Other examples of proteins having an engineered Fc region can be found in Saunders 2019 (K.O. Saunders, “Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life,” 2019, Frontiers in Immunology, V. 10, Art. 1296, pp. 1-20, the entire content of which is incorporated herein by reference for all purposes).

[0155] As used herein, the term "functional variant" with respect to the amino acid sequence of a reference polypeptide or protein refers to a polypeptide or protein that includes at least one but no more than 15%, no more than 12%, no more than 10%, no more than 8% amino acid variations (e.g., substitutions, deletions, additions), wherein the polypeptide or protein retains at least one specific function of the reference polypeptide or protein. Not all functions of the reference polypeptide or protein (e.g., wild type) need to be retained by the functional variant of the protein. In some cases, one or more functions are selectively reduced or eliminated. In some embodiments, the reference polypeptide or protein is a wild type protein. For example, a functional variant of an hIL-10 polypeptide or protein can refer to an hIL-10 protein that includes one or more amino acid substitutions compared to a reference hIL-10 protein (e.g., wild type) and that retains the ability to specifically bind to hIL-10R.

[0156] As used herein, the term "functional fragment" with respect to a polypeptide or protein refers to a fragment of the reference polypeptide or protein that retains at least one specific function. Not all functions of the reference polypeptide or protein need to be retained by the functional fragment of the polypeptide or protein. In some cases, one or more functions are selectively reduced or eliminated. In some embodiments, the reference polypeptide or protein is a wild type protein. For example, a functional fragment of hIL-10 can refer to an hIL-10 fragment that retains the ability to specifically bind to IL-10R.

[0157] As used herein, the term "fusion" and its grammatical equivalents refer to the operable linkage of at least a first polypeptide and a second polypeptide, where the first and second polypeptides are not naturally found to be operably linked together. For example, the first and second polypeptides are derived from different proteins. The term fusion encompasses both the direct linkage of at least two polypeptides by a peptide bond and the indirect linkage through a linker (e.g., a peptide linker).

[0158] As used herein, the term "fusion protein" and its grammatical equivalents refer to a protein comprising at least one polypeptide operably linked to another polypeptide, where the first and second polypeptides are different and are not naturally found to be operably linked together. For example, the first and second polypeptides of a fusion protein are each derived from different proteins. At least two polypeptides of a fusion protein can be operably linked directly by a peptide bond; or can be operably linked indirectly through a linker (e.g., a peptide linker). Thus, for example, the term fusion polypeptide encompasses embodiments where polypeptide A is operably linked directly by a peptide bond to polypeptide B (polypeptide A - polypeptide B), and embodiments where polypeptide A is operably linked to polypeptide B through a peptide linker (polypeptide A – peptide linker – polypeptide B).

[0159] As used herein, the term "half-life extending moiety" refers to a moiety (e.g., a small molecule, polypeptide, polynucleotide, carbohydrate, lipid, synthetic polymer (e.g., a polymer of PEG), etc.) that, when conjugated or otherwise operably linked (e.g., fused) to a polypeptide or protein (the subject polypeptide or protein), increases the in vivo half-life of the subject polypeptide or protein when administered to a subject (e.g., a human subject). In vivo models known in the art can be utilized to evaluate the pharmacokinetic properties of a polypeptide or protein.

[0160] As used herein, the term "half-life extending polypeptide" or "half-life extending protein" refers to a polypeptide or protein that, when operably linked to another polypeptide or protein (the subject polypeptide or protein), increases the in vivo half-life of the subject polypeptide or protein when administered to a subject (e.g., a human subject). In vivo models known in the art can be utilized to evaluate the pharmacokinetic properties of a polypeptide or protein.

[0161] As used herein, when used to describe a first element with reference to a second element, the term "heterologous" means that the first element and the second element do not exist in nature in the described arrangement. For example, a polypeptide comprising a "heterologous moiety" refers to a polypeptide linked to a moiety (such as a small molecule, polypeptide, polynucleotide, carbohydrate, lipid, synthetic polymer (such as a PEG polymer), etc.), which moiety is not naturally linked to the polypeptide. In one embodiment, the heterologous moiety is not derived from a polypeptide or protein comprising or consisting of any of the amino acid sequences of SEQ ID NOs: 108 - 454. For example, non-limiting examples of heterologous moieties are heterologous polypeptides (as defined herein). In one embodiment, a heterologous polypeptide is a polypeptide derived from a polypeptide or protein other than a polypeptide or protein comprising or consisting of any of the amino acid sequences of SEQ ID NOs: 108 - 454. For example, as described herein, a non-limiting fragment of a heterologous polypeptide is the human Ig Fc region.

[0162] As used herein, the term "heterologous signal peptide" refers to a signal peptide that is not operably linked to the subject polypeptide or protein in nature. For example, with respect to a polypeptide comprising a human IL-2 signal peptide operably linked to human IL-12, the human IL-2 signal peptide would constitute a heterologous signal peptide. The terms "signal peptide" and "signal sequence" are used interchangeably herein.

[0163] The terms "hinge" or "hinge region" are used interchangeably herein and refer to the hinge region of an immunoglobulin heavy chain. Exemplary reference to the amino acid sequence of the hIgG1 hinge region is shown in SEQ ID NO: 12; and exemplary reference to the amino acid sequence of the hIgG4 hinge region is shown in SEQ ID NO: 22.

[0164] As used herein, the term "homologous signal peptide" refers to a signal peptide that is operably linked to the subject polypeptide or protein in nature. For example, with respect to a polypeptide comprising the signal peptide of human IL-2 operably linked to human IL-2, the human IL-2 signal peptide would constitute a homologous signal peptide.

[0165] As used herein, the term "human interleukin 10" or "hIL-10" refers to a human immunomodulatory cytokine that mediates signal transduction through the human IL-10 receptor. Exemplary reference to the amino acid sequence of the mature hIL-10 protein is shown in SEQ ID NO: 2.

[0166] As used herein, the term "human IL-10 receptor" or "hIL-10R" refers to a human heterodimeric cell surface complex composed of hIL-10Rα and hIL-10Rβ through which hIL-10 mediates signal transduction.

[0167] As used herein, the term "human IL-10 receptor alpha" or "hIL-10Rα" refers to the alpha (α) subunit of the hIL-10 receptor. An exemplary reference mature hIL-10Rα polypeptide amino acid sequence is shown in SEQ ID NO:4.

[0168] As used herein, the term "human IL-10 receptor beta" or "hIL-10Rβ" refers to the beta (β) subunit of the hIL-10 receptor. An exemplary reference mature hIL-10Rβ polypeptide amino acid sequence is shown in SEQ ID NO:6.

[0169] As used herein, the term "variant Ig Fc fusion polypeptide or protein" refers to a fusion polypeptide or protein comprising an immunomodulatory polypeptide or protein as described herein and an Ig Fc region, wherein the Ig Fc region comprises one or more variations (e.g., one or more amino acid substitutions, deletions or additions)), which reduce or eliminate one or more Fc effector functions relative to a reference Ig Fc fusion protein that does not comprise the one or more variations.

[0170] As used herein, the term "IL-10 responsive disease" refers to a disease in which one or more symptoms are reduced or improved by stimulation of the IL-10 pathway.

[0171] As used herein, the term "immunogen" refers to a substance capable of inducing an immune response (e.g., an adaptive immune response) in a human. An immunogen can have one or more isotypes, sequence variants or splice variants that have equivalent biological and immunological activities and are therefore considered immunogenic equivalents of the immunogen for the purposes of this disclosure.

[0172] As used herein, the term "immunogenic peptide or protein" refers to a peptide or protein comprising an immunogen.

[0173] As used herein, the term "in combination with" means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or disorder. The treatment regimen defines the dosage and period of administration of each agent such that the effects of the individual agents coincide in the subject. In some embodiments, two or more agents are delivered simultaneously or in parallel, and the agents may be co-formulated. In other embodiments, the two or more agents are not co-formulated, but are administered sequentially as part of a prescription regimen. In some embodiments, the combined administration of two or more agents or treatments results in a greater decrease in symptoms or other parameters associated with the disorder than would be observed by delivering one agent or treatment alone or in the absence of the other. The effects of the two treatments may be partially additive, fully additive, or more than additive (e.g., synergistic). The sequential or substantially simultaneous administration of each therapeutic agent may be achieved by any suitable route including but not limited to oral, intravenous, and intramuscular routes. The therapeutic agents may be administered by the same route or by different routes.

[0174] As used herein, the term "isolated" with respect to a polypeptide, protein, or polynucleotide means a polypeptide, protein, or polynucleotide that is substantially free of other cellular components that are associated with it in its natural state.

[0175] As used herein, the term "moiety" generally refers to any macromolecule or micromolecule that can be operably linked to a polypeptide or protein described herein. Exemplary moieties include but are not limited to small molecules, polypeptides, polynucleotides (e.g., DNA, RNA), carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG).

[0176] As used herein, the use of the terms "modified nucleotide", "nucleotide modification", or the term "modification" etc. in reference to a nucleotide or nucleic acid sequence means a nucleotide that contains a chemical modification, such as a modified sugar moiety, a modified nucleobase, and / or a modified internucleoside linkage or any combination thereof. Exemplary modifications are provided herein, see for example §5.4.4.2. In certain embodiments of the instant disclosure, the inclusion of deoxynucleotides (which are considered the naturally occurring form of nucleotides) - if present within an RNA molecule - is considered to constitute a modified nucleotide.

[0177] As used herein, the term "obtaining a sample" means acquiring a sample. The term includes obtaining directly from a subject and obtaining indirectly through one or more third parties, where one of the third parties obtains the sample directly from the subject.

[0178] As used herein, the term "operably linked" refers to two parts being joined in a functional relationship. For example, when polypeptides are joined within a frame (either directly or indirectly through a peptide linker), a polypeptide is operably linked to another polypeptide such that both polypeptides are functional (e.g., a fusion protein or polypeptide as described herein). Or for example, if a transcriptional regulatory polynucleotide such as a promoter, enhancer, or other expression control element affects the transcription of a polynucleotide encoding a protein, it is operably linked to the polynucleotide encoding the protein. The term "operably linked" can also refer to the conjugation of a moiety to, for example, a polynucleotide or polypeptide (e.g., the conjugation of a PEG polymer to a protein or polypeptide).

[0179] A “percent identity” between two sequences (e.g., a peptide or protein (amino acid sequence) or a polynucleotide (nucleic acid sequence)) can be determined using a mathematical algorithm. A specific non-limiting example of a mathematical algorithm for comparing two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87:2264-2268, modified as in Karlin S & Altschul SF (1993) PNAS 90:5873-5877, each of which is incorporated herein by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al. (1990) J Mol Biol 215:403 (which is incorporated herein by reference in its entirety). BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set e.g., score = 100, wordlength = 12, to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program parameters set e.g., score 50, wordlength = 3, to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be used as described in Altschul SF et al. (1997) Nuc Acids Res 25:3389-3402 (which is incorporated herein by reference in its entirety). Alternatively, PSI BLAST can be used to perform an iterative search that detects distant relationships between molecules (ibid). When using the BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., the National Center for Biotechnology Information (NCBI) at world wide web ncbi.nlm.nih.gov). Another specific non-limiting example of a mathematical algorithm for comparing sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17 (which is incorporated herein by reference in its entirety). This algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When using the ALIGN program to compare amino acid sequences, the PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, whether or not gaps are present. When calculating the percent identity, only exact matches are usually counted.

[0180] As used herein, the term "pharmaceutical composition" refers to a composition suitable for administration to an animal, such as a human subject, and comprising a therapeutic agent and a pharmaceutically acceptable carrier or diluent. A "pharmaceutically acceptable carrier or diluent" refers to a substance that is intended for contact with the tissues of humans and / or non-human animals without undue toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable therapeutic benefit / risk ratio.

[0181] As used herein, the term "poly(A) sequence" refers to a sequence of adenosine nucleotides typically located at the 3' end of a coding linear RNA, up to about 1000 adenosine nucleotides. In some embodiments, the poly(A) sequence is substantially homopolymeric, e.g., a 100-nucleotide poly(A) sequence is substantially 100 nucleotides in length. In other embodiments, the poly(A) sequence can be interrupted by at least one nucleotide other than adenosine nucleotide, e.g., a 100-adenosine-nucleotide poly(A) sequence can have a length of more than 100 nucleotides (including the 100 adenosine nucleotides and in addition the at least one nucleotide or stretch of nucleotides other than adenosine nucleotide). It must be understood that the "poly(A) sequence" as defined herein typically pertains to mRNA - however, in the context of the present invention, the term equally pertains to the corresponding sequence in a DNA molecule (e.g., a "poly(T) sequence").

[0182] The terms "polynucleotide" and "nucleic acid molecule" are used interchangeably herein and refer to a polymer of DNA or RNA. The nucleic acid molecule can be single-stranded or double-stranded; contain natural, non-natural, or modified nucleotides; and contain natural, non-natural, or modified internucleotide linkages, such as phosphoramidate linkages or phosphorothioate linkages, rather than the phosphodiester found between the nucleotides of an unmodified nucleic acid molecule. Nucleic acid molecules include, but are not limited to, all nucleic acid molecules obtained by any means available in the art, including but not limited to recombinant means, such as cloning nucleic acid molecules from a recombinant library or a cell genome using conventional cloning techniques and polymerase chain reaction, etc., and by synthetic means. One of skill in the art will understand that, unless otherwise specified, the nucleic acid sequences presented in this application will enumerate thymidine (T) in the representative DNA sequences, but when the sequence represents RNA (e.g., mRNA), thymidine (T) will be replaced by uracil (U). Thus, any RNA polynucleotide encoded by a DNA identified by a specific sequence identifier may also comprise the corresponding RNA (e.g., mRNA) sequence encoded by the DNA, wherein each thymidine (T) sequence of the DNA is replaced by uracil (U).

[0183] As used herein, the term "polypeptide" refers to a polymer of at least 2 (e.g., at least 5) amino acids joined by peptide bonds. The term "polypeptide" does not denote a polymer chain of amino acids of a specific length. In the art, shorter amino acid polymers (e.g., about 2 - 50 amino acids) are commonly referred to as peptides; and longer amino acid polymers (e.g., about more than 50 amino acids) are referred to as polypeptides. However, the terms "peptide" and "polypeptide" may be used interchangeably herein.

[0184] As used herein, the term "protein" refers to one or more polypeptides folded into their three-dimensional structure. When polypeptides are contemplated herein, it should be understood that proteins comprising these polypeptides (i.e., polypeptides folded into their three-dimensional structure) are also provided herein. In some embodiments, the immunomodulatory polypeptides or proteins herein are immunomodulatory proteins.

[0185] "Preventive" treatment is treatment of a subject who does not exhibit signs of a disease or exhibits only early signs, with the aim of reducing the risk of developing pathology.

[0186] The terms "RNA" and "polynucleotide" are used interchangeably herein and refer to a macromolecule comprising multiple ribonucleotides polymerized via phosphodiester bonds. Ribonucleotides are nucleotides in which the sugar is ribose. RNA may contain modified nucleotides; and contains natural, unnatural, or altered internucleotide linkages, such as phosphoramidate linkages or phosphorothioate linkages, rather than the phosphodiester linkages found between nucleotides in an unmodified nucleic acid molecule.

[0187] As used herein, the term "sample" encompasses a variety of biological samples obtained from a subject. Exemplary sample types include, for example, blood and other liquid samples of biological origin (including but not limited to whole blood, peripheral blood mononuclear cells (PBMCs), serum, plasma, urine, saliva, amniotic fluid, feces, synovial fluid, etc.), nasopharyngeal swabs, solid tissue samples such as biopsies (or cells derived therefrom and their progeny), tissue cultures (or cells derived therefrom and their progeny), and cell cultures (or cells derived therefrom and their progeny). The term also includes samples that have been manipulated in any way after being obtained from a subject, such as by centrifugation, filtration, washing, precipitation, dialysis, chromatography, lysis, treatment with reagents, enrichment of certain cell populations, refrigeration, freezing, staining, etc.

[0188] As used herein, the term "translatable RNA" refers to any RNA that encodes at least one polypeptide and can be translated to produce the encoded protein in vitro, in vivo, in situ, or ex vivo. Translatable RNA can be mRNA or circular RNA encoding a polypeptide.

[0189] As used herein, the term "(scFv) 2"refers to an antibody comprising a first and a second scFv operably linked (e.g., via a peptide linker). The first and second scFvs can specifically bind the same or different antigens. In some embodiments, the first and second scFvs are operably linked via a peptide linker.

[0190] As used herein, the term "scFv-Fc" refers to an antibody comprising an scFv operably linked (e.g., via a peptide linker) to an Fc domain or a subunit of an Fc domain. In some embodiments, the scFv is operably linked only to the first Fc domain of a first and second pair of Fc domains. In some embodiments, a first scFv is operably linked to a first Fc domain and a second scFv is operably linked to the second Fc domain of a first and second pair of Fc domains.

[0191] As used herein, the term "(scFv) 2 -Fc" refers to an (scFv) operably linked (e.g., via a peptide linker) to an Fc domain or a subunit of an Fc domain. 2 In some embodiments, the (scFv) 2 is operably linked only to the first Fc domain of a first and second pair of Fc domains. In some embodiments, a first (scFv) 2 is operably linked to a first Fc domain, and a second (scFv) 2 is operably linked to the second Fc domain of a first and second pair of Fc domains.

[0192] As used herein, the term "single-domain antibody" or "sdAb" refers to an antibody having a single monomeric variable antibody domain. An sdAb is capable of specifically binding a particular antigen. VHH (as defined herein) is an example of an sdAb.

[0193] As used herein, the term "signal peptide" or "signal sequence" refers to a sequence (e.g., an amino acid sequence) that can direct the transport or localization of a protein to a specific organelle, cellular compartment, or extracellular export. The term encompasses signal sequence peptides and nucleic acid sequences encoding signal peptides. Thus, reference to a signal peptide in the context of nucleic acids refers to the nucleic acid sequence encoding the signal peptide.

[0194] As used herein, the term "specifically binds" refers to a preferential interaction between a first protein (e.g., a ligand) and a second protein (e.g., the cognate receptor of the ligand) relative to other amino acid sequences, i.e., a significantly higher binding affinity. As used herein, when a first protein or polypeptide is said to "specifically bind" a second protein or polypeptide, it is understood that the first protein or polypeptide specifically binds to an epitope of the second protein or polypeptide. The term "epitope" refers to the portion of the second protein or polypeptide that is specifically recognized by the first protein or polypeptide. The term specifically binds includes molecules that cross-react with the same epitope in different species. For example, an antibody that specifically binds human IL-10 can cross-react with IL-10 from another species (e.g., cynomolgus monkey, mouse, etc.) and is still considered herein to specifically bind human IL-10. A protein can specifically bind more than one different protein.

[0195] As used herein, the term "subject" includes any animal, e.g., a human or other animal. In some embodiments, the subject is a vertebrate (e.g., a mammal, bird, fish, reptile, or amphibian). In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a non-human mammal such as a non-human primate (e.g., monkey, ape), ungulate (e.g., cow, buffalo, sheep, goat, pig, camel, llama, alpaca, deer, horse, donkey), carnivore (e.g., dog, cat), rodent (e.g., rat, mouse) or lagomorph (e.g., rabbit). In some embodiments, the subject is a bird, such as a member of the avian taxa Galliformes (e.g., chicken, turkey, pheasant, quail), Anseriformes (e.g., duck, goose), Palaeognathae (e.g., ostrich, emu), Columbiformes (e.g., pigeon, wild pigeon) or Psittaciformes (e.g., parrot).

[0196] As used herein, the "therapeutically effective amount" of a therapeutic agent refers to any amount of the therapeutic agent that, when used alone or in combination with another therapeutic agent, ameliorates a disease condition (e.g., protects a subject from the onset of a disease (or infection)); ameliorates the symptoms of a disease or infection, e.g., reduces the severity of the disease or infection symptoms, decreases the frequency or duration of the disease or infection symptoms, increases the disease-free or infection symptom-free period; prevents or reduces damage or disability caused by a disease or infection; or promotes the resolution of a disease (or infection). The ability of a therapeutic agent to ameliorate a disease condition can be evaluated using a variety of methods known to those of skill in the art, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0197] As used herein, the terms "treat", "treating", "treatment", etc. refer to reducing or ameliorating a disease or infection and / or one or more symptoms associated therewith or obtaining a desired pharmacological and / or physiological effect. It should be understood that although not excluded, treating a disease or infection does not require complete elimination of the disease or infection and / or one or more symptoms associated therewith. In some embodiments, the effect is therapeutic, i.e., but not limited to, the effect partially or completely reduces, attenuates, eliminates, slows, alleviates, decreases the intensity of a disease and / or adverse symptoms attributable to the disease or infection or cures the disease and / or adverse symptoms attributable to the disease or infection. In some embodiments, the effect is prophylactic, i.e., the effect protects or prevents the occurrence or recurrence of a disease or infection. To this end, the methods disclosed herein include administering a therapeutically effective amount of the compositions described herein.

[0198] The terms "VL" and "VL domain" are used interchangeably and refer to the variable light chain region of an antibody.

[0199] The terms "VH" and "VH domain" are used interchangeably and refer to the variable heavy chain region of an antibody.

[0200] The term "VHH" as used herein refers to a class of single domain antibodies (sdAb) having a single monomeric heavy chain variable antibody domain (VH). Such antibodies can be found or produced or synthetically produced in camelid mammals that are naturally lacking in light chains (e.g., camels, llamas).

[0201] The term "(VHH) 2 " as used herein refers to an antibody comprising first and second VHHs operably linked (e.g., via a peptide linker). The first and second VHHs can specifically bind the same or different antigens. In some embodiments, the first and second VHHs are operably linked via a peptide linker.

[0202] As used herein, the term "VHH-Fc" refers to an antibody comprising a VHH operably linked (e.g., via a peptide linker) to an Fc domain or a subunit of an Fc domain. In some embodiments, the VHH is operably linked only to the first Fc domain of a first and second pair of Fc domains. In some embodiments, a first VHH is operably linked to a first Fc domain and a second VHH is operably linked to the second Fc domain of a first and second pair of Fc domains.

[0203] The term "(VHH) 2 -Fc" as used herein refers to a (VHH) 2 operably linked (e.g., via a peptide linker) to an Fc domain or a subunit of an Fc domain. In some embodiments, the (VHH) 2The first Fc domain operably linked only to the first and second Fc domain pairs. In some embodiments, the first (VHH) 2 is operably linked to the first Fc domain and the second (VHH) 2 is operably linked to the second Fc domain of the first Fc and second Fc pair.

[0204] As used herein, the term "5' untranslated region" or "5'-UTR" refers to a portion of a nucleic acid molecule that is located 5' (i.e., "upstream") of a coding sequence and is not translated into protein. Generally, the 5'-UTR starts at the transcription start site and ends before the start codon of the coding sequence. The 5'-UTR can contain elements for controlling gene expression, also known as regulatory elements. Such regulatory elements can be, for example, ribosome binding sites, miRNA binding sites, etc. The 5'-UTR can be post-transcriptionally modified, for example, by enzymatic or post-transcriptional addition of a 5'-cap structure.

[0205] As used herein, the term "3' untranslated region" or "3'-UTR" refers to a portion of a nucleic acid molecule that is located 3' (i.e., downstream) of a coding sequence and is not translated into protein. The 3'-UTR can be located between the coding sequence of the nucleic acid sequence and the (optional) terminal poly(A) sequence. The 3'-UTR can contain elements for controlling gene expression, also known as regulatory elements. Such regulatory elements can be, for example, ribosome binding sites, miRNA binding sites, etc. 5.2 Immunomodulatory proteins

[0206] IL-10 is the founding member of the IL-10 cytokine family, which includes IL-19, IL-20, IL-22, IL-24, and IL-26. hIL-10 is an important immunomodulatory cytokine, and part of its function is to inhibit inflammatory immune responses. hIL-10 effectively inhibits the production of pro-inflammatory cytokines (such as IFN-γ, TNFα, IL-1β, and IL-6) in several cell types and prevents dendritic cell maturation, in part by inhibiting the expression of IL-12. hIL-10 also inhibits the expression of MHC and co-stimulatory molecules that are important for cell-mediated immunity. Although hIL-10 mainly functions as an anti-inflammatory cytokine, it is inherently pleiotropic and is also known to mediate pro-inflammatory effects, including stimulating CD8+ T cells to produce IFN-γ and granzyme B.

[0207] The hIL-10-induced cellular response requires specific recognition and assembly of the hIL-10 receptor (hIL-10R). The hIL-10R consists of two distinct subunits, the hIL-10Rα subunit and the hIL-10Rβ subunit. Although the overall structures are similar, hIL-10Rβ exhibits lower affinity for hIL-10 relative to the α subunit. Due to the difference in the affinity of hIL-10Rα and hIL-10Rβ for hIL-10, each receptor subunit has a different function in activating the hIL-10 cellular response. More particularly, hIL-10Rα generally functions as the hIL-10-binding subunit, which controls the cell specificity and cell targeting of hIL-10 to immune cells that selectively express the hIL-10Rα subunit. The hIL-10Rβ subunit functions as a sensor that effectively senses hIL-10 bound to IL-10Rα and activates signal transduction according to the kinetics of the hIL-10 / hIL-10Rα interaction.

[0208] The amino acid sequences of the reference immature hIL-10 polypeptide and the mature hIL-10 polypeptide are shown as SEQ ID NO:1 and 2, respectively. The amino acid sequences of the reference immature hIL-10Rα polypeptide and the mature hIL-10Rα polypeptide are shown as SEQ ID NO:3 and 4, respectively. The amino acid sequences of the reference immature hIL-10Rβ polypeptide and the mature hIL-10Rβ polypeptide are shown as SEQ ID NO:5 and 6, respectively. See Table 1 herein. Table 1. Amino Acid Sequences of Reference hIL-10, hIL-10Rα, and hIL-10Rβ Polypeptides

[0209] In one aspect, the present disclosure provides immunomodulatory proteins and polypeptides (and their functional fragments and variants) that specifically bind to hIL-10R (such as hIL-10Rα). The amino acid sequences of the immunomodulatory proteins and polypeptides provided herein are shown in Table 2. The amino acid sequences of the immature forms (i.e., containing the native signal peptide) of the immunomodulatory proteins and polypeptides are shown in SEQ ID NO:108-118 or 127-290. The amino acid sequences of the mature forms (i.e., lacking the native signal peptide) of the immunomodulatory proteins and polypeptides are shown in SEQ ID NO:119-126 or 291-454.

[0210] Signal peptides have been computationally predicted using standard methods (see, e.g., Teufel, F., AlmagroArmenteros, JJ, Johansen, AR, et al. SignalP 6.0 predicts all five types of signal peptides using protein language models. [SignalP 6.0 predicts all five types of signal peptides using protein language models] Nat Biotechnol [Nature Biotechnology] (2022). https: / / doi.org / 10.1038 / s41587-021-01156-3, the entire contents of which are incorporated herein by reference for all purposes). One of ordinary skill in the art will know how to experimentally identify and / or validate computationally predicted signal peptides using standard methods known in the art, such as expression of immunomodulatory proteins from host cells and sequencing of intracellular and extracellular forms of the expressed proteins (see, e.g., Zhang Z, Henzel WJ. Signal peptide prediction based on analysis of experimentally verified cleavage sites. Protein Sci. 2004; 13(10): 2819-2824. doi: 10.1110 / ps.04682504, the entire contents of which are incorporated herein by reference for all purposes). Table 2. Amino Acid Sequences of Immunomodulatory Proteins

[0211] In some embodiments, the immunomodulatory protein or polypeptide specifically binds to hIL-10Rα. In some embodiments, the immunomodulatory protein or polypeptide specifically binds to hIL-10Rβ. In some embodiments, the immunomodulatory protein or polypeptide specifically binds to both hIL-10Rα and hIL-10Rβ. In some embodiments, the immunomodulatory protein or polypeptide specifically binds to both hIL-10Rα and hIL-10Rβ, but binds to hIL-10Rα with a higher affinity than hIL-10Rβ.

[0212] In some embodiments, the immunomodulatory protein or polypeptide is an hIL-10R agonist. In some embodiments, the immunomodulatory protein or polypeptide is an hIL-10Rα agonist. In some embodiments, the immunomodulatory protein or polypeptide is an hIL-10Rβ agonist. In some embodiments, the immunomodulatory protein or polypeptide is an hIL-10Rα agonist and an hIL-10Rβ agonist.

[0213] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of the polypeptide shown in Table 2. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of the polypeptide shown in Table 2. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of the polypeptide shown in Table 2. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of the polypeptide shown in Table 2. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of the polypeptide shown in Table 2. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of the polypeptide shown in Table 2. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of the polypeptide shown in Table 2. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of the polypeptide shown in Table 2. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of the polypeptide shown in Table 2. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of the polypeptide shown in Table 2.

[0214] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of the polypeptide shown in Table 2, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of the polypeptide shown in Table 2, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of the polypeptide shown in Table 2, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of the polypeptide shown in Table 2, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0215] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of the polypeptide shown in Table 2, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of the polypeptide shown in Table 2, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of the polypeptide shown in Table 2, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of the polypeptide shown in Table 2, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

[0216] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454.

[0217] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 454, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 454, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 454, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 454, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0218] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 454, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 454, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 454, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 454, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0219] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 108-114 or 116-125. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 108-114 or 116-125. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125.

[0220] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0221] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-125, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0222] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 108-118 or 127-290. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 108-118 or 127-290. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290.

[0223] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0224] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0225] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 108-114 or 116-118. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 108-114 or 116-118. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118.

[0226] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118, and further comprises or consists of the following: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118, and further comprises or consists of the following: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108-114 or 116-118, and further comprises or consists of the following: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0227] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 114 or 116 - 118, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 114 or 116 - 118, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 114 or 116 - 118, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 108 - 114 or 116 - 118, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

[0228] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 119-126 or 291-454. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence in any one of SEQ ID NOs: 119-126 or 291-454. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence in any one of SEQ ID NOs: 119-126 or 291-454. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence in any one of SEQ ID NOs: 119-126 or 291-454. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence in any one of SEQ ID NOs: 119-126 or 291-454. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 119-126 or 291-454. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence in any one of SEQ ID NOs: 119-126 or 291-454. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence in any one of SEQ ID NOs: 119-126 or 291-454. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence in any one of SEQ ID NOs: 119-126 or 291-454. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence in any one of SEQ ID NOs: 119-126 or 291-454.

[0229] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-126 or 291-454, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-126 or 291-454, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-126 or 291-454, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-126 or 291-454, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0230] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-126 or 291-454 and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-126 or 291-454 and further comprises or consists of the following: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-126 or 291-454 and further comprises or consists of the following: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-126 or 291-454 and further comprises or consists of the following: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

[0231] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 119 - 125.

[0232] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-125, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-125, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-125, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-125, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0233] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-125, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-125, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-125, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 119-125, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0234] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 109 - 111, 113, or 115. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113, or 115. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113, or 115. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113, or 115. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113, or 115. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 109 - 111, 113, or 115. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113, or 115. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113, or 115. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113, or 115. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113, or 115.

[0235] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111, 113 or 115, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111, 113 or 115, and further comprises or consists of the following: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111, 113 or 115, and further comprises or consists of the following: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111, 113 or 115, and further comprises or consists of the following: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0236] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113 or 115, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113 or 115, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113 or 115, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109 - 111, 113 or 115, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

[0237] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 109 - 111 or 113. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111 or 113. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111 or 113. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111 or 113. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111 or 113. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 109 - 111 or 113. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111 or 113. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111 or 113. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111 or 113. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 109 - 111 or 113.

[0238] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111 or 113, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111 or 113, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111 or 113, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111 or 113, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0239] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111 or 113, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111 or 113, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111 or 113, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 109-111 or 113, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0240] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NO: 108, 112, 114 or 116 - 118. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO: 108, 112, 114 or 116 - 118. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO: 108, 112, 114 or 116 - 118. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO: 108, 112, 114 or 116 - 118. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 108, 112, 114 or 116 - 118. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NO: 108, 112, 114 or 116 - 118. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO: 108, 112, 114 or 116 - 118. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO: 108, 112, 114 or 116 - 118. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO: 108, 112, 114 or 116 - 118. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 108, 112, 114 or 116 - 118.

[0241] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 108, 112, 114, or 116 - 118, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 108, 112, 114, or 116 - 118, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 108, 112, 114, or 116 - 118, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 108, 112, 114, or 116 - 118, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0242] In embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 108, 112, 114, or 116 - 118, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 108, 112, 114, or 116 - 118, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 108, 112, 114, or 116 - 118, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 108, 112, 114, or 116 - 118, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0243] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 120 - 122, 124 or 126. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122, 124 or 126. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122, 124 or 126. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122, 124 or 126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122, 124 or 126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 120 - 122, 124 or 126. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122, 124 or 126. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122, 124 or 126. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122, 124 or 126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122, 124 or 126.

[0244] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120-122, 124, or 126, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120-122, 124, or 126, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120-122, 124, or 126, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120-122, 124, or 126, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0245] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120-122, 124, or 126, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120-122, 124, or 126, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120-122, 124, or 126, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120-122, 124, or 126, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0246] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 120 - 122 or 124. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NOs: 120 - 122 or 124. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124.

[0247] In embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0248] In embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 120 - 122 or 124, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0249] In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in any one of SEQ ID NO: 119, 123, or 125. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125. The amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in any one of SEQ ID NO: 119, 123, or 125. For example, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125. The amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125.

[0250] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125, and further comprises or consists of the following: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125, and further comprises or consists of the following: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125, and further comprises or consists of the following: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0251] In an embodiment, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125, and further comprises one or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125, and further comprises or consists of the following: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125, and further comprises or consists of the following: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NO: 119, 123, or 125, and further comprises or consists of the following: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0252] In some embodiments of the immunomodulatory proteins or polypeptides mentioned herein, SEQ ID NO: 108, 111-119 or 122-126 may be preferred. Advantageously, the immunomodulatory protein or polypeptide may bind to hIL-10R with a higher potency than hIL-10. Thus, in some embodiments, the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NO: 108, 111-119 or 122-126. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126.In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126.

[0253] In some embodiments, the immunomodulatory proteins or polypeptides mentioned herein, SEQ ID NO: 112-115 or 123-126 may be more preferred. Advantageously, the immunomodulatory proteins or polypeptides can particularly effectively inhibit the production of pro-inflammatory cytokines (such as one or more of IFN-γ, IL-1β, IL-6, IL-8, TNF-α and IL-4). For example, the immunomodulatory proteins or polypeptides can inhibit the production of pro-inflammatory cytokines more effectively than hIL-10. Preferably, they also bind to hIL-10R with a higher potency than hIL-10. Thus, in some embodiments, the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in any one of SEQ ID NO: 112-115 or 123-126. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126.In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NOs: 112-115 or 123-126. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 112-115 or 123-126.

[0254] In some embodiments of the immunomodulatory proteins or polypeptides mentioned herein, SEQ ID NO: 114 or 125 may be preferred. Advantageously, the immunomodulatory protein or polypeptide may bind to hIL-10R with higher potency than hIL-10. Thus, in some embodiments, the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of either SEQ ID NO: 114 or 125. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to the amino acid sequence of either SEQ ID NO: 114 or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to the amino acid sequence of either SEQ ID NO: 114 or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of either SEQ ID NO: 114 or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to the amino acid sequence of either SEQ ID NO: 114 or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in either SEQ ID NO: 114 or 125. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to the amino acid sequence of either SEQ ID NO: 114 or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to the amino acid sequence of either SEQ ID NO: 114 or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to the amino acid sequence of either SEQ ID NO: 114 or 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to the amino acid sequence of either SEQ ID NO: 114 or 125.

[0255] In some embodiments of the immunomodulatory proteins or polypeptides mentioned herein, SEQ ID NO:114 may be preferred. Advantageously, the immunomodulatory protein or polypeptide may bind to hIL-10R with higher potency than hIL-10. Thus, in some embodiments, the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the amino acid sequences of SEQ ID NO:114. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NO:114. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NO:114. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to any one of the amino acid sequences of SEQ ID NO:114. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NO:114. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the amino acid sequences shown in SEQ ID NO:114. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NO:114. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NO:114. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to any one of the amino acid sequences of SEQ ID NO:114. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NO:114.

[0256] In some embodiments of the immunomodulatory proteins or polypeptides mentioned herein, SEQ ID NO: 125 may be preferred. Advantageously, the immunomodulatory protein or polypeptide may bind to hIL-10R with a higher potency than hIL-10. Thus, in some embodiments, the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the amino acid sequences of SEQ ID NO: 125. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NO: 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NO: 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may comprise an amino acid sequence that is at least 95% identical to any one of the amino acid sequences of SEQ ID NO: 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably comprise an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NO: 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the amino acid sequences shown in SEQ ID NO: 125. For example, in some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NO: 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NO: 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may consist of: an amino acid sequence that is at least 95% identical to any one of the amino acid sequences of SEQ ID NO: 125. In some embodiments, the amino acid sequence of the immunomodulatory protein or polypeptide may preferably consist of: an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NO: 125. 5.2.1 Signal peptide

[0257] In some embodiments, the immunomodulatory protein or polypeptide comprises a homologous or heterologous signal peptide operably linked to the N-terminus of the immunomodulatory protein or polypeptide. In some embodiments, the immunomodulatory protein or polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 108-454, and comprises a homologous signal peptide operably linked to the N-terminus of the polypeptide. In some embodiments, the immunomodulatory protein or polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 108-454, and comprises a heterologous signal peptide operably linked to the N-terminus of the polypeptide. In some embodiments, the immunomodulatory protein or polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 119-126 or 291-454, and comprises a homologous signal peptide operably linked to the N-terminus of the polypeptide. In some embodiments, the immunomodulatory protein or polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 119-126 or 291-454, and comprises a heterologous signal peptide operably linked to the N-terminus of the polypeptide. In some embodiments, the immunomodulatory protein or polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 108-118 or 127-290, and comprises a homologous signal peptide operably linked to the N-terminus of the polypeptide. In some embodiments, the immunomodulatory protein or polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 108-118 or 127-290, and comprises a heterologous signal peptide operably linked to the N-terminus of the polypeptide.

[0258] In some embodiments, the immunomodulatory protein or polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 114 or 125, and comprises a homologous signal peptide operably linked to the N-terminus of the polypeptide. In some embodiments, the immunomodulatory protein or polypeptide comprises the amino acid sequence shown in any one of SEQ ID NOs: 114 or 125, and comprises a heterologous signal peptide operably linked to the N-terminus of the polypeptide.

[0259] Commonly used signal peptides are known in the art, such as the native signal peptides of human interleukin 2 (hIL-2), human oncostatin M (hOSM), human chymotrypsinogen (hCTRB1), human trypsinogen 2 (hTRY2), and human insulin (hINS). One of ordinary skill in the art can determine a suitable signal peptide using standard methods known in the art. The amino acid sequences of exemplary signal peptides are provided in Table 3. Table 3. Amino Acid Sequences of Exemplary Signal Peptides Description Amino Acid Sequence SEQ ID NO hIL-2 MYRMQLLSCIALSLALVTNS 7 hOSM MGVLLTQRTLLSLVLALLFPSMASM 8 hCTRB1 MASLWLLSCFSLVGAAFG 9 hTRY2 MNLLLILTFVAAAVA 10 hINS MALWMRLLPLLALLALWGPDPAAA 11

[0260] In some embodiments, the amino acid sequence of the signal peptide comprises or consists of: the amino acid sequence of any one of the signal peptides listed in Table 3. In some embodiments, the amino acid sequence of the signal peptide comprises or consists of the amino acid sequence of any one of the signal peptides shown in Table 3 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the signal peptide comprises or consists of: the amino acid sequence of any one of the signal peptides shown in Table 3, which comprises 1, 2 or 3 amino acid variations (e.g., substitutions, deletions, additions). In some embodiments, the amino acid sequence of the signal peptide comprises or consists of the amino acid sequence of any one of the signal peptides shown in Table 3 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid modifications. In some embodiments, the amino acid sequence of the signal peptide comprises or consists of: the amino acid sequence of any one of the signal peptides listed in Table 3, which comprises 1, 2 or 3 amino acid substitutions.

[0261] In some embodiments, the amino acid sequence of the signal peptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 7-11. In some embodiments, the amino acid sequence of the signal peptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 7-11 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the signal peptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 7-11, which comprises 1, 2 or 3 amino acid variations (e.g., substitutions, deletions, additions). In some embodiments, the amino acid sequence of the signal peptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 7-11 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid modifications. In some embodiments, the amino acid sequence of the signal peptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 7-11, which comprises 1, 2 or 3 amino acid substitutions. 5.2.2 Potency and Affinity of Immunomodulatory Proteins

[0262] In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate (e.g., an immunomodulatory fusion protein or polypeptide)) increases the STAT3 level in cells expressing hIL-10R on the surface relative to the STAT3 level in the absence of the immunomodulatory protein or polypeptide (or fusion or conjugate (e.g., an immunomodulatory fusion protein or polypeptide)) or relative to the STAT3 level in the presence of a suitable control (e.g., a reference hIL-10 protein or polypeptide (e.g., SEQ ID NO:1 or 2) (or a reference fusion or conjugate (e.g., a reference immunomodulatory fusion protein or polypeptide) (e.g., any one of SEQ ID NO:102 - 105))). In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate (e.g., an immunomodulatory fusion protein or polypeptide)) increases the phosphorylated STAT3 level in cells expressing hIL-10R on the surface relative to the phosphorylated STAT3 level in the absence of the immunomodulatory protein or polypeptide (or fusion or conjugate (e.g., an immunomodulatory fusion protein or polypeptide)) or relative to the phosphorylated STAT3 level in the presence of a suitable control (e.g., a reference hIL-10 protein or polypeptide (e.g., SEQ ID NO:1 or 2) (or a reference fusion or conjugate (e.g., a reference immunomodulatory fusion protein or polypeptide) (e.g., any one of SEQ ID NO:102 - 105))).

[0263] In some embodiments, the immunomodulatory protein or polypeptide (or the fusions or conjugates described herein (e.g., the immunomodulatory fusion proteins or polypeptides described herein)) increases the level of phosphorylated STAT3 in cells expressing hIL-10R on the surface with an EC50 of less than about 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, 0.9 pM, 0.8 pM, 0.7 pM, 0.6 pM, 0.5 pM, 0.4 pM, 0.3 pM, 0.2 pM, or 0.1 pM. In some embodiments, the immunomodulatory protein or polypeptide (or the fusions or conjugates described herein (e.g., the immunomodulatory fusion proteins or polypeptides described herein)) preferably increases the level of phosphorylated STAT3 in cells expressing hIL-10R on the surface with an EC50 of less than about 25 pM (e.g., less than about 10 pM). In some embodiments, the immunomodulatory protein or polypeptide (or the fusions or conjugates described herein (e.g., the immunomodulatory fusion proteins or polypeptides described herein)) increases the level of phosphorylated STAT3 in cells expressing hIL-10R on the surface with an EC50 of about 500 pM–0.1 pM, 400 pM–0.1 pM, 300 pM–0.1 pM, 200 pM–0.1 pM, 100 pM–0.1 pM, 50 pM–0.1 pM, 25 pM–0.1 pM, 10 pM–0.1 pM, 5 pM–0.1 pM, or 1 pM–0.1 pM, 500 pM–0.5, 400 pM–0.5, 300 pM–0.5, 200 pM–0.5, 100 pM–0.5, 50 pM–0.5, 25 pM–0.5, 10 pM–0.5, 5 pM–0.5, or 1 pM–0.5 pM. In some embodiments, the immunomodulatory protein or polypeptide (or the fusions or conjugates described herein (e.g., the immunomodulatory fusion proteins or polypeptides described herein)) increases the level of phosphorylated STAT3 in cells expressing hIL-10R on the surface with an EC50 of no greater than about 0.1 pM, 0.2 pM, 0.3 pM, 0.4 pM, 0.5 pM, 0.6 pM, 0.7 pM, 0.8 pM, 0.9 pM, 1.0 pM, 5 pM, 10 pM, 20 pM, 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 200 pM, 300 pM, 400 pM, or 500 pM.

[0264] In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) increases the level of phosphorylated STAT3 in cells expressing hIL-10R on the surface with an EC50 that is at least about 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, or 150-fold higher than the EC50 of a reference hIL-10 protein or polypeptide (e.g., a reference hIL-10 protein or polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 or 2) (or a reference fusion or conjugate (e.g., a reference immunomodulatory fusion protein or polypeptide (e.g., a reference immunomodulatory fusion protein or polypeptide comprising the amino acid sequence shown in any one of SEQ ID NO: 102-105))). In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) increases the level of phosphorylated STAT3 in cells expressing hIL-10R on the surface with an EC50 that is about 4- to 150-fold, 10- to 150-fold, 20- to 150-fold, 30- to 150-fold, 40- to 150-fold, 50- to 150-fold, 60- to 150-fold, 70- to 150-fold, 80- to 150-fold, 90- to 150-fold, 100- to 150-fold, 110- to 150-fold, 120- to 150-fold, 130- to 150-fold, or 140- to 150-fold higher than the EC50 of a reference hIL-10 protein or polypeptide (e.g., a reference hIL-10 protein or polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 or 2) (or a reference fusion or conjugate (e.g., any one of SEQ ID NO: 102-105)).

[0265] In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) binds to cells expressing hIL-10R on the surface with an EC50 of less than about 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, 0.9 pM, 0.8 pM, 0.7 pM, 0.6 pM, 0.5 pM, 0.4 pM, 0.3 pM, 0.2 pM, or 0.1 pM. In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) preferably binds to cells expressing hIL-10R on the surface with an EC50 of less than about 25 pM (e.g., less than about 10 pM). In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) binds to cells expressing hIL-10R on the surface with an EC50 of about 500 pM–0.1 pM, 400 pM–0.1 pM, 300 pM–0.1 pM, 200 pM–0.1 pM, 100 pM–0.1 pM, 50 pM–0.1 pM, 25 pM–0.1 pM, 10 pM–0.1 pM, 5 pM–0.1 pM, or 1 pM–0.1 pM, 500 pM–0.5, 400 pM–0.5, 300 pM–0.5, 200 pM–0.5, 100 pM–0.5, 50 pM–0.5, 25 pM–0.5, 10 pM–0.5, 5 pM–0.5, or 1 pM–0.5 pM. In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) binds to cells expressing hIL-10R on the surface with an EC50 of no greater than about 0.1 pM, 0.2 pM, 0.3 pM, 0.4 pM, 0.5 pM, 0.6 pM, 0.7 pM, 0.8 pM, 0.9 pM, 1.0 pM, 5 pM, 10 pM, 20 pM, 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 200 pM, 300 pM, 400 pM, or 500 pM.

[0266] In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) binds to cells expressing hIL-10R on the surface with an EC50 that is at least about 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, or 150-fold higher than the EC50 of a reference hIL-10 protein or polypeptide (e.g., a reference hIL-10 protein or polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 or 2) (or a reference fusion or conjugate (e.g., a reference immunomodulatory fusion protein or polypeptide (e.g., any one of reference immunomodulatory fusion proteins or polypeptides (e.g., SEQ ID NO: 102 - 105)))). In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) binds to cells expressing hIL-10R on the surface with an EC50 that is about 10 - 150-fold, 20 - 150-fold, 30 - 150-fold, 40 - 150-fold, 50 - 150-fold, 60 - 150-fold, 70 - 150-fold, 80 - 150-fold, 90 - 150-fold, 100 - 150-fold, 110 - 150-fold, 120 - 150-fold, 130 - 150-fold, or 140 - 150-fold higher than the EC50 of a reference hIL-10 protein or polypeptide (e.g., a reference hIL-10 protein or polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 or 2) (or a reference fusion or conjugate (e.g., a reference immunomodulatory fusion protein or polypeptide (e.g., any one of reference immunomodulatory fusion proteins or polypeptides (e.g., SEQ ID NO: 102 - 105)))).

[0267] In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate as described herein (e.g., an immunomodulatory fusion protein or polypeptide as described herein)) binds to cells expressing hIL-10Rα on the surface with an EC50 of less than about 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, 0.9 pM, 0.8 pM, 0.7 pM, 0.6 pM, 0.5 pM, 0.4 pM, 0.3 pM, 0.2 pM, or 0.1 pM. In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate as described herein (e.g., an immunomodulatory fusion protein or polypeptide as described herein)) preferably binds to cells expressing hIL-10Rα on the surface with an EC50 of less than about 25 pM (e.g., less than about 10 pM). In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate as described herein (e.g., an immunomodulatory fusion protein or polypeptide as described herein)) binds to cells expressing hIL-10Rα on the surface with an EC50 of about 500 pM–0.1 pM, 400 pM–0.1 pM, 300 pM–0.1 pM, 200 pM–0.1 pM, 100 pM–0.1 pM, 50 pM–0.1 pM, 25 pM–0.1 pM, 10 pM–0.1 pM, 5 pM–0.1 pM, or 1 pM–0.1 pM, 500 pM–0.5, 400 pM–0.5, 300 pM–0.5, 200 pM–0.5, 100 pM–0.5, 50 pM–0.5, 25 pM–0.5, 10 pM–0.5, 5 pM–0.5, or 1 pM–0.5 pM. In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate as described herein (e.g., an immunomodulatory fusion protein or polypeptide as described herein)) binds to cells expressing hIL-10Rα on the surface with an EC50 of not more than about 0.1 pM, 0.2 pM, 0.3 pM, 0.4 pM, 0.5 pM, 0.6 pM, 0.7 pM, 0.8 pM, 0.9 pM, 1.0 pM, 5 pM, 10 pM, 20 pM, 30 pM, 40 pM, 50 pM, 60 pM, 70 pM, 80 pM, 90 pM, 100 pM, 200 pM, 300 pM, 400 pM, or 500 pM.

[0268] In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) binds to cells expressing hIL-10Rα on the surface with an EC50 that is at least about 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, or 150-fold higher than the EC50 of a reference hIL-10 protein or polypeptide (e.g., a reference hIL-10 protein or polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 or 2) (or a reference fusion or conjugate (e.g., a reference immunomodulatory fusion protein or polypeptide (e.g., any one of reference immunomodulatory fusion proteins or polypeptides (e.g., SEQ ID NO: 102 - 105)))). In some embodiments, an immunomodulatory protein or polypeptide (or a fusion or conjugate described herein (e.g., an immunomodulatory fusion protein or polypeptide described herein)) binds to cells expressing hIL-10Rα on the surface with an EC50 that is about 10 - 150-fold, 20 - 150-fold, 30 - 150-fold, 40 - 150-fold, 50 - 150-fold, 60 - 150-fold, 70 - 150-fold, 80 - 150-fold, 90 - 150-fold, 100 - 150-fold, 110 - 150-fold, 120 - 150-fold, 130 - 150-fold, or 140 - 150-fold higher than the EC50 of a reference hIL-10 protein or polypeptide (e.g., a reference hIL-10 protein or polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 or 2) (or a reference fusion or conjugate described herein (e.g., a reference immunomodulatory fusion protein or polypeptide (e.g., any one of reference immunomodulatory fusion proteins or polypeptides (e.g., SEQ ID NO: 102 - 105)))).

[0269] The assays suitable for measuring the EC50 of an immunomodulatory protein or polypeptide as described herein are standard and known to those of ordinary skill in the art. For example, the EC50 can be determined by constructing a dose-response curve and examining the effect of different concentrations of the immunomodulatory protein or polypeptide on inducing activity in a specific functional assay (e.g., STAT3 signaling, STAT3 phosphorylation, STAT3-inducible SEAP expression). An exemplary method for determining the EC50 of an immunomodulatory protein or polypeptide (including the immunomodulatory fusion proteins described herein) is to utilize the hIL-10 HEKBlue reporter cell line (InvivoGen #hkb-il10). The hIL-10 HEKBlue reporter cell line expresses the hIL-10Rα and hIL-10Rβ subunits, human STAT3, and the STAT3-inducible SEAP (secreted embryonic alkaline phosphatase) reporter. Thus, binding of the protein to hIL-10R triggers JAK1 / STAT3 signaling and subsequent production of SEAP, which can be quantified using standard methods known in the art. Additionally, for example, the level of phosphorylated STAT3 can be evaluated by contacting cells expressing hIL-10R with one or more concentrations of the immunomodulatory protein or polypeptide described herein, lysing the cells, and evaluating the level of phosphorylated STAT3, e.g., by Western blot, FRET-based assay, or chemiluminescent assay (e.g., AlphaLISA-based assay). The cells in the cell-based assay can be cells recombinantly expressing hIL-10R and / or human STAT3, such as HEK293 cells; or cells that naturally express hIL-10R and human STAT3.

[0270] In some embodiments, the immunomodulatory protein or polypeptide (or the fusion or conjugate described herein (e.g., the immunomodulatory fusion protein or polypeptide described herein)) binds to hIL-10R (e.g., hIL-10Rα) with a higher affinity relative to a reference hIL-10 protein or polypeptide (e.g., a reference hIL-10 protein or polypeptide comprising the amino acid sequence shown in SEQ ID NO: 1 or 2 (or the reference fusion or conjugate described herein) (e.g., a reference immunomodulatory fusion protein or polypeptide (e.g., any one of SEQ ID NOs: 102-105))). The binding affinity can be measured by standard assays known in the art. For example, the binding affinity can be measured by surface plasmon resonance (SPR) (e.g., based on Measured by the determination of surface plasmon resonance (SPR), which is a commonly known method in the art (see, e.g., Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 55:2560, 1993; and U.S. Patent Nos. 5,283,173, 5,468,614, the entire contents of each of which are incorporated herein by reference for all purposes). SPR measures the change in the concentration of molecules on the sensor surface when molecules bind to or dissociate from the surface. The change in the SPR signal is directly proportional to the change in the mass concentration near the surface, allowing the binding kinetics between two molecules (e.g., proteins) to be measured. When the buffer passes through the chip, the dissociation constant of the complex can be determined by monitoring the change in the refractive index over time.

[0271] Other suitable assays for measuring the binding of one protein to another (e.g., the binding of the proteins or polypeptides described herein to hIL-10R) include, for example, immunoassays such as enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), or determining binding by monitoring changes in the protein spectrum or optical properties by fluorescence, UV absorption, circular dichroism, or nuclear magnetic resonance (NMR). Other exemplary assays include, but are not limited to, Western blotting, analytical ultracentrifugation, spectroscopy, flow cytometry, sequencing, and other methods for detecting protein binding. 5.3 Immunomodulatory polypeptide / protein fusions and conjugates

[0272] In some embodiments, an immunomodulatory protein or polypeptide (e.g., as described herein) is operably linked to a heterologous moiety (e.g., a heterologous polypeptide), forming a fusion or conjugate protein or polypeptide, respectively. Accordingly, the present disclosure further provides, in particular, fusion proteins that comprise an immunomodulatory protein or polypeptide (e.g., as described herein) and one or more heterologous proteins (or functional fragments, functional variants, or domains thereof). The present disclosure further provides, in particular, conjugates that comprise an immunomodulatory protein or polypeptide (e.g., as described herein) (or a nucleic acid molecule encoding an immunomodulatory protein or polypeptide (e.g., as described herein)) and one or more heterologous moieties.

[0273] Heterologous moieties include, but are not limited to, proteins, peptides, small molecules, nucleic acid molecules (e.g., DNA, RNA, DNA / RNA hybrid molecules), carbohydrates, lipids, and synthetic polymers (e.g., polymers of PEG). In some embodiments, the heterologous moiety is a detectable moiety (e.g., a polypeptide or protein, such as a fluorescent polypeptide or protein).

[0274] In some embodiments, the heterologous moiety is a half-life extending moiety. Exemplary half-life extending moieties include, but are not limited to, immunoglobulins (e.g., human Ig (hIg), murine Ig (mIg)), Ig (e.g., hIg, mIg) fragments, Ig (e.g., hIg, mIg) constant regions, Ig (e.g., hIg, mIg) constant region fragments, Ig (e.g., hIg, mIg) Fc regions, human transferrin, human serum albumin (HSA), HSA binding proteins or peptides, and polyethylene glycol (PEG) (and its polymers). In some embodiments, the heterologous polypeptide is a half-life extending polypeptide. Exemplary half-life extending polypeptides include, but are not limited to, Ig, Ig fragments, one or more Ig heavy chain constant regions, Ig constant region fragments, Ig Fc regions, hIg, hIg fragments, one or more hIg heavy chain constant regions, hIg constant region fragments, hIg Fc regions, mIg, mIg fragments, one or more mIg heavy chain constant regions, mIg constant region fragments, mIg Fc regions, human transferrin, human serum albumin (HSA), and HSA binding proteins or peptides. Standard in vivo methods known in the art can be utilized to evaluate the pharmacokinetic properties of the immunomodulatory proteins or polypeptides described herein that are fused or conjugated to a half-life extending moiety or a half-life extending moiety. 5.3.1 Ig fusion proteins and polypeptides 5.3.1.1 Antibody fusion proteins and polypeptides

[0275] In some embodiments, the heterologous polypeptide comprises an antibody. The antibody fusion may function to further target an immunomodulatory protein or polypeptide, for example, to a specific cell type that expresses a specific cell surface protein. Exemplary antibodies include full-length antibodies, scFv, Fab, single domain antibodies (e.g., VHH), scFv-Fc, Fab-Fc, and single domain antibody-Fc (e.g., VHH-Fc). 5.3.1.2 Ig fusion proteins and polypeptides

[0276] In some embodiments, the heterologous polypeptide comprises one or more Ig heavy chain constant regions (CH2 region, CH3 region, hinge region, Fc region (e.g., in some embodiments, preferably the Fc region). In some embodiments, the Ig is IgG. In some embodiments, the IgG is IgG1, IgG2, IgG3, or IgG4 (e.g., in some embodiments, preferably IgG4).

[0277] In some embodiments, the heterologous polypeptide comprises or consists of: an IgG CH2 region and an IgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: a partial IgG hinge region, an IgG CH2 region, and an IgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an IgG hinge region, an IgG CH2 region, and an IgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an IgG1 CH2 region and an IgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: a partial IgG1 hinge region, an IgG1 CH2 region, and an IgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an IgG1 hinge region, an IgG1 CH2 region, and an IgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an IgG4 CH2 region and an IgG4 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: a partial IgG4 hinge region, an IgG4 CH2 region, and an IgG4 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an IgG4 hinge region, an IgG4 CH2 region, and an IgG4 CH3 region.

[0278] In some embodiments, the heterologous polypeptide comprises or consists of: an Ig Fc region. In some embodiments, the Ig Fc region comprises or consists of: at least a portion of the hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig Fc region comprises or consists of: a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig Fc region comprises or consists of: at least a portion of an IgG hinge region, an IgG CH2 region, and an IgG CH3 region. In some embodiments, the Ig Fc region comprises or consists of: an IgG hinge region, an IgG CH2 region, and an IgG CH3 region. In some embodiments, the Ig Fc region comprises or consists of: at least a portion of an IgG1 hinge region, an IgG1 CH2 region, and an IgG1 CH3 region. In some embodiments, the Ig Fc region comprises or consists of: an IgG1 hinge region, an IgG1 CH2 region, and an IgG1 CH3 region. In some embodiments, the Ig Fc region comprises or consists of: at least a portion of an IgG4 hinge region, an IgG4 CH2 region, and an IgG4 CH3 region. In some embodiments, the Ig Fc region comprises or consists of: an IgG4 hinge region, an IgG4 CH2 region, and an IgG4 CH3 region.

[0279] In some embodiments, the heterologous polypeptide comprises one or more hIg heavy chain constant regions (e.g., CH2 region, CH3 region, hinge region, Fc region). In some embodiments, the hIg is human IgG (hIgG). In some embodiments, the hIgG is hIgG1, IgG2, IgG3, or IgG4. In some embodiments, the hIgG is IgG1 or IgG4. In some embodiments, the hIgG is hIgG1. In some embodiments, the hIgG is hIgG4.

[0280] In some embodiments, the heterologous polypeptide comprises or consists of: hIgG CH2 region and hIgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: partial hIgG hinge region, hIgG CH2 region, and hIgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: hIgG hinge region, hIgG CH2 region, and hIgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: hIgG1 CH2 region and hIgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: partial hIgG1 hinge region, hIgG1 CH2 region, and hIgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: hIgG1 hinge region, hIgG1 CH2 region, and hIgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: hIgG4 CH2 region and hIgG4 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: partial hIgG4 hinge region, hIgG4 CH2 region, and hIgG4 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: hIgG4 hinge region, hIgG4 CH2 region, and hIgG4 CH3 region.

[0281] In some embodiments, the heterologous polypeptide comprises or consists of: an hIg Fc region. In some embodiments, the hIg Fc region comprises or consists of: at least a portion of the hinge region, a CH2 region, and a CH3 region. In some embodiments, the hIg Fc region comprises or consists of: a hinge region, a CH2 region, and a CH3 region. In some embodiments, the hIg Fc region comprises or consists of: at least a portion of the hIgG hinge region, an hIgG CH2 region, and an hIgG CH3 region. In some embodiments, the hIg Fc region comprises or consists of: an hIgG hinge region, an hIgG CH2 region, and an hIgG CH3 region. In some embodiments, the hIg Fc region comprises or consists of: at least a portion of the hIgG1 hinge region, an hIgG1 CH2 region, and an hIgG1 CH3 region. In some embodiments, the hIg Fc region comprises or consists of: an hIgG1 hinge region, an hIgG1 CH2 region, and an hIgG1 CH3 region. In some embodiments, the hIg Fc region comprises or consists of: at least a portion of the hIgG4 hinge region, an hIgG4 CH2 region, and an hIgG4 CH3 region. In some embodiments, the hIg Fc region comprises or consists of: an hIgG4 hinge region, an hIgG4 CH2 region, and an hIgG4 CH3 region.

[0282] Amino acid sequences of exemplary reference hIgG1 and hIgG4 heavy chain constant regions and hIg light chain constant regions are provided in Table 4 and can be incorporated into one or more of the embodiments described herein (e.g., fusion proteins and polypeptides). Table 4. Amino Acid Sequences of Exemplary hIg Heavy Chain Constant Region Components and hIg Light Chain Constant Regions

[0283] In some embodiments, the amino acid sequence of the heterologous polypeptide comprises the amino acid sequence shown in Table 4. In some embodiments, the amino acid sequence of the heterologous polypeptide consists of the amino acid sequence shown in Table 4. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the amino acid sequence shown in Table 4 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 4, which comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 4, which comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 4, which comprises or consists of: no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., amino acid substitutions, deletions or additions).

[0284] In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the amino acid sequence shown in Table 4 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 4, which comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 4, which comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 4, which comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions.

[0285] In some embodiments, the amino acid sequence of the heterologous polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34. In some embodiments, the amino acid sequence of the heterologous polypeptide consists of the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34, which comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34, which comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34, which comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., amino acid substitutions, deletions or additions).

[0286] In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid modifications. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34, which comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34, which comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 16-21 or 27-34, which comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

[0287] In some embodiments, wherein the heterologous polypeptide comprises a CH3 region (e.g., comprising an Fc region; hinge region, CH2 region, and CH3 region, etc.), the CH3 region lacks a C-terminal lysine (e.g., residue 232 of SEQ ID NO: 20, numbered according to SEQ ID NO: 20; or e.g., residue 229 of SEQ ID NO: 31, numbered according to SEQ ID NO: 31). In some embodiments, the CH3 region further lacks a C-terminal glycine (e.g., residue 231 of SEQ ID NO: 20, numbered according to SEQ ID NO: 20; or e.g., residue 228 of SEQ ID NO: 31, numbered according to SEQ ID NO: 31).

[0288] In some embodiments, the heterologous polypeptide comprises one or more mIg heavy chain constant regions (e.g., CH2 region, CH3 region, hinge region, Fc region). In some embodiments, the mIg is mIgG (mIgG). In some embodiments, the mIgG is mIgG1, mIgG2a, mIgG2c, mIgG2b, or mIgG3. In some embodiments, the mIgG is mIgG1 or mIgG2a. In some embodiments, the mIgG is mIgG1. In some embodiments, the mIgG is mIgG2a.

[0289] In some embodiments, the heterologous polypeptide comprises or consists of: an mIgG CH2 region and an mIgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: a partial mIgG hinge region, an mIgG CH2 region and an mIgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an mIgG hinge region, an mIgG CH2 region and an mIgG CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an mIgG1 CH2 region and an mIgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: a partial mIgG1 hinge region, an mIgG1 CH2 region and an mIgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an mIgG1 hinge region, an mIgG1 CH2 region and an mIgG1 CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an mIgG2a CH2 region and an mIgG2a CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: a partial mIgG2a hinge region, an mIg2a CH2 region and an mIgG2a CH3 region. In some embodiments, the heterologous polypeptide comprises or consists of: an mIgG2a hinge region, an mIgG2a CH2 region and an mIgG2a CH3 region.

[0290] In some embodiments, the heterologous polypeptide comprises or consists of: an mIg Fc region. In some embodiments, the mIg Fc region comprises or consists of: at least a portion of the hinge region, a CH2 region and a CH3 region. In some embodiments, the mIg Fc region comprises or consists of: a hinge region, a CH2 region and a CH3 region. In some embodiments, the mIg Fc region comprises or consists of: at least a portion of an mIgG hinge region, an mIgG CH2 region and an mIgG CH3 region. In some embodiments, the mIg Fc region comprises or consists of: an mIgG hinge region, an mIgG CH2 region and an mIgG CH3 region. In some embodiments, the mIg Fc region comprises or consists of: at least a portion of an mIgG1 hinge region, an mIgG1 CH2 region and an mIgG1 CH3 region. In some embodiments, the mIg Fc region comprises or consists of: an mIgG1 hinge region, an mIgG1 CH2 region and an mIgG1 CH3 region. In some embodiments, the mIg Fc region comprises or consists of: at least a portion of an mIgG2a hinge region, an mIgG2a CH2 region and an mIgG2a CH3 region. In some embodiments, the mIg Fc region comprises or consists of: an mIgG2a hinge region, an mIgG2a CH2 region and an mIgG2a CH3 region.

[0291] Table 10 provides exemplary reference amino acid sequences of mIgG1 and mIgG2a heavy chain constant regions that can be incorporated into one or more of the embodiments described herein (e.g., fusion proteins and polypeptides). Table 10. Amino Acid Sequences of Exemplary mIg Heavy Chain Constant Region Components

[0292] In some embodiments, the amino acid sequence of the heterologous polypeptide comprises the amino acid sequence shown in Table 10. In some embodiments, the amino acid sequence of the heterologous polypeptide consists of the amino acid sequence shown in Table 10. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the amino acid sequence shown in Table 10 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the following: the amino acid sequence shown in Table 10, which comprises or consists of the following: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the following: the amino acid sequence shown in Table 10, which comprises or consists of the following: about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the following: the amino acid sequence shown in Table 10, which comprises or consists of the following: no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., amino acid substitutions, deletions or additions).

[0293] In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the amino acid sequence shown in Table 10 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 10, which comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 10, which comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence shown in Table 10, which comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions.

[0294] In some embodiments, the amino acid sequence of the heterologous polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 459-462 or 467-470. In some embodiments, the amino acid sequence of the heterologous polypeptide consists of the amino acid sequence of any one of SEQ ID NOs: 459-462 or 467-470. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 459-462 or 467-470 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 459-462 or 467-470, which comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 459-462 or 467-470, which comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 459-462 or 467-470, which comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., amino acid substitutions, deletions or additions).

[0295] In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 459 - 462 or 467 - 470 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid modifications. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 459 - 462 or 467 - 470. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 459 - 462 or 467 - 470, which comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 459 - 462 or 467 - 470, which comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the heterologous polypeptide comprises or consists of: the amino acid sequence of any one of SEQ ID NOs: 459 - 462 or 467 - 470, which comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

[0296] In some embodiments, where the heterologous polypeptide comprises a CH3 region (e.g., comprising an Fc region; hinge region, CH2 region, and CH3 region, etc.), the CH3 region lacks a C-terminal lysine (e.g., residue 227 of SEQ ID NO: 461, numbered according to SEQ ID NO: 461; or e.g., residue 223 of SEQ ID NO: 469, numbered according to SEQ ID NO: 469). In some embodiments, the CH3 region further lacks a C-terminal glycine (e.g., residue 226 of SEQ ID NO: 461, numbered according to SEQ ID NO: 461; or e.g., residue 222 of SEQ ID NO: 469, numbered according to SEQ ID NO: 469). 5.3.1.3 Ig Effector Functions

[0297] In some embodiments, the Ig (e.g., hIg, mIg) Fc region of the fusion protein or polypeptide described herein exhibits a reduction in one or more Fc effector functions relative to a reference (e.g., wild-type) Ig (e.g., hIg, mIg) Fc region. Exemplary Ig (e.g., hIg, mIg) Fc effector functions include, but are not limited to, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and binding affinity to one or more human Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa and / or FcγRIIIb (e.g., FcγRI, FcγIIa and / or FcγIIIa))).

[0298] Standard in vitro and / or in vivo assays known in the art can be performed to assess Fc effector function, including any one or more of ADCC, CDC, ADCP, Fc receptor (e.g., Fcγ receptor) binding affinity, and CIq binding affinity.

[0299] For example, ADCC activity can be assessed using standard (radioactive and non-radioactive) methods known in the art (see, e.g., WO 2006 / 082515, WO 2012 / 130831), the entire contents of each of which are incorporated herein by reference for all purposes). For example, ADCC activity can be assessed using pentavalent chromium ( 51 Cr) determination was performed for evaluation. 51 Cr is preloaded into target cells expressing CD20, NK cells are added to the culture, and the radioactivity in the cell culture supernatant is assessed (indicating lysis of target cells by NK cells). Similar non-radioactive assays can also be used, which use similar methods, but the target cells are preloaded with fluorescent dyes such as calcein-AM, CFSE, BCECF, or lanthanide fluorophores (europium). See, for example, Parekh, Bhavin S et al. "Development and validation of an antibody-dependent cell-mediated cytotoxicity-reporter gene assay." mAbs [monoclonal antibodies] Vol. 4, 3 (2012): 310-8. Doi: 10.4161 / mabs.19873, the entire contents of which are incorporated herein by reference for all purposes. Exemplary commercially available non-radioactive assays include, for example, ACTI for flow cytometry. TMNon-radioactive cytotoxicity assay (Cell Technology, Inc., Mountain View, California; and CytoTox Non-radioactive cytotoxicity assay (Promega, Madison, Wisconsin). Other non-limiting examples of in vitro assays that can be used to evaluate the ADCC activity of the fusion proteins described herein include those described in the following: US5500362; US5821337; Hellstrom, I., et al., Proc. Nat’l Acad. Sci. USA 83 (1986) 7059-7063; Hellstrom, I., et al., Proc. Nat’l Acad. Sci. USA 82 (1985) 1499-1502; and Bruggemann, M., J. Exp. Med. 166 (1987) 1351-1361, the entire contents of each of which are incorporated herein by reference. Alternatively, or additionally, the ADCC activity of the fusion proteins described herein can be evaluated in vivo, e.g., in an animal model such as the animal model disclosed in Clynes, et al., Proc. Nat’l Acad. Sci. USA 95 (1998) 652-656 (the entire contents of which are incorporated herein by reference for all purposes).

[0300] C1q binding assays can be used to evaluate the ability of the hIg fusion proteins or polypeptides described herein to bind C1q (or bind with lower affinity than a reference fusion protein) and thus lack (or have reduced) CDC activity. Binding of the hIg fusion proteins or polypeptides described herein to C1q can be determined by a variety of in vitro assays known in the art (e.g., biochemistry- or immunology-based assays) for measuring Fc-C1q interactions, including, for example, equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetic methods (e.g., surface plasmon resonance (SPR) analysis), as well as other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis, and chromatography (e.g., gel filtration). These and other methods can utilize labels on one or more of the components being examined and / or employ a variety of detection methods, including but not limited to chromogenic, fluorescent, luminescent, or isotopic labels. A detailed description of binding affinity and kinetics can be found, for example, in Paul, W. E., ed., Fundamental Immunology, 4th ed., Lippincott-Raven, Philadelphia (1999), the entire contents of which are incorporated herein by reference. See, for example, the C1q and C3c binding ELISAs described in WO 2006 / 029879 and WO 2005 / 100402, the entire contents of each of which are incorporated herein by reference for all purposes. Other CDC activity assays include those described in, for example, Gazzano-Santoro, et al., J. Immunol. Methods 202 (1996) 163; Cragg, M. S., et al., Blood 101 (2003) 1045-1052; and Cragg, M. S., and Glennie, M. J., Blood 103 (2004) 2738-2743), the entire contents of each of which are incorporated herein by reference for all purposes.

[0301] ADCP activity can be measured by in vitro or in vivo methods known in the art as well as commercially available assays (see, e.g., van de Donk NW, Moreau P, Plesner T, et al. “Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma,” Blood, 127(6):681-695 (2016), the entire contents of each of which are incorporated herein by reference for all purposes. For example, a primary cell-based ADCP assay can be used, in which fresh human peripheral blood mononuclear cells (PBMCs) are isolated using standard procedures, monocytes are isolated and differentiated into macrophages in culture. Fluorescently labeled macrophages are added to a culture containing fluorescently labeled target cells expressing CD20 and the fusion proteins described herein. Phagocytosis events can be analyzed using FACS screening and / or microscopy. A modified reporter version of the above assay can also be used, which employs an engineered cell line stably expressing FcγRIIa (CD32a) as the effector cell line (e.g., an engineered T cell line, such as THP-1), which eliminates the requirement for primary cells. Exemplary ADCP assays are described, e.g., in Ackerman, M.E. et al. A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samples. J. Immunol. Methods 366, 8–19 (2011); and Mcandrew, E.G. et al. Determining the phagocytic activity of clinical antibody samples. J. Vis. Exp. 3588 (2011). Doi:10.3791 / 3588; the entire contents of each of which are incorporated herein by reference.

[0302] The binding of the hIg fusion proteins or polypeptides described herein to Ig (e.g., hIg, mIg) Fc receptors can be determined by various in vitro assays known in the art for determining Fc-Fc receptor interactions (i.e., specific binding of the Fc region to the Fc receptor), such as biochemical or immunological-based assays. Common assays include equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetic methods (e.g., surface plasmon resonance (SPR) analysis), as well as other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis, and chromatography (e.g., gel filtration). These and other methods can utilize labels on one or more of the components being examined and / or employ a variety of detection methods, including but not limited to chromogenic, fluorescent, luminescent, or isotopic labeling. A detailed description of binding affinity and kinetics can be found in, for example, Paul, W.E., editor, Fundamental Immunology, 4th edition, Lippincott-Raven, Philadelphia (1999), the entire contents of which are incorporated herein by reference for all purposes.

[0303] In some embodiments, the Ig (e.g., hIg, mIg) Fc region of the fusion proteins or polypeptides described herein is variant (e.g., contains one or more mutations (e.g., one or more amino acid substitutions, deletions, additions, etc.)) (referred to herein as "variant Ig (e.g., hIg, mIg) Fc fusion polypeptides or proteins"). In some embodiments, relative to a reference Ig (e.g., hIg, mIg) Fc that does not contain modifications (e.g., one or more mutations (e.g., one or more amino acid substitutions, deletions, additions, etc.)), one or more mutations (e.g., one or more amino acid substitutions, deletions, additions, etc.) reduce or eliminate one or more Fc effector functions.

[0304] In some embodiments, compared to a reference fusion protein or polypeptide that does not contain an Ig (e.g., hIg, mIg) Fc modification (e.g., one or more variants (e.g., one or more amino acid substitutions, deletions, or additions)), a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits undetectable or reduced ADCC. In some embodiments, compared to a reference fusion protein or polypeptide that does not contain an Ig (e.g., hIg, mIg) Fc modification (e.g., one or more variants (e.g., one or more amino acid substitutions, deletions, or additions)), a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits undetectable or reduced CDC. In some embodiments, compared to a reference fusion protein or polypeptide that does not contain an Ig (e.g., hIg, mIg) Fc modification (e.g., one or more variants (e.g., one or more amino acid substitutions, deletions, or additions)), a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits undetectable or reduced ADCP. In some embodiments, compared to a reference fusion protein or polypeptide that does not contain an Ig (e.g., hIg, mIg) Fc modification (e.g., one or more variants (e.g., one or more amino acid substitutions, deletions, or additions)), a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits reduced binding affinity or no binding affinity for one or more Fc receptors (e.g., human Fc receptors) (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))). In some embodiments, compared to a reference fusion protein or polypeptide that does not contain an hIg Fc modification (e.g., one or more variants (e.g., one or more amino acid substitutions, deletions, or additions)), a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits reduced binding affinity or no binding affinity for FcγRI, FcγIIa, and / or FcγIIIa. In some embodiments, compared to a reference fusion protein or polypeptide that does not contain an Ig (e.g., hIg, mIg) Fc modification (e.g., one or more variants (e.g., one or more amino acid substitutions, deletions, or additions)), a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits reduced binding affinity or no binding affinity for FcγRI. In some embodiments, compared to a reference fusion protein or polypeptide that does not contain an Ig (e.g., hIg, mIg) Fc modification (e.g., one or more variants (e.g., one or more amino acid substitutions, deletions, or additions)), a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits reduced binding affinity or no binding affinity for FcγIIa.In some embodiments, a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits a reduced binding affinity or no binding affinity for FcγIIIa compared to a reference fusion protein or polypeptide that does not contain an Ig (e.g., hIg, mIg) Fc modification (e.g., one or more mutations (e.g., one or more amino acid substitutions, deletions, or additions)). In some embodiments, a variant Ig (e.g., hIg, mIg) Fc fusion protein or polypeptide exhibits a reduced binding affinity or no binding affinity for C1q compared to a reference fusion protein or polypeptide that does not contain an Ig (e.g., hIg, mIg) Fc modification (e.g., one or more mutations (e.g., one or more amino acid substitutions, deletions, or additions)).

[0305] Amino acid substitutions that reduce or eliminate one or more Ig (e.g., hIg, mIg) Fc effector functions are known in the art. See, e.g., Saunders Kevin, “Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life,” Frontiers in Immunology, Vol. 10 (June 7, 2019) DOI = 10.3389 / fimmu.2019.01296, the entire content of which is incorporated herein by reference for all purposes, and see more specifically, e.g., Table 3 of Saunders.

[0306] In some embodiments, a variant Ig Fc fusion protein or polypeptide comprises an hIg Fc region containing one or more amino acid mutations. In some embodiments, a variant hIg Fc fusion protein or polypeptide comprises an hIg4 Fc region containing one or more amino acid mutations. In some embodiments, the hIgG4 Fc region comprises an amino acid substitution at amino acid positions S228, F234, and / or L235 according to the Kabat EU numbering. In some embodiments, the hIgG4 Fc region comprises the following amino acid substitutions S228P, F234A, and / or L235A according to the Kabat EU numbering. In some embodiments, the hIgG4 Fc region comprises the following amino acid substitutions S228P, F234A, and / or L235E according to the Kabat EU numbering. In some embodiments, hIgG4 Fc comprises the following amino acid substitutions S228P and / or L235E according to the Kabat EU numbering.

[0307] In some embodiments, the variant hIg Fc fusion protein or polypeptide comprises an hIgG1 Fc region containing one or more amino acid variations. In some embodiments, the hIgG1 Fc region comprises an amino acid substitution at amino acid positions L234, L235, and / or P329 according to the Kabat EU numbering. In some embodiments, the hIgG1 Fc region comprises the following amino acid substitutions L234A and / or L235A according to the Kabat EU numbering. In some embodiments, the hIgG1 Fc region comprises the following amino acid substitutions L234A, L235A, and P329G according to the Kabat EU numbering. In some embodiments, the hIgG1 Fc region comprises the following amino acid substitutions L234A, L235A, and P329A according to the Kabat EU numbering.

[0308] Table 5 provides the amino acid sequences of exemplary variant hIg Fc regions known in the art that exhibit reduced one or more effector functions. Table 5. Amino Acid Sequences of Exemplary Variant hIg Fc Regions

[0309] In some embodiments, the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the polypeptide shown in Table 5. For example, the variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region that comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of the polypeptide shown in Table 5. The variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region that comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of the polypeptide shown in Table 5. The variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region that comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of the polypeptide shown in Table 5. In some embodiments, the variant hIg Fc fusion protein or polypeptide preferably may comprise an hIg Fc region that comprises an amino acid sequence that is 100% identical to the amino acid sequence of the polypeptide shown in Table 5.

[0310] In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, the hIg Fc region comprising or consisting of the amino acid sequence of the polypeptide shown in Table 5, and further comprising 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, the hIg Fc region comprising or consisting of the amino acid sequence of the polypeptide shown in Table 5, and further comprising or consisting of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, the hIg Fc region comprising or consisting of the amino acid sequence of the polypeptide shown in Table 5, and further comprising or consisting of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, the hIg Fc region comprising or consisting of the amino acid sequence of the polypeptide shown in Table 5, and further comprising or consisting of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0311] In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises or consists of the amino acid sequence of the polypeptide shown in Table 5 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises or consists of the amino acid sequence of the polypeptide shown in Table 5 and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises or consists of the amino acid sequence of the polypeptide shown in Table 5 and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises or consists of the amino acid sequence of the polypeptide shown in Table 5 and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions.

[0312] In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, which comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 100% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48. For example, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region, which comprises an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48. The amino acid sequence of the variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region, which comprises an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48. The amino acid sequence of the variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region, which comprises an amino acid sequence that is at least 95% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48. In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide preferably may comprise an hIg Fc region, which comprises an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48. In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, which consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 100% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48. For example, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region, which consists of: an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48. The amino acid sequence of the variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region, which consists of: an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48. The amino acid sequence of the variant hIg Fc fusion protein or polypeptide may comprise an hIg Fc region, which consists of: an amino acid sequence that is at least 95% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48.In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide preferably may comprise an hIg Fc region consisting of an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NOs: 35-48.

[0313] In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 35-48 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 35-48 and further comprises or consists of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 35-48 and further comprises or consists of about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region that comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 35-48 and further comprises or consists of no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0314] In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, the hIg Fc region comprising the amino acid sequence of any one of SEQ ID NOs: 35-48 or consisting of said amino acid sequence, and further comprising 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, the hIg Fc region comprising the amino acid sequence of any one of SEQ ID NOs: 35-48 or consisting of said amino acid sequence, and further comprising the following or consisting of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, the hIg Fc region comprising the amino acid sequence of any one of SEQ ID NOs: 35-48 or consisting of said amino acid sequence, and further comprising the following or consisting of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the variant hIg Fc fusion protein or polypeptide comprises an hIg Fc region, the hIg Fc region comprising the amino acid sequence of any one of SEQ ID NOs: 35-48 or consisting of said amino acid sequence, and further comprising the following or consisting of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

[0315] In some embodiments, the variant mIg Fc fusion protein or polypeptide comprises an mIgG2a Fc region containing one or more amino acid variations. In some embodiments, the mIgG2a Fc region comprises amino acid substitutions at amino acid positions L234, L235 and / or P329 according to the EU numbering of Kabat. In some embodiments, the mIgG2a Fc region comprises the following amino acid substitutions L234P and / or L235P according to the EU numbering of Kabat. In some embodiments, the mIgG2a Fc region comprises the following amino acid substitutions L234P, L235P and P329G according to the EU numbering of Kabat. In some embodiments, the mIgG2a Fc region comprises the following amino acid substitutions L234P, L235P and P329A according to the EU numbering of Kabat.

[0316] In some embodiments, the variant mIg Fc fusion protein or polypeptide comprises an mIgG2a Fc region containing one or more amino acid variations. In some embodiments, the mIgG2a Fc region comprises an amino acid substitution at amino acid positions L234, L235, and / or P329 according to the Kabat EU numbering. In some embodiments, the mIgG2a Fc region comprises the following amino acid substitutions L234A and / or L235A according to the Kabat EU numbering. In some embodiments, the mIgG2a Fc region comprises the following amino acid substitutions L234A, L235A, and P329G according to the Kabat EU numbering. In some embodiments, the mIgG2a Fc region comprises the following amino acid substitutions L234A, L235A, and P329A according to the Kabat EU numbering.

[0317] The amino acid sequences of exemplary variant hIgFc regions known in the art that exhibit reduced one or more effector functions are provided in Table 11. Table 11. Amino Acid Sequences of Exemplary Variant mIg Fc Regions

[0318] In some embodiments, the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of the polypeptide shown in Table 11. For example, the variant mIg Fc fusion protein or polypeptide may comprise an mIg Fc region that comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of the polypeptide shown in Table 11. The variant mIg Fc fusion protein or polypeptide may comprise an mIg Fc region that comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of the polypeptide shown in Table 11. The variant mIg Fc fusion protein or polypeptide may comprise an mIg Fc region that comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of the polypeptide shown in Table 11. In some embodiments, the variant mIg Fc fusion protein or polypeptide preferably may comprise an mIg Fc region that comprises an amino acid sequence that is 100% identical to the amino acid sequence of the polypeptide shown in Table 11.

[0319] In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises or consists of the amino acid sequence of the polypeptide shown in Table 11, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises or consists of the amino acid sequence of the polypeptide shown in Table 11, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises or consists of the amino acid sequence of the polypeptide shown in Table 11, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises or consists of the amino acid sequence of the polypeptide shown in Table 11, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0320] In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, which comprises or consists of the amino acid sequence of the polypeptide shown in Table 11, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, which comprises or consists of the amino acid sequence of the polypeptide shown in Table 11, and further comprises or consists of: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, which comprises or consists of the amino acid sequence of the polypeptide shown in Table 11, and further comprises or consists of: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, which comprises or consists of the amino acid sequence of the polypeptide shown in Table 11, and further comprises or consists of: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions.

[0321] In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, and the mIg Fc region comprises an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 100% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478. For example, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide may comprise an mIg Fc region, and the mIg Fc region comprises an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478. The amino acid sequence of the variant mIg Fc fusion protein or polypeptide may comprise an mIg Fc region, and the mIg Fc region comprises an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478. The amino acid sequence of the variant mIg Fc fusion protein or polypeptide may comprise an mIg Fc region, and the mIg Fc region comprises an amino acid sequence that is at least 95% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478. In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide preferably may comprise an mIg Fc region, and the mIg Fc region comprises an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478. In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, and the mIg Fc region consists of: an amino acid sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 100% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478. For example, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide may comprise an mIg Fc region, and the mIg Fc region consists of: an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478. The amino acid sequence of the variant mIg Fc fusion protein or polypeptide may comprise an hIg Fc region, and the hIg Fc region consists of: an amino acid sequence that is at least 90% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478. The amino acid sequence of the variant mIg Fc fusion protein or polypeptide may comprise an mIg Fc region, and the mIg Fc region consists of: an amino acid sequence that is at least 95% identical to any one of the amino acid sequences of SEQ ID NOs: 471 - 478.In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide preferably may comprise an mIg Fc region consisting of an amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NOs: 471-478.

[0322] In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 471-478 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 471-478 and further comprises or consists of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 471-478 and further comprises or consists of about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.). In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region that comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 471-478 and further comprises or consists of no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0323] In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, the mIg Fc region comprising the amino acid sequence of any one of SEQ ID NOs: 471-478 or consisting of the amino acid sequence, and further comprising 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid substitutions. In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, the mIg Fc region comprising the amino acid sequence of any one of SEQ ID NOs: 471-478 or consisting of the amino acid sequence, and further comprising the following or consisting of the following: at least about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, the mIg Fc region comprising the amino acid sequence of any one of SEQ ID NOs: 471-478 or consisting of the amino acid sequence, and further comprising the following or consisting of the following: about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. In some embodiments, the amino acid sequence of the variant mIg Fc fusion protein or polypeptide comprises an mIg Fc region, the mIg Fc region comprising the amino acid sequence of any one of SEQ ID NOs: 471-478 or consisting of the amino acid sequence, and further comprising the following or consisting of the following: no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions. 5.3.2 Linker

[0324] As described herein, a heterologous moiety (e.g., a heterologous polypeptide) can be directly operably linked or indirectly operably linked to an immunomodulatory protein or polypeptide (e.g., as described herein). In some embodiments, the heterologous polypeptide is directly operably linked to the immunomodulatory protein or polypeptide (e.g., as described herein) by a peptide bond. In some embodiments, the heterologous polypeptide is indirectly operably linked to the immunomodulatory protein or polypeptide (e.g., as described herein) by a peptide linker.

[0325] In some embodiments, the peptide linker is one or any combination of a cleavable linker, a non-cleavable linker, a flexible linker, a rigid linker, a helical linker, and / or a non-helical linker.

[0326] In some embodiments, the peptide linker comprises or consists of from about 2 - 30, 5 - 30, 10 - 30, 15 - 30, 20 - 30, 25 - 30, 2 - 25, 5 - 25, 10 - 25, 15 - 25, 20 - 25, 2 - 20, 5 - 20, 10 - 20, 15 - 20, 2 - 15, 5 - 15, 10 - 15, 2 - 10, or 5 - 10 amino acid residues. In some embodiments, the peptide linker comprises at least about 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, or 30 amino acid residues. In some embodiments, the linker comprises or consists of: about 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, or 30 amino acid residues. In some embodiments, the linker comprises or consists of: not more than about 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, or 30 amino acid residues.

[0327] In some embodiments, the amino acid sequence of the peptide linker comprises or consists of: glycine, serine, or glycine and serine amino acid residues. In some embodiments, the amino acid sequence of the peptide linker comprises or consists of: glycine, serine, and proline amino acid residues.

[0328] The amino acid sequences of exemplary peptide linkers are provided in Table 6, which can be incorporated into one or more of the embodiments described herein (e.g., fusion proteins and polypeptides). Table 6. Amino Acid Sequences of Exemplary Peptide Linkers

[0329] In some embodiments, the amino acid sequence of the peptide linker comprises the amino acid sequence of any one of the linkers shown in Table 6. In some embodiments, the amino acid sequence of the peptide linker consists of the amino acid sequence of any one of the linkers shown in Table 6. In some embodiments, the amino acid sequence of the peptide linker comprises or consists of the amino acid sequence of any one of the linkers listed in Table 6, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the peptide linker comprises or consists of the following: the amino acid sequence of any one of the linkers listed in Table 6, which comprises 1, 2 or 3 amino acid variations (e.g., substitutions, deletions, additions). In some embodiments, the amino acid sequence of the peptide linker comprises or consists of the amino acid sequence of any one of the linkers listed in Table 6, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid modifications. In some embodiments, the amino acid sequence of the peptide linker comprises or consists of the following: the amino acid sequence of any one of the linkers listed in Table 6, which comprises 1, 2 or 3 amino acid substitutions.

[0330] In some embodiments, the amino acid sequence of the peptide linker comprises the amino acid sequence of any one of SEQ ID NO:49-57. In some embodiments, the amino acid sequence of the peptide linker consists of the amino acid sequence of any one of SEQ ID NO:49-57. In some embodiments, the amino acid sequence of the peptide linker comprises or consists of the amino acid sequence of any one of SEQ ID NO:49-57, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid variations (e.g., amino acid substitutions, deletions or additions). In some embodiments, the amino acid sequence of the peptide linker comprises or consists of the following: the amino acid sequence of any one of SEQ ID NO:49-57, which comprises 1, 2 or 3 amino acid variations (e.g., substitutions, deletions, additions). In some embodiments, the amino acid sequence of the peptide linker comprises or consists of the amino acid sequence of any one of SEQ ID NO:49-57, and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid modifications. In some embodiments, the amino acid sequence of the peptide linker comprises or consists of the following: the amino acid sequence of any one of SEQ ID NO:49-57, which comprises 1, 2 or 3 amino acid substitutions.

[0331] In some embodiments, the amino acid sequence of the peptide linker comprises the amino acid sequence of SEQ ID NO:51 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid modifications. In some embodiments, the amino acid sequence of the peptide linker comprises the amino acid sequence of SEQ ID NO:51. In some embodiments, the amino acid sequence of the peptide linker comprises the following: the amino acid sequence of any one of SEQ ID NO:51, which comprises 1, 2 or 3 amino acid variations (e.g., substitutions, additions, deletions). In some embodiments, the amino acid sequence of the peptide linker comprises the following: the amino acid sequence of any one of SEQ ID NO:51, which comprises 1, 2 or 3 amino acid substitutions. In some embodiments, the amino acid sequence of the peptide linker consists of the amino acid sequence of SEQ ID NO:51 and further comprises 1 or more but less than 15% (less than 12%, less than 10%, less than 8%) amino acid modifications. In some embodiments, the amino acid sequence of the peptide linker consists of the amino acid sequence of SEQ ID NO:51. In some embodiments, the amino acid sequence of the peptide linker consists of the following: the amino acid sequence of any one of SEQ ID NO:51, which comprises 1, 2 or 3 amino acid variations (e.g., substitutions, additions, deletions). In some embodiments, the amino acid sequence of the peptide linker consists of the following: the amino acid sequence of any one of SEQ ID NO:51, which comprises 1, 2 or 3 amino acid substitutions. 5.3.3 Orientation

[0332] The heterologous moiety (e.g., heterologous polypeptide) and the immunomodulatory protein or polypeptide (e.g., as described herein) can be arranged in any configuration or order, provided that the immunomodulatory protein or polypeptide (e.g., as described herein) retains the ability to mediate its function (e.g., bind to hIL-10R) and, in embodiments where the heterologous moiety (e.g., heterologous polypeptide) has a specific function, the heterologous moiety (e.g., heterologous polypeptide) can mediate its function.

[0333] In some embodiments, the heterologous moiety is a heterologous polypeptide that forms a fusion polypeptide or protein (e.g., an Ig (e.g., hIg, mIg) Fc region (e.g., the Ig (e.g., hIg, mIg) Fc region described herein)). In some embodiments, the fusion polypeptide or protein comprises, from the N-terminus to the C-terminus: an immunomodulatory polypeptide (e.g., as described herein) and a heterologous polypeptide (e.g., an Ig (e.g., hIg, mIg) Fc region (e.g., the Ig (e.g., hIg, mIg) Fc region described herein)). In some embodiments, the fusion polypeptide or protein comprises, from the N-terminus to the C-terminus: an immunomodulatory polypeptide (e.g., as described herein), a peptide linker (e.g., as described herein), and a heterologous polypeptide (e.g., an Ig (e.g., hIg, mIg) Fc region (e.g., the Ig (e.g., hIg, mIg) Fc region described herein)). In the particular orientation, the N-terminus of the immunomodulatory polypeptide (e.g., as described herein) is directly or indirectly operably linked, via a peptide linker (e.g., as described herein), to the C-terminus of the heterologous polypeptide (e.g., an Ig (e.g., hIg, mIg) Fc region (e.g., the Ig (e.g., hIg, mIg) Fc region described herein)).

[0334] In some embodiments, the fusion polypeptide comprises, from the N-terminus to the C-terminus: a heterologous polypeptide (e.g., an Ig (e.g., hIg, mIg) Fc region (e.g., the Ig (e.g., hIg, mIg) Fc region described herein)) and an immunomodulatory polypeptide (e.g., as described herein). In some embodiments, the fusion polypeptide comprises, from the N-terminus to the C-terminus: a heterologous polypeptide (e.g., an Ig (e.g., hIg, mIg) Fc region (e.g., the Ig (e.g., hIg, mIg) Fc region described herein)), a peptide linker (e.g., as described herein), and an immunomodulatory polypeptide (e.g., as described herein). In the particular orientation, the C-terminus of the immunomodulatory polypeptide (e.g., as described herein) is directly or indirectly operably linked, via a peptide linker (e.g., as described herein), to the N-terminus of the heterologous polypeptide (e.g., an Ig (e.g., hIg, mIg) Fc region (e.g., the Ig (e.g., hIg, mIg) Fc region described herein)). 5.3.4 Multimeric fusion proteins

[0335] In one aspect, provided herein are multimeric (e.g., dimeric) proteins that comprise at least two polypeptides or protein fusions or conjugates described herein (e.g., Ig (e.g., hIg, mIg) Fc fusion proteins or polypeptides described herein). In some embodiments, the protein is a dimer. In some embodiments, the protein is a homodimer. In some embodiments, the protein is a heterodimer. In some embodiments, at least two polypeptides or protein fusions (e.g., Ig (e.g., hIg, mIg) Fc fusion proteins or polypeptides described herein) or conjugates in the present invention associate via covalent or non-covalent interactions. In some embodiments, at least two polypeptides or protein fusions (e.g., Ig (e.g....

Claims

1. An isolated polypeptide or protein that comprises an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 108 - 454, wherein the polypeptide or protein specifically binds to the human IL-10 receptor (hIL-10R) (e.g., hIL-10Rα).

2. The isolated polypeptide or protein of claim 1, wherein the isolated polypeptide or protein consists of the following an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any one of SEQ ID NOs: 108 - 454.

3. The isolated polypeptide or protein of claim 1 or 2, wherein the isolated polypeptide or protein comprises or consists of the following an amino acid sequence that is at least about 85% identical to any one of SEQ ID NOs: 108 - 454.

4. The isolated polypeptide or protein of any one of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following an amino acid sequence that is at least about 90% identical to any one of SEQ ID NOs: 108 - 454.

5. The isolated polypeptide or protein of any one of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following an amino acid sequence that is at least about 95% identical to any one of SEQ ID NOs: 108 - 454.

6. The isolated polypeptide or protein of any one of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following an amino acid sequence that is 100% identical to any one of SEQ ID NOs: 108 - 454.

7. The isolated polypeptide or protein of any one of claims 1 - 3, wherein the isolated polypeptide or protein comprises or consists of the following an amino acid sequence that is at least about 85% identical to any one of SEQ ID NOs: 108, 111 - 119, or 122 - 126.

8. The isolated polypeptide or protein of any one of claims 1 - 4, wherein the isolated polypeptide or protein comprises or consists of the following an amino acid sequence that is at least about 90% identical to any one of SEQ ID NOs: 108, 111 - 119, or 122 - 126.

9. The isolated polypeptide or protein of any one of claims 1 - 5, wherein the isolated polypeptide or protein comprises or consists of the following an amino acid sequence that is at least about 95% identical to any one of SEQ ID NOs: 108, 111 - 119, or 122 - 126.

10. An isolated polypeptide or protein as claimed in any one of claims 1-6, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 108, 111-119 or 122-126.

11. An isolated polypeptide or protein as claimed in any one of claims 1-3, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is at least about 85% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126.

12. An isolated polypeptide or protein as claimed in any one of claims 1-4, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is at least about 90% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126.

13. An isolated polypeptide or protein as claimed in any one of claims 1-5, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is at least about 95% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126.

14. An isolated polypeptide or protein as claimed in any one of claims 1-6, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO: 112-115 or 123-126.

15. An isolated polypeptide or protein as claimed in any of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is at least about 85% identical to the amino acid sequence of any one of SEQ ID NO:

114.

16. An isolated polypeptide or protein as claimed in any of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is at least about 90% identical to the amino acid sequence of any one of SEQ ID NO:

114.

17. An isolated polypeptide or protein as claimed in any of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is at least about 95% identical to the amino acid sequence of any one of SEQ ID NO:

114.

18. An isolated polypeptide or protein as claimed in any of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO:

114.

19. An isolated polypeptide or protein as claimed in any of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is at least about 85% identical to the amino acid sequence of any one of SEQ ID NO:

125.

20. An isolated polypeptide or protein as claimed in any of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following Consisting of: An amino acid sequence that is at least about 90% identical to any one of the amino acid sequences of SEQ ID NO:

125.

21. The isolated polypeptide or protein according to any one of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following: An amino acid sequence that is at least about 95% identical to any one of the amino acid sequences of SEQ ID NO:

125.

22. The isolated polypeptide or protein according to any one of the preceding claims, wherein the isolated polypeptide or protein comprises or consists of the following: An amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NO:

125.

23. An isolated polypeptide or protein that comprises an amino acid sequence that is at least about 85% identical to any one of the amino acid sequences of SEQ ID NO: 119 - 126 or 291 - 454, wherein the polypeptide or protein specifically binds to hIL-10R (such as hIL-10Rα).

24. The isolated polypeptide or protein according to claim 23, wherein the isolated polypeptide or protein consists of: an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any one of the amino acid sequences of SEQ ID NO: 119 - 126 or 291 - 454.

25. The isolated polypeptide or protein according to claim 23 or 24, wherein the isolated polypeptide or protein comprises or consists of the following: An amino acid sequence that is at least about 85% identical to any one of the amino acid sequences of SEQ ID NO: 119 - 126 or 291 - 454.

26. The isolated polypeptide or protein according to any one of claims 23 - 25, wherein the isolated polypeptide or protein comprises or consists of the following: An amino acid sequence that is at least about 90% identical to any one of the amino acid sequences of SEQ ID NO: 119 - 126 or 291 - 454.

27. The isolated polypeptide or protein according to any one of claims 23 - 26, wherein the isolated polypeptide or protein comprises or consists of the following: An amino acid sequence that is at least about 95% identical to any one of the amino acid sequences of SEQ ID NO: 119 - 126 or 291 - 454.

28. The isolated polypeptide or protein according to any one of claims 23 - 27, wherein the isolated polypeptide or protein comprises or consists of the following: An amino acid sequence that is 100% identical to any one of the amino acid sequences of SEQ ID NO: 119 - 126 or 291 - 454.

29. An isolated polypeptide or protein that comprises an amino acid sequence that is at least about 85% identical to any one of the amino acid sequences of SEQ ID NO: 108 - 118 or 127 - 290, wherein the polypeptide or protein specifically binds to hIL-10R (such as hIL-10Rα).

30. The isolated polypeptide or protein according to claim 29, wherein the isolated polypeptide or protein consists of: an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290.

31. The isolated polypeptide or protein according to claim 29 or 30, wherein the isolated polypeptide or protein comprises or consists of the following: an amino acid sequence that is at least about 85% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290.

32. The isolated polypeptide or protein according to any one of claims 29-31, wherein the isolated polypeptide or protein comprises or consists of the following: an amino acid sequence that is at least about 90% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290.

33. The isolated polypeptide or protein according to any one of claims 29-32, wherein the isolated polypeptide or protein comprises or consists of the following: an amino acid sequence that is at least about 95% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290.

34. The isolated polypeptide or protein according to any one of claims 29-33, wherein the isolated polypeptide or protein comprises or consists of the following: an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108-118 or 127-290.

35. The isolated polypeptide or protein according to any one of the preceding claims, wherein the polypeptide or protein (a) binds to cells expressing hIL-10R (e.g., hIL-10Rα) on the surface with an EC50 of less than about 500 pM, 400 pM, 300 pM, 200 pM, 100 pM, 50 pM, 40 pM, 30 pM, 20 pM, 10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2 pM, 1 pM, 0.9 pM, 0.8 pM, 0.7 pM, 0.6 pM, 0.5 pM, 0.4 pM, 0.3 pM, 0.2 pM or 0.1 pM; or (b) binds to cells expressing hIL-10R (e.g., hIL-10Rα) on the surface with an EC50 of about 500 pM–0.1 pM, 400 pM–0.1 pM, 300 pM–0.1 pM, 200 pM–0.1 pM, 100 pM–0.1 pM, 50 pM–0.1 pM, 25 pM–0.1 pM, 10 pM–0.1 pM, 5 pM–0.1 pM, or 1 pM–0.1 pM, 500 pM–0.5, 400 pM–0.5, 300 pM–0.5, 200 pM–0.5, 100 pM–0.5, 50 pM–0.5, 25 pM–0.5, 10 pM–0.5, 5 pM–0.5, or 1 pM–0.5 pM.

36. The isolated polypeptide or protein according to any one of the preceding claims, wherein the polypeptide or protein (a) binds to cells expressing hIL-10R (e.g., hIL-10Rα) on the surface with an EC50 that is at least about 4-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 110-fold, 120-fold, 130-fold, 140-fold, or 150-fold higher than the EC50 of a reference hIL-10 polypeptide (e.g., SEQ ID NO:2); or (b) binds to cells expressing hIL-10R (e.g., hIL-10Rα) on the surface with an EC50 that is about 10 - 150-fold, 20 - 150-fold, 30 - 150-fold, 40 - 150-fold, 50 - 150-fold, 60 - 150-fold, 70 - 150-fold, 80 - 150-fold, 90 - 150-fold, 100 - 150-fold, 110 - 150-fold, 120 - 150-fold, 130 - 150-fold, or 140 - 150-fold higher than the EC50 of a reference hIL-10 protein or polypeptide (e.g., SEQ ID NO:2).

37. The isolated polypeptide or protein according to claim 35 or 36, wherein the EC50 is determined by the assay described in Example 3 herein.

38. The isolated polypeptide or protein according to any one of the preceding claims, wherein the polypeptide or protein specifically binds to hIL-10Rα.

39. The isolated polypeptide or protein according to any one of the preceding claims, wherein the polypeptide or protein specifically binds to hIL-10Rβ.

40. The isolated polypeptide or protein according to any one of the preceding claims, wherein the polypeptide or protein specifically binds to both hIL-10Rα and hIL-10Rβ.

41. The isolated polypeptide or protein according to any one of the preceding claims, wherein the polypeptide or protein is an agonist of hIL-10R (e.g., hIL-10Rα, hIL-10Rβ).

42. The isolated polypeptide or protein according to any one of the preceding claims, wherein the polypeptide or protein is an antagonist of hIL-10R (e.g., hIL-10Rα, hIL-10Rβ).

43. The isolated polypeptide or protein according to any one of the preceding claims, which further comprises a homologous or heterologous signal peptide operably linked to the N-terminus of the polypeptide or protein.

44. The isolated polypeptide or protein according to any one of the preceding claims, wherein the isolated polypeptide or protein is an isolated protein.

45. A polypeptide comprising the polypeptide or protein according to any one of claims 1-44 operably linked to a heterologous moiety.

46. A fusion polypeptide or protein comprising the polypeptide or protein according to any one of claims 1-44 operably linked to a heterologous polypeptide or protein.

47. The fusion polypeptide or protein according to claim 46, wherein the heterologous polypeptide or protein comprises a polypeptide or protein with an extended half-life.

48. The fusion polypeptide or protein according to any one of claims 46-47, wherein the heterologous polypeptide or protein comprises an immunoglobulin (Ig) (e.g., human Ig (hIg), murine Ig (mIg)) Fc region.

49. The fusion polypeptide or protein according to claim 48, wherein the Ig (e.g., hIg, mIg) Fc region comprises at least a portion of the hinge region, CH2 region, and CH3 region.

50. The fusion polypeptide or protein according to claim 48 or 49, wherein the Ig (e.g., hIg, mIg) Fc region comprises the hinge region, CH2 region, and CH3 region.

51. The fusion polypeptide or protein according to any one of claims 48-50, wherein the Ig is hIg.

52. The fusion polypeptide or protein according to claim 51, wherein the hIg is human IgG (hIgG).

53. The fusion polypeptide or protein according to any one of claims 51-52, wherein the hIgG is hIgG1 or hIgG4.

54. The fusion polypeptide or protein according to any one of claims 48-50, wherein the Ig is mIg.

55. The fusion polypeptide or protein according to claim 54, wherein the mIg is mIgG1.

56. The fusion polypeptide or protein according to claim 54, wherein the mIg is mIgG2a.

57. The fusion polypeptide or protein according to any one of claims 48-56, wherein the Ig (e.g., hIg, mIg) Fc region comprises one or more amino acid substitutions relative to a reference Ig (e.g., hIg, mIg) Fc region, and the substitution reduces or eliminates one or more of the following effector functions relative to the reference hIg Fc region: antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and / or affinity for one or more human Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))).

58. The fusion polypeptide or protein according to any one of claims 48 - 57, wherein the Ig (e.g., hIg, mIg) Fc region substantially does not mediate ADCC, substantially does not mediate CDC, and / or does not bind to one or more human Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))).

59. The fusion polypeptide or protein according to any one of claims 48 - 58, wherein the Ig is hIgG4 and the amino acid sequence of the Fc region comprises an amino acid substitution at amino acid position S228, an amino acid substitution at amino acid position F234, and / or an amino acid substitution at amino acid position L235, according to the EU index numbering of Kabat.

60. The fusion polypeptide or protein according to any one of claims 48 - 59, wherein the Ig is hIgG4 and the amino acid sequence of the Fc region comprises proline at amino acid position S228, alanine at amino acid position F234, and / or alanine at amino acid position L235, according to the EU index numbering of Kabat.

61. The fusion polypeptide or protein according to any one of claims 48 - 58, wherein the Ig is hIgG1 and the amino acid sequence of the Fc region comprises an amino acid substitution at amino acid position L234 and / or an amino acid substitution at amino acid position L235, according to the EU index numbering of Kabat.

62. The fusion polypeptide or protein according to any one of claims 48 - 58 or 61, wherein the Ig is hIgG1 and the amino acid sequence of the Fc region comprises alanine at amino acid position L234 and / or alanine at amino acid position L235, according to the EU index numbering of Kabat.

63. The fusion polypeptide or protein according to any one of claims 48 - 58 or 61 - 62, wherein the Ig is hIgG1 and the amino acid sequence of the Fc region comprises alanine at amino acid position L234, alanine at amino acid position L235, and / or glycine at position P329, according to the EU index numbering of Kabat.

64. The fusion polypeptide or protein according to any one of claims 48 - 58, wherein the Ig is mIgG2a and the amino acid sequence of the Fc region comprises an amino acid substitution at amino acid position L234 and / or an amino acid substitution at amino acid position L235, according to the EU index numbering of Kabat.

65. The fusion polypeptide or protein according to any one of claims 48 - 58 or 64, wherein the Ig is mIgG2a and the amino acid sequence of the Fc region comprises proline (or alanine) at amino acid position L234 and / or proline (or alanine) at amino acid position L235, according to the EU index numbering of Kabat.

66. A fusion polypeptide or protein according to any one of claims 48 - 58 or 64 - 65, wherein the Ig is mIgG2a and the amino acid sequence of the Fc region comprises a proline (or alanine) at amino acid position L234, a proline (or alanine) at amino acid position L235, and / or a glycine at position P329, according to the Kabat EU index numbering.

67. A fusion polypeptide or protein according to any one of claims 46 - 66, wherein the polypeptide or protein according to any one of claims 1 - 44 is directly operably linked to the heterologous polypeptide or protein by a peptide bond.

68. A fusion polypeptide or protein according to any one of claims 46 - 67, wherein the polypeptide or protein according to any one of claims 1 - 44 is indirectly operably linked to the heterologous polypeptide or protein by a peptide linker.

69. A fusion polypeptide or protein according to claim 68, wherein the amino acid sequence of the peptide linker comprises or consists of: glycine or glycine and serine amino acid residues.

70. A fusion polypeptide or protein according to any one of claims 68 - 69, wherein the amino acids of the peptide linker comprise or consist of consist of: (a) an amino acid sequence of any one of SEQ ID NOs: 49 - 57; or (b) an amino acid sequence of any one of SEQ ID NOs: 49 - 57, which comprises or consists of: 1, 2, or 3 amino acid substitutions.

71. A fusion polypeptide or protein according to any one of claims 46 - 70, wherein the fusion polypeptide or protein comprises, from the N - terminus to the C - terminus: the polypeptide or protein according to any one of claims 1 - 44, and the heterologous polypeptide or protein.

72. A fusion polypeptide or protein according to any one of claims 46 - 71, wherein the fusion polypeptide or protein comprises, from the N - terminus to the C - terminus: the polypeptide or protein according to any one of claims 1 - 44, a peptide linker, and the heterologous polypeptide or protein.

73. A fusion polypeptide or protein according to any one of claims 46 - 72, wherein the fusion polypeptide or protein comprises, from the N - terminus to the C - terminus: a signal peptide, the polypeptide or protein according to any one of claims 1 - 44, a peptide linker, and the heterologous polypeptide or protein.

74. A fusion polypeptide or protein according to any one of claims 46 - 70, wherein the fusion polypeptide or protein comprises, from the N - terminus to the C - terminus: the heterologous polypeptide or protein, and the polypeptide or protein according to any one of claims 1 - 44.

75. A fusion polypeptide or protein according to any one of claims 46 - 70 or 74, wherein the fusion polypeptide or protein comprises, from the N - terminus to the C - terminus: the heterologous polypeptide or protein, a peptide linker, and the isolated polypeptide or protein according to any one of claims 1 - 44.

76. A fusion polypeptide or protein according to any one of claims 46 - 70 or 74 - 75, wherein the fusion polypeptide or protein comprises, from the N - terminus to the C - terminus: a signal peptide, the heterologous polypeptide or protein, a peptide linker, and a separated polypeptide or protein according to any one of claims 1 - 44.

77. A fusion protein comprising a first polypeptide or protein and a second polypeptide or protein, wherein the first polypeptide or protein comprises a first Ig (e.g., hIg, mIg) Fc region operably linked to the first polypeptide or protein according to any one of claims 1 - 44; and wherein the second polypeptide or protein comprises a second Ig (e.g., hIg, mIg) Fc region operably linked to the second polypeptide or protein according to any one of claims 1 - 44.

78. The fusion protein according to claim 77, wherein the first Fc region and the second Fc region associate to form a dimer.

79. The fusion protein according to any one of claims 77 - 78, wherein the first polypeptide or protein comprises an amino acid sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of the second polypeptide or protein.

80. The fusion protein according to any one of claims 77 - 79, wherein the first Ig (e.g., hIg, mIg) Fc region comprises at least a portion of the hinge region, the CH2 region, and the CH3 region; and the second Ig (e.g., hIg, mIg) Fc region comprises at least a portion of the hinge region, the CH2 region, and the CH3 region.

81. The fusion protein according to any one of claims 77 - 80, wherein the first Ig (e.g., hIg, mIg) Fc region comprises the hinge region, the CH2 region, and the CH3 region; and the second Ig (e.g., hIg, mIg) Fc region comprises the hinge region, the CH2 region, and the CH3 region.

82. The fusion protein according to any one of claims 77 - 81, wherein the Ig of the first Ig Fc region is hIg and the Ig of the second Ig Fc region is hIg.

83. The fusion protein according to claim 82, wherein the hIg of the first hIg Fc region is hIgG and the hIg of the second hIg Fc region is hIgG.

84. The fusion protein according to claim 83, wherein the hIgG of the first hIg Fc region is hIgG4 and the hIgG of the first hIg Fc region is hIgG4.

85. The fusion protein according to claim 83, wherein the hIgG of the first hIg Fc region is hIgG1 and the hIgG of the first hIg Fc region is hIgG1.

86. The fusion protein according to any one of claims 77 - 81, wherein the Ig of the first Ig Fc region is hIg and the Ig of the second Ig Fc region is mIg.

87. The fusion protein according to claim 86, wherein the mIg of the first mIg Fc region is mIgG and the mIg of the second mIg Fc region is mIgG.

88. The fusion protein according to claim 87, wherein the mIg of the first mIg Fc region is mIgG1 and the mIg of the second mIg Fc region is mIgG1.

89. The fusion protein according to claim 87, wherein the mIg of the first mIg Fc region is mIgG2A and the mIg of the second mIg Fc region is mIgG2a.

90. The fusion protein according to any one of claims 77 - 89, wherein the first Ig (e.g., hIg, mIg) Fc region and the second Ig (e.g., hIg, mIg) Fc region each contain one or more amino acid substitutions relative to a reference Ig (e.g., hIg, mIg) Fc region, and the substitutions reduce or eliminate one or more of the following effector functions relative to the reference Ig (e.g., hIg, mIg) Fc region: ADCC, CDC, and / or binding affinity for one or more Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))).

91. The fusion protein according to any one of claims 77 - 90, wherein the fusion protein substantially does not mediate ADCC, substantially does not mediate CDC, and / or does not bind to one or more Fc receptors (e.g., Fcγ receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, and / or FcγRIIIb (e.g., FcγRI, FcγIIa, and / or FcγIIIa))).

92. The fusion protein according to any one of claims 77 - 91, wherein the Ig of the first Ig Fc region and the second Ig Fc region is hIgG4, and the amino acid sequence of each of the first Fc region and the second Fc region contains an amino acid substitution at amino acid position S228, an amino acid substitution at amino acid position F234, and / or an amino acid substitution at amino acid position E235, according to the EU index numbering of Kabat.

93. The fusion protein according to any one of claims 77 - 92, wherein the Ig of the first Ig Fc region and the second Ig Fc region is hIgG4, and the amino acid sequence of each of the first Fc region and the second Fc region contains proline at amino acid position S228, alanine at amino acid position F234, and / or alanine at amino acid position E235, according to the EU index numbering of Kabat.

94. The fusion protein according to any one of claims 77-93, wherein the Ig of the first Ig Fc region and the second Ig Fc region is hIgG1, and the amino acid sequences of the first Fc region and the second Fc region each comprise an amino acid substitution at amino acid position L234 and / or an amino acid substitution at amino acid position L235, according to the EU index numbering of Kabat.

95. The fusion protein according to any one of claims 77-91 or 94, wherein the Ig of the first Ig Fc region and the second Ig Fc region is hIgG1, and the amino acid sequences of the first Fc region and the second Fc region each comprise alanine at amino acid position L234 and / or alanine at amino acid position L235, according to the EU index numbering of Kabat.

96. The fusion protein according to any one of claims 77-91 or 95, wherein the Ig of the first Ig Fc region and the second Ig Fc region is hIgG1, and the amino acid sequences of the first Fc region and the second Fc region each comprise proline (or alanine) at amino acid position L234 and / or proline (or alanine) at amino acid position L235, according to the EU index numbering of Kabat.

97. The fusion protein according to any one of claims 77-91 or 95-96, wherein the Ig of the first Ig Fc region and the second Ig Fc region is hIgG1, and the amino acid sequences of the first Fc region and the second Fc region each comprise proline (or alanine) at amino acid position L234, proline (or alanine) at amino acid position L235, and / or glycine at amino acid position P329, according to the EU index numbering of Kabat.

98. The fusion protein according to any one of claims 77-91, wherein the Ig of the first Ig Fc region and the second Ig Fc region is mIgG2a, and the amino acid sequences of the first Fc region and the second Fc region each comprise an amino acid substitution at amino acid position L234 and / or an amino acid substitution at amino acid position L235, according to the EU index numbering of Kabat.

99. The fusion protein according to any one of claims 77-98, wherein the first Ig (e.g., hIg, mIg) Fc region comprises an amino acid sequence that is at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of the second Ig (e.g., hIg, mIg) Fc region.

100. The fusion protein according to any one of claims 77-99, wherein the first polypeptide or protein comprises, from the N-terminus to the C-terminus: the first Ig (e.g., hIg, mIg) Fc region and the first polypeptide or protein according to any one of claims 1-44; and the second polypeptide or protein comprises, from the N-terminus to the C-terminus: the second Ig (e.g., hIg, mIg) Fc region and the second polypeptide or protein according to any one of claims 1-44.

101. The fusion protein according to any one of claims 77-100, wherein the first polypeptide or protein comprises, from the N-terminus to the C-terminus: the first Ig (e.g., hIg, mIg) Fc region, a first peptide linker, and the first polypeptide or protein according to any one of claims 1-44; and the second polypeptide or protein comprises, from the N-terminus to the C-terminus: the second Ig (e.g., hIg, mIg) Fc region, a second peptide linker, and the second polypeptide or protein according to any one of claims 1-44.

102. The fusion protein according to any one of claims 77-101, wherein the first polypeptide or protein comprises, from the N-terminus to the C-terminus: the first polypeptide or protein according to any one of claims 1-44, and the first Ig (e.g., hIg, mIg) Fc region; and the second polypeptide or protein comprises, from the N-terminus to the C-terminus: the second polypeptide or protein according to any one of claims 1-44, and the second Ig (e.g., hIg, mIg) Fc region.

103. The fusion protein according to any one of claims 77-98 or 102, wherein the first polypeptide or protein comprises, from the N-terminus to the C-terminus: the first polypeptide or protein according to any one of claims 1-44, a first peptide linker, and the first Ig (e.g., hIg, mIg) Fc region; and the second polypeptide or protein comprises, from the N-terminus to the C-terminus: the second polypeptide or protein according to any one of claims 1-44, a second peptide linker, and the second Ig (e.g., hIg, mIg) Fc region.

104. The fusion protein according to claim 101 or 103, wherein the amino acid sequences of the first peptide linker and the second peptide linker each comprise or consist of the following consisting of: glycine or glycine and serine amino acid residues.

105. The fusion protein according to any one of claims 101, 103 or 104, wherein the amino acids of the first peptide linker and the second peptide linker each comprise or consist of the following consisting of: (a) the amino acid sequence of any one of SEQ ID NOs: 49-57; or (b) the amino acid sequence of any one of SEQ ID NOs: 49-57, which comprises or consists of: 1, 2 or 3 amino acid substitutions.

106. The polypeptide or fusion protein according to any one of claims 45-105, which comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NOs: 58, 61-69 or 72-79.

107. The polypeptide or fusion protein according to any one of claims 45 - 106, which comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO:58, 61 - 69 or 72 - 79.

108. The polypeptide or fusion protein according to any one of claims 45 - 107, which comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO:58, 61 - 69 or 72 - 79.

109. The polypeptide or fusion protein according to any one of claims 45 - 108, which comprises an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO:58, 61 - 69 or 72 - 79.

110. The polypeptide or fusion protein according to any one of claims 45 - 109, which comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID NO:62 - 65 or 73 - 76.

111. The polypeptide or fusion protein according to any one of claims 45 - 110, which comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID NO:62 - 65 or 73 - 76.

112. The polypeptide or fusion protein according to any one of claims 45 - 111, which comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID NO:62 - 65 or 73 - 76.

113. The polypeptide or fusion protein according to any one of claims 45 - 112, which comprises an amino acid sequence that is 100% identical to the amino acid sequence of any one of SEQ ID NO:62 - 65 or 73 - 76.

114. A conjugate, which comprises the polypeptide or protein according to any one of claims 1 - 44 operably linked to a heterologous moiety.

115. An immunogenic peptide or protein, which comprises (a) at least a portion of the polypeptide according to any one of claims 1 - 44; and / or (b) the polypeptide or protein according to any one of claims 1 - 44, which comprises at least one amino acid variation (e.g., substitution, addition, deletion), and wherein the immunogenic peptide or protein does not specifically bind to hIL - 10R (e.g., hIL - 10Rα) or binds to hIL - 10R (e.g., hIL - 10Rα) with a lower affinity relative to the reference polypeptide or protein according to any one of claims 1 - 44.

116. The immunogenic peptide or protein according to claim 115, wherein the immunogenic peptide or protein comprises at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 or 250 amino acids.

117. The immunogenic peptide or protein according to any one of claims 115 - 116, wherein the immunogenic peptide or protein comprises about 10 - 250, 10 - 200, 10 - 100, 10 - 90, 10 - 80, 10 - 70, 10 - 60, 10 - 50, 10 - 40, 10 - 30, 10 - 20, 10 - 250, 20 - 250, 30 - 250, 40 - 250, 50 - 250, 60 - 250, 70 - 250, 80 - 250, 90 - 250, 100 - 250, 10 - 200, 20 - 200, 30 - 200, 40 - 200, 50 - 200, 60 - 200, 70 - 200, 80 - 200, 90 - 200 or 100 - 200 amino acids.

118. The immunogenic peptide or protein according to any one of claims 115 - 117, wherein the amino acid sequence of the immunogenic peptide or protein comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid variations (e.g., substitutions, additions, deletions) relative to the reference polypeptide or protein according to any one of claims 1 - 44.

119. The immunogenic peptide or protein according to any one of claims 115 - 118, wherein the immunogenic peptide or protein comprises an amino acid sequence that is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a continuous segment of at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150 or 200 amino acids of any one of SEQ ID NOs: 108 - 454.

120. The immunogenic peptide or protein according to any one of claims 115 - 119, wherein the immunogenic peptide or protein comprises an amino acid sequence that is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 108 - 454, except for the at least one amino acid variation (e.g., substitution, addition, deletion).

121. The immunogenic polypeptide or protein according to any one of claims 115 - 120, wherein the immunogenic polypeptide or protein is formulated with an adjuvant.

122. An isolated antibody that specifically binds to the polypeptide according to any one of claims 1 - 44.

123. A polynucleotide that encodes the polypeptide or protein according to any one of claims 1 - 44, the polypeptide or protein according to claim 45, the fusion polypeptide or protein according to any one of claims 46 - 76, the fusion protein according to any one of claims 77 - 113, the conjugate according to claim 114, the immunogenic peptide or protein according to any one of claims 115 - 121, or the antibody according to claim 122.

124. The polynucleotide according to claim 123, wherein the polynucleotide is RNA (such as mRNA) or DNA.

125. An mRNA polynucleotide encoding a polypeptide or protein according to any one of claims 1-44, a polypeptide or protein according to claim 45, a fusion polypeptide or protein according to any one of claims 46-76, a fusion protein according to any one of claims 77-113, a conjugate according to claim 114, an immunogenic peptide or protein according to any one of claims 115-121, or an antibody according to claim 122.

126. The mRNA polynucleotide according to claim 125, wherein the mRNA comprises a heterologous 5'-untranslated region (UTR), 3'-UTR, or both 5'-UTR and 3'-UTR.

127. The mRNA polynucleotide according to any one of claims 125-126, wherein the mRNA comprises a poly(A) sequence.

128. The mRNA polynucleotide according to any one of claims 125-127, wherein the mRNA comprises a 5' cap structure.

129. The polynucleotide according to any one of claims 123-124 or the mRNA polynucleotide according to any one of claims 125-128, wherein the polynucleotide or mRNA polynucleotide comprises at least one variant nucleotide.

130. The polynucleotide according to any one of claims 123-124 or 129 or the mRNA polynucleotide according to any one of claims 125-128 or 129, wherein the nucleic acid sequence of the polynucleotide or mRNA polynucleotide is codon-optimized, respectively.

131. An expression vector comprising the polynucleotide according to any one of claims 123-124 or 129-130 or the mRNA polynucleotide according to any one of claims 125-130.

132. The expression vector according to claim 131, wherein the expression vector is a viral vector or a plasmid.

133. A cell (e.g., a host cell) comprising a polypeptide or protein according to any one of claims 1-44, a polypeptide or protein according to claim 45, a fusion polypeptide or protein according to any one of claims 46-76, a fusion protein according to any one of claims 77-113, a conjugate according to claim 114, an immunogenic peptide or protein according to any one of claims 115-121, an antibody according to claim 122, a polynucleotide according to any one of claims 123-124 or 129-130, an mRNA polynucleotide according to any one of claims 125-130, an expression vector according to any one of claims 131-132, or a carrier according to any one of claims 134-135.

134. A carrier, which comprises the polypeptide or protein as described in any one of claims 1 - 44, the polypeptide or protein as described in claim 45, the fusion polypeptide or protein as described in any one of claims 46 - 76, the fusion protein as described in any one of claims 77 - 113, the conjugate as described in claim 114, the immunogenic peptide or protein as described in any one of claims 115 - 121, the antibody as described in claim 122, the polynucleotide as described in any one of claims 123 - 124 or 129 - 130, the mRNA polynucleotide as described in any one of claims 125 - 130, the expression vector as described in any one of claims 131 - 132, or the cell as described in claim 133.

135. The carrier as described in claim 134, wherein the carrier is a lipid nanoparticle, liposome, lipid complex or nanoliposome.

136. A lipid nanoparticle, which comprises the polypeptide or protein as described in any one of claims 1 - 44, the polypeptide or protein as described in claim 45, the fusion polypeptide or protein as described in any one of claims 46 - 76, the fusion protein as described in any one of claims 77 - 113, the conjugate as described in claim 114, the immunogenic peptide or protein as described in any one of claims 115 - 121, the antibody as described in claim 122, the polynucleotide as described in any one of claims 123 - 124 or 129 - 130, the mRNA polynucleotide as described in any one of claims 125 - 130, the expression vector as described in any one of claims 131 - 132, or the cell as described in claim 133.

137. A vaccine composition, which comprises the immunogenic peptide or protein as described in any one of claims 115 - 121 (or a nucleic acid molecule encoding the immunogenic peptide or protein (or a vector encoding the nucleic acid molecule)).

138. A pharmaceutical composition, which comprises the polypeptide or protein as described in any one of claims 1 - 44, the polypeptide or protein as described in claim 45, the fusion polypeptide or protein as described in any one of claims 46 - 76, the fusion protein as described in any one of claims 77 - 113, the conjugate as described in claim 114, the immunogenic peptide or protein as described in any one of claims 115 - 121, the antibody as described in claim 122, the polynucleotide as described in any one of claims 123 - 124 or 129 - 130, the mRNA polynucleotide as described in any one of claims 125 - 130, the expression vector as described in any one of claims 131 - 132, the cell as described in claim 133, the carrier as described in any one of claims 134 - 135, or the lipid nanoparticle as described in claim 136, or the vaccine composition as described in claim 137; and a pharmaceutically acceptable excipient.

139. A kit, which comprises a polypeptide or protein as described in any one of claims 1 - 44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46 - 76, a fusion protein as described in any one of claims 77 - 113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115 - 121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as described in any one of claims 125 - 130, an expression vector as described in any one of claims 131 - 132, a cell as described in claim 133, a carrier as described in any one of claims 134 - 135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138; and optionally instructions for using any one or more of the foregoing.

140. A method for delivering a polypeptide, protein, fusion protein, conjugate, polynucleotide, mRNA polynucleotide, expression vector, cell, carrier, lipid nanoparticle, immunogenic peptide or protein, antibody, vaccine composition, or pharmaceutical composition to a subject, the method comprising administering to the subject a polypeptide or protein as described in any one of claims 1 - 44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46 - 76, a fusion protein as described in any one of claims 77 - 113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115 - 121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as described in any one of claims 125 - 130, an expression vector as described in any one of claims 131 - 132, a cell as described in claim 133, a carrier as described in any one of claims 134 - 135, or a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137 or a pharmaceutical composition as described in claim 138, thereby delivering the polypeptide, protein, fusion polypeptide, fusion protein, conjugate, immunogenic peptide or protein, antibody, mRNA polynucleotide, expression vector, cell, carrier, lipid nanoparticle, vaccine composition or pharmaceutical composition to the subject.

141. Use of a polypeptide or protein as described in any one of claims 1 - 44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46 - 76, a fusion protein as described in any one of claims 77 - 113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115 - 121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as described in any one of claims 125 - 130, an expression vector as described in any one of claims 131 - 132, a cell as described in claim 133, a carrier as described in any one of claims 134 - 135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138 in medicine.

142. A method of stimulating the IL - 10 pathway in a subject in need thereof, the method comprising administering to the subject a polypeptide or protein as described in any one of claims 1 - 44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46 - 76, a fusion protein as described in any one of claims 77 - 113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115 - 121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as described in any one of claims 125 - 130, an expression vector as described in any one of claims 131 - 132, a cell as described in claim 133, a carrier as described in any one of claims 134 - 135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137 or a pharmaceutical composition as described in claim 138, thereby stimulating the IL - 10 pathway in the subject.

143. A polypeptide or protein according to any one of claims 1-44, a polypeptide or protein according to claim 45, a fusion polypeptide or protein according to any one of claims 46-76, a fusion protein according to any one of claims 77-113, a conjugate according to claim 114, an immunogenic peptide or protein according to any one of claims 115-121, an antibody according to claim 122, a polynucleotide according to any one of claims 123-124 or 129-130, an mRNA polynucleotide according to any one of claims 125-130, an expression vector according to any one of claims 131-132, a cell according to claim 133, a carrier according to any one of claims 134-135, a lipid nanoparticle according to claim 136, a vaccine composition according to claim 137, or a pharmaceutical composition according to claim 138, for use in a method of stimulating the IL-10 pathway in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion protein or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby stimulating the IL-10 pathway in the subject.

144. Use of a polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138 in the manufacture of a medicament for stimulating the IL-10 pathway in a subject in need thereof, said use comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion protein or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby stimulating the IL-10 pathway in the subject.

145. A method for treating, preventing or ameliorating an IL-10 responsive disease in a subject in need thereof, said method comprising administering to the subject a polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138, thereby treating, preventing or ameliorating the IL-10 responsive disease.

146. A polypeptide or protein as claimed in any one of claims 1 - 44, a polypeptide or protein as claimed in claim 45, a fusion polypeptide or protein as claimed in any one of claims 46 - 76, a fusion protein as claimed in any one of claims 77 - 113, a conjugate as claimed in claim 114, an immunogenic peptide or protein as claimed in any one of claims 115 - 121, an antibody as claimed in claim 122, a polynucleotide as claimed in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as claimed in any one of claims 125 - 130, an expression vector as claimed in any one of claims 131 - 132, a cell as claimed in claim 133, a carrier as claimed in any one of claims 134 - 135, a lipid nanoparticle as claimed in claim 136, a vaccine composition as claimed in claim 137, or a pharmaceutical composition as claimed in claim 138, for use in a method of treating, preventing or ameliorating an IL-10 responsive disease in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby treating, preventing or ameliorating the IL-10 responsive disease.

147. Use of a polypeptide or protein as described in any one of claims 1 - 44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46 - 76, a fusion protein as described in any one of claims 77 - 113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115 - 121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as described in any one of claims 125 - 130, an expression vector as described in any one of claims 131 - 132, a cell as described in claim 133, a carrier as described in any one of claims 134 - 135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138 in the manufacture of a medicament for treating, preventing or ameliorating an IL-10 responsive disease in a subject in need thereof, said use comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition so as to treat, prevent or ameliorate the IL-10 responsive disease.

148. The method or use as described in any one of claims 145 - 147, wherein the IL-10 responsive disease is a pro-inflammatory disease.

149. The method or use as described in any one of claims 145 - 148, wherein the IL-10 responsive disease is an autoimmune disease.

150. The method or use as described in any one of claims 145 - 149, wherein the IL-10 responsive disease is a metabolic inflammatory disease.

151. A method for inhibiting or preventing an immune response in a subject in need thereof, the method comprising administering to the subject a polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138, thereby inhibiting or preventing an immune response in the subject.

152. A polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138, for use in a method for inhibiting or preventing an immune response in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inhibiting or preventing an immune response in the subject.

153. Use of a polypeptide or protein as described in any one of claims 1 - 44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46 - 76, a fusion protein as described in any one of claims 77 - 113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115 - 121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as described in any one of claims 125 - 130, an expression vector as described in any one of claims 131 - 132, a cell as described in claim 133, a carrier as described in any one of claims 134 - 135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138 in the manufacture of a medicament for inhibiting or preventing an immune response in a subject in need thereof, said use comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby inhibiting or preventing an immune response in the subject.

154. A method of inducing tolerance to an immunogen in a subject in need thereof, said method comprising administering to the subject a polypeptide or protein as described in any one of claims 1 - 44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46 - 76, a fusion protein as described in any one of claims 77 - 113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115 - 121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as described in any one of claims 125 - 130, an expression vector as described in any one of claims 131 - 132, a cell as described in claim 133, a carrier as described in any one of claims 134 - 135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138, thereby inducing tolerance to the immunogen in the subject.

155. The polypeptide or protein according to any one of claims 1-44, the polypeptide or protein according to claim 45, the fusion polypeptide or protein according to any one of claims 46-76, the fusion protein according to any one of claims 77-113, the conjugate according to claim 114, the immunogenic peptide or protein according to any one of claims 115-121, the antibody according to claim 122, the polynucleotide according to any one of claims 123-124 or 129-130, the mRNA polynucleotide according to any one of claims 125-130, the expression vector according to any one of claims 131-132, the cell according to claim 133, the carrier according to any one of claims 134-135, the lipid nanoparticle according to claim 136, the vaccine composition according to claim 137, or the pharmaceutical composition according to claim 138, for use in a method of inducing tolerance to an immunogen in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby inducing tolerance to the immunogen in the subject.

156. Use of the polypeptide or protein according to any one of claims 1-44, the polypeptide or protein according to claim 45, the fusion polypeptide or protein according to any one of claims 46-76, the fusion protein according to any one of claims 77-113, the conjugate according to claim 114, the immunogenic peptide or protein according to any one of claims 115-121, the antibody according to claim 122, the polynucleotide according to any one of claims 123-124 or 129-130, the mRNA polynucleotide according to any one of claims 125-130, the expression vector according to any one of claims 131-132, the cell according to claim 133, the carrier according to any one of claims 134-135, the lipid nanoparticle according to claim 136, the vaccine composition according to claim 137, or the pharmaceutical composition according to claim 138 in the manufacture of a medicament for inducing tolerance to an immunogen in a subject in need thereof, the use comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby inducing tolerance to the immunogen in the subject.

157. A method for inhibiting IgE expression in a subject in need thereof, the method comprising administering to the subject a polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138, thereby inhibiting IgE expression in the subject.

158. A polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138, for use in a method for inhibiting IgE expression in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inhibiting IgE expression in the subject.

159. Use of a polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138 in the manufacture of a medicament for inhibiting IgE expression in a subject in need thereof, said use comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby inhibiting IgE expression in the subject.

160. The method or use as described in any one of claims 151-159, wherein the level of one or more pro-inflammatory cytokines (such as IFNγ, TNFα, IL-17A) is inhibited (e.g., as measured by the assays described herein).

161. The method or use as described in any one of claims 151-160, wherein the level of immunogen-specific immunoglobulin is inhibited (e.g., as measured by the assays described herein).

162. The method or use as described in any one of claims 151-161, wherein the level of IgE (such as immunogen-specific IgE, such as allergen-specific IgE) is inhibited (e.g., as measured by the assays described herein).

163. The method or use as described in any one of claims 151-162, wherein the subject has an IL-10-responsive disease (such as, for example, the IL-10-responsive diseases described herein (such as autoimmune diseases (such as GvHD, allergic diseases, etc.))).

164. The method or use according to any one of claims 151 - 163, wherein one or more immunosuppressive agents (e.g., one or more steroids (e.g., corticosteroids)) have been administered to the subject prior to administering to the subject a polypeptide or protein according to any one of claims 1 - 44, a polypeptide or protein according to claim 45, a fusion polypeptide or protein according to any one of claims 46 - 76, a fusion protein according to any one of claims 77 - 113, a conjugate according to claim 114, an immunogenic peptide or protein according to any one of claims 115 - 121, an antibody according to claim 122, a polynucleotide according to any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide according to any one of claims 125 - 130, an expression vector according to any one of claims 131 - 132, a cell according to claim 133, a carrier according to any one of claims 134 - 135, a lipid nanoparticle according to claim 136, a vaccine composition according to claim 137, or a pharmaceutical composition according to claim 138.

165. The method or use according to claim 164, wherein the IL - 10 responsive disease is refractory to the one or more immunosuppressive agents (e.g., one or more steroids (e.g., corticosteroids)).

166. The method or use according to any one of claims 151 - 165, wherein a polypeptide or protein according to any one of claims 1 - 44, a polypeptide or protein according to claim 45, a fusion polypeptide or protein according to any one of claims 46 - 76, a fusion protein according to any one of claims 77 - 113, a conjugate according to claim 114, an immunogenic peptide or protein according to any one of claims 115 - 121, an antibody according to claim 122, a polynucleotide according to any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide according to any one of claims 125 - 130, an expression vector according to any one of claims 131 - 132, a cell according to claim 133, a carrier according to any one of claims 134 - 135, a lipid nanoparticle according to claim 136, a vaccine composition according to claim 137, or a pharmaceutical composition according to claim 138 is administered to the subject in combination with one or more immunosuppressive agents (e.g., one or more steroids (e.g., corticosteroids)).

167. The method or use according to any one of claims 151 - 166, wherein the immunogen is an allergen.

168. The method or use according to any one of claims 151 - 167, wherein the subject has been administered allergen - specific therapy (e.g., as described herein (e.g., the subject has been administered at least 1 (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses (e.g., escalating doses)) of the allergen)).

169. The method or use according to any one of claims 151 - 168, wherein the allergen - specific therapy induces a certain degree of tolerance to the immunogen in the subject.

170. The method or use according to any one of claims 151 - 169, wherein the administration of the polypeptide or protein according to any one of claims 1 - 44, the polypeptide or protein according to claim 45, the fusion polypeptide or protein according to any one of claims 46 - 76, the fusion protein according to any one of claims 77 - 113, the conjugate according to claim 114, the immunogenic peptide or protein according to any one of claims 115 - 121, the antibody according to claim 122, the polynucleotide according to any one of claims 123 - 124 or 129 - 130, the mRNA polynucleotide according to any one of claims 125 - 130, the expression vector according to any one of claims 131 - 132, the cell according to claim 133, the carrier according to any one of claims 134 - 135, the lipid nanoparticle according to claim 136, the vaccine composition according to claim 137, or the pharmaceutical composition according to claim 138 enhances the degree of tolerance induced by the immunogen - specific therapy.

171. The method or use according to any one of claims 151 - 170, wherein the subject has received an allogeneic or autologous cell, tissue, or organ transplant.

172. The method or use according to any one of claims 151 - 171, wherein the immunogen is part of an allogeneic or autologous cell, tissue, or organ.

173. The method or use according to any one of claims 151 - 172, wherein the subject has graft - versus - host disease.

174. The method or use according to any one of claims 151 - 173, wherein the graft - versus - host disease is acute or chronic.

175. A method for inducing an immune response in a subject in need thereof, the method comprising administering to the subject a polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138, thereby inducing an immune response in the subject.

176. A polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138, for use in a method for inducing an immune response in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the fusion, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition, or the pharmaceutical composition, thereby inducing an immune response in the subject.

177. Use of a polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138 in the manufacture of a medicament for inducing an immune response in a subject in need thereof, said use comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby inducing an immune response in the subject.

178. A method for preventing, treating or ameliorating a viral infection in a subject in need thereof, said method comprising administering to the subject a polypeptide or protein as described in any one of claims 1-44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46-76, a fusion protein as described in any one of claims 77-113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115-121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123-124 or 129-130, an mRNA polynucleotide as described in any one of claims 125-130, an expression vector as described in any one of claims 131-132, a cell as described in claim 133, a carrier as described in any one of claims 134-135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137 or a pharmaceutical composition as described in claim 138, thereby preventing, treating or ameliorating the viral infection in the subject.

179. A polypeptide or protein according to any one of claims 1-44, a polypeptide or protein according to claim 45, a fusion polypeptide or protein according to any one of claims 46-76, a fusion protein according to any one of claims 77-113, a conjugate according to claim 114, an immunogenic peptide or protein according to any one of claims 115-121, an antibody according to claim 122, a polynucleotide according to any one of claims 123-124 or 129-130, an mRNA polynucleotide according to any one of claims 125-130, an expression vector according to any one of claims 131-132, a cell according to claim 133, a carrier according to any one of claims 134-135, a lipid nanoparticle according to claim 136, a vaccine composition according to claim 137, or a pharmaceutical composition according to claim 138, for use in a method of preventing, treating or ameliorating a viral infection in a subject in need thereof, the method comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby preventing, treating or ameliorating the viral infection in the subject.

180. Use of a polypeptide or protein as described in any one of claims 1 - 44, a polypeptide or protein as described in claim 45, a fusion polypeptide or protein as described in any one of claims 46 - 76, a fusion protein as described in any one of claims 77 - 113, a conjugate as described in claim 114, an immunogenic peptide or protein as described in any one of claims 115 - 121, an antibody as described in claim 122, a polynucleotide as described in any one of claims 123 - 124 or 129 - 130, an mRNA polynucleotide as described in any one of claims 125 - 130, an expression vector as described in any one of claims 131 - 132, a cell as described in claim 133, a carrier as described in any one of claims 134 - 135, a lipid nanoparticle as described in claim 136, a vaccine composition as described in claim 137, or a pharmaceutical composition as described in claim 138 in the manufacture of a medicament for preventing, treating or ameliorating a viral infection in a subject in need thereof, said use comprising administering to the subject the polypeptide or protein, the polypeptide or protein, the fusion polypeptide or protein, the conjugate, the immunogenic peptide or protein, the antibody, the polynucleotide, the mRNA polynucleotide, the expression vector, the cell, the carrier, the lipid nanoparticle, the vaccine composition or the pharmaceutical composition, thereby preventing, treating or ameliorating the viral infection in the subject.

181. A method for determining the presence of a virus in a subject, said method comprising (a) obtaining a sample from the subject or providing a sample that has been obtained from the subject, and (b) determining the presence or absence in the sample of a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1 - 44 or a polynucleotide encoding a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1 - 44.

182. A method for diagnosing a viral infection in a subject, said method comprising (a) obtaining a sample from the subject or providing a sample that has been obtained from the subject, (b) determining the presence or absence of a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1 - 44 or a polynucleotide encoding a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1 - 44, and (c) diagnosing the subject as having the viral infection if a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1 - 44 or a polynucleotide encoding a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1 - 44 is determined to be present in the sample in step (b).

183. The method according to claim 181 or 182, wherein the method is an in vitro method.

184. A method for treating a viral infection in a subject, said method comprising (a) receiving test results that determine the presence of a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1-44 or a polynucleotide encoding a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1-44 in a sample from the subject, (b) diagnosing the subject as having the viral infection, and (c) administering a therapeutic agent to treat the viral infection.

185. A therapeutic agent for treating a viral infection, the therapeutic agent being used in a method for treating a viral infection in a subject, the method comprising (a) receiving test results that determine the presence of a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1-44 or a polynucleotide encoding a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1-44 in a sample from the subject, (b) diagnosing the subject as having the viral infection, and (c) administering the therapeutic agent to treat the viral infection.

186. Use of a therapeutic agent for treating a viral infection in the manufacture of a medicament for treating a viral infection in a subject, the use comprising (a) receiving test results that determine the presence of a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1-44 or a polynucleotide encoding a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1-44 in a sample from the subject, (b) diagnosing the subject as having the viral infection, and (c) administering the therapeutic agent to treat the viral infection.

187. The method or use according to any one of claims 181-186, wherein the sample is blood, cells, tissue, or saliva, or a nasal swab.

188. The method or use according to any one of claims 181-187, wherein the subject is a human.

189. The method or use according to any one of claims 181-188, wherein the antibody as claimed is used to determine the presence or absence of a polypeptide or protein (or a fragment or variant thereof) as described in any one of claims 1-44.

190. The method or use according to any one of claims 181-189, wherein the viral infection is an infection with parapoxvirus, cytomegalovirus, gammaherpesvirus, orf virus, pseudocowpox virus, betaherpesvirus, and Epstein-Barr virus.

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