Novel immunomodulatory proteins and related methods

Abstract

Provided herein are, inter alia, immunomodulatory proteins and compositions (e.g., pharmaceutical compositions) comprising the same; as well as methods of making the immunomodulatory proteins and compositions. The immunomodulatory proteins provided herein are useful in e.g., pharmaceutical compositions and methods of use, including e.g., in the modulation of an immune response in a subject.

Description

Attorney Docket No. 62801.82W001NOVEL IMMUNOMODULATORY PROTEINS AND RELATED METHODS RELATED APPLICATIONS

[0001] This application claims priority to U. S. Serial No.: 63 / 728,298, filed December 5, 2024, the entire contents of which is incorporated herein by reference.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on November 21, 2025, is named 62801_82W001_SL.xml and is 604,132 bytes in size.1. FIELD

[0003] This disclosure relates to immunomodulatory proteins and nucleic acid molecules encoding the same. The disclosure further relates to methods of making and utilizing the same, including, e.g., methods of modulating an immune response in a subject.2. BACKGROUND

[0004] The cytokine superfamily of proteins (including chemotactic cytokines (e.g., chemokines)) and their receptors are essential in generating and regulating the immune system and immune responses. Cytokines are small soluble factors with pleiotropic functions that are produced by various cell types (including e.g., various types of immune cells (e.g., T cells, macrophages, etc.)). The cytokine superfamily (and receptors) can have an effect on numerous biological processes, including, e.g., influencing growth and development, hematopoiesis, lymphocyte recruitment, immune cell differentiation (e.g., T cell subset differentiation), and inflammation.3. SUMMARY

[0005] Provided herein are, inter alia, immunomodulatory proteins and nucleic acid molecules encoding the same; fusions and conjugates comprising the immunomodulatory proteins; pharmaceutical compositions comprising the same; and methods of manufacturing the same. Further provided herein, are e.g., methods of using the same, including e.g., methods of modulating an immune response in a subject, as well as diagnostics.

[0006] Accordingly, in one aspect, provided herein are isolated proteins comprising an aminoAttorney Docket No. 62801.82W001acid sequence 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 protein set forth in Table 1 or set forth in any one of SEQ ID NOS: 1-246. 338-595, or 605-606.

[0007] In some embodiments, the amino acid sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any protein set forth in Table 1 or set forth in any one of SEQ ID NOS: 1-246. 338-595, or 605-606. In some embodiments, the amino acid sequence is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any protein set forth in Table 1 or set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606. In some embodiments, the amino acid sequence of the protein comprises the amino acid sequence of any protein set forth in Table 1 or set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606.

[0008] In one aspect, provided herein are isolated proteins comprising an amino acid sequence 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 set forth in any one of SEQ ID NOS: 1-246. 590-595, or 605.

[0009] In some embodiments, the amino acid sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. In some embodiments, the amino acid sequence is at least 95%, 96%, 97%. 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. In some embodiments, the amino acid sequence of the protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605.

[0010] In one aspect, provided herein are isolated proteins comprising an amino acid sequence 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 set forth in any one of SEQ ID NOS: 338-589 or 606.

[0011] In some embodiments, the amino acid sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606. In some embodiments, the amino acid sequence is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606. In some embodiments, the amino acid sequence of the protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606.Attorney Docket No. 62801.82W001

[0012] In one aspect, provided herein are isolated proteins comprising an amino acid sequence 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 set forth in SEQ ID NO: 17.

[0013] In some embodiments, the amino acid sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the amino acid sequence is at least 95%. 96%, 97%, 98%, 99%. or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the amino acid sequence of the protein comprises the amino acid sequence set forth in SEQ ID NO: 17.

[0014] For the sake of clarity, it should be understood that the following embodiments are applicable to any of the foregoing aspects (as if recited directly after each aspect).

[0015] In some embodiments, the protein exhibits one or more immunomodulatory property {e.g., upon administration to a subject). In some embodiments, the protein exhibits one or more anti-inflammatory property {e.g., upon administration to a subject). In some embodiments, the protein exhibits one or more pro-inflammatory property e.g., upon administration to a subject).

[0016] In some embodiments, the protein exhibits one or more cytokine like property.

[0017] In some embodiments, the protein binds {e.g., specifically binds) to one or more human proteins. In some embodiments, the protein binds {e.g., specifically binds) to one or more human proteins capable of mediating an immunomodulatory {e.g., anti-inflammatory, pro-inflammatory) effect. In some embodiments, the protein binds {e.g., specifically binds) to one or more human proteins, wherein binding to the one or more human protein mediates an immunomodulatory {e.g., anti-inflammatory, pro-inflammatory) effect. In some embodiments, the protein binds {e.g., specifically binds) to one or more human proteins, wherein binding to the one or more human protein mediates signaling through the protein. In some embodiments, the one or more human protein is a receptor. In some embodiments, the one or more human protein is a receptor {e.g., cytokine receptor) expressed by {e.g., on the surface of) one or more population of immune cells {e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells). In some embodiments, the one or more human protein is a cytokine receptor.

[0018] In some embodiments, the protein binds {e.g., specifically binds) to one or more human receptors {e.g., cytokine receptor) and binding of the protein to the receptor mediates an immunomodulatory {e.g., anti-inflammatory, pro-inflammatory) effect.Attorney Docket No. 62801.82W001

[0019] In some embodiments, the protein binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes. NK cells, NK T cells, dendritic cells) and binding of the protein to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect.

[0020] In some embodiments, the protein binds (e.g., specifically binds) to one or more human cytokine receptor and binding of the protein to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect.

[0021] In some embodiments, the protein binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) and binding of the protein to the receptor mediates signaling through the receptor (e.g., cytokine receptor).

[0022] In some embodiments, the protein binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes. NK cells, NK T cells, dendritic cells) and binding of the protein to the receptor mediates signaling through the receptor (e.g., cytokine receptor).

[0023] In some embodiments, the protein binds (e.g., specifically binds) to one or more human cytokine receptor and binding of the protein to the receptor mediates signaling through the cytokine receptor.

[0024] In some embodiments, the protein comprises a homologous or heterologous signal peptide (e.g., operably connected to the N-terminus of the protein).

[0025] In some embodiments, the protein is operably connected to a heterologous moiety (e.g., described herein). In some embodiments, the heterologous moiety is a protein, peptide, small molecule, nucleic acid molecule (e.g., DNA, RNA, DNA / RNA hybrid molecule), lipid, or synthetic polymer. In some embodiments, the heterologous moiety is a protein.

[0026] In one aspect, provided herein are conjugates comprising an immunomodulatory protein described herein operably connected to a heterologous moiety (e.g., described herein).

[0027] In one aspect, provided herein are radioligands comprising an immunomodulatory protein described herein operably connected to a radionuclide.

[0028] In one aspect, provided herein are fusion proteins comprising an immunomodulatory protein described herein operably connected to a heterologous protein.Attorney Docket No. 62801.82W001

[0029] In some embodiments, the heterologous protein comprises an antibody. In some embodiments, the heterologous protein comprises a half-life extension protein.

[0030] In some embodiments, the heterologous protein comprises an immunoglobulin (Ig) (e.g., a human Ig (hlg)) Fc region. In some embodiments, the Ig (e.g., hlg) Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig (e.g., hlg) Fc region comprises a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig is a hlg. In some embodiments, the hlg is a human IgG (hlgG). In some embodiments, the hlgG is hlgGl or hIgG4.

[0031] In some embodiments, the protein is directly operably connected to the heterologous protein through a peptide bond. In some embodiments, the protein is indirectly operably connected to the heterologous protein through a peptide linker.

[0032] In one aspect, provided herein are immunogenic peptides or proteins comprising at least an immunogenic fragment of an immunomodulatory protein described herein.

[0033] In some embodiments, the immunogenic peptide or protein comprises a full-length an immunomodulatory protein described herein.

[0034] In some embodiments, the immunogenic peptide or protein comprises an immunogenic fragment of an immunomodulatory protein described herein. In some embodiments, the immunogenic peptide or protein comprises at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 amino acids. In some embodiments, the immunogenic peptide or protein comprises about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 amino acids. In some embodiments, the immunogenic peptide or protein comprises no more than about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120. or 130 amino acids.

[0035] In some embodiments, the amino acid sequence of the immunogenic peptide or protein comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid variations (e.g., substitutions, additions, deletions) relative to a reference immunomodulatory protein described herein.

[0036] 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 stretch of at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 amino acids set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606. In some embodiments, the immunogenic peptide or protein comprises an amino acid sequenceAttorney Docket No. 62801.82W001that, other than the one or more amino acid variation (e.g., substitution, addition, deletion), is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246. 338-595, or 605-606.

[0037] In some embodiments, the immunogenic peptide or protein is formulated with an adjuvant.

[0038] In one aspect, provided herein are isolated antibodies that specifically binds to an immunomodulatory protein described herein.

[0039] In one aspect, provided herein are nucleic acid molecules encoding an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, or an antibody described herein.

[0040] In some embodiments, the nucleic acid molecule is an RNA (e.g., mRNA, circular RNA) molecule or a DNA molecule.

[0041] In one aspect, provided herein are mRNA molecules encoding an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, or an antibody described herein.

[0042] In some embodiments, the nucleic acid molecule or the mRNA molecule comprises a heterologous 5'-untranslated region (UTR), 3'-UTR, or both a 5'-UTR and 3'-UTR. In some embodiments, the nucleic acid molecule or the mRNA molecule comprises a poly(A) sequence. In some embodiments, the nucleic acid molecule or the mRNA molecule comprises a 5' cap structure. In some embodiments, the nucleic acid molecule or the mRNA molecule comprises at least one variant nucleotide. In some embodiments, the nucleic acid molecule or the mRNA molecule comprises a codon optimized nucleotide sequence.

[0043] In one aspect, provided herein are vectors (e.g., expression vectors) comprising a nucleic acid molecule described herein or an mRNA molecule described herein. In some embodiments, the vector is a viral vector or a non- viral vector (e.g., a plasmid).

[0044] In one aspect, provided herein are carriers comprising an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, or a vectorAttorney Docket No. 62801.82W001described herein.

[0045] In some embodiments, the carrier is a lipid nanoparticle (LNP), liposome, lipoplex, or nanoliposome. In some embodiments, the carrier is an LNP. In some embodiments, the LNP comprises a cationic lipid, a neutral lipid, a cholesterol, and / or a PEG lipid. In some embodiments, the LNP comprises a cationic lipid, a neutral lipid, a cholesterol, and a PEG lipid. In some embodiments, the LNP has a mean particle size of between 80 nm and 160 nm.

[0046] In one aspect, provided herein are carriers conjugated to an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, or a fusion protein described herein.

[0047] In some embodiments, the carrier is a lipid nanoparticle (LNP), liposome, lipoplex, or nanoliposome. In some embodiments, the carrier is an LNP. In some embodiments, the LNP comprises a cationic lipid, a neutral lipid, a cholesterol, and / or a PEG lipid. In some embodiments, the LNP comprises a cationic lipid, a neutral lipid, a cholesterol, and a PEG lipid. In some embodiments, the LNP has a mean particle size of between 80 nm and 160 nm.

[0048] In one aspect, provided herein are viral particles conjugated to an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, or a fusion protein described herein.

[0049] In one aspect, provided herein are cells (e.g., host cells) or population of cells comprising an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, a vector described herein, a carrier described herein, a vaccine composition described herein, or a pharmaceutical composition described herein.

[0050] In one aspect, provided herein are vaccine compositions comprising an immunogenic peptide or protein described herein (or a nucleic acid molecule encoding the same (or a vector encoding the nucleic acid molecule) or a carrier comprising any of the foregoing).

[0051] In one aspect, provided herein are pharmaceutical compositions comprising an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, a vector described herein, a carrier described herein, a vaccine composition describedAttorney Docket No. 62801.82W001herein, or a cell or population of cells described herein, and a pharmaceutically acceptable excipient.

[0052] In one aspect, provided herein are kits comprising an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, a vector described herein, a carrier described herein, a cell or population of cells described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, and optionally comprising instructions for use of the foregoing.

[0053] In one aspect, provided herein are methods of delivering a protein, a conjugate, a radioligand, a fusion protein, an immunogenic peptide or protein, an antibody, a nucleic acid molecule, an mRNA molecule, a vector, a carrier, a viral particle, a vaccine composition, a cell or population of cells, or a pharmaceutical composition to a subject in need thereof, the method comprising administering to the subject an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, a vector described herein, a carrier described herein, a cell or population of cells described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, to thereby deliver the protein, the conjugate, the radioligand, the fusion protein, the immunogenic peptide or protein, the antibody, the nucleic acid molecule, the mRNA molecule, the vector, the carrier, the viral particle, the vaccine composition, the cell or population of cells, or the pharmaceutical composition to the subject.

[0054] In one aspect, provided herein are methods of modulating an immune response in a subject in need thereof, the method comprising administering to the subject an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, a vector described herein, a carrier described herein, a cell or population of cells described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, to thereby modulate an immune response in the subject in need thereof.Attorney Docket No. 62801.82W001

[0055] In one aspect, provided herein are methods of suppressing or preventing an immune response in a subject in need thereof, the method comprising administering to the subject an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, a vector described herein, a carrier described herein, a cell or population of cells described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, to thereby suppress or prevent an immune response in the subject in need thereof.

[0056] In one aspect, provided herein are methods of inducing or enhancing an immune response in a subject in need thereof, the method comprising administering to the subject an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, a vector described herein, a carrier described herein, a cell or population of cells described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, to thereby induce or enhance an immune response in the subject in need thereof.

[0057] In one aspect, provided herein are methods of treating, ameliorating, or preventing a disease in a subject in need thereof, the method comprising administering to the subject an immunomodulatory protein described herein, a conjugate described herein, a radioligand described herein, a fusion protein described herein, an immunogenic peptide or protein described herein, an antibody described herein, a nucleic acid molecule described herein, an mRNA molecule described herein, a vector described herein, a carrier described herein, a cell or population of cells described herein, a vaccine composition described herein, or a pharmaceutical composition described herein, to thereby treat, ameliorate, or prevent the disease in the subject.

[0058] In some embodiments, the disease is a proinflammatory disease (e.g., an autoimmune disease) or an immunosuppressive disease.

[0059] In one aspect, provided herein are methods of vaccinating a subject in need thereof (e.g., against a viral infection), the method comprising administering to the subject (i) a immunogenic peptide or protein described herein (or a conjugate or a fusion protein thereof); (ii) a nucleic acid molecule encoding (i); (iii) a vector comprising (ii); (iv) a carrier comprising (i), (ii), or (iii); a vaccine composition comprising (i), (ii), (iii), or (iv); or a pharmaceuticalAttorney Docket No. 62801.82W001composition comprising (i), (ii), (iii), (iv), or (v), to thereby vaccinate the subject in need thereof (e.g., against a virus).

[0060] In one aspect, provided herein are methods of determining the presence of a virus in a subject, the method comprising (a) obtaining the sample from a subject or providing a sample that has been obtained from a subject, and (b) determining the presence or absence of an immunomodulatory protein described herein (or a fragment or variant thereof) or a nucleic acid molecule encoding an immunomodulatory protein described herein (or the fragment or variant thereof) in the sample.

[0061] In one aspect, provided herein are methods of diagnosing a viral infection in a subject, the method comprising (a) obtaining a sample from a subject or providing a sample that has been obtained from a subject, (b) determining the presence or absence of an immunomodulatory protein described herein (or a fragment or variant thereof) or a nucleic acid molecule encoding an immunomodulatory protein described herein (or a fragment or variant thereof), and (c) diagnosing the subject as having the viral infection if the immunomodulatory protein described herein (or a fragment or variant thereof) or a nucleic acid molecule encoding the immunomodulatory protein described herein (or the 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.

[0062] In one aspect, provided herein are methods of treating a viral infection in a subject, the method comprising (a) receiving testing results that determined the presence of an immunomodulatory protein described herein (or a fragment or variant thereof) or a nucleic acid molecule encoding an immunomodulatory protein described herein (or the 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.

[0063] In some embodiments, the sample is a blood, cell, tissue, or saliva, or nasal swab. In some embodiments, an antibody described herein is utilized to determine the presence or absence of an immunomodulatory protein described herein (or the fragment or variant thereof).

[0064] In some embodiments, the subject is a human.4. BRIEF DESCRIPTION OF THE FIGURES

[0065] FIG. 1A is a line graph showing the % IL- 10 activity (Y-axis) of Fc-hIL-10 fusion protein at the indicated concentration (Y-axis) in vitro. FIG. IB is a line graph showing the % IL-Attorney Docket No. 62801.82W00110 activity (Y-axis) of Fc-IMP-17 fusion protein at the indicated concentration (Y-axis) in vitro.FIG. 1C is a line graph showing the % IL- 10 activity (Y-axis) of Fc-IMP-247 fusion protein at the indicated concentration (Y-axis) in vitro. FIG. ID is a line graph showing the % IL- 10 activity (Y-axis) of Fc-IMP-248 fusion protein at the indicated concentration (Y-axis) in vitro. FIG. IE is a line graph showing the % IL- 10 activity (Y-axis) of Fc-IMP-249 fusion protein at the indicated concentration (Y-axis) in vitro. FIG. IF is a line graph showing the % IL-10 activity (Y-axis) of Fc-IMP-250 fusion protein at the indicated concentration (Y-axis) in vitro. FIG. 1G is a line graph showing the % IL- 10 activity (Y-axis) of Fc-IMP-251 fusion protein at the indicated concentration (Y-axis) in vitro. FIG. 1H is a line graph showing the % IL- 10 activity (Y-axis) of Fc-IMP-252 fusion protein at the indicated concentration (Y-axis) in vitro.

[0066] FIG. 2A is a bar graph showing the expression level (pg / mL) of IL-6 from human PBMCs treated with LPS (or untreated control) and IgG4-Fc, human IL-10, or IMP-17. FIG. 2B is a bar graph showing the expression level (pg / mL) of TNFa from human PBMCs treated with LPS (or untreated control) and IgG4-Fc, human IL-10, or IMP-17. FIG.2C is a bar graph showing the expression level (pg / mL) of IL-10 from human PBMCs treated with LPS (or untreated control) and IgG4-Fc, human IL-10, or IMP-17. FIG. 2D is a bar graph showing the expression level (pg / mL) of IFNy from human PBMCs treated with LPS (or untreated control) and IgG4-Fc, human IL-10, or IMP-17.

[0067] FIG.3A is a bar graph showing the expression level (pg / mL) of IFNy from CD3 / CD28 stimulated T-cells (or untreated control) and IgG4-Fc, human IL-10, or IMP-17. FIG.3B is a bar graph showing the expression level (pg / mL) of TNFa from CD3 / CD28 stimulated T-cells (or untreated control) and IgG4-Fc, human IL-10, or IMP-17. FIG. 3C is a bar graph showing the expression level (pg / mL) of IL- 13 from CD3 / CD28 stimulated T-cells (or untreated control) and IgG4-Fc, human IL-10, or IMP-17.5. DETAILED DESCRIPTION

[0068] The inventors have, inter alia, identified and developed proteins with one or more immunomodulatory properties, e.g., one or more cytokine-like property, e.g., the ability to bind to one or more cytokine or cytokine receptor (e.g., human cytokine or cytokine receptor). Accordingly, the novel immunomodulatory proteins disclosed herein may be useful for various methods, including, e.g., methods of modulating an immune response e.g., suppressing anAttorney Docket No. 62801.82W001immune response or enhancing an immune response) (e.g., in a subject in need thereof), methods of treating a disease (e.g., a proinflammatory disease or an anti-inflammatory disease), as well as in diagnostic assays. As such, the current disclosure provides, inter alia, novel immunomodulatory proteins, nucleic acid molecules encoding the same, the methods for utilizing the same.TABLE OF CONTENTS5.1 Definitions5.2 Immunomodulatory Proteins5.3 Exemplary Properties of Immunomodulatory Proteins5.4 Immunomodulatory Protein Fusions & Conjugates5.4.1 Radioligands5.4.2 Chimeric Antigen Receptors5.4.3 Signal Peptides5.4.4 Half-Life Extension Moieties5.4.5 Ig Fusion Proteins5.4.5.1 Antibody Fusion Proteins5.4.5.2 Ig Fusion Proteins5.4.5.3 Half-Life Extension5.4.5.4 Ig Effector Function5.4.5.4(i) Reduced Ig Effector Function5.4.5.4(ii) Enhanced Ig Effector Function5.4.6 Linkers5.4.7 Orientation5.4.8 Multimeric Fusion Proteins5.4.9 Exemplary Ig Fusion Proteins5.5 Immunogenic Peptides & Proteins5.5.1 Fragments of IMPs5.5.2 Variants of IMPs5.5.3 Peptide and Protein-Based Vaccines5.5.4 Nucleic Acid-Based Vaccines5.5.4.1 DNA Molecules5.5.4.2 RNA MoleculesAttorney Docket No. 62801.82W001Methods of Making ProteinsNucleic Acid MoleculesDNA MoleculesRNA MoleculesVectorsNon-Viral VectorsViral VectorsCellsAntibodiesCarriersCarriers of Immunomodulatory ProteinsCarriers Conjugated to Immunomodulatory ProteinsLipid Based Carriers / Lipid NanoformulationsCationic Lipids (Positively Charged) and Ionizable LipidsNon-Cationic Lipids (e.g., Phospholipids)Structural LipidsPolymers and Polyethylene Glycol (PEG) - LipidsPercentages of Lipid Nanoformulation ComponentsAdjuvantsPharmaceutical CompositionsMethods of UseMethods of DeliveryMethods of Modulating an Immune ResponseMethods of Suppressing or Preventing a Pro-Inflammatory Immune ResponseMethods of Inducing or Enhancing a Pro- Inflammatory Immune Response Methods of Preventing, Treating, or Ameliorating a Disease in a Subject in Need ThereofMethods of Vaccinating a SubjectDiagnostic MethodsKitsAttorney Docket No. 62801.82W0015.1 Definitions

[0069] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0070] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed.

[0071] Use of the singular herein includes the plural unless specifically stated otherwise. For example, as used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0072] It is understood that wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of’ and “consisting essentially of’ are also provided.

[0073] The term “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following 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).

[0074] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0075] The term “about” refers to a value or composition that is within an acceptable error range for the 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 measurement system. When particular values or compositions are provided herein, unless otherwise stated, the meaning of “about” should be assumed to be within an acceptable error range for that particular value or composition.Attorney Docket No. 62801.82W001

[0076] Where proteins and / or polypeptides are described herein, it is understood that nucleic acid molecules (e.g., RNA (e.g., mRNA) or DNA molecules) encoding the protein are also provided herein.

[0077] Where proteins, peptides, nucleic acid molecules, vectors, carriers, etc. are described herein, it is understood that isolated forms of the proteins, peptides, nucleic acid molecules, vectors, carriers, etc. are also provided herein.

[0078] Where proteins, peptides, nucleic acid molecules, etc. are described herein, it is understood that recombinant forms of the proteins, peptides, nucleic acid molecules, etc. are also provided herein.

[0079] Where polypeptides or sets of polypeptides are described herein, it is understood that proteins comprising the polypeptides or sets of polypeptides folded into their three-dimensional structure (z.e., tertiary or quaternary structure) are also provided herein and vice versa.

[0080] 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.

[0081] As used herein, the term “administering” refers to the physical introduction of an agent, e.g., a therapeutic agent (or a precursor of the therapeutic agent that is metabolized or altered within the body of the subject to produce the therapeutic agent in vivo) or vaccine to a subject, using any of the various methods and delivery systems known to those skilled in the art. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. Administering includes self-administration by the subject and administration by a another to the subject.

[0082] As used herein, the term “affinity” refers to the strength of the binding of one protein (e.g., a Ligand) to another protein (e.g., 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 the unbound Ligand and [Receptor] is the molar concentration of the unbound Receptor. The affinity constant Ka is defined by 1 / Kd. Standard methods of measuring affinity are known to the person of ordinary skill in the art and described herein, see, e.g., § 5.3.

[0083] As used herein, the term “agent” is used generically to describe any macro or micro molecule. Exemplary agents include, but are not limited proteins, peptides, nucleic acid molecules (e.g., DNA molecules, RNA molecules), vectors, carriers, carbohydrates, lipids, syntheticAttorney Docket No. 62801.82W001polymers, etc.

[0084] As used herein, the term “antibody” or “antibodies” is used in the broadest sense and encompasses various immunoglobulin (Ig) (e.g., human Ig (hlg), murine Ig (mlg)) 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). The term antibody thus includes, for example, full-length antibodies; antigen-binding fragments of full-length antibodies; molecules comprising antibody CDRs, VH regions, and / or VL regions; and antibody-like scaffolds (e.g., fibronectins). Examples of antibodies include, without limitation, monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, camelized antibodies, intrabodies, affybodies, diabodies, tribodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies (e.g., VHH, (VHH)2), single chain antibodies, single-chain Fvs (scFv; (scFv)2, Fab fragments (e.g., Fab, single chain Fab (scFab), F(ab’)2 fragments, disulfide-linked Fvs (sdFv), Fc fusions (e.g., Fab-Fc, scFv-Fc, VHH-Fc, (scFv)2-Fc, (VHH)2-Fc), and antigen-binding fragments of any of the above, and conjugates or fusion proteins comprising any of the above. Antibodies can be of Ig isotype (e.g., IgG, IgE, IgM, IgD, or IgA), any class (e.g., IgGi, IgG2, IgG3, IgG4, IgAi or IgA2), or any subclass (e.g., IgG2a or IgG2b) of Ig). In certain embodiments, antibodies described herein are IgG antibodies, or a class (e.g., human IgGi or IgG4) or subclass thereof. In certain embodiments, antibodies described herein are mlgG antibodies, or a class (e.g., mlgGl or mIgG2a) or subclass thereof. In some embodiments, the antibody is a human, humanized, or chimeric IgGi or IgG4 monoclonal antibody. In some embodiments, the term antibodies refers to a monoclonal or polyclonal antibody population. Antibodies described herein can be produced by any standard methods known in the art, e.g., recombinant production in host cells, see, e.g., § 5.6; or synthetic production.

[0085] As used herein, the term “antibody mimetic” refers to non-Ig based antigen binding domain. Various antibody-like scaffolds are known in the art. For example, 10th type III domain of fibronectin (e.g., AdNectins®) and designed ankyrin repeat proteins (e.g., DARPins®) have been used as alternative scaffolds for antigen-binding domains, see, e.g., Gebauer and Skerra, Engineered protein scaffolds as next-generation antibody therapeutics. Curr Opin Chem Biol 13:245-255 (2009) and Stumpp et al., Darpins: A new generation of protein therapeutics. DrugAttorney Docket No. 62801.82W001Discovery Today 13: 695-701 (2008), the full contents of each of which is incorporated by reference herein for all purposes. Exemplary antibody-like scaffolds include, but are not limited to, lipocalins {see, e.g., US7250297) {e.g., Anticalin®), protein A-derived molecules such as z-domains of protein a see, e.g., US5831012) {e.g., Affibody®), A domains of membrane receptors stabilized by disulfide bonds and Ca2+ {see, e.g., US7803907) {e.g., Avimer / Maxibody®), a serum transferrin {see, e.g., US2004023334) {e.g., Transbody®); a designed ankyrin repeat protein {see, e.g., US7417130) {e.g., DARPin®), a fibronectin {see, e.g., US6818418) {e.g., AdNectin®), a C-type lectin domain {see, e.g., US2004132094) {e.g., Tetranectin®); a human gamma-crystallin or ubiquitin {see, e.g., US7838629) {e.g., Affilin®); a kunitz type domain of human protease inhibitors {see, e.g., US2004209243), C-Type Lectins {see, e.g., US2004132094) {e.g., Tetranectins®), cysteine knots or knottins {see, e.g., US7186524) {e.g., Microbodies®), nucleic acid aptamers {see, e.g., US5475096), thioredoxin A scaffold {see, e.g., US6004746) (peptide aptamers), and 10th type III domain of fibronectin {see, e.g., US6818418) {e.g., AdNectins®), and cystine-dense peptides {see, e.g., W02023023031). Additional exemplary antibody-like scaffolds are known in the art and for example described in Storz U. Intellectual property protection: strategies for antibody inventions. MAbs. 2011;3(3):310-317. doi:10.4161 / mabs.3.3.15530. The entire contents of each of the foregoing references is incorporated herein by reference for all purposes. Antibody like scaffolds include e.g., naturally occurring antigen binders, variant {e.g., functional variants) of naturally occurring antigen binders, fragments {e.g., functional fragments) of naturally occurring antigen binders, and synthetic antigen binders {i.e., not naturally occurring antigen binders).

[0086] The terms “CHI” and “CHI region” are used interchangeably herein and refer to the first constant region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl CHI region is set forth in SEQ ID NO: 252; and the amino acid sequence of an exemplary reference hIgG4 CHI region is set forth in SEQ ID NO: 267.

[0087] The terms “CH2” and “CH2 region” are used interchangeably herein and refer to the second constant region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl CH2 region is set forth in SEQ ID NO: 254; and the amino acid sequence of an exemplary reference hIgG4 CH2 region is set forth in SEQ ID NO: 269.

[0088] The terms “CH3” and “CH3 region” are used interchangeably herein and refer to the third constant region of an immunoglobulin heavy chain. The amino acid sequence of anAttorney Docket No. 62801.82W001exemplary reference hlgGl CH3 region is set forth in SEQ ID NO: 255; and the amino acid sequence of an exemplary reference hIgG4 CH3 region is set forth in SEQ ID NO: 270.

[0089] As used herein, the term “chimeric antigen receptor” or “CAR” refers to a recombinant polypeptide construct comprising at least an extracellular antigen-binding domain (e.g., comprising an IMP described herein), a transmembrane domain, and an intracellular signaling domain comprising one or more functional signaling domains derived from a stimulatory molecule. In some embodiments, the domains in the CAR polypeptide construct are in the same polypeptide chain. In some embodiments, the domains in the CAR polypeptide construct are not contiguous with each other, for example, are in different polypeptide chains.

[0090] As used herein, the term “circular RNA” refers to a translatable RNA molecule that forms a circular structure through covalent or non-covalent bonds. In some embodiments, the circular RNA is covalently closed.

[0091] As used herein, the term “conjugation” refers to chemical conjugation of a protein with a moiety (e.g., small molecule, polypeptide, nucleic acid molecule, carbohydrate, lipid, synthetic polymer (e.g., polymers of polyethylene glycol (PEG)), etc.). The moiety can be directly connected to the protein or indirectly connected through a linker, e.g., as described herein. Chemical conjugation methods are well known in the art, as are commercially available conjugation reagents and kits, with detailed instructions for their use readily available from the commercial suppliers.

[0092] As used herein, the term “derived from,” with reference to a nucleic acid molecule refers to a nucleic acid molecule that has at least 70% sequence identity to a reference nucleic acid molecule (e.g., a naturally occurring nucleic acid molecule) or a fragment thereof. The term “derived from,” with reference to a protein refers to a protein that comprises an amino acid sequence that has at least 70% sequence identity to the amino acid sequence of a reference protein (e.g., a naturally occurring protein). The term “derived from” as used herein does not denote any specific process or method for obtaining the nucleic acid molecule, polypeptide, or protein. For example, the nucleic acid molecule, polypeptide, or protein can be recombinantly produced or chemically synthesized.

[0093] As used herein, the term “diagnosing” or “diagnosis” refers to a determination of the presence, absence, severity, or course of treatment of a disease (e.g., an infection, e.g., a viral infection). The term “diagnosing” encompasses an initial determination as well as subsequent determinations (e.g., monitoring) after the initial determination.Attorney Docket No. 62801.82W001

[0094] As used herein, the term “disease” refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition, or syndrome in which physiological function is impaired, irrespective of the nature of the etiology.

[0095] The terms “DNA” and “polydeoxyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple deoxyribonucleotides that are polymerized via phosphodiester bonds. Deoxyribonucleotides are nucleotides in which the sugar is deoxyribose.

[0096] The term “effector function” when used in reference to an antibody refers to those biological activities attributable to the Fc region of an antibody, which therefore vary with the antibody isotype. Antibody effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), Fc receptor binding (e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb (e.g., FcyRI, Fcylla, and / or Fcyllla)), and Clq binding.

[0097] As used herein, the term “Fc region” refers to the C -terminal region of an Ig heavy chain that comprises from N- to C-terminus at least a CH2 region operably connected to a CH3 region. In some embodiments, the Fc region comprises an Ig hinge region or at least a portion of an Ig hinge region operably connected 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., § 5.4.5.4. Additional examples of proteins with engineered Fc regions 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 contents of which is incorporated by reference herein for all purposes).

[0098] The term “functional variant” as used herein in reference to a protein refers to a protein that comprises at least one but no more than 15%, not more than 12%, no more than 10%, no more than 8% amino acid variation (e.g., substitution, deletion, addition) compared to the amino acid sequence of a reference protein, wherein the protein retains at least one particular function of the reference protein. Not all functions of the reference protein (e.g., wild type) need be retained by the functional variant of the protein. In some instances, one or more functions are selectively reduced or eliminated. In some embodiments, the reference protein is a wild type protein.

[0099] The term “functional fragment” as used herein in reference to a protein refers to a fragment of a reference protein that retains at least one particular function. Not all functions of theAttorney Docket No. 62801.82W001reference protein need be retained by a functional fragment of the protein. In some instances, one or more functions are selectively reduced or eliminated. In some embodiments, the reference protein is a wild type protein.

[0100] As used herein, the term “fuse” and grammatical equivalents thereof refer to the operable connection of at least a first polypeptide to a second polypeptide, wherein the first and second polypeptides are not naturally found operably connected together. For example, the first and second polypeptides are derived from different proteins. The term fuse encompasses both a direct connection of the at least two polypeptides through a peptide bond, and the indirect connection through a linker (e.g., a peptide linker).

[0101] As used herein, the term “fusion protein” and grammatical equivalents thereof refers to a protein that comprises at least one polypeptide operably connected to another polypeptide, wherein the first and second polypeptides are not naturally found operably connected together. For example, the first and second polypeptides of the fusion protein are each derived from different proteins. The at least two polypeptides of the fusion protein can be directly operably connected through a peptide bond; or can be indirectly operably connected through a linker (e.g., a peptide linker). Therefore, for example, the term fusion polypeptide encompasses embodiments, wherein Polypeptide A is directly operably connected to Polypeptide B through a peptide bond (Polypeptide A - Polypeptide B), and embodiments, wherein Polypeptide A is operably connected to Polypeptide B through a peptide linker (Polypeptide A - peptide linker - Polypeptide B).

[0102] As used herein, the term “half-life extension moiety” refers to a moiety (e.g., small molecule, polypeptide, nucleic acid molecule, carbohydrate, lipid, synthetic polymer (e.g., polymers of PEG), etc.) that when conjugated or otherwise operably connected (e.g., fused) to a protein (the subject protein), increases the half-life of the subject protein in vivo when administered to a subject (e.g., a human subject). The pharmacokinetic properties of the protein can be evaluated utilizing in vivo models known in the art.

[0103] As used herein, the term “half-life extension polypeptide” or “half-life extension protein” refers to a protein that when operably connected to another protein (the subject protein), increases the half-life of the subject protein in vivo when administered to a subject (e.g., a human subject). The pharmacokinetic properties of the protein can be evaluated utilizing in vivo models known in the art.

[0104] As used herein, the term “heterologous”, when used to describe a first element inAttorney Docket No. 62801.82W001reference to a second element means that the first element and second element do not exist in nature disposed as described. For example, a polypeptide comprising a “heterologous moiety” means a polypeptide that is joined to a moiety (e.g., small molecule, polypeptide, nucleic acid molecule, carbohydrate, lipid, synthetic polymer (e.g., polymers of PEG), etc.) that is not joined to the polypeptide in nature. In one embodiment, the heterologous moiety is not derived from a protein comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606. For example, a non-limiting example of a heterologous moiety is a heterologous polypeptide (as defined herein). In one embodiment, the heterologous polypeptide is a polypeptide derived from a protein other than a protein comprising or consisting of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606. For example, a non-limiting example of a heterologous polypeptide, as described herein, is a human Ig Fc region.

[0105] As used, herein the term “heterologous signal peptide” refers to a signal peptide that is not operably connected to a subject protein in nature. For example, in reference to a polypeptide comprising a signal peptide from human IL-2 operably connected 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.

[0106] The terms “hinge” or “hinge region” are used interchangeably herein and refer to the hinge region of an immunoglobulin heavy chain. The amino acid sequence of an exemplary reference hlgGl hinge region is set forth in SEQ ID NO: 253; and the amino acid sequence of an exemplary reference hIgG4 hinge region is set forth in SEQ ID NO: 268.

[0107] As used herein, the term “homologous signal peptide” refers to a signal peptide that is operably connected to a subject protein in nature. For example, in reference to a polypeptide comprising a signal peptide from human IL-2 operably connected to human IL-2, the human IL-2 signal peptide would constitute a homologous signal peptide.

[0108] As used herein, the term “immunogen” refers to a substance that is capable of inducing an immune response (e.g., an adaptive immune response) in a subject (e.g., a human subject). An immunogen may have one or more isoforms, sequence variants, or splice variants that have equivalent biological and immunological activity, and are thus also considered for the purposes of this disclosure to be immunogenic equivalents of the immunogen.

[0109] As used herein, the term “immunogenic peptide or protein” refers to a peptide or protein that comprises an immunogen.Attorney Docket No. 62801.82W001

[0110] 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 condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In other embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the condition is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive {e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, and intramuscular routes. The therapeutic agents can be administered by the same route or by different routes.

[0111] As used herein, the term “isolated” with reference to a polypeptide, protein, or nucleic acid molecule refers to a polypeptide, protein, or nucleic acid molecule that is substantially free of other cellular components with which it is associated in the natural state.

[0112] As used herein, the term “moiety” is used generically to describe any macro or micro molecule that can be operably connected to a protein described herein. Exemplary moieties include, but are not limited small molecules, polypeptides, nucleic acid molecules (e.g., DNA, RNA), carbohydrates, lipids, synthetic polymers (e.g., polymers of PEG).

[0113] As used herein, the term “modified nucleotide,” “nucleotide modification,” or use of the term “modification” and the like in reference to a nucleotide or nucleic acid sequence refers to a nucleotide comprising a chemical modification, e.g., a modified sugar moiety, a modified nucleobase, and / or a modified intemucleoside linkage, or any combination thereof. Exemplary modifications are provided herein, see, e.g., § 5.5.4.2. In certain embodiments of the instant disclosure, inclusion of a deoxynucleotide - which is acknowledged as a naturally occurring form of nucleotide - if present within an RNA molecule is considered to constitute a modified nucleotide.

[0114] As used herein, the term “obtaining a sample” refers to the acquisition of a sample. TheAttorney Docket No. 62801.82W001term includes the direct acquisition from a subject and the indirect acquisition through one or more third parties wherein one of the third parties directly acquired the sample from the subject.

[0115] As used herein, the term “operably connected” refers to the linkage of two moieties in a functional relationship. For example, a polypeptide is operably connected to another polypeptide when they are linked (either directly or indirectly via a peptide linker) in frame such that both polypeptides are functional (e.g., a fusion protein described herein). Or for example, a transcription regulatory nucleic acid molecule e.g., a promoter, enhancer, or other expression control element is operably linked to a nucleic acid molecule that encodes a protein if it affects the transcription of the nucleic acid molecule that encodes the protein. The term “operably connected” can also refer to the conjugation of a moiety to e.g., a nucleic acid molecule or polypeptide (e.g., the conjugation of a PEG polymer to a protein).

[0116] The determination of “percent identity” between two sequences (e.g., peptide or protein (amino acid sequences) or polynucleotide (nucleic acid sequences)) can be accomplished using a mathematical algorithm. A specific, non-limiting example of a mathematical algorithm utilized for the comparison of 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 herein incorporated 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 herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing 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., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers andAttorney Docket No. 62801.82W001Miller, 1988, CABIOS 4:11-17, which is herein incorporated by reference in its entirety. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM 120 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, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0117] As used herein, the term “pharmaceutical composition” means a composition that is suitable for administration to an animal, e.g., a human subject, and comprises a therapeutic agent and a pharmaceutically acceptable carrier or diluent. A “pharmaceutically acceptable carrier or diluent” means a substance intended for use in contact with the tissues of human beings and / or non-human animals, and without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable therapeutic benefit / risk ratio.

[0118] As used herein, the term “plurality” means 2 or more (e.g., 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 9 or more, or 10 or more).

[0119] 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, of up to about 1000 adenosine nucleotides. In some embodiments, the poly(A) sequence is essentially homopolymeric, e.g., a poly(A) sequence of e.g., 100 adenosine nucleotides having essentially the length of 100 nucleotides. In other embodiments, the poly(A) sequence may be interrupted by at least one nucleotide different from an adenosine nucleotide, e.g., a poly(A) sequence of e.g., 100 adenosine nucleotides may have a length of more than 100 nucleotides (comprising 100 adenosine nucleotides and in addition said at least one nucleotide - or a stretch of nucleotides - different from an adenosine nucleotide). It has to be understood that “poly(A) sequence” as defined herein typically relates to mRNA - however in the context of the invention, the term likewise relates to corresponding sequences in a DNA molecule (e.g., a “poly(T) sequence”).

[0120] 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 altered nucleotides; and contain a natural, nonnatural, or altered intemucleotide linkage, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester found between the nucleotides of anAttorney Docket No. 62801.82W001unmodified nucleic acid molecule. Nucleic acid molecules include, but are not limited to, all nucleic acid molecules which are obtained by any means available in the art, including, without limitation, recombinant means, e.g., the cloning of nucleic acid molecules from a recombinant library or a cell genome, using ordinary cloning technology and polymerase chain reaction, and the like, and by synthetic means. The skilled artisan will appreciate that, except where otherwise noted, nucleic acid sequences set forth in the instant application will recite thymidine (T) in a representative DNA sequence but where the sequence represents RNA {e.g., mRNA), the thymidines (Ts) would be substituted for uracils (Us). Thus, any of the RNA molecules encoded by a DNA identified by a particular sequence identification number may also comprise the corresponding RNA e.g., mRNA) sequence encoded by the DNA, where each thymidine (T) of the DNA sequence is substituted with uracil (U).

[0121] As used herein, the terms “protein” and “polypeptide” refers to a polymer of at least 2 {e.g., at least 5) amino acids linked by a peptide bond. The term “polypeptide” does not denote a specific length of the polymer chain of amino acids. It is common in the art to refer to shorter polymers of amino acids {e.g., approximately 2-50 amino acids) as peptides; and to refer to longer polymers of amino acids {e.g., approximately over 50 amino acids) as polypeptides. However, the terms “peptide” and “polypeptide” and “protein” are used interchangeably herein. In some embodiments, the protein is folded into its three-dimensional structure. Where linear polypeptides are contemplated herein {i.e., primary structure (amino acid sequence)), it should be understood that proteins folded into their three-dimensional structure are also provided herein. Where proteins are contemplated herein {i.e., folded into their three-dimensional structure) polypeptides in their primary structure {i.e., the amino acid sequence) are also provided herein.

[0122] A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology.

[0123] The terms “RNA” and “polyribonucleotide” are used interchangeably herein and refer to macromolecules that include multiple ribonucleotides that are polymerized via phosphodiester bonds. Ribonucleotides are nucleotides in which the sugar is ribose. RNA may contain modified nucleotides; and contain natural, non-natural, or altered internucleotide linkages, such as a phosphoroamidate linkage or a phosphorothioate linkage, instead of the phosphodiester linkage found between the nucleotides of an unmodified nucleic acid molecule.Attorney Docket No. 62801.82W001

[0124] As used herein, the term “sample” encompass a variety of biological specimens obtained from a subject. Exemplary sample types include, e.g., 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, stool, synovial fluid, etc.), nasopharyngeal swabs, solid tissue samples such as biopsies (or cells derived therefrom and the progeny thereof), tissue cultures (or cells derived therefrom and the progeny thereof), and cell cultures (or cells derived therefrom and the progeny thereof). The term also includes samples that have been manipulated in any way after their procurement from a subject, such as by centrifugation, filtration, washing, precipitation, dialysis, chromatography, lysis, treatment with reagents, enriched for certain cell populations, refrigeration, freezing, staining, etc.

[0125] 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. A translatable RNA may be an mRNA or a circular RNA encoding a polypeptide.

[0126] The term “(scFv ’ as used herein refers to an antibody that comprises a first and a second scFv operably connected (e.g., via a peptide linker). The first and second scFv can specifically bind the same or different antigens. In some embodiments, the first and second scFv are operably connected by a peptide linker.

[0127] The term “scFv-Fc” as used herein refers to an antibody that comprises a scFv operably linked e.g., via a peptide linker) to an Fc domain or subunit of an Fc domain. In some embodiments, a scFv is operably connected to only a first Fc domain of a first and a second Fc domain pair. In some embodiments, a first scFv is operably connected to a first Fc domain and a second scFv is operably connected to a second Fc domain of a first and second Fc domain pair.

[0128] The term “(scFv)2-Fc” as used herein refers to a (scFv)2 operably linked (e.g., via a peptide linker) to an Fc domain or a subunit of an Fc domain. In some embodiments, a (scFv is operably connected to only a first Fc domain of a first and a second Fc domain pair. In some embodiments, a first (scFv)2 is operably connected to a first Fc domain and a second (scFv)2 is operably connected to a second Fc domain of a first and second Fc domain pair.

[0129] As used herein, the term “single domain antibody” or “sdAb” refers to an antibody having a single monomeric variable antibody domain. A sdAb is able to specifically bind to a specific antigen. A VHH (as defined herein) is an example of a sdAb.

[0130] As used herein, the term “signal peptide” or “signal sequence” refers to a sequenceAttorney Docket No. 62801.82W001(e.g., an amino acid sequence) that can direct the transport or localization of a protein to a certain organelle, cell compartment, or extracellular export. The term encompasses both the signal sequence peptide and the nucleic acid sequence encoding the signal peptide. Thus, references to a signal peptide in the context of a nucleic acid refers to the nucleic acid sequence encoding the signal peptide.

[0131] As used herein, the term “specifically binds” refers to preferential interaction, i.e., significantly higher binding affinity, between a first protein (e.g., a ligand) and a second protein (e.g., the ligand’s cognate receptor) relative to other amino acid sequences. Herein, when a first protein is said to “specifically bind” to a second protein, it is understood that the first protein specifically binds to an epitope of the second protein. The term “epitope” refers to the portion of the second protein that the first protein specifically recognizes. The term specifically binds includes molecules that are cross reactive with the same epitope of a different species.

[0132] As used herein, the term “subject” includes any animal, such as a human or other animal. In some embodiments, the subject is a vertebrate animal (e.g., mammal, bird, fish, reptile, or amphibian). In some embodiments, the subject is a human. In some embodiments, the method subject is a non-human mammal. In some embodiments, the subject is a non-human mammal is such as a non-human primate (e.g., monkeys, apes), ungulate (e.g., cattle, buffalo, sheep, goat, pig, camel, llama, alpaca, deer, horses, donkeys), 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., chickens, turkeys, pheasants, quail), Anseriformes (e.g., ducks, geese), Paleaognathae (e.g., ostriches, emus), Columbiformes (e.g., pigeons, doves), or Psittaciformes (e.g., parrots).

[0133] As used herein, the term “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, improves a disease condition, e.g., protects a subject against the onset of a disease (or infection); improves a symptom of disease or infection, e.g., decreases severity of disease or infection symptoms, decreases frequency or duration of disease or infection symptoms, increases disease or infection symptom-free periods; prevents or reduces impairment or disability due to the disease or infection; or promotes disease (or infection) regression. The ability of a therapeutic agent to improve a disease condition can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal modelAttorney Docket No. 62801.82W001systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0134] As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disease or infection and / or symptom(s) associated therewith or obtaining a desired pharmacologic and / or physiologic effect. It will be appreciated that, although not precluded, treating a disease or infection does not require that the disease or infection, or symptom(s) associated therewith be completely eliminated. In some embodiments, the effect is therapeutic, i.e., without limitation, the effect partially or completely reduces, diminishes, abrogates, abates, alleviates, decreases the intensity of, or cures a disease and / or adverse symptom attributable to the disease or infection. In some embodiments, the effect is preventative, i.e., the effect protects or prevents an occurrence or reoccurrence of a disease or infection. To this end, the presently disclosed methods comprise administering a therapeutically effective amount of a composition as described herein.

[0135] As used herein, the term “variant” or “variation” with reference to a nucleic acid molecule, refers to a nucleic acid molecule that comprises at least one substitution, alteration, inversion, addition, or deletion of nucleotide compared to a reference nucleic acid molecule. As used herein, the term “variant” or “variation” with reference to a protein refers to a protein that comprises at least one substitution, alteration, inversion, addition, or deletion of an amino acid residue compared to a reference protein.

[0136] As used herein, the term “variant Ig Fc fusion protein” refers to a fusion protein comprising an IMP described herein and an Ig Fc region, wherein the Ig Fc region comprises one or more variation (e.g., one or more amino acid substitution, deletion, or addition)) that decreases or abolishes one or more Fc effector function, relative to a reference Ig Fc fusion protein that does not comprise the one or more variation.

[0137] The terms “VL” and “VL domain” are used interchangeably to refer to the light chain variable region of an antibody.

[0138] The terms “VH” and “VH domain” are used interchangeably to refer to the heavy chain variable region of an antibody.

[0139] The term “VHH” as used herein refers to a type of single domain antibody (sdAb) that has a single monomeric heavy chain variable antibody domain (VH). Such antibodies can be found in or produced from camelid mammals (e.g., camels, llamas) which are naturally devoid of light chains or synthetically produced.Attorney Docket No. 62801.82W001

[0140] As used herein, the term “5'-untranslated region” or “5'-UTR” refers to a part of a nucleic acid molecule located 5' (i.e., “upstream”) of a coding sequence and which is not translated into protein. Typically, a 5'-UTR starts with the transcriptional start site and ends before the start codon of the coding sequence. A 5'-UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, e.g., ribosomal binding sites, miRNA binding sites etc. The 5'-UTR may be post-transcriptionally modified, e.g., by enzymatic or post-transcriptional addition of a 5'-cap structure.

[0141] As used herein the term “3'-untranslated region” or “3'-UTR” refers to a part of a nucleic acid molecule located 3' i.e., downstream) of a coding sequence and which is not translated into protein. A 3'-UTR may located between a coding sequence and an (optional) terminal poly(A) sequence of a nucleic acid sequence. A 3'-UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, e.g., ribosomal binding sites, miRNA binding sites etc.5.2 Immunomodulatory Proteins

[0142] The present disclosure provides, inter alia, immunomodulatory proteins (IMPs) (and functional fragments and variants thereof). The amino acid sequence of the immunomodulatory proteins provided herein is set forth in Table 1 (SEQ ID NOS: 1-246 and 338-595). The amino acid sequence of the mature form of the immunomodulatory proteins and polypeptides (z.e., lacking the native signal peptide) is set forth in SEQ ID NOS: 1-246 and 590-595. The amino acid sequence of the immature form of the immunomodulatory proteins and polypeptides (i.e., containing the native signal peptide) is set forth in SEQ ID NOS: 338-589 or 606.

[0143] The signal peptides have been computationally predicted using standard methods (see, e.g., Teufel, F„ Almagro Armenteros, J. J.. Johansen, A. R. et al. SignalP 6.0 predicts all five types of signal peptides using protein language models. Nat Biotechnol (2022). https: / / doi.org / 10.1038 / s41587-021-01156-3, the entire contents of which is incorporated by reference herein for all purposes). A person of ordinary skill in the art would know how to experimentally identify and / or validate a computationally predicted signal peptide using standard methods known in the art. e.g., expression of the immunomodulatory protein from a host cell and sequencing of the intracellular form and the extracellular form of the expressed protein (see, e.g., Zhang Z, Henzel WJ. Signal peptide prediction based on analysis of experimentally verifiedAttorney Docket No. 62801.82W001cleavage sites. Protein Sci. 2004; 13(10):2819-2824. doi:10.1110 / ps.04682504, the entire contents of which is incorporated by reference herein for all purposes).Table 1. The Amino Acid Sequence of Immunomodulatory Proteins.SEQ ID Amino Acid Sequence ID NO IMP Sequences without Native Signal Sequence MILVFSCFLVVIDDMVVHLPKTPYQGLIVACILTTRNLCIEPMHNLITITKIVL IMP-1 1 DRSSTRFIVKHVKNLTKIHRGS IWSTVTNQPKNDTIGMVLKHDVFIHP YLT CDLPQTHNLRNKKILTLLAQMRRLSPLSCLKDRKDFGFPQEKVDAQQIQEAQAI PVLSELTQQILTLFTSKDSSAAWNATLLDSFCTGLHQLLNDLQGCLMQLVGMKE IMP-2 LPLTQEDSQLAMKKYFHRITVYLREKKHSPCAWEWRAEVWRALSSSVNLLARL 2 SEEKE ECHIKDKEGKAYESVLMISIDELDKMTGTDSNCPNNEPNFFRKHVCDDTKEAAF IMP-3 LNRAARKLKQFLKMNISEEFNVHLLTVSQGTQTLVNCTSKEEKNVKEQKKNDAC 3 FLKRLLREIKTCWNKILKGSI LAKRKCCLNPTNRPIPNPLLQELSRVDYQAIGHDCGREAFRVTLQDGRQGCVSV IMP-4 4 GNKSLLDWLRGHKDLCPQIWSGCESL APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQEPTC IMP-5 LQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKE 5 NLKDFLLVIPFDCWEPVQE LSFGARPHPAAFGPPSLTVPRESLPFPQRLPLHLLFPPRHQLPRRALRALRDPL IMP-6 PDNDKIISCLSSKCCWLGAPLSTCLPGPGFVQ 6 IMP-7 MQSLFSCLCSPSCYRGSRTQCETCCLMKETRQQATKGVR 7 YALFISGESNCNVIGEKNFPAKNGAGTVPPPQDGEYTVDDLKTALEESERSLHD IMP-8 AVFIARQVWEKDCDAVKFDIDDLVQIESALQEICNITAGIDSGDDGE 8 MSFIAFMLIVIFPFLNFRVQQSDCCWIRKLPACCYFPPLLLRSIHEEPLQMQQC IMP-9 KY 9 MASLYATFFFQFFFSIADSSLRCQCSIRILISTDTPFHAENAVMAKLIAINKQI IMP- 10 NSPHYFHRSKRKATI 10 IMP- 11 SCPLRLPRGFCAWPLCCRPRVSLPRRCCLRG 11 IMP- 12 MVALLLTKPLISHGIYSSCWCLISEDCLCSRPTATCNRISVFLLSV 12 MHWMRRTLRKSRRSKKSADWKQIALLYLIIIGQSAKCPSDNPTDIPKRYLKICR IMP- 13 KIAVICCALKKIGQILLPRSAI YVSFSDNEHNICTIMDSTVDFPRDNPQQIQTY 13 TVTVTI IMP-14 MIDTTRLILARTSALWARISAFCARFSVSSKCCCLRSSERPPALIW 14 ELKCDRLPNGDATNCVWIDGYRDPMTVITTPPPSPAVLKKQRQAEFEEALQREV IMP- 15 D HRMF T EN I S S AQ AVE D I LAGRP RRK 15 IMP- 16 CCHTTLLP IKYGYNYINFLLQSEVKQLFKTLFYFL 16 MLCCTGLSTCQMVLLMFSLQHHSNACRI YSLLVLRCQNTKHLQQFCEFLQIHNN IMP- 17 VLRFRVRSCHISHHLSVFQKFVDEIHLTFSTSSCITSPCEIAERPGVAPESYSS 17 LRLRQHCQYCRIGEIKKWRVAPFGAVGRDTLPTGVGGCCGIAPHSKTEESD CATKPLPLSVNCPEPAPLPVHLKESCLPDAQACSREAQAWLNDVKKWLETAQQS IMP- 18 TTQ 18 IMP- 19 MAHFGTLSHFFVPLSHFWPTCQCGLFVAISRKSRCCPIWPTYFSIKLN 19 MKYVITRMFISMAWRWLCCFIFLKTAQRCCCFPVFGQLGCSCWYLWNRSFTF IMP-20 20LNSSAVGLNSSPLYSMAttorney Docket No. 62801.82W001GKKIVNRYVKISCNLRKNLCGQAFGSSGFQFGKKTAANPNVAAKGSVFDALFFA IMP-21 ECVDVAVQVRHKNTPIFVQVYKCTEFCTKELTCTEVCTIIQTWAVQNAVQYKLS 21 TPLY MRSLLMVLPSLRRLQPPNFLHTQQRRAPAFVGDCNRHPLARGDWVMSPSPGDTL IMP-22 FCCALKKAGGYRTNVKTPGRQNRELLVIALACF 22 STKKCDDVSFDYILKDLRSEFSKIKSFVQDNDQENMMLLSQSMLDKLTSRIGCK IMP-23 SLSDMIKFYLNDVLPNAEKIEHMKNKITSIGEKLKSLKEKLISCDFLHCENHDE 23 IKTVKTIFNKLKDKGIYKAMGEFDIFINYLEKYIVKK STKKCDDVSFDYILKDLRSEFSKIKSFVQDNDQENMMLLSQSMLDKLTSRIGCK IMP-24 SLSDMIKFYLNDVLPNAEKIEHMKNKITSIGEKLKSLKEKLISCDFLHCENHDE 24 IKTVKTIFNKLKDKGIYKAMGEFDIFINYLEKYIVKK ASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQLCSKPGVIFLTKRGRQVCADQSK IMP-25 DWVKKLMQQLPATAR 25 DNRYDGQDGNDCPTLPISLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-26 DFKGYLGCQALSEMIQFYLEEVMPQAENHSPDQDKNKVNSLGEKLKTLRVRLRR 26 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN DNRYDGQDGNDCPTLPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-27 DFKGYLGCQALSEMIQFYLEEVMPQAENHSPDQDKNKVNSLGEKLKTLRVRLRR 27 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN DNKYDSESGDDCPTLPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-28 DFKGYLGCQALSEMIQFYLEEVMPQAENHSPDQDKNKVNSLGEKLKTLRVRLRR 28 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN DNKYDSESGNDCPTLPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-29 DFKGYLGCQALSEMIQFYLEEVMPQAENHSTDQEKDKVNSLGEKLKTLRVRLRR 29 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN DNKYDSESGNDCPTLPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-30 DFKGYLGCQALSEMIQFYLEEVMPQAENHSTDQEKDKVNSLGEKLKTLRVRLRR 30 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN DNKYDSESGDDCPTLPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-31 DFKGYLGCQALSEMIQFYLEEVMPQAENHSTGQEKDKVNSLGEKLKTLRVRLRR 31 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN DNKYDSESGNDCPTLPISLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-32 DFKGYLGCQALSEMIQFYLEEVMPQAENHSTGQEKDKVNSLGEKLKTLRVRLRR 32 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN DNKYDSESGNDCPTLPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-33 DFKGYLGCQALSEMIQFYLEEVMPQAENHSTGQEKDKVNSLGEKLKTLRVRLRR 33 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN YCIEYAESDEDKQQCSGSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP-34 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 34 S YCVQYEESDEDRQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-35 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 35 KI YCVEYAESEEDRQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-36 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 36 KS AKPATTTTIKNTKPQCRPEDYATRLQDLRVTFHRVKPTLQREDDYSVWLDGTMV IMP-37 37KGCWGCSVMDWLLRRYLEIVFPAGDHVYPGLKTELHSMRSTLESIYKDMRQWPLAttorney Docket No. 62801.82W001LGCGDKSVISRLSQEAERKSDNGTRKGLSELDTLFSRLEEYLHSRK MPLSCGTDCCETGKKYADAVIDRDLCVLLCNLQYLISNETGIGQTLKQCCLSGN ATSETKEDLRECLAKCPPLPDPGCTGGCCDLRENVNNLRAINPLGCCDNYTKVS IMP-38 SSSLNEDDWDCRKSSTSCEDRGYLLVRNNGSWCIPENSTNENIGFYFSSDCS 38 GLSRRAKRYLYETNGND MLFLSILLYLGLRYLYRKIERYIFPPWAKEKCSRLYFPAVTDLIELLPPGIQKT IMP-39 VGPNISVARFALIYQPDGTLEPKICCICIENECCFKCANRPHSLYCIAWKAYAT 39 EMCYRIYK YFVEYLESDEDRQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP-40 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 40 I HHRKICPNGYYGLAPDPYDCNSYYLCPDTVQLYCPPSMQFDLTAYTCVDNDYPN IMP-41 41 GCVEILNKNLLL AGSLVSYTPNSCCYGFQQHPPPVQILKEWYPTSPACPKPGVILLTKRGRQICAD IMP-42 P SKNWVRQLMQRLPAI A 42 EITSAQTPRCLAANNSFPRSVMVTLSIRNWNTSSKRASDYYNRSTSPWTLYRNE IMP-43 DQDRYPSVIWEAKCRYLGCVNADGNVDYHMNSVPIQQEILWRKGHNPCPNSFR 43 LEKMLVTVGCTCVTP I VHNVD TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNLLLKESLLEDFKGYLGCQALS IMP-44 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 44 VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKAR EITSAQTPRCLAANNSFPRSVMVTLSIRNWNTSSKRASDYYNRSTSPWTLHRNE IMP-45 DQDRYPSVIWEAKCRYLGCVNADGNVDYHMNSVPIQQEILWRKGHQPCPNSFR 45 LEKMLVTVGCTCVTP I VHNVD DNKYDSESGDDCPTLPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-46 DFKGYLGCQALSEMIQFYLEEVMPQAENHSTDQEKDKVNSLGEKLKTLRVRLRR 46 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN ISLESLAVDKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-47 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 47 HICL ASWHRPDKCCLGYQKRPLPQVLLSSWYPTSQLCSKPGVIFLTKRGRQVCADKSK IMP-48 DWVKKLMQQLPVTAR 48 APLPSQLSGLLGSILFQVDSLINGSCSNFHCDGRNGVILFEQSQLPTPAPECLS IMP-49 SNFNKTQCLKWSLDSIASYYDFFNNMKPDGNVQGLQSSLKGLRQSLQQNYPNAE 49 IHLINKTESNNLSQTPSMQRYQDGKELAVMQGLSGLIQTLQRWRL MPLSCGTDCCETGKKYADAVIDRDLCVLLCNLQYLISNETGIGQTLKQCCLSGN ATSETKEDLRKCLAKCPPLPDPGCTGGCCDLRENVNNLRAINPLGCCDNYTKVS IMP-50 SSSLNEDDWDCRKSSTSCEDRGYLLVRNNGSWCIPENSTNENIGFYFSSDCS 50 GLSRRAKRYLYETNGND DSSKKRWSEVLKGSECRPRP IVVPVSETHPDLTSQRFNPPCVTLMRCGGCCNDE IMP-51 SLECVPTEEANGTMELMGASGSGNNGKQHLSFGEHKNCDCRPRFTTTPPKTTRP 51 PRRRR DNRYDGQDGNDCPTLPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLDGSLLE IMP-52 DFKGYLGCQALSEMIQFYLEEVMPQAENHSTDQEKDKVNSLGEKLKTLRVRLRR 52 CHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKN ESENNCTHFPTSLPHMLHELRAAFSRVKTFFQMKDQLDNMLLNGSLLEDFKGYL IMP-53 GCQALSEMIQFYLEEVMPQAENHSGGGGPDIKEHVNSLGEKLKTLRVRLRRCHR 53 FLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIFINYIEAYMTTKMKNKK MGSMSGPAPEVCCLGYITKLPPPAAVATYYYTSSQCSLDAVILETPRGQKLCAN IMP-54 54P GDD GVRKLMQKVDKRPKRNKGRRTRRS LAED ASND GLDS GS GFAttorney Docket No. 62801.82W001LRDLRDAFSRVKTFFQTKDEVDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEV IMP-55 MPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNK 55 LQEKGIYKAMSEFDIFINYIEAYMTIKAR YCVEYEESEEDKQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-56 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 56 KM FLCTGDGCVQMPDHTSRRFDSKAQCEDVMLRAIDKVWERHQLWRAVCTP YFLS IMP-57 STEVPGFYSPPPQPPTGMNHMWDSWIRGGSIPSYEPGRGWSE 57 VELRCPCSNGLSYPIGGFFWIGYNPPDPPKCEKPQHFLLPPKGKPVCLSPDHVL IMP-58 SKWLHGKSSNTWHKVLLRTKGGDGPHVEERTASNGRPPWKLKF 58 TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP-59 SPDHLFSKWLDKYNDNRWYNVNITKSPGPRRINITLIGVRG 59 YCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLREKLKTLRL IMP-60 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 60 T YCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP-61 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 61 S YCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP-62 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGDYKAMSEFDIFINYIESYMTTK 62 S EQRCQCIGKKYNRIPHKTLCLSIEHAGPRCEVTEAIASFNPIHNRPPICLNYEN IMP-63 LRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVTLE 63 SELRCSCVKYYYGIPWTATCVYLKPKSVECNNYELIVYDGSPHKTCVRVRNPSV IMP-64 FDRLDKQTWFTVTKKPNRHISLKPQRTSCAVPKS 64 SELRCQCLQVTQGIHPKNIQSMTITKPNGGCDRREIIATLKNGQKVCLNPEAPM IMP-65 MKKVLSKFPGGTYSSFWQHFMTLFTD 65 IEPDISKIFENSQCKPRSTKINVYSLAGSDVSIMYKPACIYVDKCGGCCNDEAL IMP-66 ACKP IEKTTVNVTVLS IGNRNAQFQQFPWTHTKCNCLPKPSRRGPR 66 YSSDSSDCCLRHSTRPIPFKVLQSYQHQLPTIGCHLNAIVFYTVKRRTICANPG IMP-67 D KWVRL AMKF I D KKNN S TMR YKF 67 KPATTTTIKNTKPQCRPEDYATRLQDLRVTFDRVKPTLQREDDYSVWLDGTWK IMP-68 GCWGCSVMDWLLRRYLEIVFPAGDHVYPGLKTELHSMRSTLESIYKDMRQCPLL 68 GCGDKSVISRLSQEAERKSDNGTRKGLSELDTLFSRLEEYLHSRK YCVEYEESEEDRQQCSGSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-69 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 69 KM VSNCGNLPHMLRDLRDAFSRVKTFFQMKDQLDNILLKESLLEDFKGYLGCQALS IMP-70 EMIQFYLEEVMPQAENQDPNAKEHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 70 VEQVKNAFSKLQEKGVYKAMSEFDIFINYIEAYMTMKTRR TDQCDNFPQMLRDLRDAFSRVKTFFQTKDAVDNLLLKESLLEDFKGYLGCQALS IMP-71 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 71 VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKAR TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNLLLKESLLEDFKGYLGCQALS IMP-72 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 72VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKARAttorney Docket No. 62801.82W001RELRCPCTHKALHHPIGGLFWVGRDPPNPPECDKPQHYLLPPRGKPVCLAPDHH IMP-73 L S KWLD GKKDN S WH KVL VKVKD S N GP H VE E NAVI NKRP RWK 73 IMP-74 CGYDGTIRYPCQEPDNWSSKECQSPYCDVTGTCPRDLVPHLFESEDDGKAN 74 KKCDDVSFDYILKDLRSEFSKIKSFVQDNDQENMMLLSQSMLDKLTSRIGCKSL IMP-75 SDMIKFYLNDVLPNAEKIEHMKNKIISIGEKLKSLKEKLISCDFLHCENHDEIK 75 TVKT IFNKLKDKGI YKAMGEFD IF INYLEKYI VKK KRVKVKFGACLSHLRDILNISTECFNITLNNNKTGCENETLGNPDKKPGLPCRD IMP-76 CLNLTLSNNSTKCQHEESRLESVLLEVGLMLHNRSIQVSGQFENTTCSSFVNVT 76 LSELLQGWLSMLQRSYAYRYCGDPSPNHTRCQAFCPK RELRCPCTHKALHQPIGGLFWVGRDPPNPPECDKPQHYLLPPRGKPVCLAPDHH IMP-77 LSKWLDGKKDNSWHKVLVKVKDSNGPHVEENAVTNKRPRWK 77 MELRCPCGSNGLSYPIGGLFLIGYNPPDPPKCEKPQHFLWPPKGKPVCLSPDHV IMP-78 LSKWLHGKLSNTWHKVLLRTKGGDGPHVEERTASNGRPPWKLKF 78 APYAIRLSYDCCYTFVNRLPHISKLNGYIKTSSFCTKGNGVIFITKRLKTFCYK IMP-79 LNKQSKSYIEKLDKSYIYEDFNENKS IS WK 79 APYAIRLSYDCCYTFVNRLPHISKLNGYIKTSSFCTKGNGVIFITKRLKTFCYK IMP-80 LNKQSKSYIEKLDKSYIYEDFNENKINFCSKK 80 NHPRCLCPRTMKGINATDIQIVRIKLPSSECDKTEIIVQRRNGFEVCLDTTSPL IMP-81 GKKLMEKYLKRYEQ 81 SELRCQCLQVTQGIHPKNIQSMTITKPNGGCDRREI IATLKNGQKVCLNPEAP I IMP-82 MKKVLSKFPGGTYSSFWQHFMTLFTD 82 ELRCQCVSTIQGVHPKNIQSVYIKTPGPHCSHTEVIATLKNGQKVCLNPDSPMA IMP-83 KKFVSTVKGKLNTAS 83 DIEVLERCYCLQTTQGISAKNIKSVELKEPRDACPKLEVIATLKNGLEVCLNPD IMP-84 APMVKKIVKRIRDYESKQIKQLQQ 84 SELRCRCVKYYYGIPWTATCVYLEPRSIACNHHELIVYDGSIKKTCVRVANPSA IMP-85 FKNVNKVAWFTVKREGQGNQLKLKRHNGSCSVVH 85 ELRCQCLHVTRGIRPSNIKDITITKPNAGCDRKEIIATLKNGKQVCLDPEAPMM IMP-86 KKLLSKVPEGKYPSFWEQYKEHFLKMFTE 86 EHPRCLCLRTTKGIHPKHIKTVEIKEPRSECNKIEI IAHLKNGVEVCLDPESAM IMP-87 GKKLIEKYQKQYEQ 87 ISLESLAVDKRCKCVKVTNRPTGLGPIIAVDVIPPSIHCRRTEIIFALKKNRKV IMP-88 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 88 HICL ISLESLAVGKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-89 CVDPEAPWVQQFIKKLERQHRIRKENLMVGEHGGKSTVRPVKNTIEPTPPTIGS 89 HICL TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNLLLKESLLEDFKGYLGCQALS IMP-90 EMIQFYLEKVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 90 VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKAR GIRPVVSTQLLLNGSLAEEEVVIRSENFTNNAKNIIVQLNTSVEINCTRPNNNNT IMP-91 RKSIPIGPGRAFYATGEIIGDIRQAHCNISGENWNNTLKQIVKKLREQFNKTIV 91 FDQ TANNRAQKCFCFDGSNAGNSEETNTAAFQKKCDSEIPESLPYMLRDLRNSSVQT RRYFQEKDEENSPLLTQKLLEDFKGYLGCQALSEMIQFYLEEVMPQAEDSNPSA IMP-92 KDSVTSLGEKLKTLRLRLRRCHRFLPCENKSKAVENLKSKFGDLGNQGVHKAMS 92 EFDIFINYIETYMTTKMK TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNLLLKESLLEDFKGYLGCQALS IMP-93 EMIQFYLEEVMPQAENQDPGAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 93VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKARIMP-94 QSAAECIP YCRVSSCLAYCNGFENKNFFVRTCPLNEGVKLNVCDDLVCENTSES 94Attorney Docket No. 62801.82W001QGDSGCYCCCGYQLQYFNGR YCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT IMP-95 QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL 95 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIES TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNLFLKESLLEDFKGYLGCQALS IMP-96 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 96 VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKAR YCVEYEESEEDRQQCSSSNFPASLPHMPRELRAAFGKVKTFFQMKDQLNSMLLT IMP-97 QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL 97 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIES YCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT IMP-98 QSLLDDFKGYLGCQAFSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL 98 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIES YCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT IMP-99 QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSPGEKLKTLRL 99 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIES YCVEYEESEEDRQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP- 100 LRLRRCHRFLPCEDKSKAVEQVKRVFNMLQERGVYKAMSEFDILINYIESYMTT 100 KM YCVEYAESDEDKQQCSGSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPRAENHGPDIKEHVNSLGEKLKTLRL IMP- 101 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 101M YCIQYEESEEDKQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIRFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP- 102 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 102 M YCVEYEESDEDRQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP- 103 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 103 KM YCVEYEESDEDRQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP- 104 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMAT 104 KM YCVEYAESDEDRQQCSGSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP- 105 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 105 M YCVEYAESDEDRQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP- 106 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 106 KM YCVEYAESDEDKQQCSGSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP- 107 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 107 M MRMMSSAIPILHTADCCAFQVLAVILRTERRSNNCCCTSLLLLSRGHFIGTSRL IMP- 108 CSLCIRIRHCRCIRDFRGIGLKAHLASPLSTTPKARKPHRSRHSLACQLLFAL 108IMP- 109 MRLHLLWVLALRTCNKCQRSLFICTCRIDFQIRAVKQRQKKAMEVFGSLSNHVW 109Attorney Docket No. 62801.82W001CRCPHDTGLRTGCCEQLPGQTQVCFCQPHATKSMI ASNCGNLPHMLRDLRDAFSRVKTFFQMKDQLDNILLKESLLEDFRGYLGCQALS IMP- 110 EMIQFYLEEVMPQAENQDPHSKEHVNSLGENLKTLRLRLRRCHRFLPCENKGKA 110 VEQVKNAFSKLQEKGVYKAMSEFDIFINYIEAYMTMKLRR YCVEYEESEEDKQQCGSNGGPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP-111 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 111M GDTVLESIMESSCQPRPTKVQLSGYDMYIPACAYVPRCGGCCSGGEATTCRPTA IMP-112 TSTVNVTAYKLVFHDTQQWVSVLTHTACACKFKRAFLQHLRGPRRR 112 TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDSLLLKESLLEDFKGYLGCQALS IMP- 113 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 113 VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKAR TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNILLKESLLEDFKGYLGCQALS IMP-114 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 114 VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKAR TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNLLLKESLLEDFKGYLGCQALS IMP- 115 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTIRLRLRRCHRFLPCENKSKA 115 VEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKAR TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNLLLKESLLEDFKGYLGCQALS IMP- 116 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 116 VEQIKNAFNKLQEKGIYKAMSEFHIFINYIEAYMTIKAR LPILETIKLSMCKPRDTKIDVYKLDRADVSKIYTPSCVYVKRCGGCCNGDQFTC IMP-117 EASHKNITELTLFQTNALLMSKHNRVAPITPIIFKVVEHTACKCVSTIRHLIRP 117 LIR VGGLTGLYQPRCCNGYQRRPLPWWLMESWSPTSQSCHKSAVIFLTKKGRQVCMD IMP- 118 PSKDWVQKLMQRVSVTT 118 YCVEYEESKEDEQQCSGSNGASASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-119 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 119 KM YCVEYLESREDEQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP- 120 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 120 KM QGNDSPPSVNEWMQTLGKSGCEPRDTWKLGDEYPHNTDKNYNPKCVTVKRCSG IMP- 121 CCNGDRQVCTAVETKNTTWVSVTSVSSSSGANSGVSNSLQRISVTEHTKCECI 121DGTTTPPTTTTREPRR AEGWQLTECPPGEPCRPRGKPLDVKTACELDLVSLAIVAAKGTRIRCDKLTTKK IMP- 122 EAR 122 IDIRYCGAPARDLDGTIHRSVQKISEFKRAHPCPANGINKGACPGWAIDHVIPL IMP- 123 VCGGCDDIFNMQWLPNKIKSAAGI YPKDRWEQHVYCSAGK 123 TELRCRCLHKKWPPNRIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP- 124 SPDHLFSKWLDKRNDNRWYNVNITRSPEPRRINITLIGVRG 124 TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP- 125 SPDHLFSKWLDKYNDNRWYNVNITKSPEPRRINITLIGVRG 125 YCVEYEETKEDEQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP- 126 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 126KMAttorney Docket No. 62801.82W001LAKRRCCLNPTNRPIPNPLLQDLSRVDYQAIGHDCGREAFRVTLQDGRQGCVSV IMP- 127 GNKSLLDWLRGHKDLCPQIWSGCESL 127 AKPATTTIKNTKPQCRPEDYATRLQDLRVTFHRIKPTLQREDDYSVWLDGTWK IMP- 128 GCWGCSVMDWLLRRYLEIVFPAGDHVYPGLKTELHSMRSTLESI YKDMRQCPLL 128 GCGDKSVISRLSQEAERKSDNGTRKGLSELDTLFSRLEEYLHSRK EQRCQCINSYYPRIPRTITCIYIQHPGPTCHRTEAIAYFNPTYHGP ICLDYNKL IMP- 129 QNRLPKQQGSWCRFNRTLIDTPVRDCRNCDKFRIL 129 IELRCQCVNYYSGIPWTAKCVYLKPKSPECNKYELIVYYDSAMKTCVRVRNSYV IMP- 130 FDNINEHTWFQVTNKPGTKQIKLKKQKTSCAVVS 130 EQSIDLMQRCWCSQTTQGIGRQHIKSLQLRDPTDMCPKTELIATLTDGREVCLN IMP- 131 PEAPMSVKMISKIKEHEKDYIKKVTT 131DELRCECTDVTQGIHPKNIQSVIVKYPGPHCSHQEI IATLKTGQKVCLNGEAPM IMP- 132 VKKMIEKRKN 132 NHPRCLCPRTMKGINATDIQIVRIKLPSSECDKTEIIVQRKNGFEVCLDPKSAL IMP- 133 GKKLMEKYLKRYGQ 133 SELRCNCVKYYFGIPWTATCVYLKPKSIECNNYELIVYDGSPHKTCVRVRNPSV IMP- 134 FDRLDKQTWFTVTKKPNRHISLKPQRTSCAVPKS 134 EQRCQCIGKKYNRIPHKTLCLSIEYAGPRCEVTEAVASFNPIHNRPPICLNYEN IMP- 135 IRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVTLE 135 EQRCQCIGKKYNRIPRKAICLSIENAGPRCEVSEAVVSFNPIHNRSPMCLDYES IMP-136 IRKRFPATPGTWCRVGKSLIKVNDKNCEICNRFVTLE 136 EYPRCLCLRTTKGIHPKHIKTVEIKEPRSECNKMEI IAHLKNGVEVCLDPESAM IMP- 137 GKKLIEKSQKQYEQ 137 TETEYCECVNVTLFTS IPNDTLYLQPLAPNENCTKQEVIAVLQNNTRACLNPHA IMP- 138 LAVRVFFNRLFFRIIKNEDGLYDVIDTQLELPSWNITRKYYKRYLKQKVNSENA 138 KILSRMIL VNELYCQCTHVTQGISANVIKTVTITSPTSGCDHREIILTLKDGRQTCLNPHSP IMP- 139 LGKKLLATVKH 139 NHPRCLCPRTMKGVNASDIQIVKIKLPSSECHKTEIIVQRKNGFEVCLDTKSPL IMP-140 GKKLMEKYLKRYEQ 140 EQRCQCIGKKYNRIPHRTLCLSIEYAGPRCEVTEAVASFNPIHNRPPICLNYEN IMP-141 IRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVTLE 141 ELRCQCLQVMKGIPPSNIQRLSITRPNAGCERREIIATLKNGKQVCLDPEAPMM IMP-142 KKMLSKIPGGTYPSFWEHLMTLFRD 142 ELRCQCLQVMKGIPPSNIQRLSITRPNAGCERREIIATLKNGKQVCLDPEAPMM IMP-143 KKMLSNSRRNVP IVLGTSDDAV 143 TPHSVAPTCCTTFVNKPIPRQLLKGYIEVINSRCPRKAVIFKTKLGKEICAKPH IMP- 144 EKHTRLDGRKLYLNLEASMCKKILKVSRNKKRRKIV 144 TPHSVAPTCCTTFVNKPIPRQLLKGYIEVINSRCPRKAVIFKTKLGKEICAKPH IMP- 145 EKWVQDSMDHLNKMNSKGHNYR 145 TELRCSCINYYHTIPWKAKCVYFQPKSPACDKYELIVYYQNSPTKTCVRVKNPS IMP- 146 VFDNINEQAWFTVTKVPGKKQLSFRRQATSCAWS 146 ATELRCWCPEATQGIHPKNIQNVTVKYPDQNCPRKEIIATLKNGDKVCLNPDAP IMP- 147 MFNQTKKVKKVKKVKKVKKVIKRS S 147 MCAQCLSLSCSCFCCSCRCCLRPRCTPEEPGVQEGRGAEHVQMQPCLTQPSPQP IMP- 148 SMLIGCPQPIHLPPSSPVCPPSGPHGLTGAAVAHAAALPHYPMPGSRQ 148 TELRCRCLHRKWPPNKIILGSYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP- 149 SPDHLFSKWLDKHNDNRWYNVNIMKSPGPRRINITLIGVRG 149 RELRCPCTHKALHHPIGGLFWVARDPPNPPECDKPQHYLLPPRGKPVCLAPDHH IMP-150 150LSKWLDGKKDNSWHKVLVKVKDSNGPHVEENAVTNKRPRWKAttorney Docket No. 62801.82W001IMP- 151 MDFLSFSILCPLRLQVCPWCPCSRLLKRRCCSAPRR 151TYLSRDGAQQIASHEGYRLVAYPDPATGGAPWTICRGHTKGVYRGMRATHEQCD IMP- 152 QWYAEDLHVAERAVQRNVRVPLKQGEYDAMVSFVFNVGESNLRASTLLRKVNAG 152 DRRGSCNQYPRWIYANKMVLNGLVTRRYEEQATCLKDGPYVYLP CAPADTPKVAEKAPTPAPEQLEPAGPAPFEFIVYSTGVRNLRALVHVRTGCVWI IMP-153 ASPQSGYVDGYGATFKLEEPDGKGGMRQVCDPSIRPATPK 153 ISLESLAVGKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIMFALKKNRKV IMP- 154 CVDPEAPWVQQLIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTTGS 154 HICL ISLESLAVGKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIMFALKKNRKV IMP-155 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 155 HICL ISLESLAVDKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIMFALKKNRKV IMP- 156 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 156 HICL MMCALCTILLATEACRTPRPSRWFEANLEVWVQQIRRGCQTSTNLHQLSLKQEK IMP-157 TGRMCVLCTIP 157 VELRCQCLQVTQGINPKNIQSMTITKPNGGCDRREI IATLKNGQKVCLNPEAPM IMP-158 MKKILSKFPGGTYSSFWQHFMTLFTD 158 NHPRCLCPRTMKGINATDIQIVRIKPPSSECDKTEIIVQRRNGFEVCLDTTSPL IMP-159 GKKLMEKYLKRYEQ 159 EQRCQCIGKKYNRIPRKAICLSIEHAGPRCEVTEAVASFNPIHNRPPMCLDYNN IMP- 160 IRNIFPATPGTWCRVGKSLIKVNDKNCEICNRFVTLE 160 MFVGSKRTFSFFGMLSYVVRTLCPFQCQRPVSSIFSIARLYIRRYSPHHLLRTM IMP-161 ASLTFGNISTFRDIIAFFGIATLPVMFAGENSGDCDDVFCELCCR 161 RELRCPCTHKALHHPIGGLFWVGRDPPNPPECDKPQHYLLPPRGKPACLAPDHH IMP- 162 LSKWLDGKKDNSWHRVLVKIKDSNGPHVEENAVTNKRPRWK 162 TELRCRCLHRKWPPNKIILGNYWLHRDPGGPGCDKNEHLLYPNGRKPPGVCLSP IMP- 163 DHLFSKWLDKHDDNRWYNVNITKSPGPRRINITLIGVGG 163 SPTAQSPNTTPRKWTDVLGSGSCKPRETWRIGDEYPSLISQRFSPPCVSVMRC IMP- 164 GGCCNDESLECVPTEEANITMEVMSVSVSSTGSNPGMQNMQFVEHLRCDCKPKT 164 TPTPEPQGQPRR MPHVPATCCTQYATKALKFNKILTYVSVSSSNCAFPGVIFITKKGQMVCANPSD IMP- 165 PWVKDYVERLDKLPSVQQA 165 DSTKTWSEVFESSKCKPRPTWPVGEAHPELTSQRFNPQCVTVMRCGGCCNDES IMP- 166 LECVPTEEANVTMQLMGASVSGGNGMQHLIFVEHKKCDCKPRLTTTPPTTTRPP 166 RRRR PMIFKVQGGILGFFFFYLFGPPGPRLGVREKITTSHRSQARGRLQPMPNAPQAR IMP- 167 GGHWAHPLYPCIENRDGGGGGGCCLPPPPGPR 167 QSTTELRCQCTQTVQGIHPKNIQSVS IKDRGPNCPNKEVIATLKNGQKVCLNPD IMP- 168 APMTKKILETAEKRN 168 DMEQRCLCRNTARGIDPKHIKGVKMELPKQTCMKTELIATLKDGREICLDTESP IMP- 169 MAKKIIEKLNEIKNSS 169 TELRCRCVNYYSGIPWTATCVYLKPKSIGCNKYELIVYDGSETKTCVRVSNPSK IMP- 170 FDTITKHTWFKVTKLPGKNQIRLQKQNTPCSVVQ 170 QSTTELRCQCTQTVQGIHPKNIQSVS IKDKGPNCPNQEVIATLKNGQKVCLNPT IMP- 171 APMVQKILKKTITDN 171DKEERCLCPKTIQGTHPKNIQSVELHEPRDMCPNVEVIAKLKNGNEVCLNTEGP IMP- 172 MVKKIIEKMRDREIERIQQQSQ 172 KELRCQCINYYSGIPWTATCVYLKPKSAACNQYELIVYNGSERKTCVRVRNTSA IMP- 173 173FERFNRVTWFKVTKGKGKNISLKLHNGSCAWSAttorney Docket No. 62801.82W001YCTSCSHHQCTEDENQKQDCEDANHSLPHMLRELRAAFGKVKTFFQMKDQLHSL LLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPEEHDNSLSEHGPDVK IMP- 174 EHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEKVKRVFSELQERGVYKAMSE 174 FDIFINYIETYMTT IMP- 175 IHKECSIQECCENQPYQIEDPCPIHYYSDWFIKIGSM 175 EQRCQCIGKKYNRIPHKTLCLSIEYAGPRCEVTEAIASFNPIHNRPPICLNYEN IMP- 176 IRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVTLE 176 EECCEFTNVNHPPERCYDFKMCNRFTVALRCPDGEVCYSPEKTAEIRGIVTTMT IMP- 177 HSLTRQWHNKLTSCNYNLLYLEADGRIRCGKVNDKAQYLLGAVGSVP YRWINL 177 EYDKITRIVGLDQYLESVKKHKRLDVCRAKMGYMLQ GNTVLESIMESSCQPRPTKVQLSSYSMYIPACTYVPRCGGCCSGDEATTCRPTA IMP- 178 TGTVNVTAFKLVFRTTQQWLS WTHTACACKFKRAYLRGPRRR 178 AKPATTTTIKNTKPQCRPEDYATRLQDLRVTFHRVKPTLQREDDYSVWLDGTVV IMP- 179 KGCWGCSVMDWLLRRYLETVFPAGDHVYPGLKTELHSMRSTLES IYKDMRQCPL 179 LGCGDKSVISRLSQEAERKSDNGTRKGLSELDTLFSRLEEYLHSRK ISLESLAVGKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP- 180 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTTGS 180 HICF ISLESLAVGKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-181 CVDPGAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 181 HICL ISLES L AVGKRCKC VKVTNRP I GL GP I T AVD V I P P G I H CRRT E II F ALKKNRKV IMP- 182 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 182 HICL INYRNVSGIYHVTNDCPNSS IVYETDHHILHLPGCVPCVRAENRSHCWVALTPT IMP- 183 VAGPYIGAPLESLRSHVDLMGGAATACSPLYIGDLCGGLFLVGQMFSFRPRRHW 183 TTQDCNC INYHNTSGIYHVTNDCPNSS IVYEADHHILHLPGCVPCVRVGNQSRCWVALTPT IMP- 184 VAGP YVGAPLESLRSHVDLMVGTATACSPLYIGDLCGGLFLVGQMFSFRPRRHW 184 TTQDCNC NHPRCLCPHTMKGINATDIQIVRIKLPSSECDKTEIIVQRRNGFEVCLDTTSPL IMP- 185 GKKLMEKYLKRYEQ 185 EQRCQCIGKKYNRIPHRTLCLSIEYAGPRCEVTEAVASFNPIHNRPPICLNYEN IMP- 186 IRNRFPAAPGTWCRVGKSLIKVNDKNCEICNRFVTLE 186 NHPRCLCPRTMKGVNASDTQIVKIKLPSSECHKPETIVQRKNGFEVCLDTKSPL IMP- 187 GKKLMEKYLKRYEQ 187 ELRCQCLQVMKGIPPSNIQRISITRPNAGCERREIIATLKNGKQVCLDPEAPMM IMP- 188 KKMCQKFPGGTYPSFWEHLMTLFRDWMLTPQA 188 MITLSCSGIMPFSSDSRMSAGPSRSCAVSDCPFSQSSCFPQPHRLCISFLKIFM SFSCSACITAHFIQPLDILPRPVTKPDLQMLKKTLNPCGIFGVKKGQSGDECAI CIREPAMAVCLNNVSRPQTEPYLRLPRVALRPLRSGRPHRACRTCFSFRSLWAC IMP- 189 RACRTGISLWTLWTCISRQTGLSPLSPVTFRPLRACRTSITCRSPFAGCPDRAG 189 VTALSLITLRPSRTCWPRVPFISFRTGNTTSCCSLFCLCFRFICHIHCRFHRFR GGSLRFTITVRCAA SELRCSCVNYYSGIPWTATCVYVKPKSIECNKYELIVYNGSPNKTCVRVRNQSV IMP- 190 FDRITKQKWFKVTKGAKHQLSLTPQRASCAVSK 190 AELRCQCLQVTQGINPKNIQSMTITKPNGGCDRREI IATLKNGQKVCLNPEAPM IMP-191 MKKLLSKFPGETYASFWQHFMTLFTD 191 EQRCQCIGKKYNRIPHKTLCLSIEHAGPRCEVTEAIASFNPIHNRPPICLNYEK IMP- 192 LRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVTLE 192IMP- 193 TELRCRCLHKKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL 193Attorney Docket No. 62801.82W001SPDHLFSKWLDERNDNRWYNVNITKSPEPRRINITLIGVRG KELRCNCVQYYHGIPWTATCVYLEPKNNHCNKYELIVYDGSEKKTCVRFSDPSK IMP- 194 FKNVHQKTWFTVTRGAGRQIRLKKQSTSCAWQ 194 VHELHCECPNTRSGIYPGHIKTVLVKKPGVNCPVTEVIATLKNGQKVCLDPDAP IMP- 195 MVKNKILTKVSI 195 RELRCSCVRYYHGIPWTATCVYLKPKSAVCDRYELIVYNKSPTKTCVRVKNPSV IMP- 196 FDKINEHAWFKVTNKPGTKQISLRRQNTPCSVVQ 196 QSATELRCQCTNTQSGIHPKNIQSLEIRKPGATCPNKEVIATLKNGQKVCLNPE IMP- 197 APMVKNKILKKN 197 AVSPNELRCRCKPGQNYEGLELQHIMIVAVYPHNPYCNWQDTIAYLYGKKAWTC IMP-198 FDFSKLKTEIEKNMVSKTTREGITVYRRHFKETGIQVSESSQSLPTATVLGMPQ 198 PPVYFSSNASHATCQMQHNGESCSCSCT LPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALK IMP- 199 KNRKVCVDPEAPWVQQFIKKLERRHRTRKENLMVGEDGGKSTVGPVKNTIEPTP 199 PTIGSHICL ISLESLAVDKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-200 CVDPEAPWVQQFIKKLERRHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 200 HICL KRVKVKFGACLSHLRDILNISTECFNITLNNNKTGCENETLGNPDKKPGLPCRD IMP-201 CLNLTLSNNSTKCQHEESRLESVLLEVGLMLHNRSIQVSGQFENTTCSSFVNVT 201 LSELLQGWLSMLQRSYAYRYCGDPSPNHTRCQAFCP YCVEYEESEEDKQQCGSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-202 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 202 KM YCVEYLESGEDEQQCGSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-203 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 203 KM MLLAFHRNLGASLGGIRLPQVASARASCPPQFPSPRASGPLRPRPPETRASGPA IMP-204 SPVTLLEPQPGHMCQTPWPLRPSGPPGPRPQQPCCSPP 204 AMLTYNIWDVNQKIFYLRNNQLVAGHIQDNSLAEKITAKLIGGNDIFLGVKNGE IMP-205 KSLECTEHGDKVTLSLSDKKTNSLDESQDKRFAFIRSDNGHTSTFESVAFPGWF 205 LCTSSGDGIEPVGLTYKGDKDDDNDENNIYFYFEEED ISLESLAVDKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-206 CVDPEAPWVQQFIKKLERQHRIREENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 206 HICL ISLESLAADKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-207 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 207 HICL ISLESLAVDKRCKCVKVINRPIGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-208 CVDPEAPWVQQLIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIEPTPPTIGS 208 HICL MRSIVLSVGFVPIVLFYWRAARNVCFIQYSHTCLLITYVQSHLAARQCLLPTLT IMP-209 ATCHFQPPAQNTPHPLRLAATIREPPPRPHSP YRGGNVLAFCHFARFASVPCYK 209 ARRFSPSPHVLS TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGSGVCL IMP-210 SPDHLFSKWLDKYNDNRWYNVNITKSPGPRRINITLIGVRG 210 RELRCPCTHKALHHPIGGLFWVGRDPPNPPECDKPQHYLLPPRGKPVCLAPDHH IMP-211 L S KWLD GKKDN S WHKVLRKVKD SN GP HVEE NAVI NKRP RWK 211IMP-212 TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGHGVCL 212Attorney Docket No. 62801.82W001SPDHLFSKWLDKRNDNRWYNVNITKSPEPRRINITLIGVRG DSTKTWFEVFENSGCKPRPMVFRVHDEYPTLTSQRFNPPCVTLMRCGGCCNDES IMP-213 LECVPTEEANVTMQLMGASVSGGNGMQHLSFVEHKKCDCKPPLTTTPPTTTRLP 213 RRRR MGSMSGPAPEVCCLGYINKLPPSGAVALYYYTSSQCTLDAVILETHRGQKLCAN IMP-214 P GDD GVRKLLQKVDNRPKRNKGRRTRRS LLDD AS DE GLES GS GF 214 TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP-215 SPDHLFSKWLDKHNDNRWYNVNITKSPGPRRINITLIGVRG 215 TELRCRCLHRKWPPNKIILGSYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP-216 SPDHLFSKWLDKHNDNRWYNVNITKSPGPRRINITLIGVRG 216 RELRCPCTHKALHHPIGGLFWVGRDPPNPPECDKPQHYLLPPRGKPVCLAPDHH IMP-217 L S KWLD GKKDN S WH KVLVKVKD SNGP HVQE NAVT NKRP RWK 217 TELRCRCLHKKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP-218 SPDHLFSKWLDKYNDNRWYNVNITKSPGPRRINITLIGVKG 218 TELRCRCLHKKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP-219 SPDHLFSKWLDKRNDNRWYNVNITKSPEPRRINITLIGVRG 219 TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPDGRKPPGPGVCL IMP-220 SPDHLFSKWLDKYNDNRWYNVNITKSPGPRRINITLIGVKG 220 RELRCPCTHKALHHPIGGLFWVGRDPPNPPECDKPQHYLLPPRGKPVCLAPDHH IMP-221 LSKWLDGKKDNSWHRVLVKVKDSNGPHVGENAVTNKRPRWK 221TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPNGKKPPGVCLSP IMP-222 DHLFSKWLDKHDDNRWYNVNITKSPGPRRINITLIGVGG 222 TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYPNGRKPPGVCLSP IMP-223 DHLFSKWLDKHDDNRWYNVNITKSPGPRRINITLIGVGG 223 TELRCRCLHRKWPPNKIILGNYWLHRDPRGPGCDKNEHLLYLDGRKPPGPGVCL IMP-224 SPDHLFSKWLDKHNDDRWYNVNITKSPGPRRINITLIGVRG 224 RELRCPCTHKALHHPIGGLFWVGRDPPNPPECDKPQHYLLPPRGKPVCLAPDHH IMP-225 LSKWLDGKKDNSWHKVLVKVKDGNGPHVEENAVTNKRPRWK 225 YCVEYKESEEDRQQCSSSSFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT IMP-226 QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL 226 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK DSSTKRWSEVLKGSECRPRPIVVPVSETHPELTSQRFNPPCVTLMRCGGCCNDE IMP-227 SLECVPTEEANVTMEFMGVGVSSTGSSVSTQHLEFVEHTKCDCQPRGGQQTTPT 227 PPRRRRRAY YCVEYLESREDEQQCSGSNGASASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-228 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 228 KM LSLLSSPNLCPGVISTPYKLTCLSNASLPISWYCNNTRLFRLTERTVFPVTIAC IMP-229 NFTCVEQSGHRQSIWITW 229 VWFRGLCPGVISTPYKLTCLSNASLPISWYCNNTRLLRLTERTLFPVTIACNFT IMP-230 CVEQSGHRQSIWITW 230 DSTKTWSEVFENSGCKPRPMVFRVHDEHPELTSQRFNPPCVTLMRCGGCCNDES IMP-231 LECVPTEEANVTMQLMGASVSGGNGMQHLSFVEHKKCDCKPPLTTTPPTTTRPP 231 RRRR MGSMSGPAPELCCLGYVTHLPPPGLVVSYSHTSSQCSVDAVILNTRRGKKLCAN IMP-232 PGDDAVKKLLQAVDKRPKKGRRTRRSLIDDSEEGLGSGI 232 YCVEYEESDEDKQQCSSSTGAPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-233 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 233KMAttorney Docket No. 62801.82W001ISLESLAVDKRCECVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-234 CVDPEAPWVRQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKKHN 234 ISLESLAVDKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-235 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKKHN 235 KPWSTQLLLNGSLAEDKIIIRSKNISQNTNIIIVHLNASVPIICTRPNNNTRK IMP-236 G I H I GP GRAF YATGDIIGDI RKAH CNVS GP KWND T LKNVT AE LKVHFP DNT I T F 236 N VSNCGNLPHMLRDLRDAFSRVKTFFQMKDQLDNILLKESLLEDFKGYLGCQALS IMP-237 EMIQFYLEEVMPQAENQDPHAKEHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 237 VEQVKNAFSKLQEKGVYKAMSEFDIFINYIEAYMTMKIRR MRACSSAWVAGPSSPKALRRSFSRSCCNFNRPMSVRAPSVSPAKLATLRMTPLS IMP-238 CMPCLIWLKVFECTKRLPVLYSQRPVEFSALVMRDPRLPQLMAPPLKLESPMWW 238 SLRAHPPRCGDSAA ISLESLAVDKRCKCVKVTNRPTGLGPIIAVDVIPPGIHCRRTEIIFALKKNRKV IMP-239 CVDPEAPWVQQFIKKLERQHRTRKENLMVGEDGGKSTVGPVKNTIDAPHLLLLV 239 PISVSLINCYLL ETCGNIPHMLRDLRDAFSRVKTFFQMKDQLDNILLKESLLEDFKGYLGCQALSE IMP-240 MIQFYLEEVMPQAEAMSLKSQEHVNFLGENLNTLRLRLRRCHRFLPCENKSKAV 240 EQVKNAFSKLQEKGVYKAMSEFDIFINYIEAYMTMKLRR TDQCDNFPQMLRDLRDAFSRVKTFFQTKDEVDNLLLKESLLEDFKGYLGCQALS IMP-241 EMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLRRCHRFLPCENKSKA 241VEQIKMPLTSCRKKEFTKP SGPATLVASDCCEAARRVRLPVRSLAGWYWTSKVYCRRQAVIFLTRPGRKVCAW IMP-242 P D ART RRLMARVP E L S F Q E KMARART 242 VGGMVGHGNRYCCTGYQRKPLPRWLLGSWYPTSHLCTKPGVIFLTKRGRQVCAD IMP-243 P S KD WVQKLMQQVP AT A 243 MPHVPATCCTQYATKALKFNRILTYVSVSSSNCAFPGVIFITKKGQMVCANPSD IMP-244 PWVKDYVERLDKSPSVQQA 244 FFPLRTDLTCVCGNGNGWRAFEPVNSTDPFLLIGSLQLSGHCVPPEATMTLKSD IMP-245 QRRRCVNPFLLGDALLFGVEQGKPES ILTEGLKSELLQFVHILKSHVSKRPPSL 245 R YCIHDEDCFENECCVNHVCVECNNLRLKRNVPNGCSGCLGICVCIGENCICMP I IMP-246 NK 246 KPATTTTIKNTKPQCRPEDYATRLQDLRVTFDRVKPTLQREDDYSVWLDGTWK IMP-247 GCWGCSVMDWLLRRYLEIVFPAGDHVYPGLKTELHSMRSTLEST YKDMRQCPLL 590 GCGDKSVISRLSQEAERKSDNGTRKGLSELDTLFSRLEEYLHSRK AKPATTTIKNTKPQCRPEDYATRLQDLRVTFHRIKPTLQREDDYSVWLDGTWK IMP-248 GCWGCSVMDWLLRRYLEIVFPAGDHVYPGLKTELHSMRSTLES I YKDMRQCPLL 591 GCGDKSVISRLSQEAERKSDNGTRKGLSELDTLFSRLEEYLHSRK YCIEYAESDEDKQQCSGSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP-249 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 592 S YFVEYLESDEDRQQCSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLLT QSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLRL IMP-250 RLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTTK 593 T YCVQYEESDEDRQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-251 LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 594KIAttorney Docket No. 62801.82W001YCVEYAESEEDRQQCSSSSNFPASLPHMLRELRAAFGKVKTFFQMKDQLNSMLL TQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPDIKEHVNSLGEKLKTLR IMP-252LRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAMSEFDIFINYIESYMTT 595 KS DNGLLNLKMKLYLLSIAHKGRLPASLFKDSSPPPETPGTPHPTRKPPPDETRIK IMP-253 RESLALPPRRPLIYDADEDDEHNKENLPPDDDRKGYGRKQVLQYLLEKLEEDLQ 605 LYQDEVLRELSVLRQKLGIPQ IMP Sequences with Native Signal Sequence MILVFSCFLVVIDDMVVHLPKTPYQGLIVACILTTRNLCIEPMHNLITITKIVL IMP-1DRSSTRFIVKHVKNLTKIHRGS IWSTVTNQPKNDTIGMVLKHDVFIHP YLT 338 MARPFAFLMVLVVISYWSTCSLGCDLPQTHNLRNKKILTLLAQMRRLSPLSCLK DRKDFGFPQEKVDAQQIQEAQAIPVLSELTQQILTLFTSKDSSAAWNATLLDSF IMP-2CTGLHQLLNDLQGCLMQLVGMKELPLTQEDSQLAMKKYFHRITVYLREKKHSPC 339 AWEVVRAEVWRALSSSVNLLARLSEEKE MFHVSFRYIFGIPPLILVLLPVTSSECHIKDKEGKAYESVLMISIDELDKMTGT IMP-3 DSNCPNNEPNFFRKHVCDDTKEAAFLNRAARKLKQFLKMNISEEFNVHLLTVSQ 340 GTQTLVNCTSKEEKNVKEQKKNDACFLKRLLREIKTCWNKILKGSI MRGGDVFASVVLMLLLALPRPGVSLAKRKCCLNPTNRP IPNPLLQELSRVDYQA IMP-4 341 IGHDCGREAFRVTLQDGRQGCVSVGNKSLLDWLRGHKDLCPQIWSGCESL MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMN IMP-5 ETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPT 342 PETSCATQIITFESFKENLKDFLLVIPFDCWEPVQE MACTRVCFLSYFLFLAARALSFGARPHPAAFGPPSLTVPRESLPFPQRLPLHLL IMP-6 FPPRHQLPRRALRALRDPLPDNDKIISCLSSKCCWLGAPLSTCLPGPGFVQ 343 IMP-7 MQSLFSCLCSPSCYRGSRTQCETCCLMKETRQQATKGVR 344 MGLPALFVSAWSACSCGVCHGYALFISGESNCNVIGEKNFPAKNGAGTVPPPQ IMP-8 DGEYTVDDLKTALEESERSLHDAVFIARQVWEKDCDAVKFDIDDLVQIESALQE 345 ICNITAGIDSGDDGE MSFIAFMLIVIFPFLNFRVQQSDCCWIRKLPACCYFPPLLLRSIHEEPLQMQQC IMP-9 KY 346 MASLYATFFFQFFFSIADSSLRCQCSIRILISTDTPFHAENAVMAKLIAINKQI IMP- 10 NSPHYFHRSKRKATI 347 IMP- 11 MIYLAIVPSLSCPLRLPRGFCAWPLCCRPRVSLPRRCCLRG 348 IMP- 12 MVALLLTKPLISHGIYSSCWCLISEDCLCSRPTATCNRISVFLLSV 349 MHWMRRTLRKSRRSKKSADWKQIALLYLIIIGQSAKCPSDNPTDIPKRYLKICR IMP- 13 KIAVICCALKKIGQILLPRSAIYVSFSDNEHNICTIMDSTVDFPRDNPQQIQTY 350 TVTVTI IMP- 14 MIDTTRLILARTSALWARISAFCARFSVSSKCCCLRSSERPPALIW 351 MNKICFLTIALSFFLSSPVMAELKCDRLPNGDATNCVWIDGYRDPMTVITTPPP IMP- 15 SPAVLKKQRQAEFEEALQREVDHRMFTENISSAQAVEDILAGRPRRK 352 MPHYLSTLLHCCLLKPLRASEGACCHTTLLPIKYGYNYINFLLQSEVKQLFKTL IMP- 16 FYFL 353 MLCCTGLSTCQMVLLMFSLQHHSNACRI YSLLVLRCQNTKHLQQFCEFLQIHNN IMP- 17 VLRFRVRSCHISHHLSVFQKFVDEIHLTFSTSSCITSPCEIAERPGVAPESYSS 354 LRLRQHCQYCRIGEIKKWRVAPFGAVGRDTLPTGVGGCCGIAPHSKTEESD MNIERKNGVKPNSSRTRGMHLSALALSLLICGLTLTGCATKPLPLSVNCPEPAP IMP- 18 LP VHLKE S CLPD AQAC SREAQAWLND VKKWLE TAQQ S I TQ 355IMP- 19 MAHFGTLSHFFVPLSHFWPTCQCGLFVAISRKSRCCPIWPTYFSIKLN 356Attorney Docket No. 62801.82W001MKYVITRMFISMAWRWLCCFTFLKTAQRCCCFPVFGQLGCSCWYLWNRSFTF IMP-20 LNSSAVGLNSSPLYSM 357 MRLLGRVFFLVAGKKIVNRYVKISCNLRKNLCGQAFGSSGFQFGKKTAANPNVA IMP-21 AKGSVFDALFFAECVDVAVQVRHKNTPIFVQVYKCTEFCTKELTCTEVCTIIQT 358 WAVQNAVQYKLSTPLY MRSLLMVLPSLRRLQPPNFLHTQQRRAPAFVGDCNRHPLARGDWVMSPSPGDTL IMP-22 FCCALKKAGGYRTNVKTPGRQNRELLVIALACF 359 MKTNTKIILFCYVIFLSLYVFSCVVASTKKCDDVSFDYILKDLRSEFSKIKSFV QDNDQENMMLLSQSMLDKLTSRIGCKSLSDMIKFYLNDVLPNAEKIEHMKNKIT IMP-23 SIGEKLKSLKEKLISCDFLHCENHDEIKTVKTIFNKLKDKGIYKAMGEFDIFIN 360 YLEKYIVKK MKTNTKIILFCYVIFLSLYVFSCVVASTKKCDDVSFDYILKDLRSEFSKIKSFV QDNDQENMMLLSQSMLDKLTSRIGCKSLSDMIKFYLNDVLPNAEKIEHMKNKIT IMP-24 SIGEKLKSLKEKLISCDFLHCENHDEIKTVKTIFNKLKDKGIYKAMGEFDIFIN 361YLEKYIVKK MDTKGILLVAVLTALLCLQSGDTLGASWHRPDKCCLGYQKRPLPQVLLSSWYPT IMP-25 SQLCSKPGVIFLTKRGRQVCADQSKDWVKKLMQQLPATAR 362 MFRALLLCCLALLAGVWADNRYDGQDGNDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSPDQDKN IMP-26 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 363 DIFINYIEAYMTIKMKN MFRALLLCCLALLAGVWADNRYDGQDGNDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSPDQDKN IMP-27 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 364 D I F I N Y I E AYMT TKMKN MFRASLLCCLVLLAGVWADNKYDSESGDDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSPDQDKN IMP-28 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 365 D I F I N Y I E AYMT TKMKN MFRASLLCCLVLLAGVWADNKYDSESGNDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSTDQEKD IMP-29 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 366 D I F I N Y I E AYMT TKMKN MFRASLLCCLVLLAGVWADNKYDSESGNDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSTDQEKD IMP-30 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 367 DIFINYIEAYMTIKMKN MFRASLLCCLVLLAGVWADNKYDSESGDDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSTGQEKD IMP-31 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 368 D I F I N Y I E AYMT TKMKN MFRASLLCCLVLLAGVWADNKYDSESGNDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSTGQEKD IMP-32 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 369 D I F I N Y I E AYMT TKMKN MFRASLLCCLVLLAGVWADNKYDSESGNDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSTGQEKD IMP-33 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 370 DIFINYIEAYMTIKMKN MSNNKILVCVAI ILTYTLYTDAYCIEYAESDEDKQQCSGSNFPASLPHMLRELR IMP-34 371AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAEAttorney Docket No. 62801.82W001NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG VYKAMSEFDIFINYIESYMTTKS MSNNKILVCVVIILTYTLYTDAYCVQYEESDEDRQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-35 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 372 GVYKAMSEFDTFINYIESYMTTKI MSNNKILVCVAIILTYTLYTDAYCVEYAESEEDRQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-36 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 373 GVYKAMSEFDIFINYIESYMTTKS MLSVMVSSSLVLIVFFLGASEEAKPATTTTIKNTKPQCRPEDYATRLQDLRVTF HRVKPTLQREDDYSVWLDGTMVKGCWGCSVMDWLLRRYLEIVFPAGDHVYPGLK IMP-37 TELHSMRSTLES I YKDMRQWPLLGCGDKSVISRLSQEAERKSDNGTRKGLSELD 374 TLFSRLEEYLHSRK MYIRYKLGLLFLVINFYNILSMPLSCGTDCCETGKKYADAVIDRDLCVLLCNLQ YLISNETGIGQTLKQCCLSGNATSETKEDLRECLAKCPPLPDPGCTGGCCDLRE IMP-38 NVNNLRAINPLGCCDNYTKVSSSSLNEDDVVDCRKSSTSCEDRGYLLVRNNGSV 375 VCIPENSTNENIGFYFSSDCSGLSRRAKRYLYETNGND MLFLSILLYLGLRYLYRKIERYIFPPWAKEKCSRLYFPAVTDLIELLPPGIQKT IMP-39 VGPNISVARFALIYQPDGTLEPKICCICIENECCFKCANRPHSLYCIAWKAYAT 376 EMCYRIYK MSNNKILVCAVIILTYTLYTDAYFVEYLESDEDRQQCSSSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP-40 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 377 VYKAMSEFDIFINYIESYMTTKT MWLLLAFFIIVKLLVFHKMQKLHLDLHHRKICPNGYYGLAPDPYDCNSYYLCPD IMP-41 TVQLYCPPSMQFDLTAYTCVDNDYPNGCVEILNKNLLL 378 MAPVHVLCCVSVLLATFYLTPTESAGSLVS YTPNSCCYGFQQHPPPVQILKEWY IMP-42 PTSPACPKPGVILLTKRGRQICADPSKNWVRQLMQRLPAIA 379 MTFRKTSLVLLLLLSIDCIVKSEIISAQIPRCLAANNSFPRSVMVTLSIRNWNT IMP-43 SSKRASDYYNRSTSPWTLYRNEDQDRYPSVIWEAKCRYLGCVNADGNVDYHMNS 380 VPIQQEILWRKGHNPCPNSFRLEKMLVTVGCTCVTPIVHNVD MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN IMP-44 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIE 381 AYMTIKAR MTFRMTSLVLLLLLSIDCIVKSEITSAQTPRCLAANNSFPRSVMVTLSIRNWNT IMP-45 SSKRASDYYNRSTSPWTLHRNEDQDRYPSVIWEAKCRYLGCVNADGNVDYHMNS 382 VPIQQEILWRKGHQPCPNSFRLEKMLVTVGCTCVTPIVHNVD MFRASLLCCLVLLAGVWADNKYDSESGDDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSTDQEKD IMP-46 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 383 DIFINYIEAYMTTKMKN MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDV IMP-47 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED 384 GGKSTVGPVKNTIEPTPPTIGSHICL MDTKGILLVAVLTALLCLQSGDTLGASWHRPDKCCLGYQKRPLPQVLLSSWYPT IMP-48 SQLCSKPGVIFLTKRGRQVCADKSKDWVKKLMQQLPVTAR 385 MKLVFAAALWYNYLSYTTLAPLPSQLSGLLGS ILFQVDSLINGSCSNFHCDGRN IMP-49 GVILFEQSQLPTPAPECLSSNFNKTQCLKWSLDS IASYYDFFNNMKPDGNVQGL 386QSSLKGLRQSLQQNYPNAEIHLINKTESNNLSQTPSMQRYQDGKELAVMQGLSGAttorney Docket No. 62801.82W001LIQTLQRVVRL MYIRYKLGLLFLVINFYNILSMPLSCGTDCCETGKKYADAVIDRDLCVLLCNLQ YLISNETGIGQTLKQCCLSGNATSETKEDLRKCLAKCPPLPDPGCTGGCCDLRE IMP-50 NVNNLRAINPLGCCDNYTKVSSSSLNEDDVVDCRKSSTSCEDRGYLLVRNNGSV 387 VCIPENSTNENIGFYFSSDCSGLSRRAKRYLYETNGND MKLLVGIIVTVCLHQYLLNADSSKKRWSEVLKGSECRPRPIVVPVSETHPDLTS IMP-51 QRFNPPCVTLMRCGGCCNDESLECVPTEEANGTMELMGASGSGNNGKQHLSFGE 388 HKNCDCRPRFTTTPPKTTRPPRRRR MFRALLLCCLALLAGVWADNRYDGQDGNDCPTLPTSLPHMLHELRAAFSRVKTF FQMKDQLDNMLLDGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSTDQEKD IMP-52 KVNSLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEF 389 DIFINYIEAYMTIKMKN MPGAALLYCLFFVTGVWAESENNCTHFPTSLPHMLHELRAAFSRVKTFFQMKDQ LDNMLLNGSLLEDFKGYLGCQALSEMIQFYLEEVMPQAENHSGGGGPDIKEHVN IMP-53 SLGEKLKTLRVRLRRCHRFLPCENKSKAVEQVKSAFSKLQEKGVYKAMSEFDIF 390 INYIEAYMTTKMKNKK MRGLVAGVFFAVFACVVDYAFPMGSMSGPAPEVCCLGYITKLPPPAAVATYYYT IMP-54 SSQCSLDAVILETPRGQKLCANPGDDGVRKLMQKVDKRPKRNKGRRTRRSLAED 391 ASNDGLDSGSGF MERRLVVTLQCLVLLYLAPECGEMLRDLRDAFSRVKTFFQTKDEVDNLLLKESL IMP-55 LEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGENLKTLRLRLR 392 RCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTIKAR MSNNKILLCVAIILTYTLYTDAYCVEYEESEEDKQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-56 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 393 GVYKAMSEFDIFINYIESYMTTKM MASITVWIATAFLCTGDGCVQMPDHTSRRFDSKAQCEDVMLRAIDKVWERHQLV IMP-57 VRAVCTPYFLSSTEVPGFYSPPPQPPTGMNHMWDSWIRGGSIPSYEPGRGWSE 394 MRFIFSLFGLLIALYYKVESVELRCPCSNGLS YP IGGFFWIGYNPPDPPKCEKP IMP-58 QHFLLPPKGKPVCLSPDHVLSKWLHGKSSNTWHKVLLRTKGGDGPHVEERTASN 395 GRPPWKLKF MRLIFGVLIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP-59 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKYNDNRWYNVNITKSPGPRRI 396 NITLIGVRG MSKNKFLVCVVIILTYTLYTDAYCVEYEESEEDRQQCSSSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP-60 NHGPDIKEHVNSLREKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 397 VYKAMSEFDIFINYIESYMTTKT MSKNKILVCVVIILTYILYTDAYCVEYEESEEDRQQCSSSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP-61 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 398 VYKAMSEFDIFINYIESYMTTKS MSKNKILVCVVIILTYTLYTDAYCVEYEESEEDRQQCSSSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP-62 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 399 DYKAMSEFDIFINYIESYMTTKS MRVCVAYVLLCLSVHGLVAEQRCQCIGKKYNRIPHKTLCLSIEHAGPRCEVTEA IMP-63 IASFNPIHNRPPICLNYENLRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVT 400 LE MNTVRVNIAAMLLICLILSGFSGSQGSELRCSCVKYYYGIPWTATCVYLKPKSV IMP-64 401ECNNYELIVYDGSPHKTCVRVRNPSVFDRLDKQTWFTVTKKPNRHISLKPQRTSAttorney Docket No. 62801.82W001CAVPKS MNCAIFNPRVLGVALLLMTLIAHHQTAASELRCQCLQVTQGIHPKNIQSMTITK IMP-65 PNGGCDRREIIATLKNGQKVCLNPEAPMMKKVLSKFPGGTYSSFWQHFMTLFTD 402 MKPFYILLLCTSIVYAIEPDISKIFENSQCKPRSTKINVYSLAGSDVSIMYKPA IMP-66 CIYVDKCGGCCNDEALACKP IEKTTVNVTVLS IGNRNAQFQQFPWTHTKCNCL 403 PKPSRRGPR MMSVGRNLLLVALVIVLFFLCCGETYSSDSSDCCLRHSTRPIPFKVLQSYQHQL IMP-67 P T I GCHLNAI VF YT VKRRT I CANP GDKWVRLAMKF I DKKNNS TMRYKF 404 MLSMMVSSSLVLIVFFLGAFEEAKPATTTTIKNTKPQCRPEDYATRLQDLRVTF DRVKPTLQREDDYSVWLDGTWKGCWGCSVMDWLLRRYLEIVFPAGDHVYPGLK IMP-68 TELHSMRSTLES I YKDMRQCPLLGCGDKSVISRLSQEAERKSDNGTRKGLSELD 405 TLFSRLEEYLHSRK MSNNKILVCVVIILTYTLYTDAYCVEYEESEEDRQQCSGSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-69 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 406 GVYKAMSEFDIFINYIESYMTTKM MGPRAGLALQCLLLLYLAPACKGVSNCGNLPHMLRDLRDAFSRVKTFFQMKDQL DNILLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPNAKEHVNSLGEN IMP-70 LKTLRLRLRRCHRFLPCENKSKAVEQVKNAFSKLQEKGVYKAMSEFDIFINYIE 407 AYMTMKTRR MERRLMVTLQCLVLLYLAPECGSTDQCDNFPQMLRDLRDAFSRVKTFFQTKDAV DNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN IMP-71 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIE 408 AYMTIKAR MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN IMP-72 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIE 409 AYMTMKAR MRLIFCSLISLLMAFMYYHGVHSRELRCPCTHKALHHP IGGLFWVGRDPPNPPE IMP-73 CDKPQHYLLPPRGKPVCLAPDHHLSKWLDGKKDNSWHKVLVKVKDSNGPHVEEN 410 AVTNKRPRWK MKLILLVLALLLTGCGYDGTIRYPCQEPDNWSSKECQSPYCDVTGTCPRDLVPH IMP-74 LFESEDDGKAN 411 MKTNTKIILFCYVIFLSLYVFSCVVASAKKCDDVSFDYILKDLRSEFSKIKSFV QDNDQENMMLLSQSMLDKLTSRIGCKSLSDMIKFYLNDVLPNAEKIEHMKNKIT IMP-75 SIGEKLKSLKEKLISCDFLHCENHDEIKTVKTIFNKLKDKGIYKAMGEFDIFIN 412 YLEKYIVKK MEGRRVLVLCLLSILFAAWLQPNDSKRVKVKFGACLSHLRDILNISTECFNITL NNNKTGCENETLGNPDKKPGLPCRDCLNLTLSNNSTKCQHEESRLESVLLEVGL IMP-76 MLHNRSIQVSGQFENTTCSSFVNVTLSELLQGWLSMLQRSYAYRYCGDPSPNHT 413 RCQAFCPK MRLIFGSLISLLMAFMYYHGVHSRELRCPCTHKALHQP IGGLFWVGRDPPNPPE IMP-77 CDKPQHYLLPPRGKPVCLAPDHHLSKWLDGKKDNSWHKVLVKVKDSNGPHVEEN 414 AVTNKRPRWK MRFIFSLFGLLIVLYYKVESMELRCPCGSNGLSYPIGGLFLIGYNPPDPPKCEK IMP-78 PQHFLWPPKGKPVCLSPDHVLSKWLHGKLSNTWHKVLLRTKGGDGPHVEERTAS 415 NGRPPWKLKF MKQILLLCIMYMVMYNNHVLSAPYAIRLSYDCCYTFVNRLPHISKLNGYIKTSS IMP-79 FCTKGNGVIFITKRLKTFCYKLNKQSKSYIEKLDKSYIYEDFNENKSISVVK 416 MKQILLLCIMYMVMYNNHVLSAPYAIRLSYDCCYTFVNRLPHISKLNGYIKTSS IMP-80 417FCTKGNGVIFITKRLKTFCYKLNKQSKS YIEKLDKS YI YEDFNENKINFCSKKAttorney Docket No. 62801.82W001MQFNKLACNIFVVTMVFMLILSGTVFANHPRCLCPRTMKGINATDIQIVRIKLP IMP-81 S SECDKTE I IVQRRNGFEVCLDTT SP LGKKLMEKYLKRYEQ 418 MNCAIFNPRVLGVALLLMTLIAHHQTAASELRCQCLQVTQGIHPKNIQSMTITK IMP-82 PNGGCDRREIIATLKNGQKVCLNPEAPIMKKVLSKFPGGTYSSFWQHFMTLFTD 419 MHAAMNSRFLAIALLLVSMIALEPCAGELRCQCVSTIQGVHPKNIQSVYIKTPG IMP-83 PHCSHTEVIATLKNGQKVCLNPDSPMAKKFVSTVKGKLNTAS 420 MEHGFSKKLVPATLLMLLLIGRISSDIEVLERCYCLQTTQGISAKNIKSVELKE IMP-84 PRDACPKLEVIATLKNGLEVCLNPDAPMVKKIVKRIRDYESKQIKQLQQ 421 MSNLRVTIGAIFFICIMLSGFSDSWGSELRCRCVKYYYGIPWTATCVYLEPRS I IMP-85 ACNHHELIVYDGSIKKTCVRVANPSAFKNVNKVAWFTVKREGQGNQLKLKRHNG 422 SCSVVH MNRAIFNPRVLGVALLLMTLIAYHQTEAELRCQCLHVTRGIRPSNIKDITITKP IMP-86 NAGCDRKEIIATLKNGKQVCLDPEAPMMKKLLSKVPEGKYPSFWEQYKEHFLKM 423 FTE MKFNKLTCNIFIVTLVVMLLVSNAVFAEHPRCLCLRTTKGIHPKHIKTVEIKEP IMP-87 RSECNKIEIIAHLKNGVEVCLDPESAMGKKLIEKYQKQYEQ 424 MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDV IMP-88 IPPSIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED 425 GGKSTVGPVKNTIEPTPPTIGSHICL MQASLLVLVLFIVQIYLLPGNGISLESLAVGKRCKCVKVTNRPTGLGPIIAVDV IMP-89 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGEH 426 GGKSTVRPVKNTIEPTPPTIGSHICL MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DNLLLKESLLEDFKGYLGCQALSEMIQFYLEKVMPQAENQDPEAKDHVNSLGEN IMP-90 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIE 427 AYMTIKAR GIRPVVSTQLLLNGSLAEEEVVIRSENFTNNAKNIIVQLNTSVEINCTRPNNNNT IMP-91 RKSIPIGPGRAFYATGEIIGDIRQAHCNISGENWNNTLKQIVKKLREQFNKTIV 428 FDQ MAYGKKIVAASLLVIPAYWFTNATANNRAQKCFCFDGSNAGNSEETNTAAFQK KCDSEIPESLPYMLRDLRNSSVQTRRYFQEKDEENSPLLTQKLLEDFKGYLGCQ IMP-92 ALSEMIQFYLEEVMPQAEDSNPSAKDSVTSLGEKLKTLRLRLRRCHRFLPCENK 429 SKAVENLKSKFGDLGNQGVHKAMSEFDIFINYIETYMTTKMK MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPGAKDHVNSLGEN IMP-93 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIE 430 AYMTIKAR MGNYQKTCAILIVLVSLFVCYSTAQSAAECIP YCRVSSCLAYCNGFENKNFFVR IMP-94 TCPLNEGVKLNVCDDLVCENTSESQGDSGCYCCCGYQLQYFNGR 431 ILVCFVIILTYTLYTDAYCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGK VKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPD IMP-95 IKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAM 432 SEFDIFINYIES MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DNLFLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN IMP-96 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIE 433 AYMTIKAR ILVCFVIILTYTLYTDAYCVEYEESEEDRQQCSSSNFPASLPHMPRELRAAFGK VKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPD IMP-97 IKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAM 434SEFDIFINYIESAttorney Docket No. 62801.82W001ILVCFVIILTYTLYTDAYCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGK VKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQAFSEMIQFYLEEVMPQAENHGPD IMP-98 IKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAM 435 SEFDIFINYIES ILVCFVIILTYTLYTDAYCVEYEESEEDRQQCSSSNFPASLPHMLRELRAAFGK VKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAENHGPD IMP-99 IKEHVNSPGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGVYKAM 436 SEFDIFINYIES MSNNKILVCVVIILTYTLYTDAYCVEYEESEEDRQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP- 100 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCEDKSKAVEQVKRVFNMLQER 437 GVYKAMSEFDILINYIESYMTTKM MSNNKILVCVAI ILTYTLYTDAYCVEYAESDEDKQQCSGSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPRAE IMP-101 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 438 VYKAMSEFDIFINYIESYMTTKM MSNNKILVCAVI ILTYTLYTDAYCIQYEESEEDKQQCSSSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIRFYLEEVMPQAE IMP- 102 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 439 VYKAMSEFDIFINYIESYMTTKM MSNNKILVCAVI ILTYTLYTDAYCVEYEESDEDRQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP- 103 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 440 GVYKAMSEFDIFINYIESYMTTKM MSNNKILVCAVI ILTYTLYTDAYCVEYEESDEDRQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP- 104 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 441 GVYKAMSEFDIFINYIESYMATKM MSNNKILVCAVI ILTYTLYTDAYCVEYAESDEDRQQCSGSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP- 105 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 442 VYKAMSEFDIFINYIESYMTTKM MSNNKILVCAVI ILTYTLYTDAYCVEYAESDEDRQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP- 106 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 443 GVYKAMSEFDIFINYIESYMTTKM MSNNKILVCVAI ILTYTLYTDAYCVEYAESDEDKQQCSGSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP- 107 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 444 VYKAMSEFDIFINYIESYMTTKM MRMMSSAIPILHTADCCAFQVLAVILRTERRSNNCCCTSLLLLSRGHFIGTSRL IMP- 108 CSLCIRIRHCRCIRDFRGIGLKAHLASPLSTTPKARKPHRSRHSLACQLLFAL 445 MRLHLLWVLALRTCNKCQRSLFICTCRIDFQIRAVKQRQKKAMEVFGSLSNHVW IMP- 109 CRCPHDTGLRTGCCEQLPGQTQVCFCQPHATKSMI 446 MELRSGLTLQCLVMLQCLVMLYLAPACKGASNCGNLPHMLRDLRDAFSRVKTFF QMKDQLDNILLKESLLEDFRGYLGCQALSEMIQFYLEEVMPQAENQDPHSKEHV IMP- 110 NSLGENLKTLRLRLRRCHRFLPCENKGKAVEQVKNAFSKLQEKGVYKAMSEFDI 447 FINYIEAYMTMKLRR MSKNKVLVCFVI ILTYTLYTDAYCVE YEESEEDKQQCGSNGGPASLPHMLRELR IMP-111 AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE 448NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERGAttorney Docket No. 62801.82W001VYKAMSEFDIFINYIESYMTTKM MKCTALLLAIVAVAWAGDTVLESIMESSCQPRPTKVQLSGYDMYIPACAYVPRC IMP- 112 GGCCSGGEATTCRPTATSTVNVTAYKLVFHDTQQWVSVLTHTACACKFKRAFL 449 QHLRGPRRR MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DSLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN IMP- 113 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIE 450 AYMTIKAR MERRLMVTLQCLVLLYLAPECGSTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DNILLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN IMP- 114 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFDIFINYIE 451 AYMTIKAR MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN IMP-115 LKTIRLRLRRCHRFLPCENKSKAVEQTKNAFNKLQEKGTYKAMSEFDTFINYIE 452 AYMTIKAR MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV DNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN IMP-116 LKTLRLRLRRCHRFLPCENKSKAVEQIKNAFNKLQEKGIYKAMSEFHIFINYIE 453 AYMTIKAR MKLCCISMCFLATIVYNIYCLPILETIKLSMCKPRDTKIDVYKLDRADVSKIYT IMP-117 PSCVYVKRCGGCCNGDQFTCEASHKNITELTLFQTNALLMSKHNRVAPITPIIF 454 K V VE HTACKCVSTIRHLIRPLIR MKGGTLTLLAVFLFKVFLQSGDSVGGLTGLYQPRCCNGYQRRPLPWWLMESWSP IMP- 118 TSQSCHKSAVIFLTKKGRQVCMDPSKDWVQKLMQRVSVTT 455 MSKNKILVCVAIILTYTLYTDAYCVEYEESKEDEQQCSGSNGASASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-119 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 456 GVYKAMSEFDIFINYIESYMTTKM MSKNKILVCVAIILTYTLYTDAYCVEYLESREDEQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP- 120 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 457 GVYKAMSEFDIFINYIESYMTTKM MKLTATLQWALLICMYNLPECVSQGNDSPPSVNEWMQTLGKSGCEPRDTWKL IMP- 121 GDEYPHNTDKNYNPKCVTVKRCSGCCNGDRQVCTAVETKNTTWVSVTSVSSSS 458 GANSGVSNSLQRISVTEHTKCECIDGTTTPPTTTTREPRR MS P TRHWLVGP AFALAGAI LFAMCAP KAAAAE GWQLTE CP P GEP CRPRGKP LD V IMP- 122 KTACELDLVSLAIVAAKGTRIRCDKLTTKKEAR 459 MRIFVALVCMQP ILAGAIDIRYCGAPARDLDGTIHRSVQKISEFKRAHPCPANG IMP- 123 INKGACPGWAIDHVIPLVCGGCDDIFNMQWLPNKIKSAAGIYPKDRWEQHVYCS 460 AGK MRLIFGALIIFLAYVYHYEVNGTELRCRCLHKKWPPNRTILGNYWLHRDPRGPG IMP- 124 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKRNDNRWYNVNITRSPEPRRI 461 NITLIGVRG MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP- 125 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKYNDNRWYNVNITKSPEPRRI 462 NITLIGVRG MSKNKILVCVAIILTYTLYTDAYCVEYEETKEDEQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP- 126 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 463GVYKAMSEFDIFINYIESYMTTKMAttorney Docket No. 62801.82W001MRGGDVFASWLMLLLALPRPGVSLAKRRCCLNPTNRP IPNPLLQDLSRVDYQA IMP- 127 IGHDCGREAFRVTLQDGRQGCVSVGNKSLLDWLRGHKDLCPQIWSGCESL 464 MLSVMVSSSLVLIVFFLGASEEAKPATTTIKNTKPQCRPEDYATRLQDLRVTFH RIKPTLQREDDYSVWLDGTWKGCWGCSVMDWLLRRYLEIVFPAGDHVYPGLKT IMP- 128 ELHSMRSTLESIYKDMRQCPLLGCGDKSVISRLSQEAERKSDNGTRKGLSELDT 465 LFSRLEEYLHSRK MRTYVICFLMCICLIGTLGEQRCQCINSYYPRIPRTITCIYIQHPGPTCHRTEA IMP- 129 IAYFNPTYHGPICLDYNKLQNRLPKQQGSWCRFNRTLIDTPVRDCRNCDKFRIL 466 MNVLRFWIRALFCICVLLSVLQYVFGIELRCQCVNYYSGIPWTAKCVYLKPKSP IMP- 130 ECNKYELIVYYDSAMKTCVRVRNS YVFDNINEHTWFQVTNKPGTKQIKLKKQKT 467 SCAWS MNFWKAATVPAALLVMFLVFSKVSGEQSIDLMQRCWCSQTTQGIGRQHIKSLQL IMP-131 RDPTDMCPKTELIATLTDGREVCLNPEAPMSVKMISKIKEHEKDYIKKVTT 468 MKNLLNPRFLGVALLIISLMSYSGFADELRCECTDVTQGIHPKNIQSVIVKYPG IMP- 132 PHCSHQEI IATLKTGQKVCLNGEAPMVKKMIEKRKN 469 MQFNKLACNIFWTMVFMLILSGTVFANHPRCLCPRTMKGINATDIQIVRIKLP IMP- 133 S SECDKTE I I VQRKNGFE VCLDPKS ALGKKLMEKYLKRYGQ 470 MNTVRINIAAMLLICLILSGLSGSRGSELRCNCVKYYFGIPWTATCVYLKPKS I IMP- 134 ECNNYELIVYDGSPHKTCVRVRNPSVFDRLDKQTWFTVTKKPNRHISLKPQRTS 471 CAVPKS MRVYMACVLLCLYVHGLVAEQRCQCIGKKYNRIPHKTLCLSIEYAGPRCEVTEA IMP- 135 VASFNPIHNRPPICLNYENIRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVT 472 LE MRVFVACVLLYLSVHGLVAEQRCQCIGKKYNRIPRKAICLSIENAGPRCEVSEA IMP-136 WSFNPIHNRSPMCLDYESIRKRFPATPGTWCRVGKSLIKVNDKNCEICNRFVT 473 LE MTLCNVNHKLFIFALAIILLVSHTVFAEYPRCLCLRTTKGIHPKHIKTVEIKEP IMP- 137 RSECNKMEIIAHLKNGVEVCLDPESAMGKKLIEKSQKQYEQ 474 MQYFGFHTRFISVTFAIFLFSWLTIGNGTETEYCECVNVTLFTSIPNDTLYLQP IMP- 138 LAPNENCTKQEVIAVLQNNTRACLNPHALAVRVFFNRLFFRI IKNEDGLYDVID 475 TQLELPSWNITRKYYKRYLKQKVNSENAKILSRMIL MNTSSSSRFLGVALLLMTLIAYGHSVNELYCQCTHVTQGISANVIKTVTITSPT IMP- 139 SGCDHREI ILTLKDGRQTCLNPHSPLGKKLLATVKH 476 MKFDKLACNIFWTMVFMLILSGTVFANHPRCLCPRTMKGVNASDIQIVKIKLP IMP- 140 S SECHKTE 11 VQRKNGFEVCLDTKSP LGKKLMEKYLKRYEQ 477 MRVYVACVLLCLYVHGLVAEQRCQCIGKKYNRIPHRTLCLSIEYAGPRCEVTEA IMP-141 VASFNPTHNRPPICLNYENIRNRFPATPGTWCRVGKSLTKVNDKNCEICNRFVT 478 LE MNRAIFNPRVLGVALLLMTLIAHHQTAAELRCQCLQVMKGLPPSNIQRLS ITRP IMP- 142 NAGCERREIIATLKNGKQVCLDPEAPMMKKMLSKIPGGTYPSFWEHLMTLFRD 479 MNRAIFNPRVLGVALLLMTLIAHHQTAAELRCQCLQVMKGLPPSNIQRLS ITRP IMP- 143 NAGCERREIIATLKNGKQVCLDPEAPMMKKMLSNSRRNVPIVLGTSDDAV 480 MNVYAIPVALMLVSAAFIPQGFATPHSVAPTCCTTFVNKPIPRQLLKGYIEVIN IMP-144 SRCPRKAVIFKTKLGKEICAKPHEKHTRLDGRKLYLNLEASMCKKILKVSRNKK 481 RRKIV MNVYAIPVALMLVSAAFIPQGFATPHSVAPTCCTTFVNKP IPRQLLKGYIEVIN IMP- 145 SRCPRKAVIFKTKLGKEICAKPHEKWVQDSMDHLNKMNSKGHNYR 482 MNASRLMIGALLCVCVILSNFQYAWGTELRCSCINYYHTIPWKAKCVYFQPKSP IMP- 146 ACDKYELIVYYQNSPTKTCVRVKNPSVFDNINEQAWFTVTKVPGKKQLSFRRQA 483T SCAWSAttorney Docket No. 62801.82W001MNNLFNPRFIGVLLMVTTLIAYIESATELRCWCPEATQGIHPKNIQNVTVKYPD IMP- 147 QNCPRKEI IATLKNGDKVCLNPDAPMFNQTKKVKKVKKVKKVKKVIKRSS 484 MCAQCLSLSCSCFCCSCRCCLRPRCTPEEPGVQEGRGAEHVQMQPCLTQPSPQP IMP- 148 SMLIGCPQPIHLPPSSPVCPPSGPHGLTGAAVAHAAALPHYPMPGSRQ 485 MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGSYWLHRDPRGPG IMP-149 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKHNDNRWYNVNIMKSPGPRRI 486 NITLIGVRG MRLIFGSLISLLMAFMYYHGVHSRELRCPCTHKALHHP IGGLFWVARDPPNPPE IMP-150 CDKPQHYLLPPRGKPVCLAPDHHLSKWLDGKKDNSWHKVLVKVKDSNGPHVEEN 487 AVTNKRPRWK IMP-151 MDFLSFSILCPLRLQVCPWCPCSRLLKRRCCSAPRR 488 MNVSKRVMAALLALALAGGGATYLSRDGAQQIASHEGYRLVAYPDPATGGAPWT ICRGHTKGVYRGMRATHEQCDQWYAEDLHVAERAVQRNVRVPLKQGEYDAMVSF IMP-152 VFNVGESNLRASTLLRKVNAGDRRGSCNQYPRWI YANKMVLNGLVTRRYEEQAT 489 CLKDGPYVYLP MKKSLLLIAMAGGLLTACAPADTPKVAEKAPTPAPEQLEPAGPAPFEFIVYSTG IMP-153 VRNLRALVHVRTGCVWIASPQSGYVDGYGATFKLEEPDGKGGMRQVCDPS IRPA 490 TPK MQASLLVLVLFIVQIYLLPGNGISLESLAVGKRCKCVKVTNRPTGLGPIIAVDV IMP- 154 IPPGIHCRRTEIMFALKKNRKVCVDPEAPWVQQLIKKLERQHRTRKENLMVGED 491 GGKSTVGPVKNTIEPTPPTIGSHICL MQASLLVLVLFIVQIYLLPGNGISLESLAVGKRCKCVKVTNRPTGLGPIIAVDV IMP- 155 IPPGIHCRRTEIMFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED 492 GGKSTVGPVKNTIEPTPPTIGSHICL MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDV IMP-156 IPPGIHCRRTEIMFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED 493 GGKSTVGPVKNTIEPTPPTIGSHICL MMCALCTILLATEACRTPRPSRWFEANLEVWVQQIRRGCQTSTNLHQLSLKQEK IMP-157 TGRMCVLCTIP 494 MNRAIFNPRVLGVALLLMTLIAYHQTAAVELRCQCLQVTQGINPKNIQSMTITK IMP- 158 PNGGCDRREIIATLKNGQKVCLNPEAPMMKKILSKFPGGTYSSFWQHFMTLFTD 495 MQFNKLACNIFVVTMAFMLILSGTVFANHPRCLCPRTMKGINATDIQIVRIKPP IMP-159 S SECDKTE I IVQRRNGFEVCLDTT SP LGKKLMEKYLKRYEQ 496 MRVYVACVLLCVYAHGLAAEQRCQCIGKKYNRIPRKAICLSIEHAGPRCEVTEA IMP- 160 VASFNPIHNRPPMCLDYNNIRNIFPATPGTWCRVGKSLIKVNDKNCEICNRFVT 497 LE MFVGSKRTFSFFGMLSYVVRTLCPFQCQRPVSSIFSIARLYIRRYSPHHLLRTM IMP- 161 ASLTFGNISTFRDIIAFFGIATLPVMFAGENSGDCDDVFCELCCR 498 MRLIFSSLISLLMVFMYYHGVHSRELRCPCTHKALHHP IGGLFWVGRDPPNPPE IMP- 162 CDKPQHYLLPPRGKPACLAPDHHLSKWLDGKKDNSWHRVLVKIKDSNGPHVEEN 499 AVTNKRPRWK MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPGGPG IMP- 163 CDKNEHLLYPNGRKPPGVCLSPDHLFSKWLDKHDDNRWYNVNITKSPGPRRINI 500 TLIGVGG MKLLSFKLSVIITVCLHQYCMLSASPTAQSPNTTPRKWTDVLGSGSCKPRETVV IMP- 164 RIGDEYPSLISQRFSPPCVSVMRCGGCCNDESLECVPTEEANITMEVMSVSVSS 501 TGSNPGMQNMQFVEHLRCDCKPKTTPTPEPQGQPRR MRKMRAYLGTAVLIAILVVGLEVMRTDAMPHVPATCCTQYATKALKFNKILTYV IMP- 165 S VS S SNCAFPGVIF ITKKGQMVCANP SDPWVKD YVERLDKLP SVQQA 502 MRLLVGILVAVCLHQYLLNADSTKTWSEVFESSKCKPRPTWPVGEAHPELTSQ IMP- 166 503RFNPQCVTVMRCGGCCNDESLECVPTEEANVTMQLMGASVSGGNGMQHLIFVEHAttorney Docket No. 62801.82W001KKCDCKPRLTTTPPTTTRPPRRRR PMIFKVQGGILGFFFFYLFGPPGPRLGVREKITTSHRSQARGRLQPMPNAPQAR IMP- 167 504 GGHWAHPLYPCIENRDGGGGGGCCLPPPPGPR MKALYNPRFLGVALLLMSLIAYCQSTTELRCQCTQTVQGIHPKNIQSVSIKDRG IMP- 168 PNCPNKEVIATLKNGQKVCLNPDAPMTKKILETAEKRN 505 MQYLKVLSVTLLVTLLLSSAFGDMEQRCLCRNTARGIDPKHIKGVKMELPKQTC IMP- 169 MKTELIATLKDGREICLDTESPMAKKIIEKLNEIKNSS 506 MNGMRFTVGATVCLYVLLTNLQNAYTTELRCRCVNYYSGTPWTATCVYLKPKS I IMP- 170 GCNKYELIVYDGSETKTCVRVSNPSKFDTITKHTWFKVTKLPGKNQIRLQKQNT 507 PCSVVQ MKALYNPRFLGVTLLLMSLIAYCQSTTELRCQCTQTVQGIHPKNIQSVSIKDKG IMP-171 PNCPNQEVIATLKNGQKVCLNPTAPMVQKILKKTITDN 508 MQYSLSHLLVATLLGTLLASTMVFADKEERCLCPKTIQGIHPKNIQSVELHEPR IMP- 172 509 DMCPNVEVIAKLKNGNEVCLNTEGPMVKKIIEKMRDREIERIQQQSQ MNTSRLLVGTILCLCVLLSDLHYAWGKELRCQCINYYSGIPWTATCVYLKPKSA IMP- 173 ACNQYELIVYNGSERKTCVRVRNTSAFERFNRVTWFKVTKGKGKNISLKLHNGS 510 CAWS MANVVYWLVISIMMANIHVSKTYCTSCSHHQCTEDENQKQDCEDANHSLPHML RELRAAFGKVKTFFQMKDQLHSLLLTQSLLDDFKGYLGCQALSEMIQFYLEEVM IMP- 174 PQAENHGPEEHDNSLSEHGPDVKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSK 511 AVEKVKRVFSELQERGVYKAMSEFDIFINYIETYMTT IMP- 175 MKLLIVFGLLTSVYCIHKECSIQECCENQPYQIEDPCPIHYYSDWFIKIGSM 512 MRVYVACVLLCVYVHGLVAEQRCQCIGKKYNRIPHKTLCLSIEYAGPRCEVTEA IMP- 176 IASFNPIHNRPPICLNYENIRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVT 513 LE MSPKNLTPFLTALWLLLGHSRVPRVRAEECCEFINVNHPPERCYDFKMCNRFTV ALRCPDGEVCYSPEKTAEIRGIVTTMTHSLTRQVVHNKLTSCNYNLLYLEADGR IMP- 177 514 IRCGKVNDKAQYLLGAVGSVPYRWINLEYDKITRIVGLDQYLESVKKHKRLDVC RAKMGYMLQ MKCTALLLLAIVAVAWAGNTVLESIMESSCQPRPTKVQLSSYSMYIPACTYVPR IMP- 178 CGGCCSGDEATTCRPTATGTVNVTAFKLVFRTTQQVVLSVVTHTACACKFKRAY 515 LRGPRRR MLSVMVSSSLVLIVFFLGASEEAKPATTTTIKNTKPQCRPEDYATRLQDLRVTF HRVKPTLQREDDYSVWLDGTWKGCWGCSVMDWLLRRYLETVFPAGDHVYPGLK IMP- 179 TELHSMRSTLES I YKDMRQCPLLGCGDKSVTSRLSQEAERKSDNGTRKGLSELD 516 TLFSRLEEYLHSRK MQASLLVLVLFIVQIYLLPGNGISLESLAVGKRCKCVKVTNRPTGLGPIIAVDV IMP- 180 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED 517 GGKSTVGPVKNTIEPTPPTIGSHICF MQASLLVLVLFIVQIYLLPGNGISLESLAVGKRCKCVKVTNRPTGLGPIIAVDV IMP- 181 IPPGIHCRRTEIIFALKKNRKVCVDPGAPWVQQFIKKLERQHRTRKENLMVGED 518 GGKSTVGPVKNTIEPTPPTIGSHICL MQAS LLVLVLF I VQ I YLLP GNG ISLES LAVGKRCKCVKVTNRPT GLGP I T AVD V IMP- 182 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED 519 GGKSTVGPVKNTIEPTPPTIGSHICL LLALLSCLTVPASAINYRNVSGIYHVTNDCPNSS IVYETDHHILHLPGCVPCVR IMP- 183 AENRSHCWVALTPTVAGPYIGAPLESLRSHVDLMGGAATACSPLYIGDLCGGLF 520 LVGQMFSFRPRRHWTTQDCNC LLALLSCLTVPASAINYHNTSGIYHVTNDCPNSSIVYEADHHILHLPGCVPCVR IMP- 184 VGNQSRCWVALTPTVAGPYVGAPLESLRSHVDLMVGTATACSPLYIGDLCGGLF 521LVGQMFSFRPRRHWTTQDCNCAttorney Docket No. 62801.82W001MQFNKLACNIFVVTMVFMLILSGTVFANHPRCLCPHTMKGINATDIQIVRIKLP IMP- 185 S SECDKTE I IVQRRNGFEVCLDTT SP LGKKLMEKYLKRYEQ 522 MRVYVACVLLCLYVHGLVAEQRCQCIGKKYNRIPHRTLCLSIEYAGPRCEVTEA IMP- 186 VASFNPIHNRPPICLNYENIRNRFPAAPGTWCRVGKSLIKVNDKNCEICNRFVT 523 LE MKFDKLACNIFVVTMVFMLILSGTVFANHPRCLCPRTMKGVNASDIQIVKIKLP IMP- 187 S SECHKPE 11 VQRKNGFE VCLDTKSP LGKKLMEKYLKRYEQ 524 MNRAIFNPRVLGVALLLMTLIAHHQTAAELRCQCLQVMKGIPPSNIQRIS ITRP IMP- 188 NAGCERREIIATLKNGKQVCLDPEAPMMKKMCQKFPGGTYPSFWEHLMTLFRDW 525 MLTPQA MITLSCSGIMPFSSDSRMSAGPSRSCAVSDCPFSQSSCFPQPHRLCISFLKIFM SFSCSACITAHFIQPLDILPRPVTKPDLQMLKKTLNPCGIFGVKKGQSGDECAI CIREPAMAVCLNNVSRPQTEPYLRLPRVALRPLRSGRPHRACRTCFSFRSLWAC IMP- 189 526 RACRTGISLWTLWTCISRQTGLSPLSPVTFRPLRACRTSITCRSPFAGCPDRAG VTALSLTTLRPSRTCWPRVPFISFRTGNTTSCCSLFCLCFRFTCHIHCRFHRFR GGSLRFIITVRCAA MRVLSNEMNTFRVPVAAMLLICLILSGFSGSQCSELRCSCVNYYSGIPWTATCV IMP- 190 YVKPKSIECNKYELIVYNGSPNKTCVRVRNQSVFDRITKQKWFKVTKGAKHQLS 527 LTPQRASCAVSK MNRAIFNPRVLGVALLLMTLIAYHQTAAAELRCQCLQVTQGINPKNIQSMTITK IMP-191 PNGGCDRREI IATLKNGQKVCLNPEAPMMKKLLSKFPGETYASFWQHFMTLFTD 528 MRVCVAYVLLCLSVHGLVAEQRCQCIGKKYNRIPHKTLCLSIEHAGPRCEVTEA IMP- 192 IASFNPIHNRPPICLNYEKLRNRFPATPGTWCRVGKSLIKVNDKNCEICNRFVT 529 LE MRLIFGALIIFLAYVYHYEVNGTELRCRCLHKKWPPNKIILGNYWLHRDPRGPG IMP- 193 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDERNDNRWYNVNITKSPEPRRI 530 NITLIGVRG MI ILRYILGAILCAFVLLCGLPNVWSKELRCNCVQYYHGIPWTATCVYLEPKNN IMP- 194 HCNKYELIVYDGSEKKTCVRFSDPSKFKNVHQKTWFTVTRGAGRQIRLKKQSTS 531 CAWQ MKALYNPRFIGVALLLMSLIAYSECVHELHCECPNTRSGIYPGHIKTVLVKKPG IMP- 195 532 VNCPVTEVIATLKNGQKVCLDPDAPMVKNKILTKVS I MNTSRLTVGAIVCLCVLLSGLHTAWGRELRCSCVRYYHGIPWTATCVYLKPKSA IMP-196 VCDRYELIVYNKSPTKTCVRVKNPSVFDKINEHAWFKVTNKPGTKQISLRRQNT 533 PCSVVQ MKALYNPRFLGVALLLMSLIAYCQSATELRCQCTNTQSGIHPKNIQSLEIRKPG IMP- 197 ATCPNKEVIATLKNGQKVCLNPEAPMVKNKILKKN 534 MRITWTWYVTILSCVLLTAAMAAVSPNELRCRCKPGQNYEGLELQHIMIVAVY IMP- 198 PHNPYCNWQDTIAYLYGKKAWTCFDFSKLKTEIEKNMVSKTTREGITVYRRHFK 535 ETGIQVSESSQSLPTATVLGMPQPPVYFSSNASHATCQMQHNGESCSCSCT MQALLLVLVLF I VQ I Y S LP GNG ISLES LAVDKRCKCVKVTNRPT GLGP 11 AVD V IMP- 199 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERRHRTRKENLMVGED 536 GGKSTVGPVKNTIEPTPPTIGSHICL MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDV IMP-200 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERRHRTRKENLMVGED 537 GGKSTVGPVKNTIEPTPPTIGSHICL LVLCLLSILFAAWLQPNDSKRVKVKFGACLSHLRDILNISTECFNITLNNNKTG CENETLGNPDKKPGLPCRDCLNLTLSNNSTKCQHEESRLESVLLEVGLMLHNRS IMP-201 IQVSGQFENTTCSSFVNVTLSELLQGWLSMLQRSYAYRYCGDPSPNHTRCQAFC 538PIMP-202 MSKNKILVCLVIILTYTLYTDAYCVEYEESEEDKQQCGSSSNFPASLPHMLREL 539Attorney Docket No. 62801.82W001RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER GVYKAMSEFDIFINYIESYMITKM MSKNKILVCVAIILTYTLYTDAYCVEYLESGEDEQQCGSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-203 ENHGPDTKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 540 GVYKAMSEFDIFINYIESYMITKM MLLAFHRNLGASLGGIRLPQVASARASCPPQFPSPRASGPLRPRPPETRASGPA IMP-204 SPVTLLEPQPGHMCQTPWPLRPSGPPGPRPQQPCCSPP 541MKKLILLLVLYINIFNSRAAMLTYNIWDVNQKIFYLRNNQLVAGHIQDNSLAEK ITAKLIGGNDIFLGVKNGEKSLECTEHGDKVTLSLSDKKTNSLDESQDKRFAFI IMP-205 RSDNGHTSTFESVAFPGWFLCTSSGDGIEPVGLTYKGDKDDDNDENNIYFYFEE 542 ED MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDV IMP-206 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFTKKLERQHRTREENLMVGED 543 GGKSTVGPVKNTIEPTPPTIGSHICL MQALLLVLVLFIVQIYLLPGNGISLESLAADKRCKCVKVTNRPTGLGPIIAVDV IMP-207 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED 544 GGKSTVGPVKNTIEPTPPTIGSHICL MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDV IMP-208 IPPGIHCRRTEI IFALKKNRKVCVDPEAPWVQQLIKKLERQHRTRKENLMVGED 545 GGKSTVGPVKNTIEPTPPTIGSHICL MRSIVLSVGFVPIVLFYWRAARNVCFIQYSHTCLLITYVQSHLAARQCLLPTLT IMP-209 ATCHFQPPAQNTPHPLRLAATTREPPPRPHSP YRGGNVLAFCHFARFASVPCYK 546 ARRFSPSPHVLS MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP-210 CDKNEHLLYPDGRKPPGSGVCLSPDHLFSKWLDKYNDNRWYNVNITKSPGPRRI 547 NITLIGVRG MRLIFGSLISLLMAFMYYHGVHSRELRCPCTHKALHHP IGGLFWVGRDPPNPPE IMP-211 CDKPQHYLLPPRGKPVCLAPDHHLSKWLDGKKDNSWHKVLRKVKDSNGPHVEEN 548 AVTNKRPRWK MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP-212 CDKNEHLLYPDGRKPPGHGVCLSPDHLFSKWLDKRNDNRWYNVNITKSPEPRRI 549 NITLIGVRG MKLLVCILWVCLHQHFVNADSTKTWFEVFENSGCKPRPMVFRVHDEYPTLTSQ IMP-213 RFNPPCVTLMRCGGCCNDESLECVPTEEANVTMQLMGASVSGGNGMQHLSFVEH 550 KKCDCKPPLTTTPPTTTRLPRRRR MRVLVIGAFFAVFACVVDYAFPMGSMSGPAPEVCCLGYINKLPPSGAVALYYYT IMP-214 SSQCTLDAVILETHRGQKLCANPGDDGVRKLLQKVDNRPKRNKGRRTRRSLLDD 551ASDEGLESGSGF MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP-215 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKHNDNRWYNVNITKSPGPRRI 552 NITLIGVRG MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGSYWLHRDPRGPG IMP-216 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKHNDNRWYNVNITKSPGPRRI 553 NITLIGVRG MRLIFSSLISLLMAFMYYHGVHSRELRCPCTHKALHHP IGGLFWVGRDPPNPPE IMP-217 CDKPQHYLLPPRGKPVCLAPDHHLSKWLDGKKDNSWHKVLVKVKDSNGPHVQEN 554 AVTNKRPRWK MRLIFGALIIFLAYVYHYEVNGTELRCRCLHKKWPPNKIILGNYWLHRDPRGPG IMP-218 555CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKYNDNRWYNVNITKSPGPRRIAttorney Docket No. 62801.82W001NITLIGVKG MRLIFGALIIFLAYVYHYEVNGTELRCRCLHKKWPPNKIILGNYWLHRDPRGPG IMP-219 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKRNDNRWYNVNITKSPEPRRI 556 NITLIGVRG MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP-220 CDKNEHLLYPDGRKPPGPGVCLSPDHLFSKWLDKYNDNRWYNVNITKSPGPRRI 557 NITLIGVKG MRLIFGTLISLLMAFMYYHGVHSRELRCPCTHKALHHP IGGLFWVGRDPPNPPE IMP-221 CDKPQHYLLPPRGKPVCLAPDHHLSKWLDGKKDNSWHRVLVKVKDSNGPHVGEN 558 AVTNKRPRWK MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP-222 CDKNEHLLYPNGKKPPGVCLSPDHLFSKWLDKHDDNRWYNVNITKSPGPRRINI 559 TLIGVGG MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP-223 CDKNEHLLYPNGRKPPGVCLSPDHLFSKWLDKHDDNRWYNVNITKSPGPRRINI 560 TLIGVGG MRLIFGALIIFLAYVYHYEVNGTELRCRCLHRKWPPNKIILGNYWLHRDPRGPG IMP-224 CDKNEHLLYLDGRKPPGPGVCLSPDHLFSKWLDKHNDDRWYNVNITKSPGPRRI 561 NITLIGVRG MRLISGSLISLLMAFMYYHGVHSRELRCPCTHKALHHP IGGLFWVGRDPPNPPE IMP-225 CDKPQHYLLPPRGKPVCLAPDHHLSKWLDGKKDNSWHKVLVKVKDGNGPHVEEN 562 AVTNKRPRWK MSNKKILVCVVIILTYTLYTDAYCVEYKESEEDRQQCSSSSFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP-226 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 563 VYKAMSEFDIFINYIESYMTTK MKLLVGILVAVCLHQYLLNADSSTKRWSEVLKGSECRPRPIVVPVSETHPELTS IMP-227 QRFNPPCVTLMRCGGCCNDESLECVPTEEANVTMEFMGVGVSSTGSSVSTQHLE 564 FVEHTKCDCQPRGGQQTTPTPPRRRRRAY MSKNKILVCVAI ILTYTLYTDAYCVEYLESREDEQQCSGSNGASASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-228 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 565 GVYKAMSEFDTFINYIESYMTTKM MFLYWCSLAVCFRGLLSLSLLSSPNLCPGVISTPYKLTCLSNASLPISWYCNN IMP-229 TRLFRLTERTVFPVTIACNFTCVEQSGHRQSIWITW 566 MFLYWCSLAVWFRGLCPGVISTP YKLTCLSNASLP ISWYCNNTRLLRLTERTL IMP-230 FPVTIACNFTCVEQSGHRQSIWITW 567 MKFLVGILVAVCLHQYLLNADSTKTWSEVFENSGCKPRPMVFRVHDEHPELTSQ IMP-231 RFNPPCVTLMRCGGCCNDESLECVPTEEANVTMQLMGASVSGGNGMQHLSFVEH 568 KKCDCKPPLTTTPPTTTRPPRRRR MRGLFVCVFFAVFACVVDYAFPMGSMSGPAPELCCLGYVTHLPPPGLVVS YSHT IMP-232 SSQCSVDAVILNTRRGKKLCANPGDDAVKKLLQAVDKRPKKGRRTRRSLIDDSE 569 EGLGSGI MSKNKILVCVAI ILTYTLYTDAYCVE YEESDEDKQQCSSSTGAP AS LPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-233 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 570 GVYKAMSEFDIFINYIESYMTTKM MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCECVKVTNRPTGLGPIIAVDV IMP-234 IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVRQFIKKLERQHRTRKENLMVGED 571GGKSTVGPVKKHNIMP-235 MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDV 572Attorney Docket No. 62801.82W001IPPGIHCRRTEIIFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED GGKSTVGPVKKHN KPWSTQLLLNGSLAEDKIIIRSKNISQNTNIIIVHLNASVPIICTRPNNNTRK IMP-236 G I H I GP GRAF YATGDIIGDI RKAH CNVS GP KWND TLKNVT AE LKVHFP DNT I T F 573 N MGLRSGLTLQCLVILQCLVMLYLAPACKGVSNCGNLPHMLRDLRDAFSRVKTFF QMKDQLDNILLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPHAKEHV IMP-237 NSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFSKLQEKGVYKAMSEFDI 574 FINYIEAYMTMKIRR MRACSSAWVAGPSSPKALRRSFSRSCCNFNRPMSVRAPSVSPAKLATLRMTPLS IMP-238 CMPCLIWLKVFECTKRLPVLYSQRPVEFSALVMRDPRLPQLMAPPLKLESPMWW 575 SLRAHPPRCGDSAA MQALLLVLVLFIVQIYLLPGNGISLESLAVDKRCKCVKVTNRPTGLGPIIAVDV IMP-239 IPPGIHCRRTEI IFALKKNRKVCVDPEAPWVQQFIKKLERQHRTRKENLMVGED 576 GGKSTVGPVKNTIDAPHLLLLVPISVSLINCYLL MELSLGLTLHFLVFLCLAPACGRAETCGNIPHMLRDLRDAFSRVKTFFQMKDQL DNILLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAEAMSLKSQEHVNFLGEN IMP-240 LNTLRLRLRRCHRFLPCENKSKAVEQVKNAFSKLQEKGVYKAMSEFDIFINYIE 577 AYMTMKLRR MERRLVVTLQCLVLLYLAPECGGTDQCDNFPQMLRDLRDAFSRVKTFFQTKDEV IMP-241 DNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPEAKDHVNSLGEN 578 LKTLRLRLRRCHRFLPCENKSKAVEQIKMPLTSCRKKEFTKP MWRGLLLLCLWGDWLCGFCAASGPATLVASDCCEAARRVRLPVRSLAGWYWTS IMP-242 KVYCRRQAVIFLTRPGRKVCAWPDARTRRLMARVPELSFQEKMARART 579 MKIRVWLLMTALLFALYLHCGEGVGGMVGHGNRYCCTGYQRKPLPRWLLGSWYP IMP-243 TSHLCTKPGVIFLTKRGRQVCADPSKDWVQKLMQQVPATA 580 MRKMRAYLGTAVLIAILVVGLEVMRTDAMPHVPATCCTQYATKALKFNRILTYV IMP-244 S VS S SNCAFPGVIF ITKKGQMVCANP SDPWVKD YVERLDKSP SVQQA 581 MKALLFFLLILTSASEAFFPLRTDLTCVCGNGNGWRAFEPVNSTDPFLLIGSLQ IMP-245 LSGHCVPPEATMTLKSDQRRRCVNPFLLGDALLFGVEQGKPESILTEGLKSELL 582 QFVHILKSHVSKRPPSLR MFKQIYIGLLLITLTLGYCIHDEDCFENECCVNHVCVECNNLRLKRNVPNGCSG IMP-246 CLGICVCIGENCICMP INK 583 MLSMMVSSSLVLIVFFLGAFEEAKPATTTTIKNTKPQCRPEDYATRLQDLRVTF DRVKPTLQREDDYSVWLDGTWKGCWGCSVMDWLLRRYLEIVFPAGDHVYPGLK IMP-247 TELHSMRSTLES I YKDMRQCPLLGCGDKSVISRLSQEAERKSDNGTRKGLSELD 584 TLFSRLEEYLHSRK MSNNKILVCVAI ILTYTLYTDAYCIEYAESDEDKQQCSGSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP-248 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 585 VYKAMSEFDIFINYIESYMTTKS MSNNKILVCVAI ILTYTLYTDAYCIEYAESDEDKQQCSGSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLIQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP-249 NHGP D I KE HVNS LGEKLKTLRLRLRRCHRF LP CENKSKAVEQVKRVFNMLQERG 586 VYKAMSEFDIFINYIESYMTTKS MSNNKILVCAVIILTYTLYTDAYFVEYLESDEDRQQCSSSNFPASLPHMLRELR AAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAE IMP-250 NHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQERG 587 VYKAMSEFDIFINYIESYMTTKT MSNNKILVCVVIILTYTLYTDAYCVQYEESDEDRQQCSSSSNFPASLPHMLREL IMP-251 588RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQAAttorney Docket No. 62801.82W001ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER GVYKAMSEFDIFINYIESYMTTKI MSNNKILVCVAIILTYTLYTDAYCVEYAESEEDRQQCSSSSNFPASLPHMLREL RAAFGKVKTFFQMKDQLNSMLLTQSLLDDFKGYLGCQALSEMIQFYLEEVMPQA IMP-252 ENHGPDIKEHVNSLGEKLKTLRLRLRRCHRFLPCENKSKAVEQVKRVFNMLQER 589 GVYKAMSEFDIFINYIESYMTTKS MKGFILWFLLPMLTVIVLQDNGLLNLKMKLYLLSIAHKGRLPASLFKDSSPPPE IMP-253 TPGTPHPTRKPPPDETRIKRESLALPPRRPLI YDADEDDEHNKENLPPDDDRKG 606YGRKQVLQYLLEKLEEDLQLYQDEVLRELSVLRQKLGIPQ

[0144] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence 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 a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence at least about 85% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence at least about 90% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence at least about 95% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence at least about 99% identical to the amino acid sequence of a protein set forth in Table 1.

[0145] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence 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 a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence about 85% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence about 90% identical to the amino acid sequence of a protein setAttorney Docket No. 62801.82W001forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence about 95% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence about 99% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence about 100% identical to the amino acid sequence of a protein set forth in Table 1.

[0146] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence 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 a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP consists of an amino acid sequence at least about 85% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence at least about 90% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence at least about 95% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence at least about 99% identical to the amino acid sequence of a protein set forth in Table 1.

[0147] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence 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 a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence about 85% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence ofAttorney Docket No. 62801.82W001the IMP (or a functional fragment, functional variant, or functional fragmen t / vari ant thereof) consists of an amino acid sequence about 90% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence about 95% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence about 99% identical to the amino acid sequence of a protein set forth in Table 1. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence about 100% identical to the amino acid sequence of a protein set forth in Table 1.

[0148] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence of a protein set forth in Table 1, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence of a protein set forth in Table 1, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence of a protein set forth in Table 1, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence of a protein set forth in Table 1, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence of a protein set forth in Table 1, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises theAttorney Docket No. 62801.82W001amino acid sequence of a protein set forth in Table 1, and further comprises or no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0149] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence of a protein set forth in Table 1, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence of a protein set forth in Table 1, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence of a protein set forth in Table 1, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence of a protein set forth in Table 1, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence of a protein set forth in Table 1, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence of a protein set forth in Table 1, and further comprises or no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions, deletions, etc.).

[0150] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence 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 set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606. For example, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-Attorney Docket No. 62801.82W001606. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595. or 605-606. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 95% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246. 338-595, or 605-606. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606.

[0151] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence 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 set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606. For example, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595. or 605-606. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 95% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595. or 605-606.

[0152] In embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof)Attorney Docket No. 62801.82W001comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606, 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.).

[0153] In embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246. 338-595, or 605-606. and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246. 338-595, or 605-606, and further consists of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid variations (e.g., substitutions, additions,Attorney Docket No. 62801.82W001deletions, etc.). In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246. 338-595, or 605-606. 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.).

[0154] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises a homologous signal peptide operably connected to the IMP. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises a homologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606 and comprises a homologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606 and comprises a homologous signal peptide operably connected to the N-terminus of the IMP.

[0155] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence 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 set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. For example, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 95% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functionalAttorney Docket No. 62801.82W001fragment / variant thereof) may comprise an amino acid sequence 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605.

[0156] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence 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 set forth in any one of SEQ ID NOS: 1-246. 590-595, or 605. For example, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 95% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605.

[0157] In embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246. 590-595, or 605, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605, and further comprises 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 IMP (or a functionalAttorney Docket No. 62801.82W001fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246. 590-595, or 605, 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.).

[0158] In embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605, 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.).

[0159] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises a homologous signal peptide operably connectedAttorney Docket No. 62801.82W001to the IMP. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises a homologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605 and comprises a homologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605 and comprises a homologous signal peptide operably connected to the N-terminus of the IMP.

[0160] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence 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 set forth in any one of SEQ ID NOS: 338-589 or 606. For example, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 95% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606.

[0161] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence 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 set forth in any one of SEQ ID NOS: 338-589 or 606. For example, the amino acid sequence of the IMP (or a functional fragment, functional variant, orAttorney Docket No. 62801.82W001functional fragment / variant thereof) may consist of an amino acid sequence at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 95% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606.

[0162] In embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, 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.).Attorney Docket No. 62801.82W001

[0163] In embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606, 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.).

[0164] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises a homologous signal peptide operably connected to the IMP. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises a homologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606 and comprises a homologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606 and comprises a homologous signal peptide operably connected toAttorney Docket No. 62801.82W001the N-terminus of the IMP.

[0165] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises an amino acid sequence 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 set forth in any one of SEQ ID NOS: 17, 590-595, or 605. For example, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595. or 605. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence at least 95% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may comprise an amino acid sequence 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605.

[0166] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of an amino acid sequence 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 set forth in any one of SEQ ID NOS: 17, 590-595, or 605. For example, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 85% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 90% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605. The amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) may consist of an amino acid sequence at least 95% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant,Attorney Docket No. 62801.82W001or functional fragmen t / vari ant thereof) may consist of an amino acid sequence 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605.

[0167] In embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605, 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.).

[0168] In embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595. or 605, 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605, and further comprises 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 IMP (or aAttorney Docket No. 62801.82W001functional fragment, functional variant, or functional fragmen t / vari ant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605, and further comprises 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595. or 605, and further 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 IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605, 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.).

[0169] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises a homologous signal peptide operably connected to the IMP. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises a homologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) comprises the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605 and comprises a homologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) consists of the amino acid sequence set forth in any one of SEQ ID NOS: 17, 590-595, or 605 and comprises a homologous signal peptide operably connected to the N-terminus of the IMP.

[0170] In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) no more than 300, 250. 200, 150, 100, 95, 90, 80, 70, 60, 50, 40, or 30 amino acids in length. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) is less than 300, 250, 200, 150, 100, 95, 90, 80, 70, 60, or 50 amino acids in length. In some embodiments, the amino acid sequence of the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) is from about 300-30. 300-50, 300-100, 300-150, 300-200, 300-250, 200-30, 200-50, 200-100, 200-150, 150-30, 150-50, 150-100, 30-250, 30-200,Attorney Docket No. 62801.82W00130-150, 30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-250, 40-200, 40-150, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-250, 50-200, 50-150, 50-100, 50-90, 50-80, 50-70, 50-60, 40-250, 40-200, 40-150, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50. 50-250, 50-200, 50-150, 50-100, 50-90, 50-80, 50-70, 50-60, 60-250, 60-200, 60-150, 60-100, 60-90, 60-80, 60-70, 60-60, 60-50, 60-40, 70-250, 70-200, 70-150, 70-100, 70-90, 70-80, 80-250, 80-200, 80-150, 80-100, 80-90, 90-250, 90-200, 90-150, 90-100. 100-250, 100-200, or 100-150.5.3 Exemplary Properties of Immunomodulatory Proteins

[0171] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more immunomodulatory property. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more immunomodulatory property upon administration to a subject.

[0172] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more anti-inflammatory property. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more anti-inflammatory property upon administration to a subject.

[0173] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more pro-inflammatory property. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more pro-inflammatory property upon administration to a subject.

[0174] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more anti-inflammatory property and one or more pro-inflammatory property. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more anti-inflammatory property and one or more pro-inflammatory property upon administration to a subject.

[0175] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more cytokine like property. In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) exhibits one or more human cytokine like property. In some embodiments, the cytokine is an interleukin. In some embodiments, the interleukin is IL-10 (e.g., human IL-10).

[0176] In some embodiments, the IMP (or a functional fragment, functional variant, orAttorney Docket No. 62801.82W001functional fragment / variant thereof) binds (e.g., specifically binds) to one or more protein. In some embodiments, the protein is a receptor. In some embodiments, the protein is a receptor (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells). In some embodiments, the protein is a cytokine receptor. In some embodiments, the cytokine receptor is an interleukin receptor. In some embodiments, the interleukin receptor is the IL- 10 receptor (e.g., the human IL- 10 receptor).

[0177] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) binds (e.g., specifically binds) to one or more human protein. In some embodiments, the human protein is a receptor. In some embodiments, the human protein is a receptor (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells). In some embodiments, the human protein is a cytokine receptor. In some embodiments, the cytokine receptor is an interleukin receptor. In some embodiments, the interleukin receptor is the IL-10 receptor (e.g., the human IL-10 receptor).

[0178] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) binds (e.g., specifically binds) to one or more proteins capable of mediating an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect. In some embodiments, the protein is a receptor. In some embodiments, the protein is a receptor (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells). In some embodiments, the protein is a cytokine receptor. In some embodiments, the cytokine receptor is an interleukin receptor. In some embodiments, the interleukin receptor is the IL-10 receptor (e.g., the human IL- 10 receptor).

[0179] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) binds (e.g., specifically binds) to one or more human proteins capable of mediating an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect. In some embodiments, the human protein is a receptor. In some embodiments, the human protein is a receptor (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells. NK T cells, dendritic cells). In some embodiments, the human protein is a cytokine receptor. In some embodiments, theAttorney Docket No. 62801.82W001cytokine receptor is an interleukin receptor. Tn some embodiments, the interleukin receptor is the IL-10 receptor {e.g., the human IL-10 receptor).

[0180] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) binds {e.g., specifically binds) to one or more proteins, wherein binding to the one or more protein mediates an immunomodulatory {e.g., antiinflammatory, pro-inflammatory) effect. In some embodiments, the protein is a receptor. In some embodiments, the protein is a receptor {e.g., cytokine receptor) expressed by {e.g., on the surface of) one or more population of immune cells {e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells). In some embodiments, the protein is a cytokine receptor. In some embodiments, the cytokine receptor is an interleukin receptor. In some embodiments, the interleukin receptor is the IL-10 receptor {e.g., the human IL-10 receptor).

[0181] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) binds {e.g., specifically binds) to one or more human proteins, wherein binding to the one or more human protein mediates an immunomodulatory {e.g., antiinflammatory, pro-inflammatory) effect. In some embodiments, the human protein is a receptor. In some embodiments, the human protein is a receptor {e.g., cytokine receptor) expressed by {e.g., on the surface of) one or more population of immune cells {e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells). In some embodiments, the human protein is a cytokine receptor. In some embodiments, the cytokine receptor is an interleukin receptor. In some embodiments, the interleukin receptor is the IL- 10 receptor {e.g., the human IL- 10 receptor).

[0182] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) binds {e.g., specifically binds) to one or more proteins, wherein binding to the one or more protein mediates signaling through the protein. In some embodiments, the protein is a receptor. In some embodiments, the protein is a receptor {e.g., cytokine receptor) expressed by {e.g., on the surface of) one or more population of immune cells {e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells). In some embodiments, the protein is a cytokine receptor. In some embodiments, the cytokine receptor is an interleukin receptor. In some embodiments, the interleukin receptor is the IL-10 receptor {e.g., the human IL- 10 receptor).

[0183] In some embodiments, the IMP (or a functional fragment, functional variant, or functional fragment / variant thereof) binds {e.g., specifically binds) to one or more human proteins,Attorney Docket No. 62801.82W001wherein binding to the one or more human protein mediates signaling through the protein. In some embodiments, the human protein is a receptor. In some embodiments, the human protein is a receptor (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells). In some embodiments, the human protein is a cytokine receptor. In some embodiments, the cytokine receptor is an interleukin receptor. In some embodiments, the interleukin receptor is the IL-10 receptor (e.g., the human IL-10 receptor).

[0184] In some embodiments, the IMP binds (e.g., specifically binds) to one or more receptors (e.g., cytokine receptor) and binding of the IMP to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more receptors (e.g., cytokine receptor) and binding of the IMP to the receptor mediates an anti-inflammatory effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more receptors (e.g., cytokine receptor) and binding of the IMP to the receptor mediates a pro-inflammatory effect.

[0185] In some embodiments, the IMP binds (e.g., specifically binds) to one or more receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells) and binding of the IMP to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells) and binding of the IMP to the receptor mediates an anti-inflammatory effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells) and binding of the IMP to the receptor mediates a pro-inflammatory effect.

[0186] In some embodiments, the IMP binds (e.g., specifically binds) to one or more cytokine receptor and binding of the IMP to the receptor mediates an immunomodulatory (e.g., antiinflammatory, pro-inflammatory) effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more cytokine receptor and binding of the IMP to the receptor mediates an antiinflammatory effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or moreAttorney Docket No. 62801.82W001cytokine receptor and binding of the IMP to the receptor mediates a pro-inflammatory effect.

[0187] In some embodiments, the IMP binds (e.g., specifically binds) to one or more receptors (e.g., cytokine receptor) and binding of the IMP to the receptor mediates signaling through the receptor (e.g., cytokine receptor).

[0188] In some embodiments, the IMP binds (e.g., specifically binds) to one or more receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells) and binding of the IMP to the receptor mediates signaling through the receptor (e.g., cytokine receptor).

[0189] In some embodiments, the IMP binds (e.g., specifically binds) to one or more cytokine receptor and binding of the IMP to the receptor mediates signaling through the cytokine receptor.

[0190] In some embodiments, the IMP binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) and binding of the IMP to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) and binding of the IMP to the receptor mediates an anti-inflammatory effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) and binding of the IMP to the receptor mediates a pro-intlammatory effect.

[0191] In some embodiments, the IMP binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells) and binding of the IMP to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells) and binding of the IMP to the receptor mediates an anti-inflammatory effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells) and binding of the IMP to the receptor mediates a pro-inflammatory effect.

[0192] In some embodiments, the IMP binds (e.g., specifically binds) to one or more human cytokine receptor and binding of the IMP to the receptor mediates an immunomodulatory (e.g.,Attorney Docket No. 62801.82W001anti-inflammatory, pro-inflammatory) effect. Tn some embodiments, the IMP binds (e.g., specifically binds) to one or more human cytokine receptor and binding of the IMP to the receptor mediates an anti-inflammatory effect. In some embodiments, the IMP binds (e.g., specifically binds) to one or more human cytokine receptor and binding of the IMP to the receptor mediates a pro-inflammatory effect.

[0193] In some embodiments, the IMP binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) and binding of the IMP to the receptor mediates signaling through the receptor (e.g., cytokine receptor). In some embodiments, the IMP binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes. NK cells, NK T cells, dendritic cells) and binding of the IMP to the receptor mediates signaling through the receptor (e.g., cytokine receptor). In some embodiments, the IMP binds (e.g., specifically binds) to one or more human cytokine receptor and binding of the IMP to the receptor mediates signaling through the cytokine receptor.

[0194] Binding affinity can be measured by standard assays known in the art. For example, binding affinity can be measured by surface plasmon resonance (SPR) (e.g., BIAcore®-based assay), a common method known 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 full contents of each of which are incorporated by reference herein for all purposes). SPR measures changes in the concentration of molecules at a sensor surface as molecules bind to or dissociate from the surface. The change in the SPR signal is directly proportional to the change in mass concentration close to the surface, thereby allowing measurement of binding kinetics between two molecules (e.g., proteins). The dissociation constant for the complex can be determined by monitoring changes in the refractive index with respect to time as buffer is passed over the chip.

[0195] Other suitable assays for measuring the binding of one protein to another include, for example, immunoassays such as enzyme linked immunosorbent assays (ELISA) and radioimmunoassays (RIA), or determination of binding by monitoring the change in the spectroscopic or optical properties of the proteins through fluorescence, UV absorption, circular dichroism, or nuclear magnetic resonance (NMR). Other exemplary assays include, but are not limited to, Western blot, analytical ultracentrifugation, spectroscopy, flow cytometry, sequencing and other methods for detection of binding of proteins.Attorney Docket No. 62801.82W0015.4 Immunomodulatory Protein Fusions & Conjugates

[0196] In some embodiments, an IMP described herein is operably connected to a heterologous moiety (e.g., a heterologous polypeptide) forming a fusion or conjugate protein, respectively. As such, further provided herein are, inter alia, fusion proteins comprising an IMP described herein and one or more heterologous proteins (or a functional fragment, functional variant, or domain thereof). Further provided herein are, inter alia, conjugates comprising an IMP described herein (or a nucleic acid molecule encoding an IMP described herein and one or more heterologous moieties.

[0197] 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, synthetic polymers (e.g., polymers of PEG), and any combination thereof. In some embodiments, the heterologous moiety is a detectable moiety (e.g., a protein, e.g., a fluorescent protein). In some embodiments, the heterologous moiety is an imaging agent. In some embodiments, the heterologous moiety comprises a radioligand. In some embodiments, the heterologous moiety is a diagnostic agent. In some embodiments, the heterologous moiety is a non-effector moiety, e.g., a protein sequence that acts as a “handle” or linker but has otherwise no independent biological effect. In some embodiments, the heterologous moiety is a therapeutic agent.

[0198] In some embodiments, the heterologous moiety (e.g., protein) comprises an antibody, an antibody mimetic, or one or more Ig constant region (Fc region). In some embodiments, the heterologous moiety comprises one or more Ig constant region (Fc region). In some embodiments, the heterologous moiety comprises an Fc region.

[0199] In some embodiments, the heterologous moiety (e.g., protein) is an immunomodulatory protein. In some embodiments, the heterologous moiety (e.g., protein) comprises a cytokine. In some embodiments, the heterologous moiety (e.g., protein) comprises a chemokine.

[0200] The heterologous moiety can be any one or more of (any combination of) the foregoing. For example, in some embodiments, a fusion protein comprises a plurality of heterologous moieties.5.4.1 Radioligands

[0201] In some embodiments, the heterologous moiety comprises a radioisotope. As such,Attorney Docket No. 62801.82W001provided herein are radioligands comprising an IMP (e.g., described herein) operably connected (e.g., through a linker) to one more radioisotope. In some embodiments, the radioisotope acts as a therapeutic agent. In some embodiments, the radioisotope acts as an imaging agent. In some embodiments, the IMP (e.g., described herein) acts as a targeting moiety for the radioisotope. In some embodiments, the radioisotope and the IMP e.g., described herein) are operably connected through a linker.

[0202] Radioisotopes are known in the art. See, e.g., Sgouros, G., Bodei, L., McDevitt, M. R. et al. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov 19, 589-608 (2020). https: / / doi.org / 10.1038 / s41573-020-0073-9; and Zhang, Longjiang et al. “Delivery of therapeutic radioisotopes using nanoparticle platforms: potential benefit in systemic radiation therapy.” Nanotechnology, science and applications vol. 3 159-70. 3 Dec. 2010, doi: 10.2147 / NSA. S7462; the entire contents of each of which are incorporated herein by reference for all purposes.

[0203] Exemplary radioisotopes include, but are not limited to, Lutetium- 177, Radium-223, Iodine-131, Iodine-125, Fluorine-18, Ir-192, Xenon-133, Yttrium-90, Carbon-11, Idium-111, Strontium-89, Copper-67, Copper-64, Rhenium-186, Actinium-225, Astatine-211, Bismuth-213, Bismuth-212, Samarium-153, Holmium-166, Thorium-227, and Lead-212.

[0204] Methods of operably connecting proteins to radionuclides (e.g., through one or more linkers) are known in the art. See, e.g., Gupta, Suprit et al. “Antibody labeling with radioiodine and radiometals.” Methods in molecular biology (Clifton, N. J.) vol. 1141 (2014): 147-57. doi:10.1007 / 978-l-4939-0363-4_9; Marion Chomet, State of the Art in Radiolabeling of Antibodies with Common and Uncommon Radiometals for Preclinical and Clinical Immuno-PET, Bioconjugate Chem. 2021, 32, 7, 1315-1330; Martina Steiner, Dario Neri; Antibody-Radionuclide Conjugates for Cancer Therapy: Historical Considerations and New Trends. Clin Cancer Res 15 October 2011; 17 (20): 6406-6416. https: / / doi.org / 10.1158 / 1078-0432. CCR-ll-0483; the entire contents of each of which are incorporated herein by reference for all purposes.5.4.2 Chimeric Antigen Receptors

[0205] In some embodiments, an IMP described herein is part of a chimeric antigen receptor (CAR). In some embodiments, an IMP described herein is the extracellular antigen-binding domain of a CAR. Standard CAR domains are known in art, including, e.g., transmembraneAttorney Docket No. 62801.82W001domains and intracellular signaling domains. See, e.g., W02024056809, W02023240064A1, and WO2023205148A1, WO2023133092A1, the entire contents of each of which is incorporated herein by reference for all purposes.

[0206] Exemplary transmembrane domains include, e.g., the alpha, beta or zeta chain of T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8 (for example, CD8 alpha, CD8 beta), CD9, CD 16, CD22, CD33, CD37, CD64, CD80. CD86. CD134, CD137, CD154. In some embodiments, a transmembrane domain may include at least the transmembrane region(s) of a costimulatory molecule, for example, MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, 0X40, CD2, CD7, CD27, CD28, CD30, CD40. CDS, ICAM-1, LFA-1 (CDUa / CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD 19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma. IL7R alpha, ITGA4, VLA1. CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDlld, ITGAE, CD103, ITGAL, CDlla, LFA-1, ITGAM, CDllb, ITGAX, CDllc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, LAT, GADS. SLP-76, PAG / Cbp, CD 19a, and a ligand that specifically binds with CD83. In some instances, the transmembrane domain can be attached to the extracellular region of the CAR, for example, the antigen-binding domain of the CAR, via a hinge, for example, a hinge from a human protein. For example, in some embodiments, the hinge can be a human Ig (immunoglobulin) hinge, for example, an IgG4 hinge, or a CD8a hinge.

[0207] Exemplary intracellular signaling domains include, e.g., the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any recombinant sequence that has the same functional capability. In some embodiments, the intracellular signaling domain comprises a primary signaling domain and one or more costimulatory signaling domain. Exemplary primary signaling domains, include, e.g., intracellular signaling domains of TCR zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon,Attorney Docket No. 62801.82W001CD5, CD22, CD79a, CD79b, CD278 (also known as “ICOS”), FccRI, DAP10, DAP12, CD32, and CD66d. Exemplary of proteins with costimulatory domains suitable for use in CAR described herein include, e.g., MHC class I molecule, TNF receptor proteins. Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, 0X40, CD2, CD7, CD27, CD28, CD30, CD40, CDS. ICAM-1, LFA-1 (CD1 la / CD18). 4-1BB (CD137). B7-H3, CDS. ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD 19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD lid, ITGAE, CD 103, ITGAL, CDlla, LFA-1, ITGAM, CDllb, ITGAX, CDllc, ITGB1, CD29, ITGB2. CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD 160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3). BLAME (SLAMF8). SELPLG (CD 162), LTBR, LAT, GADS. SLP-76, PAG / Cbp, CD 19a, and a ligand that specifically binds with CD83, and the like.5.4.3 Signal Peptides

[0208] In some embodiments, the heterologous polypeptide is a heterologous signal peptide. Heterologous signal peptides are known in the art. In some embodiments, the IMP comprises a heterologous signal peptide operably connected to the IMP. In some embodiments, the IMP comprises a heterologous signal peptide operably connected to the N-terminus of the IMP.

[0209] In some embodiments, the amino acid sequence of the IMP comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606 and comprises a heterologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP consists of the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606 and comprises a heterologous signal peptide operably connected to the N-terminus of the IMP.

[0210] In some embodiments, the amino acid sequence of the IMP comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605 and comprises a heterologous signal peptide operably connected to the N-terminus of the IMP. In some embodiments, the amino acid sequence of the IMP consists of the amino acid sequence set forthAttorney Docket No. 62801.82W001in any one of SEQ ID NOS: 1-246, 590-595, or 605 and comprises a heterologous signal peptide operably connected to the N-terminus of the IMP.

[0211] Commonly used heterologous signal peptides are known in the art, for example, the native signal peptide of human interleukin 2 (hIL-2), human oncostatin M (hOSM), human chymotrypsinogen (hCTRBl), human trypsinogen 2 (hTRY2), and human insulin (hINS). A person of ordinary skill can determine the appropriate signal peptide using standard methodology known in the art. The amino acid sequence of exemplary signal peptides is provided in Table 2.Table 2. The Amino Acid Sequence of Exemplary Signal Peptides.Description Amino Acid Sequence SEQ ID NO hIL-2 MYRMQLLSCIALSLALVTNS 247 hOSM MGVLLTQRTLLSLVLALLFP SMASH 248 hCTRBl MASLWLLSCFSLVGAAFG 249 hTRY2 MNLLLI LTF VAAAVA 250 hINS MALWMRLLP LLALLALWGP DP AAA 251

[0212] In some embodiments, the amino acid sequence of the signal peptide comprises the amino acid sequence of any one of the signal peptides set forth in Table 2. In some embodiments, the amino acid sequence of the signal peptide comprises the amino acid sequence of any one of the signal peptides set forth 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., amino acid substitutions, deletions, or additions). In some embodiments, the amino acid sequence of the signal peptide comprises the amino acid sequence of any one of the signal peptides set forth in Table 2, comprising 1, 2, or 3 amino acid variations (e.g., substitutions, deletions, additions). In some embodiments, the amino acid sequence of the signal peptide comprises the amino acid sequence of any one of the signal peptides set forth 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 signal peptide comprises the amino acid sequence of any one of the signal peptides set forth in Table 2, comprising 1, 2, or 3 amino acid substitutions.

[0213] In some embodiments, the amino acid sequence of the signal peptide consists of the amino acid sequence of any one of the signal peptides set forth in Table 2. In some embodiments, the amino acid sequence of the signal peptide consists of the amino acid sequence of any one of the signal peptides set forth in Table 2, and further consists of 1 or more but less than 15% (lessAttorney Docket No. 62801.82W001than 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 consists of the amino acid sequence of any one of the signal peptides set forth in Table 2, comprising 1, 2, or 3 amino acid variations (e.g., substitutions, deletions, additions). In some embodiments, the amino acid sequence of the signal peptide consists of the amino acid sequence of any one of the signal peptides set forth in Table 2, and further consists of 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 signal peptide consists of the amino acid sequence of any one of the signal peptides set forth in Table 2, comprising 1, 2, or 3 amino acid substitutions.

[0214] In some embodiments, the amino acid sequence of the signal peptide comprises the amino acid sequence set forth in any one of SEQ ID NOS: 247-251. In some embodiments, the amino acid sequence of the signal peptide comprises the amino acid sequence set forth in any one of SEQ ID NOS: 247-251, 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 the amino acid sequence set forth in any one of SEQ ID NOS: 247-251, comprising 1, 2, or 3 amino acid variations (e.g., substitutions, deletions, additions). In some embodiments, the amino acid sequence of the signal peptide comprises the amino acid sequence set forth in any one of SEQ ID NOS: 247-251, 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 signal peptide comprises the amino acid sequence set forth in any one of SEQ ID NOS: 247-251, comprising 1, 2, or 3 amino acid substitutions.

[0215] In some embodiments, the amino acid sequence of the signal peptide consists of the amino acid sequence set forth in any one of SEQ ID NOS: 247-251. In some embodiments, the amino acid sequence of the signal peptide consists of the amino acid sequence set forth in any one of SEQ ID NOS: 247-251, and further consists of 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 consists of the amino acid sequence set forth in any one of SEQ ID NOS: 247-251, comprising 1, 2, or 3 amino acid variations (e.g., substitutions, deletions, additions). In some embodiments, the amino acid sequence of the signal peptide consists of the amino acid sequence set forth in any one of SEQ IDAttorney Docket No. 62801.82W001NOS: 247-251, and further consists of 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 signal peptide consists of the amino acid sequence set forth in any one of SEQ ID NOS: 247-251, comprising 1, 2, or 3 amino acid substitutions.5.4.4 Half-Life Extension Moieties

[0216] In some embodiments, the heterologous moiety (e.g., protein) is a half-life extension moiety (e.g., protein). Various half-life extension moieties are known in the art. See, e.g., Ko S, Jo M, Jung ST. Recent Achievements and Challenges in Prolonging the Serum Half-Lives of Therapeutic IgG Antibodies Through Fc Engineering. BioDrugs. 2021;35(2):147-157. doi:10.1007 / s40259-021-00471-0 (hereinafter “Ko 2021”); Bech, E. M., Pedersen, S. L., & Jensen, K. J. (2018). Chemical Strategies for Half-Life Extension of Biopharmaceuticals: Lipidation and Its Alternatives. ACS medicinal chemistry letters, 9(1), 577-580. https: / / doi.org / 10.1021 / acsmedchemlett.8b00226 (hereinafter “Bech 2018”); Mester S, Evers M, Meyer S, et al. Extended plasma half-life of albumin-binding domain fused human IgA upon pH-dependent albumin engagement of human FcRn in vitro and in vivo. MAbs. 2021; 13(1): 1893888. doi:10.1080 / 19420862.2021.1893888 (hereinafter “Mester 2021”); Kontermann RE. Strategies for extended serum half-life of protein therapeutics. Curr Opin Biotechnol. 2011;22(6):868-876. doi: 10.1016 / j. copbio.2011.06.012 (hereinafter “Kontermann 2011”); Strohl W. R. (2015). Fusion Proteins for Half-Life Extension of Biologies as a Strategy to Make Biobetters. BioDrugs: clinical immunotherapeutics, biopharmaceuticals and gene therapy, 29(4), 215-239. https: / / doi.org / 10.1007 / s40259-015-0133-6; Zaman R, Islam RA, Ibnat N, et al. Current strategies in extending half-lives of therapeutic proteins. J Control Release. 2019;301:176-189. doi:10.1016 / j.jconrel.2019.02.016; Chen C, Constantinou A, Chester KA, et al. Glycoengineering approach to half-life extension of recombinant biotherapeutics. Bioconjug Chem.2012:23(8): 1524-1533. doi:10.1021 / bc200624a; Gupta, Vijayalaxmi et al. “Protein PEGylation for cancer therapy: bench to bedside.” Journal of cell communication and signaling vol. 13,3 (2019): 319-330. doi:10.1007 / sl2079-018-0492-0; Martin Schlapschy, et al, PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins, Protein Engineering, Design and Selection, Volume 26, Issue 8, August 2013, Pages 489-501, https: / / doi.org / 10.1093 / protein / gzt023; Strohl, William R. “Fusion Proteins for HalfAttorney Docket No. 62801.82W001Life Extension of Biologies as a Strategy to Make Biobetters.” BioDrugs: clinical, immunotherapeutics, biopharmaceuticals and gene therapy vol. 29,4 (2015): 215-39. doi:10.1007 / s40259-015-0133-6: the entire contents of each of which are incorporated by reference herein for all purposes.

[0217] Exemplary half-life extension moieties include, but are not limited to, an immunoglobulin (e.g., human Ig (hlg), murine Ig (mlg)), a fragment of an Ig (e.g., hlg, mlg), an Ig (e.g., hlg, mlg) constant region, a fragment of an Ig (e.g., hlg, mlg) constant region, an Ig (e.g., hlg, mlg) Fc region, human transferrin, a human transferrin binding moiety (e.g., small molecule, lipid, protein, peptide, etc.), human serum albumin (HSA), a fragment of HSA, an HSA binding moiety (e.g., small molecule, lipid, protein, peptide, etc.) (e.g., an antibody, a Streptococcal protein G (see, e.g., Mester 2021), polyethylene glycol (PEG) (and polymers thereof) (e.g., pegylation), lipids, small molecules, carbohydrates (e.g., glycosylation, polysialic acid (polysialylation), hydroxyethyl starch (HES) (HESylation), heparosan (HEPylation)).

[0218] In some embodiments, the heterologous polypeptide is a half-life extension polypeptide. Exemplary half-life extension polypeptides include, but are not limited to, an Ig, a fragment of an Ig, one or more Ig heavy chain constant region, a fragment of an Ig constant region, an Ig Fc region, a hlg, a fragment of a hlg, one or more hlg heavy chain constant region, a fragment of a hlg constant region, a hlg Fc region, a mlg, a fragment of a mlg, one or more mlg heavy chain constant region, a fragment of a mlg constant region, a mlg Fc region, human transferrin, a fragment of human transferrin, a human transferrin binding protein (e.g., an antibody) HSA, and HSA binding proteins (e.g., an antibody, a Streptococcal protein G). In some embodiments, the half-life extension polypeptide comprises an Ig Fc region (e.g., hlg Fc region). In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein comprises one or more amino acid variation (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wildtype Ig (e.g., hlg, mlg) Fc region)) that enhances serum half-life of the fusion protein (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)). See, e.g., § 5.4.5.2.

[0219] In some embodiments, half-life extension is mediated through one or more of lipidation, glycosylation, polysialylation, HESylation, HEPylation, and / or pegylation. In some embodiments, half-life extension is mediated through one or more of lipidation, HESylation, HEPylation, and / or pegylation. In some embodiments, half-life extension is mediated throughAttorney Docket No. 62801.82W001glycosylation. In some embodiments, half-life extension is mediated through polysialylation.

[0220] In some embodiments, the half-life extension moiety comprises one or more lipids. See, e.g., Bech 2018. In some embodiments, the half-life extension moiety comprises one or more post translational modifications (e.g., glycosylation, polysialylation, etc.).

[0221] In some embodiments, the half-life extension moiety (e.g., protein) is altered (e.g., compared to a reference half-life extension moiety (e.g., protein)) to further enhance half-life of the fusion protein or conjugate. Various alterations to known half-life extension moieties (e.g., proteins) are known in the art. See, e.g., Ko 2021, Bech 2018, Mester 2021, and Kontermann 2011. Modifications include, e.g., amino acid variations (e.g., substitutions, additions, deletions) and post translational modifications (e.g., altered lipidation, glycosylation, polysialylation, HESylation, HEPylation, pegylation, etc.).

[0222] The IMP described herein fused or conjugated to a half-life extending moiety or a halflife extending moiety can be evaluated for their pharmacokinetic properties utilizing standard in vivo methods known in the art. See, e.g., Avery, Lindsay B et al. “Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies.” mAbs vol. 8,6 (2016): 1064-78. doi:10.1080 / 19420862.2016.1193660; Conner, Christopher M et al. “A precisely humanized FCRN transgenic mouse for preclinical pharmacokinetics studies.” Biochemical pharmacology vol. 210 (2023): 115470. doi:10.1016 / j.bcp.2023.115470; and Kathryn Ball et al., PK and Biodistribution of Therapeutic Proteins, Drug Metabolism and Disposition June 1, 2022, 50 (6) 858-866; DOI: https: / / doi.org / 10.1124 / dmd.121.000463 (hereinafter “Ball 2022”), the entire contents of each of which are incorporated herein by reference for all purposes.5.4.5 Ig Fusion Proteins5.4.5.1 Antibody Fusion Proteins

[0223] In some embodiments, the heterologous protein comprises an antibody. In some embodiments, the antibody can act to further target the IMP e.g., to a specified cell or tissue type expressing a specific protein (e.g., cell surface protein). Exemplary antibodies include, full-length antibodies, scFvs, Fabs, single domain antibodies (e.g., VHHs), scFv-Fcs, Fab-Fcs, and single domain antibody-Fcs (e.g., VHH-Fcs). In some embodiments, the antibody comprises a full-length antibody. In some embodiments, the antibody comprises a scFv. In some embodiments, theAttorney Docket No. 62801.82W001antibody comprises a Fab. In some embodiments, the antibody comprises a single domain antibody. In some embodiments, the antibody comprises a VHH. In some embodiments, the antibody comprises an Fc region.5.4.5.2 Ig Fusion Proteins

[0224] In some embodiments, the heterologous protein comprises one or more Ig heavy chain constant regions (e.g., a CH2 region, a CH3 region, a hinge region, an Fc region e.g., in some embodiments, preferably an Fc region) (or any combination of the foregoing). In some embodiments, the Ig is an IgG. In some embodiments, the IgG is IgGl, IgG2, IgG3, or IgG4 (e.g., in some embodiments preferably an IgGl or IgG4).

[0225] In some embodiments, the heterologous protein comprises an IgG CH2 region and an IgG CH3 region. In some embodiments, the heterologous protein comprises a partial IgG hinge region, IgG CH2 region, and IgG CH3 region. In some embodiments, the heterologous protein comprises an IgG hinge region, IgG CH2 region, and IgG CH3 region. In some embodiments, the heterologous protein comprises an IgGl CH2 region and an IgGl CH3 region. In some embodiments, the heterologous protein comprises a partial IgGl hinge region, IgGl CH2 region, and IgGl CH3 region. In some embodiments, the heterologous protein comprises an IgGl hinge region, IgGl CH2 region, and IgGl CH3 region. In some embodiments, the heterologous protein comprises an IgG4 CH2 region and an IgG4 CH3 region. In some embodiments, the heterologous protein comprises a partial IgG4 hinge region, IgG4 CH2 region, and IgG4 CH3 region. In some embodiments, the heterologous protein comprises an IgG4 hinge region, IgG4 CH2 region, and IgG4 CH3 region.

[0226] In some embodiments, the heterologous protein consists of an IgG CH2 region and an IgG CH3 region. In some embodiments, the heterologous protein consists of a partial IgG hinge region, IgG CH2 region, and IgG CH3 region. In some embodiments, the heterologous protein consists of an IgG hinge region, IgG CH2 region, and IgG CH3 region. In some embodiments, the heterologous protein consists of an IgGl CH2 region and an IgGl CH3 region. In some embodiments, the heterologous protein consists of a partial IgGl hinge region, IgGl CH2 region, and IgGl CH3 region. In some embodiments, the heterologous protein consists of an IgGl hinge region, IgGl CH2 region, and IgGl CH3 region. In some embodiments, the heterologous protein consists of an IgG4 CH2 region and an IgG4 CH3 region. In some embodiments, the heterologous protein consists of a partial IgG4 hinge region, IgG4 CH2 region, and IgG4 CH3 region. In someAttorney Docket No. 62801.82W001embodiments, the heterologous protein consists of an IgG4 hinge region, IgG4 CH2 region, and IgG4 CH3 region.

[0227] In some embodiments, the heterologous protein comprises an Ig Fc region. In some embodiments, the Ig Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig Fc region comprises a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig Fc region comprises 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 an IgG hinge region, an IgG CH2 region, and an IgG CH3 region. In some embodiments, the Ig Fc region comprises at least a portion of an IgGl hinge region, an IgGl CH2 region, and an IgGl CH3 region. In some embodiments, the Ig Fc region comprises an IgGl hinge region, an IgGl CH2 region, and an IgGl CH3 region. In some embodiments, the Ig Fc region comprises 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 an IgG4 hinge region, an IgG4 CH2 region, and an IgG4 CH3 region.

[0228] In some embodiments, the heterologous protein consists of an Ig Fc region. In some embodiments, the Ig Fc region consists of at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig Fc region consists of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the Ig Fc region 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 consists of an IgG hinge region, an IgG CH2 region, and an IgG CH3 region. In some embodiments, the Ig Fc region consists of at least a portion of an IgGl hinge region, an IgGl CH2 region, and an IgGl CH3 region. In some embodiments, the Ig Fc region consists of an IgGl hinge region, an IgGl CH2 region, and an IgGl CH3 region. In some embodiments, the Ig Fc region 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 consists of an IgG4 hinge region, an IgG4 CH2 region, and an IgG4 CH3 region.

[0229] In some embodiments, the heterologous protein comprises one or more hlg heavy chain constant regions (e.g., a CH2 region, a CH3 region, a hinge region, an Fc region). In some embodiments, the hlg is a human IgG (hlgG). In some embodiments, the hlgG is hlgGl, IgG2, IgG3, or IgG4. In some embodiments, the hlgG is IgGl or IgG4. In some embodiments, the hlgG is hlgGl. In some embodiments, the hlgG is hIgG4.Attorney Docket No. 62801.82W001

[0230] In some embodiments, the heterologous protein comprises a hlgG CH2 region and a hlgG CH3 region. In some embodiments, the heterologous protein comprises a partial hlgG hinge region, hlgG CH2 region, and hlgG CH3 region. In some embodiments, the heterologous protein comprises a hlgG hinge region, hlgG CH2 region, and hlgG CH3 region. In some embodiments, the heterologous protein comprises a hlgGl CH2 region and a hlgGl CH3 region. In some embodiments, the heterologous protein comprises a partial hlgGl hinge region, hlgGl CH2 region, and hlgGl CH3 region. In some embodiments, the heterologous protein comprises a hlgGl hinge region, hlgGl CH2 region, and hlgGl CH3 region. In some embodiments, the heterologous protein comprises a hIgG4 CH2 region and a hIgG4 CH3 region. In some embodiments, the heterologous protein comprises a partial hIgG4 hinge region, hIgG4 CH2 region, and hIgG4 CH3 region. In some embodiments, the heterologous protein comprises a hIgG4 hinge region, hIgG4 CH2 region, and h!gG4 CH3 region.

[0231] In some embodiments, the heterologous protein consists of a hlgG CH2 region and a hlgG CH3 region. In some embodiments, the heterologous protein consists of a partial hlgG hinge region, hlgG CH2 region, and hlgG CH3 region. In some embodiments, the heterologous protein consists of a hlgG hinge region, hlgG CH2 region, and hlgG CH3 region. In some embodiments, the heterologous protein consists of a hlgGl CH2 region and a hlgGl CH3 region. In some embodiments, the heterologous protein consists of a partial hlgGl hinge region, hlgGl CH2 region, and hlgGl CH3 region. In some embodiments, the heterologous protein consists of a hlgGl hinge region, hlgGl CH2 region, and hlgGl CH3 region. In some embodiments, the heterologous protein consists of a hIgG4 CH2 region and a hIgG4 CH3 region. In some embodiments, the heterologous protein consists of a partial hIgG4 hinge region, hIgG4 CH2 region, and hIgG4 CH3 region. In some embodiments, the heterologous protein consists of a h!gG4 hinge region, hIgG4 CH2 region, and hIgG4 CH3 region.

[0232] In some embodiments, the heterologous protein comprises a hlg Fc region. In some embodiments, the hlg Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the hlg Fc region comprises a hinge region, a CH2 region, and a CH3 region. In some embodiments, the hlg Fc region comprises at least a portion of a hlgG hinge region, a hlgG CH2 region, and a hlgG CH3 region. In some embodiments, the hlg Fc region comprises a hlgG hinge region, a hlgG CH2 region, and a hlgG CH3 region. In some embodiments, the hlg Fc region comprises at least a portion of a hlgGl hinge region, a hlgGl CH2 region, and aAttorney Docket No. 62801.82W001hlgGl CH3 region. In some embodiments, the hlg Fc region comprises a hlgGl hinge region, a hlgGl CH2 region, and a hlgGl CH3 region. In some embodiments, the hlg Fc region comprises at least a portion of a hIgG4 hinge region, a hIgG4 CH2 region, and a hIgG4 CH3 region. In some embodiments, the hlg Fc region comprises a hIgG4 hinge region, a hIgG4 CH2 region, and a hIgG4 CH3 region.

[0233] In some embodiments, the heterologous protein consists of a hlg Fc region. In some embodiments, the hlg Fc region consists of at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the hlg Fc region consists of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the hlg Fc region consists of at least a portion of a hlgG hinge region, a hlgG CH2 region, and a hlgG CH3 region. In some embodiments, the hlg Fc region consists of a hlgG hinge region, a hlgG CH2 region, and a hlgG CH3 region. In some embodiments, the hlg Fc region consists of at least a portion of a hlgGl hinge region, a hlgGl CH2 region, and a hlgGl CH3 region. In some embodiments, the hlg Fc region consists of a hlgGl hinge region, a hlgGl CH2 region, and a hlgGl CH3 region. In some embodiments, the hlg Fc region consists of at least a portion of a hIgG4 hinge region, a h!gG4 CH2 region, and a hIgG4 CH3 region. In some embodiments, the hlg Fc region consists of a hIgG4 hinge region, a hIgG4 CH2 region, and a hIgG4 CH3 region.

[0234] The amino acid sequence of exemplary reference hlgGl and hIgG4 heavy chain constant regions and hlg light chain constant regions, which can be incorporated in one or more of the embodiments described herein (e.g., fusion proteins and polypeptide), is provided in Table 3.Table 3. The Amino Acid Sequence of Exemplary hlg heavy chain constant region components and hlg light chain constant regions.SEQDescription Amino Acid SequenceID NO ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNShlgGl CHI Region GALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN 252 HKPSNTKVDKKVhlgGl Hinge Region EPKSCDKTHTCP 253 PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDhlgGl CH2 Region PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW 254 LNGKEYKCKVSNKALPAPIEKTISKAKhlgGl CH3 Region GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD PAVE WES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK 255 With C-tenninal LysineAttorney Docket No. 62801.82W001hlgGl CH3 Region GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPG 256 Without C-terminalLysinePCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDhlgGl CH2 Region + PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWCH3 Region LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 257 With C-terminal Lysine SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGK PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDhlgGl CH2 Region + PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWCH3 Region LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 258 Without C-terminal SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS Lysine LSPGTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVShlgGl Partial Hinge HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLH Region + CH2 Region + QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCH3 Region SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 259 VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKWith C-terminal Lysine SLSLSPGKhlgGl Partial Hinge TCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVWDVS Region + CH2 Region + HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHCH3 Region QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 260 Without C-terminal VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK Lysine SLSLSPG DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVhlgGl Partial Hinge VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVL Region + CH2 Region + TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYCH3 Region TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK 261 TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHWith C-terminal Lysine YTQKSLSLSPGKhlgGl Partial Hinge DKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVV Region + CH2 Region + VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLCH3 Region TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK 262 Without C-terminal TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH Lysine YTQKSLSLSPG EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEhlgG 1 Hinge Region + VTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRCH2 Region + CH3 VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR Region EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP 263 ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEWith C-terminal Lysine ALHNHYTQKSLSLSPGKhlgGl Hinge Region + EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPECH2 Region + CH3 VTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR 264 RegionEPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPAttorney Docket No. 62801.82W001Without C-terminal ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE Lysine ALHNHYTQKSLSLSPG ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNhlgGl CH1+ Hinge HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK Region + CH2 Region + P KDT LMI S RIPE VI CVWDVS HEDPE VKFNWYVD GVEVHNAKTCH3 Region KPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAP I 265 EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSWith C-terminal Lysine DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNShlgGl CHI + Hinge GALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN Region + CH2 Region + HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKCH3 Region P KDT LMI S RTPE VT CVWDVS HEDPE VKFNWYVD GVEVHNAKT KPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAP I 266 Without C-terminal EKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS Lysine DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSh!gG4 CHI Region GALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVD 267 HKPSNTKVDKRVh!gG4 Hinge Region ESKYGPPCPSCP 268 h!gG4 Hinge Region AESKYGPPCPSCP269 (Variant)APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVh!gG4 CH2 Region QFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNG 270 KEYKCKVSNKGLPSSTEKTTSKAKh!gG4 CH3 Region GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCS 271 With C-terminal Lysine VMHEALHNHYTQKSLSLSLGKh!gG4 CH3 Region GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCS272 Without C-terminal VMHEALHNHYTQKSLSLSLGLysineAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVhIgG4 CH2 Region + QFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGCH3 Region KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 273 With C-terminal Lysine SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK APEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVh!gG4 CH2 Region + QFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGCH3 Region KEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG 274 Without C-terminal SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSL Lysine Gh!gG4 Partial Hinge PCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS Region + CH2 Region + QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP 275 CH3 RegionSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPAttorney Docket No. 62801.82W001With C-terminal Lysine VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK SLSLSLGKh!gG4 Partial Hinge PCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS Region + CH2 Region + QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHCH3 Region QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 276 Without C-terminal VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK Lysine SLSLSLG ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCh!gG4 Hinge Region + VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSCH2 Region + CH3 VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ Region VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN 277 YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHWith C-terminal Lysine NHYTQKSLSLSLGKh!gG4 Hinge Region + ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCCH2 Region + CH3 VVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWS Region VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN 278 Without C-terminal YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH Lysine NHYTQKSLSLSLGh!gG4 Hinge Region + AESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCH2 Region + CH3 CVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV Region SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN 279 (Variant)NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALWith C-terminal Lysine HNHYTQKSLSLSLGKh!gG4 Hinge Region + AESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCH2 Region + CH3 CVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV Region SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP (Variant) QVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN 280 NYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALWithout C-terminal HNHYTQKSLSLSLGLysineASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDh!gG4 CHI + Hinge HKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKD Region + CH2 Region + TLMISRTPEVTCWVDVSQEDPEVQFNWYVDGVEVHNAKTKPRCH3 Region EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT 281ISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAWith C-terminal Lysine VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK ASTKGP SVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSh!gG4 CHI + Hinge GALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVD Region + CH2 Region + HKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDCH3 Region T LMI S RTP E VTC WVD VS QE DP E VQFNW YVD GVE VHNAKT KP R EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT 282 Without C-terminal ISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA Lysine VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGAttorney Docket No. 62801.82W001RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVIg light chain kappa DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA 283 constant region (KCL) CEVTHQGLSSPVTKSFNRGEC GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKIg light chain kappa ADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYS 284 constant region (XCL)CQVTHEGSTVEKTVAPTECS

[0235] In some embodiments, the amino acid sequence of the heterologous protein comprises an amino acid sequence set forth in Table 3. In some embodiments, the amino acid sequence of the heterologous protein comprises an amino acid sequence set forth 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 heterologous protein comprises an amino acid sequence set forth in Table 3, comprising 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 protein comprises an amino acid sequence set forth in Table 3, comprising 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 protein comprises an amino acid sequence set forth in Table 3, comprising no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid variations (e.g., amino acid substitutions, deletions, or additions).

[0236] In some embodiments, the amino acid sequence of the heterologous protein consists of an amino acid sequence set forth in Table 3. In some embodiments, the amino acid sequence of the heterologous protein consists of an amino acid sequence set forth 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 heterologous protein consists of an amino acid sequence set forth in Table 3, comprising 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 protein consists of an amino acid sequence set forth in Table 3, comprising 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 protein consists of an amino acid sequence set forth in Table 3, comprising no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid variations (e.g., amino acid substitutions, deletions, or additions).

[0237] In some embodiments, the amino acid sequence of the heterologous protein comprisesAttorney Docket No. 62801.82W001the amino acid sequence set forth in any one of SEQ ID NOS: 252-284. In some embodiments, the amino acid sequence of the heterologous protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 252-284, 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 protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 252-284, comprising 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 protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 252-284, comprising 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 protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 252-284, comprising 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).

[0238] In some embodiments, the amino acid sequence of the heterologous protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 252-284. In some embodiments, the amino acid sequence of the heterologous protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 252-284, 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 heterologous protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 252-284, comprising 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 protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 252-284, comprising 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 protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 90-120, comprising 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).

[0239] In some embodiments, wherein the heterologous protein comprises a CH3 region (e.g., comprises an Fc region; a hinge region, CH2 region, and CH3 region, etc.), the CH3 region lacksAttorney Docket No. 62801.82W001the C-terminal lysine (e.g., residue 232 of SEQ ID NO: 263, numbering according to SEQ ID NO: 263; or e.g., residue 229 of SEQ ID NO: 277, numbering according to SEQ ID NO: 277). In some embodiments, the CH3 region further lacks the C-terminal glycine e.g., residue 231 of SEQ ID NO: 263, numbering according to SEQ ID NO: 263; or e.g., residue 228 of SEQ ID NO: 277, numbering according to SEQ ID NO: 277).

[0240] In some embodiments, the heterologous protein comprises one or more mlg heavy chain constant regions (e.g., a CH2 region, a CH3 region, a hinge region, an Fc region). In some embodiments, the mlg is mlgG (mlgG). In some embodiments, the mlgG is mlgGl, mIgG2a, mIgG2c, mIgG2b, or mIgG3. In some embodiments, the mlgG is mlgGl or mIgG2a. In some embodiments, the mlgG is mlgGl. In some embodiments, the mlgG is mIgG2a.

[0241] In some embodiments, the heterologous protein comprises a mlgG CH2 region and a mlgG CH3 region. In some embodiments, the heterologous protein comprises a partial mlgG hinge region, mlgG CH2 region, and mlgG CH3 region. In some embodiments, the heterologous protein comprises a mlgG hinge region, mlgG CH2 region, and mlgG CH3 region. In some embodiments, the heterologous protein comprises a mlgGl CH2 region and a mlgGl CH3 region. In some embodiments, the heterologous protein comprises a partial mlgGl hinge region, mlgGl CH2 region, and mlgGl CH3 region. In some embodiments, the heterologous protein comprises a mlgGl hinge region, mlgGl CH2 region, and mlgGl CH3 region. In some embodiments, the heterologous protein comprises a mIgG2a CH2 region and a m!gG2a CH3 region. In some embodiments, the heterologous protein comprises a partial mIgG2a hinge region, mlg2a CH2 region, and mIgG2a CH3 region. In some embodiments, the heterologous protein comprises a mIgG2a hinge region, mIgG2a CH2 region, and mIgG2a CH3 region.

[0242] In some embodiments, the heterologous protein comprises a mlg Fc region. In some embodiments, the mlg Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the mlg Fc region comprises a hinge region, a CH2 region, and a CH3 region. In some embodiments, the mlg Fc region comprises at least a portion of a mlgG hinge region, a mlgG CH2 region, and a mlgG CH3 region. In some embodiments, the mlg Fc region comprises a mlgG hinge region, a mlgG CH2 region, and a mlgG CH3 region. In some embodiments, the mlg Fc region comprises at least a portion of a mlgGl hinge region, a mlgGl CH2 region, and a mlgGl CH3 region. In some embodiments, the mlg Fc region comprises a mlgGl hinge region, a mlgGl CH2 region, and a mlgGl CH3 region. In some embodiments, theAttorney Docket No. 62801.82W001mlg Fc region comprises at least a portion of a m!gG2a hinge region, a mTgG2a CH2 region, and a m!gG2a CH3 region. In some embodiments, the mlg Fc region comprises a mIgG2a hinge region, a mIgG2a CH2 region, and a mIgG2a CH3 region.

[0243] In some embodiments, the heterologous protein consists of a mlgG CH2 region and a mlgG CH3 region. In some embodiments, the heterologous protein consists of a partial mlgG hinge region, mlgG CH2 region, and mlgG CH3 region. In some embodiments, the heterologous protein consists of a mlgG hinge region, mlgG CH2 region, and mlgG CH3 region. In some embodiments, the heterologous protein consists of a mlgGl CH2 region and a mlgGl CH3 region. In some embodiments, the heterologous protein consists of a partial mlgGl hinge region, mlgGl CH2 region, and mlgGl CH3 region. In some embodiments, the heterologous protein consists of a mlgGl hinge region, mlgGl CH2 region, and mlgGl CH3 region. In some embodiments, the heterologous protein consists of a mIgG2a CH2 region and a mIgG2a CH3 region. In some embodiments, the heterologous protein consists of a partial mIgG2a hinge region, mlg2a CH2 region, and mIgG2a CH3 region. In some embodiments, the heterologous protein consists of a mIgG2a hinge region, mIgG2a CH2 region, and mIgG2a CH3 region.

[0244] In some embodiments, the heterologous protein consists of a mlg Fc region. In some embodiments, the mlg Fc region consists of at least a portion of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the mlg Fc region consists of a hinge region, a CH2 region, and a CH3 region. In some embodiments, the mlg Fc region consists of at least a portion of a mlgG hinge region, a mlgG CH2 region, and a mlgG CH3 region. In some embodiments, the mlg Fc region consists of a mlgG hinge region, a mlgG CH2 region, and a mlgG CH3 region. In some embodiments, the mlg Fc region consists of at least a portion of a mlgGl hinge region, a mlgGl CH2 region, and a mlgGl CH3 region. In some embodiments, the mlg Fc region consists of a mlgGl hinge region, a mlgGl CH2 region, and a mlgGl CH3 region. In some embodiments, the mlg Fc region consists of at least a portion of a mIgG2a hinge region, a mIgG2a CH2 region, and a mIgG2a CH3 region. In some embodiments, the mlg Fc region consists of a mIgG2a hinge region, a mIgG2a CH2 region, and a mIgG2a CH3 region.

[0245] The amino acid sequence of exemplary reference mlgGl and mIgG2a heavy chain constant regions, which can be incorporated in one or more of the embodiments described herein (e.g., fusion proteins and polypeptide), is provided in Table 4.Table 4. The Amino Acid Sequence of Exemplary mlg heavy chain constant regionAttorney Docket No. 62801.82W001components.SEQDescription Amino Add SequenceID NO AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGmlgGl CHI Region SLSSGVHTFPAVLQSDLYTLSSSVTVPSSPRPSETVTCNVAHPA 285 SSTKVDKKImlgGl Hinge Region VPRDCGCKPCICT 286 VPEVSSVFIFPPKPKDVLTITLTPKVTCVWAISKDDPEVQFSWmlgGl CH2 Region FVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKC 287 RVNSAAFPAPIEKTISKTKmlgGl CH3 Region GRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWN GQPAENYKNTQPIMNTNGSYFVYSKLNVQKSNWEAGNTFTCSVL HEGLHNHHTEKSLSHSPGK 288 With C-terminal LysinemlgGl CH3 Region GRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWN GQPAENYKNTQPIMNTNGSYFVYSKLNVQKSNWEAGNTFTCSVL HEGLHNHHTEKSLSHSPG 289 Without C-terminalLysineVPEVSSVFIFPPKPKDVLTITLTPKVTCVWAISKDDPEVQFSWmlgGl CH2 Region + FVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCCH3 Region RVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSL 290 TCMITDFFPEDITVEWQWNGQPAENYKNTQPIMNTNGSYFVYSKWith C-terminal Lysine LNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGKmlgGl CH2 Region + VPEVSSVFIFPPKPKDVLTITLTPKVTCVWAISKDDPEVQFSWCH3 Region FVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKC RVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSL 291 Without C-terminal TCMITDFFPEDITVEWQWNGQPAENYKNTQPIMNTNGSYFVYSK Lysine LNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPG VPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCWVmlgGl Hinge Region + AISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELP ICH2 Region + CH3 MHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIP Region PPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQP 292 IMNTNGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSWith C-terminal Lysine LSHSPGKmlgGl Hinge Region + VPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCWVCH2 Region + CH3 AISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPI Region MHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIP PPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQP 293 Without C-terminal IMNTNGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKS Lysine LSHSPGKm!gG2a Hinge Region EPRGPTIKPCPPCKCP 294 APNAAGGPSVFIFLLKIKDVLMISLSPIVTCWVDVSEDDPDVQ ISWFVNNVEVHTAQTQTHREDYNSTLRWSALPIQHQDWMSGKEm!gG2a CH2 Region FKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQ 295 VIm!gG2a CH3 Region LTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK 296Attorney Docket No. 62801.82W001With C-terminal LysinemIgG2a CH3 Region LTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYS KLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG297 Without C-terminalLysineAPNAAGGPSVFIFLLKIKDVLMISLSPIVTCWVDVSEDDPDVQm!gG2a CH2 Region + ISWFVNNVEVHTAQTQTHREDYNSTLRWSALPIQHQDWMSGKECH3 Region FKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQ 298 VTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGS YEMWith C-terminal Lysine YSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGKm!gG2a CH2 Region + APNAAGGPSVFIFLLKIKDVLMISLSPIVTCWVDVSEDDPDVQCH3 Region ISWFVNNVEVHTAQTQTHREDYNSTLRWSALP IQHQDWMSGKE FKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQ 299 Without C-terminal VTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGS YEM Lysine YSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG EPRGPTIKPCPPCKCPAPNAAGGPSVF IFLLKIKDVLMI SLSP Im!gG2a Hinge Region VTCWVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRV+ CH2 Region + CH3 VSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAP Region QVYVLPPPEEEMTKKQVTLTCMVTDFMPEDI YVEWTNNGKTELN 300 YKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNWith C-terminal Lysine HHTTKSFSRTPGKm!gG2a Hinge Region EPRGPTIKPCPPCKCPAPNAAGGPSVF IFLLKIKDVLMI SLSP I+ CH2 Region + CH3 VTCWVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRV Region VSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAP QVYVLPPPEEEMTKKQVTLTCMVTDFMPEDI YVEWTNNGKTELN 301 Without C-terminal YKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHN Lysine HHTTKSFSRTPG AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSG SLSSGVHTFPAVLQSDLYTLSSSVTVPSSPRPSETVTCNVAHPAm!gG2a CHI Region + SSTKVDKKIEPRGPTIKPCPPCKCPAPNAAGGPSVFIFLLKIKD Hinge Region + CH2 VLMISLSPIVTCVWDVSEDDPDVQISWFVNNVEVHTAQTQTHR Region + CH3 Region EDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTIS 302 KPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWWith C-terminal Lysine TNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNS YSC SWHEGLHNHHTTKSFSRTPGK AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGm!gG2a CHI Region + SLSSGVHTFPAVLQSDLYTLSSSVTVPSSPRPSETVTCNVAHPA Hinge Region + CH2 SSTKVDKKIEPRGPTIKPCPPCKCPAPNAAGGPSVFIFLLKIKD Region + CH3 Region VLMISLSPIVTCVWDVSEDDPDVQISWFVNNVEVHTAQTQTHRED YNS TLRVVS ALP IQHQDWMSGKEFKCKVNNKDLPAP TERT I S 303 Without C-terminal KPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEW Lysine TNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNS YSC SWHEGLHNHHTTKSFSRTPG RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDIg light chain kappa GSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCE constant region (KCL) 304 ATHKTSTSPIVKSFNRNEC QPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGWTVDWKVDIg light chain kappa GTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQV 305 constant region (XCL)THEGHTVEKSLSRADCS

[0246] In some embodiments, the amino acid sequence of the heterologous protein comprisesAttorney Docket No. 62801.82W001an amino acid sequence set forth in Table 4. In some embodiments, the amino acid sequence of the heterologous protein comprises an amino acid sequence set forth 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 protein comprises an amino acid sequence set forth in Table 4, comprising 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 protein comprises an amino acid sequence set forth in Table 4, comprising 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 protein comprises an amino acid sequence set forth in Table 4, comprising no more than about 1, 2, 3, 4, 5. 6, 7, 8, 9, 10, or more amino acid variations (e.g., amino acid substitutions, deletions, or additions).

[0247] In some embodiments, the amino acid sequence of the heterologous protein consists of an amino acid sequence set forth in Table 4. In some embodiments, the amino acid sequence of the heterologous protein consists of an amino acid sequence set forth 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 protein consists of an amino acid sequence set forth in Table 4, comprising 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 protein consists of an amino acid sequence set forth in Table 4, comprising 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 protein consists of an amino acid sequence set forth in Table 4, comprising no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. or more amino acid variations (e.g., amino acid substitutions, deletions, or additions).

[0248] In some embodiments, the amino acid sequence of the heterologous protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 285-305. In some embodiments, the amino acid sequence of the heterologous protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 285-305, 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 proteinAttorney Docket No. 62801.82W001comprises the amino acid sequence set forth in any one of SEQ ID NOS: 285-305, comprising 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 protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 285-305, comprising 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 protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 285-305, comprising 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).

[0249] In some embodiments, the amino acid sequence of the heterologous protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 285-305. In some embodiments, the amino acid sequence of the heterologous protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 285-305, 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 protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 285-305, comprising 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 protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 285-305, comprising 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 protein consists of the amino acid sequence set forth in any one of SEQ ID NOS: 285-305, comprising 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).

[0250] In some embodiments, wherein the heterologous protein comprises a CH3 region (e.g., comprises an Fc region; a hinge region, CH2 region, and CH3 region, etc.), the CH3 region lacks the C-terminal lysine (e.g., residue 227 of SEQ ID NO: 292, numbering according to SEQ ID NO: 292; or e.g., residue 223 of SEQ ID NO: 300, numbering according to SEQ ID NO: 300). In some embodiments, the CH3 region further lacks the C-terminal glycine (e.g., residue 226 of SEQ ID NO: 292, numbering according to SEQ ID NO: 292; or e.g., residue 222 of SEQ ID NO: 300, numbering according to SEQ ID NO: 300).Attorney Docket No. 62801.82W0015.4.5.3 Half-Life Extension

[0251] In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein (an Fc region, an antibody, etc.) exhibits enhanced serum half-life, e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region e.g., a wild-type Ig (e.g., hlg, mlg) Fc region).

[0252] Standard in vitro and / or in vivo assays known in the art can be conducted to evaluate serum half-life. See, e.g., Ko S, Jo M, Jung ST. Recent Achievements and Challenges in Prolonging the Serum Half-Lives of Therapeutic IgG Antibodies Through Fc Engineering. BioDrugs. 2021;35(2):147-157. doi:10.1007 / s40259-021-00471-0, the entire contents of which are incorporated herein by reference for all purposes.

[0253] In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein (an Fc region, an antibody, etc.) exhibits enhanced serum half-life (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) through enhanced binding affinity for the FcRn receptor (e.g., the human FcRn receptor) (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)).

[0254] In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein (an Fc region, an antibody, etc.) exhibits enhanced serum half-life (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) through enhanced binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of from about 5.5-6.5 (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)). In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein (an Fc region, an antibody, etc.) exhibits enhanced serum half-life (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) through enhanced binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of from about 5.5-6.5 and no substantial change in binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of from about 7.0-7.5 (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)). In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein (an Fc region, an antibody, etc.) exhibits enhanced serum half-life (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wildtype Ig (e.g., hlg, mlg) Fc region)) through enhanced binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of from about 6.0-6.5 (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) and a decrease in binding affinityAttorney Docket No. 62801.82W001for the FcRn receptor (e.g., the human FcRn receptor) at a pH of from about 7.0-7.5 (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)).

[0255] In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein (an Fc region, an antibody, etc.) exhibits enhanced serum half-life (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) through enhanced binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of about 6 (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)). In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein (an Fc region, an antibody, etc.) exhibits enhanced serum half-life (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) through enhanced binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of about 6 and no substantial change in binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of about 7.4 (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wildtype Ig (e.g., hlg, mlg) Fc region)). In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein (an Fc region, an antibody, etc.) exhibits enhanced serum half-life (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) through enhanced binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of about 6 (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) and a decrease in binding affinity for the FcRn receptor (e.g., the human FcRn receptor) at a pH of about 7.4 (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)).

[0256] In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein comprises one or more amino acid variation (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) that enhances serum half-life of the fusion protein (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)).

[0257] In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein comprises one or more amino acid variation (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) that enhances serum half-life of the fusion protein (e.g., relative to a reference Ig (e.g., hlg, mlg) Fc region (e.g., a wild-type Ig (e.g., hlg, mlg) Fc region)) through altered binding to the FcRn receptor (e.g., as described herein) (e.g.,Attorney Docket No. 62801.82W001an FcRn binding profile described herein).

[0258] Exemplary amino acid variations of an Ig (e.g., hlg, mlg) Fc region that enhance serum half-life of the Ig Fc region (or a protein comprising the same) are known in the art. See, e.g., Ko 2021 (and references cited therein) (including e.g., Table 1 of Ko 2021); Xinhua Wang, Mary Mathieu, Randall J Brezski, IgG Fc engineering to modulate antibody effector functions, Protein & Cell. Volume 9. Issue 1, January 2018, Pages 63-73. https: / / doi.org / 10.1007 / sl3238-017-0473-8; US8546543B2; WO2024059652A1; US 11591368 (e.g., H433K / N434F); Ko, S., Park, S„ Sohn, M. H. et al. An Fc variant with two mutations confers prolonged serum half-life and enhanced effector functions on IgG antibodies. Exp Mol Med 54, 1850-1861 (2022). https: / / doi.org / 10.1038 / sl2276-022-00870-5; the entire contents of each of which is incorporated herein by reference for all purposes.

[0259] Table 5 below, provides exemplary amino acid substitutions (and combinations thereof) and glycoengineering that can be utilized to extend half-life of proteins (e.g., fusion proteins described herein) comprising an Ig Fc region (or fragment thereof). Amino acids in Table 5 are numbered according to the EU numbering scheme. The amino acid substitutions set forth in Table 5 are with reference to an IgGl Fc region (except where noted). However, a person of ordinary skill in the could identify the corresponding amino acid in a non-IgGl Fc region, for example in an IgG2 or IgG4 Fc region, should the base amino acid be different between the IgGl and non-IgGl Fc region.Table 5. Exemplary hlg Fc Variations to Extend Half-Life.Variation / Glycoengineering Exemplary Effects on Effector Function (Non-Limiting)Amino Acid VariationsR435H Extended Half-LifeN434A Extended Half-LifeN434W Extended Half-Life M252Y / S254T / T256E Extended Half-LifeM252Y / T256D Extended Half-LifeM428L / N434S Extended Half-Life E294A / R307P / N434Y Extended Half-LifeT256D / T307Q Extended Half-LifeT256D / T307W Extended Half-Life T256N / A378V / S383N / N434Y Extended Half-Life T307Q / Q311V / A378V Extended Half-LifeT256D / H286D / T307R / Q311V / A378V Extended Half-LifeAttorney Docket No. 62801.82W001L309D / Q311H / N434S Extended Half-LifeH433K / N434F Extended Half-LifeH433K / N434F (IgG4) Extended Half-LifeE294A Extended Half-Life

[0260] In some embodiments, the Ig Fc region is a hlg Fc region. In some embodiments, the hlg Fc (e.g., IgGl Fc) region comprises any one or more of the amino acid substitutions set forth in Table 5 (z.e., any one or more amino acid substitution set forth in any set of amino acid substitutions set forth in Table 5). In some embodiments, the hlg Fc (e.g., IgGl Fc) comprises any one or more of the sets of amino acid substitutions set forth in Table 5. In some embodiments, the hlg Fc (e.g., IgGl Fc) region comprises any one or more of the glycosylation changes set forth in Table 5.

[0261] For example, amino acid variations include, but are not limited to, M428L / N434S, EU numbering according to Kabat; M252Y / S254T / T256E, EU numbering according to Kabat; N434A, EU numbering according to Kabat; N434W, EU numbering according to Kabat; T256D / T307Q, EU numbering according to Kabat: T256D / T307W, EU numbering according to Kabat; M252Y / T256D, EU numbering according to Kabat; T307Q / Q311V / A378V, EU numbering according to Kabat; T256D / H286D / T307R / Q311V / A378V, EU numbering according to Kabat; and L309D / Q311H / N434S. EU numbering according to Kabat. Further amino acid modifications include, H433K / N434F (of IgGl) or H433K / N434F (of IgG4), EU numbering according to Kabat.

[0262] In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein comprises one or more alteration (including various post-translational modifications e.g., glycosylation, sialylation) that mediates enhanced serum half-life, e.g., relative to a reference (e.g., wild type) Ig (e.g., hlg, mlg) Fc region. In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein comprises one or more post-translational modification (e.g., glycosylation, sialylation) that mediates enhanced serum half-life, e.g., relative to a reference (e.g., wild type) Ig (e.g., hlg, mlg) Fc region. In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein comprises altered glycosylation that mediates enhanced serum half-life, e.g., relative to a reference (e.g., wild type) Ig (e.g., hlg, mlg) Fc region. In some embodiments, the Ig (e.g., hlg, mlg) Fc region of a fusion protein described herein comprises altered lipidation that mediates enhanced serum half-life, e.g., relative to a reference (e.g., wild type) Ig (e.g., hlg, mlg) Fc region. In some embodiments, the Ig (e.g., hlg, mlg) Fc region of aAttorney Docket No. 62801.82W001fusion protein described herein comprises altered sialylation that mediates enhanced serum halflife, e.g., relative to a reference {e.g., wild type) Ig {e.g., hlg, mlg) Fc region. In some embodiments, the Ig {e.g., hlg, mlg) Fc region of a fusion protein described herein is pegylated, which mediates enhanced serum half-life, e.g., relative to a reference e.g., wild type) Ig {e.g., hlg, mlg) Fc region.5.4.5.4 Ig Effector Function

[0263] In some embodiments, the Ig {e.g., hlg, mlg) Fc region of a fusion protein described herein exhibits modulation {e.g., a decrease or increase) of one or more Fc effector function, e.g., relative to a reference {e.g., wild type) Ig {e.g., hlg, mlg) Fc region. Exemplary Ig {e.g., hlg, mlg) 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 receptor {e.g., an Fey receptor {e.g., FcyRI, FcyRIIa, FcyRIIc, FcyRIIIa, and / or FcyRIIIb {e.g., FcyRI, Fcylla, and / or Fcyllla))).

[0264] Standard in vitro and / or in vivo assays known in the art can be conducted to evaluate Fc effector function, including, any one or more of ADCC, CDC, ADCP. Fc receptor {e.g., Fey receptor) binding affinity, and Clq binding affinity.

[0265] For example, ADCC activity can be assessed utilizing standard (radioactive and nonradioactive) methods known in the art {see, e.g., W02006 / 082515. WO2012 / 130831), the entire contents of each of which is incorporated by reference herein for all purposes). For example, ADCC activity can be assessed using a chromium-5 (51Cr) assay. Briefly,51Cr is pre-loaded into target cells expressing CD20, NK cells are added to the culture, and radioactivity in the cell culture supernatant is assessed (indicative of lysis of the target cells by the NK cells). Similar nonradioactive assays can also be utilized that employ a similar method, but the target cells are pre-loaded with fluorescent dyes, such as calcein-AM, CFSE, BCECF, or lanthanide flurophore (Europium). See, e.g., Parekh, Bhavin S et al. “Development and validation of an antibodydependent cell-mediated cytotoxicity-reporter gene assay.” mAbs vol. 4,3 (2012): 310-8. Doi:10.4161 / mabs.19873, the entire contents of which is incorporated by reference herein for all purposes. Exemplary commercially available non-radioactive assays include, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (Cell Technology, Inc. Mountain View, Calif.; and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, Wis.). Additional non-limiting examples of in vitro assays that can be used to assess ADCC activity of aAttorney Docket No. 62801.82W001fusion protein described herein include those described in 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„ et al., J. Exp. Med. 166 (1987) 1351-1361, the entire contents of each of which is incorporated by reference herein. Alternatively, or additionally, ADCC activity of a fusion protein described herein may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes, et al., Proc. Nat’l Acad. Sci. USA 95 (1998) 652-656, the entire contents of which is incorporated by reference herein for all purposes.

[0266] C Iq binding assays can be utilized to assess the ability of a hlg fusion protein described herein to bind Clq (or bind with less affinity than a reference fusion protein) and hence lack (or have decreased) CDC activity. The binding of a hlg fusion protein described herein to Clq can be determined by a variety of in vitro assays (e.g., biochemical or immunological based assays) known in the art for determining Fc-Clq interactions, including e.g., equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetic methods (e.g., surface plasmon resonance (SPR) analysis), and 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 may utilize a label 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 affinities and kinetics can be found in e.g., Paul, W. E., ed., Fundamental Immunology, 4thEd., Lippincott-Raven, Philadelphia (1999), the entire contents of which is incorporated by reference herein. For example, see, e.g., C1q and C3c binding ELISAs described in W02006 / 029879 and W02005 / 100402, the entire contents of each of which is incorporated by reference herein for all purposes. Additional CDC activity assays include those described in e.g., 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 is incorporated by reference herein for all purposes.

[0267] ADCP activity can be measured by in vitro or in vivo methods known in the art and also 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 is incorporated by reference herein for all purposes). For example, a primary cell based ADCP assayAttorney Docket No. 62801.82W001can be used in which fresh human peripheral blood mononuclear cells (PBMCs) are isolated, monocytes isolated and differentiated in culture to macrophages using standard procedures. The macrophages are fluorescently labeled added to cultures containing fluorescently labeled target cells expressing CD20 and a fusion protein described herein. Phagocytosis events can be analyzed using FACS screening and / or microscopy. A modified reporter version of the above described assay can also be used that employs an engineered cell line that stably expresses FcyRIIa (CD32a) as the effector cell line (e.g., an engineered T cell line, e.g., THP-1), removing the requirement for primary cells. Exemplary ADCP assays are described in e.g., 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 is incorporated by reference herein.

[0268] Binding of a hlg fusion protein described herein to an Ig (e.g., hlg, mlg) Fc receptor can be determined by a variety of in vitro assays e.g., biochemical or immunological based assays) known in the art for determining Fc-Fc receptor interactions, i.e., specific binding of an Fc region to an Fc receptor. 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), and 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 may utilize a label 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 affinities and kinetics can be found in e.g., Paul, W. E., ed., Fundamental Immunology, 4” Ed., Lippincott-Raven, Philadelphia (1999). the entire contents of which is incorporated by reference herein for all purposes.(i) Reduced Ig Effector Function

[0269] In some embodiments, the Ig Fc region exhibits a decrease in or no detectable activity of one or more Fc effector. As described above, exemplary Ig Fc effector functions include, but are not limited to, ADCC, ADCP, CDC, binding affinity to Clq, and binding affinity to one or more human Fc receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and / or FcyRIIIb)).Attorney Docket No. 62801.82W001

[0270] In some embodiments, the hlg Fc region is modified (e.g., comprises one or more variation (e.g., one or more amino acid substitution, deletion, addition, etc.); altered glycosylation)) (referred to herein as a “modified hlg Fc”). In some embodiments, the modification (e.g., the variation (e.g., one or more amino acid substitution, deletion, addition, etc.); altered glycosylation decreases or abolishes one or more Fc effector function, relative to a reference hlg Fc that does not comprise the modification (e.g., the one or more variation (e.g., the one or more amino acid substitution, deletion, addition, etc.; the altered glycosylation)).

[0271] In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibits no detectable or decreased ADCC compared to a reference fusion protein that does not comprise the Ig (e.g., hlg, mlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibits no detectable or decreased CDC compared to a reference fusion protein that does not comprise the Ig (e.g., hlg, mlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibits no detectable or decreased ADCP compared to a reference fusion protein that does not comprise the Ig (e.g., hlg, mlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0272] In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibits decreased or no binding affinity to one or more Fc receptor (e.g., human Fc receptor) (e.g., an Fey receptor (e.g., an Fey receptor (e.g., FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa, and / or FcyRIIIb)) compared to a reference fusion protein that does not comprise the Ig (e.g., hlg, mlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)).

[0273] In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibits decreased or no binding affinity to FcyRI. FcyRIIa, FcyRIIIa. and / or FcyRIIIb compared to a reference fusion protein that does not comprise the hlg Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibits decreased or no binding affinity to FcyRI compared to a reference fusion protein that does not comprise the Ig (e.g., hlg, mlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibitsAttorney Docket No. 62801.82W001decreased or no binding affinity to FcyRIIa compared to a reference fusion protein that does not comprise the Ig (e.g., hlg, mlg) Fc modification {e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibits decreased or no binding affinity to FcyRIIIa compared to a reference fusion protein that does not comprise the Ig (e.g., hlg, mlg) Fc modification (e.g., the one or more variation (e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, the modified Ig (e.g., hlg, mlg) Fc fusion protein exhibits decreased or no binding affinity to FcyRIIIb compared to a reference fusion protein that does not comprise the Ig (e.g., hlg, mlg) Fc modification {e.g., the one or more variation {e.g., one or more amino acid substitution, deletion, or addition)).

[0274] In some embodiments, the modified Ig {e.g., hlg, mlg) Fc fusion protein exhibits increased binding affinity to one or more Fc receptor {e.g., human Fc receptor) {e.g., an Fey receptor {e.g., FcyRIIb)) compared to a reference fusion protein that does not comprise the hlg Fc modification {e.g., the one or more variation {e.g., one or more amino acid substitution, deletion, or addition)). In some embodiments, the modified Ig {e.g., hlg, mlg) Fc fusion protein exhibits increased binding affinity to FcyRIIb compared to a reference fusion protein that does not comprise the Ig {e.g., hlg, mlg) Fc modification {e.g., the one or more variation {e.g., one or more amino acid substitution, deletion, or addition)).

[0275] In some embodiments, the modified Ig {e.g., hlg, mlg) Fc fusion protein exhibits decreased or no binding affinity to Clq compared to a reference fusion protein that does not comprise the Ig {e.g., hlg, mlg) Fc modification {e.g., the one or more variation {e.g., one or more amino acid substitution, deletion, or addition)).

[0276] Amino acid substitutions that decrease or abolish one or more Ig {e.g., hlg, mlg) Fc effector function are known in the art. See for example, Saunders Kevin, “Conceptual Approaches to Modulating Antibody Effector Functions and Circulation Half-Life,” Frontiers in Immunology, v10 (June 7, 2019) DOI=10.3389 / fimmu.2019.01296, the full contents of which is incorporated by reference herein for all purposes, see more particularly for example, e.g., Table 2 of Saunders.

[0277] Table 6 below provides exemplary amino acid substitutions (and combinations thereof) and glycoengineering that can be utilized to decrease one or more hlg Fc effector function. Amino acids in Table 6 are numbered according to the EU numbering scheme. The effects on effector function set forth in Table 6 are exemplary only and not intended to be limiting. The amino acidAttorney Docket No. 62801.82W001substitutions set forth in Table 6 are with reference to an IgG1 Fc region (except where noted). However, a person of ordinary skill in the could identify the corresponding amino acid in a non-IgGl Fc region, for example in an IgG2 or IgG4 Fc region, should the base amino acid be different between the IgGl and non-IgGl Fc region.Table 6. Exemplary hlg Fc Variations and Glycoengineering to Decreases Effector Function.Exemplary Effects on Effector Function Variation / Glycoengineering(Non-Limiting)Amino Acid SubstitutionsL235E Decreased binding to cell surface FcyRsDecreased ADCCL234A / L235A Decreased binding to FcyRI, RII, IIIDecreased ADCC, ADCP, CDCS228P / L235E (IgG4) Decreased binding to FcyRIL234A / L235A / P329G Eliminates binding to Decreased binding to FcyRI, RII, III,ClqDecreased ADCPL234A / L235A / P329A Eliminates binding to Decreased binding to FcyRI, RII, III,ClqDecreased ADCPL235A / G237A / P329G Reduced ADCC, ADCP, CDCL235A / G237A / P329A Reduced ADCC, ADCP, CDCP331S / L234E / L235F Eliminates binding to Decreased binding to FcyRI, RII, III,ClqDecreased CDCD235A Decreased binding to FcyRI, RII, IIIReduced ADCC, ADCPG237A Decreased binding to FcyRIIDecreased ADCPE318A Decreased binding to FcyRIIDecreased ADCPE233P Decreased binding to FcyRI, RII, IIIG236R / L328R Decreased binding to all FcyRsDecreased ADCCA330L Decreased Clq bindingDecreased CDCD270A Decreased Clq bindingDecreased CDCK332A Decreased Clq bindingDecreased CDCP329A Decreased Clq bindingDecreased CDCP331A Decreased Clq bindingAttorney Docket No. 62801.82W001Decreased CDCV264A Decreased Clq bindingDecreased CDCF241A Decreased C Iq bindingDecreased CDCN297A Decreased binding to FcyRI, RlllaDecreased Clq bindingDecreased ADCCDecreased ADCPDecreased CDCN297G Decreased binding to FcyRI, RlllaDecreased Clq bindingDecreased ADCCDecreased ADCPDecreased CDCN297Q Decreased binding to FcyRI, RlllaDecreased Clq bindingDecreased ADCCDecreased ADCPDecreased CDCS228P / F234A / L235A (IgG4) Decreased binding to FcyRI, Rlla, RlllaDecreased ADCCDecreased CDCS228P / F234A / L235E (IgG4) Decreased binding to FcyRI, Rlla, RlllaDecreased ADCCDecreased CDCGlycoengineeringHigh mannose glycosylation Decreased Clq bindingDecreased CDC

[0278] In some embodiments, the Ig Fc region is a hlg Fc region. In some embodiments, the hlg Fc (e.g., IgGl Fc) region comprises any one or more of the amino acid substitutions set forth in Table 6 (z.e., any one or more amino acid substitution set forth in any set of amino acid substitutions set forth in Table 6). In some embodiments, the hlg Fc (e.g., IgGl Fc) comprises any one or more of the sets of amino acid substitutions set forth in Table 6. In some embodiments, the hlg Fc (e.g., IgGl Fc) region comprises any one or more of the glycosylation changes set forth in Table 6.

[0279] In some embodiments, the modified Ig Fc fusion protein comprises a hlg Fc region comprising one or more amino acid variation. In some embodiments, the modified hlg Fc fusion protein comprises a hlg4 Fc region comprising one or more amino acid variation. In some embodiments, the hIgG4 Fc region comprises an amino acid substitution at amino acid positions S228, F234, and / or L235, EU numbering according to Kabat. In some embodiments, the hIgG4 Fc region comprises the following amino acid substitutions S228P, F234A, and / or L235A, EUAttorney Docket No. 62801.82W001numbering according to Kabat. In some embodiments, the h!gG4 Fc region comprises the following amino acid substitutions S228P, F234A, and / or L235E, EU numbering according to Kabat. In some embodiments, the hIgG4 Fc comprises the following amino acid substitutions S228P and / or L235E, EU numbering according to Kabat.

[0280] In some embodiments, the S228P variation stabilized the hinge region. See, e.g., Silva, John-Paul et al. “The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation.” The Journal of biological chemistry vol. 290,9 (2015): 5462-9. doi: 10.1074 / jbc. M 114.600973, the entire contents of which is incorporated herein by reference for all purposes.

[0281] In some embodiments, the modified hlg Fc fusion protein comprises a hlgGl Fc region comprising one or more amino acid variations. In some embodiments, the hlgGl Fc region comprises an amino acid substitution at amino acid positions L234, L235, and / or P329, EU numbering according to Kabat. In some embodiments, the hlgGl Fc region comprises the following amino acid substitutions L234A and / or L235A, EU numbering according to Kabat. In some embodiments, the hlgGl Fc region comprises the following amino acid substitutions L234A, L235A, and P329G, EU numbering according to Kabat. In some embodiments, the hlgGl Fc region comprises the following amino acid substitutions L234A, L235A, and P329A, EU numbering according to Kabat.

[0282] In some embodiments, the modified hlg Fc fusion protein comprises a hlgGl Fc region comprising one or more amino acid variations. In some embodiments, the hlgGl Fc region comprises an amino acid substitution at amino acid positions L235. G237. and / or P329, EU numbering according to Kabat. In some embodiments, the hlgGl Fc region comprises the following amino acid substitutions L235A and / or G237A, EU numbering according to Kabat. In some embodiments, the hlgGl Fc region comprises the following amino acid substitutions L235A, G237A, and P329G, EU numbering according to Kabat. In some embodiments, the hlgGl Fc region comprises the following amino acid substitutions L235A, G237A, and P329A, EU numbering according to Kabat.

[0283] The amino acid sequence of exemplary variant hlg Fc regions that are known in the art to exhibit a decrease in one more effector function is provided in Table 7.Attorney Docket No. 62801.82W001Table 7. The amino acid sequence of exemplary variant hlg Fc Regions.SEQDescription Amino Acid SequenceID NOhlgGl CH2 Region + PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDCH3 Region PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKIISKAKGQPREPQVYTLPPSRDL234A / L235A ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 306 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSWith C-terminal Lysine LSPGKhlgGl CH2 Region + PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDCH3 Region PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDL234A / L235A ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 307 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSWithout C-terminal LSPGLysinehlgGl Partial Hinge TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS Region + CH2 Region + HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHCH3 Region QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP 308 L234A / L235A VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKWith C-terminal LysinehlgGl Partial Hinge TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS Region + CH2 Region + ...

Claims

Attorney Docket No. 62801.82W001CLAIMSWhat is claimed is:

1. An isolated protein comprising an amino acid sequence 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 protein set forth in Table 1 or set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606.

2. The isolated protein of claim 1, wherein the amino acid sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any protein set forth in Table 1 or set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606.

3. The isolated protein of claim 1 or 2, wherein the amino acid sequence is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any protein set forth in Table 1 or set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606.

4. The isolated protein of any one of claims 1-3. wherein the amino acid sequence of the protein comprises the amino acid sequence of any protein set forth in Table 1 or set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606.

5. An isolated protein comprising an amino acid sequence 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 set forth in any one of SEQ ID NOS: 1-246, 590-595, or 605.

6. The isolated protein of claim 5, wherein the amino acid sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246. 590-595, or 605.

7. The isolated protein of claim 5 or 6, wherein the amino acid sequence is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595. or 605.

8. The isolated protein of any one of claims 5-7, wherein the amino acid sequence of the protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 590-595. or 605.

9. An isolated protein comprising an amino acid sequence 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 set forth in any one of SEQ ID NOS: 338-589 or 606.Attorney Docket No. 62801.82W00110. The isolated protein of claim 9, wherein the amino acid sequence is at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606.

11. The isolated protein of claim 9 or 10, wherein the amino acid sequence is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606.

12. The isolated protein of any one of claims 9-11, wherein the amino acid sequence of the protein comprises the amino acid sequence set forth in any one of SEQ ID NOS: 338-589 or 606.

13. An isolated protein comprising an amino acid sequence 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 set forth in SEQ ID NO: 17.

14. The isolated protein of claim 13, wherein the amino acid sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17.

15. The isolated protein of claim 13 or 14, wherein the amino acid sequence is at least 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 17.

16. The isolated protein of any one of claims 13-15, wherein the amino acid sequence of the protein comprises the amino acid sequence set forth in SEQ ID NO: 17.

17. The isolated protein of any one of the preceding claims, wherein the protein exhibits one or more immunomodulatory property (e.g., upon administration to a subject).

18. The isolated protein of any one of the preceding claims, wherein the protein exhibits one or more anti-inflammatory property (e.g., upon administration to a subject).

19. The isolated protein of any one of the preceding claims, wherein the protein exhibits one or more pro-inflammatory property (e.g., upon administration to a subject).

20. The isolated protein of any one of the preceding claims, wherein the protein exhibits one or more cytokine like property.

21. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human proteins.Attorney Docket No. 62801.82W00122. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human proteins capable of mediating an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect.

23. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human proteins, wherein binding to the one or more human protein mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect.

24. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human proteins, wherein binding to the one or more human protein mediates signaling through the protein.

25. The isolated protein of any one of the preceding claims, wherein the one or more human protein is a receptor.

26. The isolated protein of any one of the preceding claims, wherein the one or more human protein is a receptor (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells).

27. The isolated protein of any one of the preceding claims, wherein the one or more human protein is a cytokine receptor.

28. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) and binding of the protein to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect.

29. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes. NK cells, NK T cells, dendritic cells) and binding of the protein to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect.

30. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human cytokine receptor and binding of the protein to the receptor mediates an immunomodulatory (e.g., anti-inflammatory, pro-inflammatory) effect.Attorney Docket No. 62801.82W00131. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) and binding of the protein to the receptor mediates signaling through the receptor e.g., cytokine receptor).

32. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human receptors (e.g., cytokine receptor) expressed by (e.g., on the surface of) one or more population of immune cells (e.g., T cells, B cells, macrophages, monocytes, NK cells, NK T cells, dendritic cells) and binding of the protein to the receptor mediates signaling through the receptor (e.g., cytokine receptor).

33. The isolated protein of any one of the preceding claims, wherein the protein binds (e.g., specifically binds) to one or more human cytokine receptor and binding of the protein to the receptor mediates signaling through the cytokine receptor.

34. The isolated protein of any one of the preceding claims, wherein the protein comprises a homologous or heterologous signal peptide (e.g., operably connected to the N-terminus of the protein).

35. The protein of any one of the preceding claims operably connected to a heterologous moiety (e.g., described herein).

36. The protein of claim 35, wherein the heterologous moiety is a protein, peptide, small molecule, nucleic acid molecule (e.g., DNA, RNA, DNA / RNA hybrid molecule), lipid, or synthetic polymer.

37. The protein of claim 36, wherein the heterologous moiety is a protein.

38. A conjugate comprising the protein of any one of claims 1-37 operably connected to a heterologous moiety (e.g., described herein).

39. A radioligand comprising the protein of any one of claims 1-37 operably connected to a radionuclide.

40. A fusion protein comprising the protein of any one of claims 1-37 operably connected to a heterologous protein.

41. The fusion protein of claim 40, wherein the heterologous protein comprises an antibody.

42. The fusion protein of claim 40 or 41, wherein the heterologous protein comprises a halflife extension protein.

43. The fusion protein of any one of claims 40-42, wherein the heterologous protein comprises an immunoglobulin (Ig) (e.g., a human Ig (hlg)) Fc region.Attorney Docket No. 62801.82W00144. The fusion protein of claim 43, wherein the Ig (e.g., hIg) Fc region comprises at least a portion of a hinge region, a CH2 region, and a CH3 region.

45. The fusion protein of claim 43 or 44, wherein the Ig (e.g., hlg) Fc region comprises a hinge region, a CH2 region, and a CH3 region.

46. The fusion protein of any one of claims 43-45, wherein the Ig is a hlg.

47. The fusion protein of claim 46. wherein the hlg is a human IgG (hlgG).

48. The fusion protein of any one of claims 46-47, wherein the hlgG is hlgGl or hIgG4.

49. The fusion protein of any one of claims 40-48, wherein the protein of any one of claims 1-37 is directly operably connected to the heterologous protein through a peptide bond.

50. The fusion protein of any one of claims 40-48, wherein the protein of any one of claims 1-37 is indirectly operably connected to the heterologous protein through a peptide linker.

51. An immunogenic peptide or protein comprising at least an immunogenic fragment of the protein of any one of claims 1-37.

52. The immunogenic peptide or protein of claim 51. wherein the immunogenic peptide or protein comprises a full-length protein of any one of claims 1-37.

53. The immunogenic peptide or protein of any one of claims 51-52, wherein the immunogenic peptide or protein comprises an immunogenic fragment of a protein of any one of claims 1-37.

54. The immunogenic peptide or protein of any one of claims 51-53, wherein the immunogenic peptide or protein comprises at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 amino acids.

55. The immunogenic peptide or protein of any one of claims 51-54, wherein the immunogenic peptide or protein comprises about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 amino acids.

56. The immunogenic peptide or protein of any one of claims 51-55, wherein the immunogenic peptide or protein comprises no more than about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 amino acids.

57. The immunogenic peptide or protein of any one of claims 51-56, wherein the amino acid sequence of the immunogenic peptide or protein comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) amino acid variations (e.g., substitutions, additions, deletions) relative to a reference protein of any one of claims 1-37.Attorney Docket No. 62801.82W00158. The immunogenic peptide or protein of any one of claims 51-57, 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 contiguous stretch of at least about 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, or 130 amino acids set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606.

59. The immunogenic peptide or protein of any one of claims 51-58, wherein the immunogenic peptide or protein comprises an amino acid sequence that, other than the one or more amino acid variation (e.g., substitution, addition, deletion), is at least about 80%. 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in any one of SEQ ID NOS: 1-246, 338-595, or 605-606.

60. The immunogenic peptide or protein of any one of claims 51-59, wherein the immunogenic peptide or protein is formulated with an adjuvant.

61. An isolated antibody that specifically binds to a protein of any one of claims 1-37.

62. A nucleic acid molecule encoding the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, or the antibody of claim 61.

63. The nucleic acid molecule of claim 62, wherein the nucleic acid molecule is an RNA (e.g., mRNA, circular RNA) molecule or a DNA molecule.

64. An mRNA molecule encoding the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, or the antibody of claim 61.

65. The nucleic acid molecule of any one of claims 62-63 or the mRNA molecule of claim 64, comprising a heterologous 5'-untranslated region (UTR), 3'-UTR, or both a 5'-UTR and 3'-UTR.

66. The nucleic acid molecule of any one of claims 62-63 or 65 or the mRNA molecule of any one of claims 64-65, comprising a poly(A) sequence.

67. The nucleic acid molecule of any one of claims 62-63 or 65-66 or the mRNA molecule of any one of claims 64-66, comprising a 5' cap structure.

68. The nucleic acid molecule of any one of claims 62-63 or 65-67 or the mRNA molecule of any one of claims 64-67, comprising at least one variant nucleotide.Attorney Docket No. 62801.82W00169. The nucleic acid molecule of any one of claims 62-63 or 65-68 or the mRNA molecule of any one of claims 64-68, wherein the sequence of the nucleic acid molecule or mRNA molecule, respectively, is codon optimized.

70. A vector (e.g., expression vector) comprising the nucleic acid molecule of any one of claims 62-69 or the mRNA molecule of any one of claims 64-69.

71. The vector of claim 70, wherein the vector is a viral vector or a non-viral vector (e.g., a plasmid).

72. A carrier comprising the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, the antibody of claim 61, the nucleic acid molecule of any one of claims 62-69. the mRNA molecule of any one of claims 64-69, or the vector of any one of claims 70-71.

73. A carrier conjugated to the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39. or the fusion protein of any one of claims 40-50.

74. The carrier of claim 72 or 73, wherein the carrier is a lipid nanoparticle (LNP), liposome, lipoplex, or nanoliposome.

75. The carrier of claim 74, wherein the carrier is an LNP76. The carrier of claim 74 or 75, wherein the LNP comprises a cationic lipid, a neutral lipid, a cholesterol, and / or a PEG lipid.

77. The carrier of any one of claims 74-76, wherein the LNP comprises a cationic lipid, a neutral lipid, a cholesterol, and a PEG lipid.

78. The carrier of any one of claims 72-77, wherein the LNP has a mean particle size of between 80 nm and 160 nm.

79. A viral particle conjugated to the protein of any one of claims 1-37, the conjugate of claim 38. the radioligand of claim 39, or the fusion protein of any one of claims 40-41.

80. A cell (e.g., host cell) or population of cells comprising the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, the antibody of claim 61, the nucleic acid molecule of any one of claims 62-69, the mRNA molecule of any one of claims 64-69, the vector of any one of claims 70-71, the carrier of any one of claims 72-78, the vaccine composition of claim 81, or the pharmaceutical composition of claim 82.Attorney Docket No. 62801.82W00181. A vaccine composition comprising the immunogenic peptide or protein of any one of claims 51-60 (or a nucleic acid molecule encoding the same (or a vector encoding the nucleic acid molecule) or a carrier comprising any of the foregoing).

82. A pharmaceutical composition comprising the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60. the antibody of claim 61. the nucleic acid molecule of any one of claims 62-69, the mRNA molecule of any one of claims 64-69, the vector of any one of claims 70-71, the carrier of any one of claims 72-78. the viral particle of claim 79, the cell or population of cells of claim 80, or the vaccine composition of claim 81, and a pharmaceutically acceptable excipient.

83. A kit comprising the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, the antibody of claim 61, the nucleic acid molecule of any one of claims 62-69. the mRNA molecule of any one of claims 64-69. the vector of any one of claims 70-71, the carrier of any one of claims 72-78, the viral particle of claim 79, the cell or population of cells of claim 80, the vaccine composition of claim 81, or the pharmaceutical composition of claim 82, and optionally comprising instructions for use of the foregoing.

84. A method of delivering a protein, a conjugate, a radioligand, a fusion protein, an immunogenic peptide or protein, an antibody, a nucleic acid molecule, an mRNA molecule, a vector, a carrier, a viral particle, a vaccine composition, a cell or population of cells, or a pharmaceutical composition to a subject in need thereof, the method comprising administering to the subject the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, the antibody of claim 61, the nucleic acid molecule of any one of claims 62-69, the mRNA molecule of any one of claims 64-69, the vector of any one of claims 70-71, the carrier of any one of claims 72-78, the viral particle of claim 79, the cell or population of cells of claim 80, the vaccine composition of claim 81, or the pharmaceutical composition of claim 82, to thereby deliver the protein, the conjugate, the radioligand, the fusion protein, the immunogenic peptide or protein, the antibody, the nucleic acid molecule, the mRNA molecule, the vector, the carrier, the viral particle, the vaccine composition, the cell or population of cells, or the pharmaceutical composition to the subject.Attorney Docket No. 62801.82W00185. A method of modulating an immune response in a subject in need thereof, the method comprising administering to the subject the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, the antibody of claim 61, the nucleic acid molecule of any one of claims 62-69, the mRNA molecule of any one of claims 64-69, the vector of any one of claims 70-71, the carrier of any one of claims 72-78. the viral particle of claim 79, the cell or population of cells of claim 80, the vaccine composition of claim 81, or the pharmaceutical composition of claim 82, to thereby modulate an immune response in the subject in need thereof.

86. A method of suppressing or preventing an immune response in a subject in need thereof, the method comprising administering to the subject the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, the antibody of claim 61, the nucleic acid molecule of any one of claims 62-69, the mRNA molecule of any one of claims 64-69, the vector of any one of claims 70-71, the carrier of any one of claims 72-78, the viral particle of claim 79, the cell or population of cells of claim 80, the vaccine composition of claim 81, or the pharmaceutical composition of claim 82, to thereby suppress or prevent an immune response in the subject in need thereof.

87. A method of inducing or enhancing an immune response in a subject in need thereof, the method comprising administering to the subject the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, the antibody of claim 61. the nucleic acid molecule of any one of claims 62-69, the mRNA molecule of any one of claims 64-69, the vector of any one of claims 70-71, the carrier of any one of claims 72-78, the viral particle of claim 79, the cell or population of cells of claim 80, the vaccine composition of claim 81, or the pharmaceutical composition of claim 82, to thereby induce or enhance an immune response in the subject in need thereof.

88. A treating, ameliorating, or preventing a disease in a subject in need thereof, the method comprising administering to the subject the protein of any one of claims 1-37, the conjugate of claim 38, the radioligand of claim 39, the fusion protein of any one of claims 40-50, the immunogenic peptide or protein of any one of claims 51-60, the antibody of claim 61, the nucleicAttorney Docket No. 62801.82W001acid molecule of any one of claims 62-69, the mRNA molecule of any one of claims 64-69, the vector of any one of claims 70-71, the carrier of any one of claims 72-78, the viral particle of claim 79, the cell or population of cells of claim 80, the vaccine composition of claim 81, or the pharmaceutical composition of claim 82, to thereby treat, ameliorate, or prevent the disease in the subject.

89. The method of claim 88, wherein the disease is a proinflammatory disease (e.g., an autoimmune disease) or an immunosuppressive disease.

90. A method of vaccinating a subject in need thereof (e.g., against a viral infection), the method comprising administering to the subject (i) the immunogenic peptide or protein of any one of claims 51-60 (or a conjugate or a fusion protein thereof); (ii) a nucleic acid molecule encoding (i); (iii) a vector comprising (ii); (iv) a carrier comprising (i), (ii), or (iii); a vaccine composition comprising (i), (ii), (iii), or (iv); or a pharmaceutical composition comprising (i), (ii), (iii), (iv), or (v), to thereby vaccinate the subject in need thereof (e.g., against a virus).

91. A method of determining the presence of a virus in a subject, the method comprising (a) obtaining the sample from a subject or providing a sample that has been obtained from a subject, and(b) determining the presence or absence of the protein of any one of claims 1-37 (or a fragment or variant thereof) or a nucleic acid molecule encoding the protein of any one of claims 1-37 (or the fragment or variant thereof) in the sample.

92. A method of diagnosing a viral infection in a subject, the method comprising(a) obtaining a sample from a subject or providing a sample that has been obtained from a subject.(b) determining the presence or absence of the protein of any one of claims 1-37 (or a fragment or variant thereof) or a nucleic acid molecule encoding the protein of any one of claims 1-37 (or a fragment or variant thereof), and(c) diagnosing the subject as having the viral infection if the protein of any one of claims 1-37 (or a fragment or variant thereof) or a nucleic acid molecule encoding the protein of any one of claims 1-37 (or the fragment or variant thereof) is determined to be present in the sample in step (b).

93. The method of claim 90 or 91, wherein the method is an in vitro method.

94. A method of treating a viral infection in a subject, the method comprisingAttorney Docket No. 62801.82W001(a) receiving testing results that determined the presence of the protein of any one of claims 1-37 (or a fragment or variant thereof) or a nucleic acid molecule encoding the protein of any one of claims 1-37 (or the 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.

95. The method or use of any one of claims 90-94, wherein the sample is a blood, cell, tissue, or saliva, or nasal swab.

96. The method or use of any one of claims 90-95, wherein the antibody of claim 61 is utilized to determine the presence or absence of the protein of any one of claims 1-37 (or the fragment or variant thereof).

97. The method or use of any one of claims 84-96, wherein the subject is a human.

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