IMMUNOMODULATING MOLECULES LOCATED IN COLLAGEN AND METHODS OF THE SAME

Abstract

The present invention provides immunomodulatory fusion proteins comprising a collagen-binding domain operably linked to an immunomodulatory fusion domain. The description also presents compositions and methods for using the same, for example, to treat cancer.

Description

IMMUNOMODULATORY MOLECULES LOCALIZED IN COLLAGEN AND METHODS THEREOF CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit of the priority date of US Provisional Application No. 62 / 738,981, filed September 28, 2018, the contents of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION Although immunotherapy has transformed oncology with durable curative responses in a minority of patients, immune related adverse events (irAEs) limit its broader application (Michot et al 2016, Eur J Cancer, 54:139-148). It is desired to restrict the most potent immune activation events to tumor tissue, while preserving healthy non-tumor tissue. An accepted goal of new immunotherapies is to “warm up” immunologically “cold” tumors, leading to inflammation and immune cell infiltration (Chen and Mellman 2017, Nature, 541:321-330). Several tumor localization procedures have been proposed: linking immunomodulatory agents to tumor-targeting modules on immunocytokines (Hutmacher and Neri 2018, Adv Drug Deliv Rev); masking the activity of the agent systemically, with localized proteolytic activation in the tumor (Thomas and Daugherty 2009, Protein Sci 18:2053-2059); intratumoral injection of the agents (Singh and Overwijk 2015, Nat Commun 8:1447; Ager et al 2017, Cancer Immunol Res 5:676-684; Bommareddy et al 2017, Cancer J 23:40-47; Milling et al 2017, Adv Drug Deliv Rev 114:79-101; Singh et al 2017, Nat Commun 8:1447; Sagiv-Barfi et al 2018, Sci Transí Med 10:eaan4488); peritumoral injection of a solid biomaterial to entrap the agent (Park et al. 2018, Sci Transí Med, 10:eaar1916); conjugation with a solid particle (Kwong et al. 2013, Cancer Res 73:1547-1558) or conjugation of basic charged peptides to drive some non-specific adhesion of the agent to the tumor extracellular matrix (Ishihara et al. 2017, Sci Transí Med 9: eaan0401; Ishihara et al 2018, Mol Cancer Ther 17:2399-2411). A related but distinct procedure is localizing growth factors in tissue to drive tissue regeneration (Nishi et al 1998, Proc Nati Acad Sci 95:7018-7023; Martino et al 2014, Science 343:885-888; Mitchell et al. collaborators 2016, Acta BiomaterSO'AA?.). There are significant problems with each of the present above methods. Immunocytokines systemically expose immune cells to the immunomodulatory agent (Tzeng et al. 2015, Proc Nati Acad Sci 112:3320-3325). Masking agents can be unmasked outside of target tissues, and the masking agent can complicate manufacturing and immunogenicity. Intratumoral injection of cebenn / Lznz / B / YiAi frequently leads to rapid spread of the tumor compartment. Conjugation of peptides at random sites is difficult to produce, can negatively impact specific activity, does not completely prevent tumor exit, and creates significant CMC problems due to the heterogeneous products of random conjugation methods. Accordingly, there is a need for novel immunotherapy methods to promote tumor localization and increase efficacy, while preventing systemic toxicity. BRIEF DESCRIPTION OF THE INVENTION The present disclosure is based, at least in part, on the discovery that an immunomodulatory domain (eg, cytokine, anti-immune receptor antibody, anti-tumor associated antigen antibody, etc.) can be conjugated to a binding domain. to collagen, resulting in improved anti-tumor efficacy relative to the unconjugated immunomodulatory domain. Without wishing to be limited by theory, collagen localization of an immunomodulatory domain results in improved antitumor efficacy because T cells are trapped in the collagen-rich areas around tumors, thereby making the sites of cells for targeting of immunomodulatory agents. Nearly half of human tumors display an immune excluded phenotype, where CD8+ T cells are evidently trapped within collagen-rich desmoplastic (Mariathasan, et al., Nature, 2018, 554:544-548). Given the primary importance of CD8+ T cells in immunotherapeutic efficacy, there is a desire to target immunomodulatory agents to this collagen-rich, CD8+ T cell-rich compartment of tumors. The specificity is significant because previous agents that use non-specific electrostatic interactions on small unstructured peptides for retention (Martino, et al., Science, 2014, 343:885888), bind promiscuously to the vast majority of components of negatively charged extracellular matrix rather than within the particular collagen-rich compartment of interest. These unstructured, positively charged peptides also lead to relatively weak retention kinetics, where in some cases half the payload of the injected conjugate leaks into the systemic circulation (Ishihara, et al. Mol Cancer Ther. 2018, 17:2399 -2411). Accordingly, immunomodulatory fusions to structured proteins with specific affinity for collagen are provided herein, leading to increased retention within the particular collagen-rich compartments of interest. In some aspects described herein, immunomodulatory fusion proteins comprise a cytokine, wherein the collagen-binding domain increases tumor retention and prevents systemic exposure to the cytokine after tumor delivery in preclinical animal models, thereby reducing way toxicity related to cefrenn / Lznz / B / YiAi treatment. In addition, immunomodulatory fusion proteins have increased antitumor efficacy and reduced toxicity compared with equivalent fusion proteins lacking collagen-binding domains when combined with one or more additional immunotherapies (eg, tumor-targeting antibodies, blockade of checkpoint, cancer vaccines, and T-cell therapy. As provided herein, these immunomodulatory fusion proteins display durable and systemic anti-tumor responses, enable localized immunity against the injected tumor, and systemic immunity for effective treatment of a contralateral non-injected tumor. Neoadjuvant administration of immunomodulatory fusion proteins also improved survival by preventing metastasis after surgical excision of the residual primary tumor, further showing that immunomodulatory fusion proteins promote systemic antitumor immunity. Thus, the immunomodulatory fusion proteins of the disclosure are useful for treating metastatic tumors and / or mediate the abscopal effect in therapeutic modalities (eg, anti-cancer). Also provided herein are variant collagen-binding domains that have altered (eg, increased or decreased) binding affinities for collagen. By discovering a selection of variant collagen-binding domains with different collagen-binding affinities, the disclosures herein provide options for selecting immunomodulatory fusion proteins with different binding affinities for collagen-rich compartments (eg, tumors expressing collagen). The compositions and methods of binding to collagen provided herein allow agnostic local targeting of tumor charge and payload of active therapeutic agents. Collagen-binding compositions also show increased efficacy with a concomitant decrease in toxicity associated with systemic immunotherapies. In some aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) an immunomodulatory fusion domain; (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a Kd < 500 nM, and wherein the binding domain Collagen has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa; and (iii) optionally, a linker, wherein the immunomodulatory domain is operably linked with or without the linker to the collagen-binding domain. cebenn / Lznz / B / YiAi In some aspects, the KD of the collagen-binding domain for type I and / or type IV collagen is less than the Kd of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen. In some aspects, the collagen-binding domain has a MW (molecular weight) of about 5-100 kDa, about 10-80 kDa, about 20-60 kDa, about 30-50 kDa, or about 10 kDa, about 20 kDa. , about 30 kDa, about 40 kDa, about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa or about 100 kDa. In some aspects, the immunomodulatory fusion protein comprises a collagen-binding domain comprising one or more leucine-rich repeats that bind collagen. In some aspects, the collagen-binding domain comprises two, three, four, five, six, seven, eight, nine, or ten leucine-rich repeats that bind collagen. In some aspects, the collagen-binding domain comprises one or more leucine-rich repeats of a human proteoglycan Class II member of the small leucine-rich proteoglycan (SLRP) family. In some aspects, the SLRP is selected from lumican, decorin, biglycan, fibromodulin, chondroaderin, asporin, PRELP, osteoaderin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen. In some respects, the SLRP is lumican. In some aspects, the immunomodulatory fusion protein comprises a collagen-binding domain that comprises a human SLRP. In some aspects, the SLRP is selected from lumican, decorin, biglycan, fibromodulin, chondroaderin, asporin, PRELP, osteoaderin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen. In some respects, the SLRP is lumican. In some aspects, the lumican comprises the amino acid sequence as set forth in SEQ ID NO: 107. In some aspects, the immunomodulatory fusion protein comprises a collagen-binding domain comprising a human type I glycoprotein having an Ig-like domain, or an extracellular portion thereof that binds collagen. In some aspects, the type I glycoprotein competes with lumican for binding to type I collagen. In some aspects, the human type I glycoprotein is selected from LAIR1, LAIR2, and Glycoprotein IV. In some aspects, the human type I glycoprotein is LAIR1. In some aspects, the human type I glycoprotein is LAIR1 and the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set forth in SEQ ID NO: 98. In some embodiments, LAIR1 is a variant comprising one or more amino acid substitutions, additions or deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the sequence of crfrcnn / Lznz / E / YiAi amino acids of SEQ ID NO: 98. In some embodiments, the LAIR1 variant has increased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In still other embodiments, the LAIR1 variant has decreased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In any of the above aspects, the immunomodulatory domain comprises a polypeptide that activates, enhances, or promotes a response by an immune cell. In other aspects, the immunomodulatory domain comprises a polypeptide that inhibits, reduces, or suppresses a response by an immune cell. In some aspects, the immune cell is a lymphoid cell selected from an innate lymphoid cell, a T cell, a B cell, an NK cell, and a combination thereof. In other aspects, the immune cell is a myeloid cell selected from a monocyte, a neutrophil, a granulocyte, a mast cell, a macrophage, a dendritic cell, and a combination thereof. In some aspects, the response by the immune cell comprises cytokine production, antibody production, antigen-specific immune cell production, increased effector function and / or cytotoxicity, and a combination thereof. In any of the above aspects, the immunomodulatory domain comprises one or more selected from a cytokine, a chemokine, an activating ligand / receptor, an inhibitory ligand / receptor, or a combination thereof. In some aspects, the immunomodulatory domain comprises one or more cytokines. In some aspects, the cytokine is a human common chain receptor gamma interleukin selected from IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-15 / IL-15RA, IL-21, and a combination thereof. In some aspects, the cytokine is IL-2. In some aspects, the cytokine is a member of the human IL-12 family selected from IL-12(p35), IL-12(p40), IL-12(p35) / IL-12(p40), IL-23, IL-27 IL-35, and a combination thereof. In some aspects, the cytokine is a single chain IL-12(p35) / IL-12(p40) fusion. In other aspects, the cytokine is a member of the human IL-1 family selected from IL-1, IL-18, IL-33, and a combination thereof. In some aspects, the cytokine is IL-18. In still other aspects, the cytokine is selected from TNFa, INFa, IFN-γ, GM-CSF, FLT3L, G-CSF, M-CSF, and a combination thereof. In some aspects, the immunomodulatory domain comprises one or more chemokines. In some aspects, the chemokine is selected from LIF, MIP-2, ΜΙΡ-1α, ΜΙΡ-1β, CXCL1, CXCL9, CXCL10, MCP-1, Eotaxin, RANTES, LIX, and a combination thereof. In other aspects, the chemokine is selected from CCL3, CCL4, CCL5, Eotaxin, and a cefrenn / Lznz / B / YiAi combination thereof. In any of the above aspects, the immunomodulatory domain comprises one or more activation ligands / receptors. In some aspects, the activation ligand / receptor is selected from a TNF superfamily, a CD28 receptor superfamily, a B7 ligand family, and a T cell receptor. In other aspects, the activation ligand / receptor is an activation ligand / receptor. the TNF superfamily selected from TNF-alpha, CD40L, 4-1BBL, 0X40, and a combination thereof. In still other aspects, the activation ligand / receptor is a receptor of the TNF superfamily and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from an anti-TNFR1 antibody, an anti-TNFR2 antibody, an anti-CD40 antibody , an anti-4-1BB antibody and an anti-OX40 antibody. In other aspects, the activation ligand / receptor is a member of the CD28 superfamily or a member of the B7 family selected from ICOS ligand, CD80, and CD86, and a combination thereof. In still other aspects, the activation ligand / receptor is a member of the CD28 superfamily and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from an anti-ICOS antibody and an anti-CD28 antibody. In additional aspects, the activation ligand / receptor is a T cell receptor and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from an anti-CD3y antibody, an anti-CD3o antibody, an anti-CD3C antibody, and an anti-CD3¿ antibody. In some aspects, the activation ligand / receptor is selected from a TNF superfamily, a CD28 receptor superfamily, a B7 ligand family, a T cell receptor, a Killer cell Ig-like receptor, a leukocytes, a family of the CD94 / NKG2 receptor, and an Fe receptor. In other aspects, the activating receptor / ligand is an Ig-Like Receptor Ligand of Killer Cells and the immunomodulatory domain comprises the antibody or antigen-binding fragment of the itself selected from an anti-KIR 2DS1 antibody, an anti-KIR 2DS2 antibody, an anti-KIR 2DS3 antibody, an anti-KIR 2DS4 antibody, an anti-KIR 2DS5 antibody and an anti-KIR 3DS1 antibody. In additional aspects, the activation ligand / receptor is a Leukocyte Ig-like receptor and the immunomodulatory domain comprises an anti-LIRA2 antibody or an antigen-binding fragment thereof. In other aspects, the activation ligand / receptor is a member of the CD94 / NKG2 receptor family selected from MICA, MICB, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5 (¡soform 1), ULBP5 (¡soform 2), and ULBP6. . In still other aspects, the activating ligand / receptor is a member of the CD94 / NKG2 receptor family and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from an anti-CD94 / NKG2D antibody, an anti-CD94 antibody / NKG2C, an anti-CD94 / NKG2E antibody, and an anti-CD94 / NKG2H antibody. In additional aspects, the ligand / receptor activation is cefrenn / ίζηζ / Β / γίΛΐ a member of the Fe receptor family and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from the anti-FcyRI antibody, an antibody anti-FcyRIIC, an anti-FcyRIIIA antibody, an anti-FcyRIIIB antibody, an anti-FceRI antibody, an anti-FcsRH antibody, an anti-FcaR antibody, and an anti-FcpR antibody. In any of the above aspects, the immunomodulatory domain comprises one or more inhibitory ligands / receptors. In some aspects, the ligand / receptor inhibitor is selected from a CD28 receptor superfamily, a TNF superfamily, and a checkpoint inhibitor. In other aspects, the inhibitory ligand / receptor is a member of the CD28 superfamily and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L1 antibody, anti-PD-L2, an anti-CTLA4 antibody. In still further aspects, the inhibitory ligand / receptor is a member of the TNF superfamily and the immunomodulatory domain comprises an antibody or antigen-binding fragment selected from an anti-TIGIT antibody and an anti-BTLA antibody. In some aspects, the inhibitory ligand / receptor is a checkpoint inhibitor and the immunomodulatory domain comprises an antibody or antigen-binding fragment selected from an anti-VISTA antibody, an anti-TIM-3 antibody, an anti-LAG antibody -3, an anti-CD47 antibody, and an anti-SIRPa y antibody. In some aspects, the inhibitory ligand / receptor is selected from a CD28 receptor superfamily, a TNF superfamily, a Siglec family, a CD94 / NKG2A family, a Leukocyte Ig-like receptor family, Cell Ig-like Receptor Ligand Terminators, an Fe Receptor, an adenosine pathway molecule, and a checkpoint inhibitor. In other aspects, the inhibitory ligand / receptor comprises a member of the Siglec family and the immunomodulatory domain comprises an antibody or antigen-binding fragment selected from an anti-Siglec 1 antibody, an anti-Siglec 2 antibody, an anti-Siglec antibody 3, an anti-Siglec 4a antibody, an anti-Siglec 5 antibody, an anti-Siglec 6 antibody, an anti-Siglec 7 antibody, an anti-Siglec 8 antibody, an anti-Siglec 9 antibody, an anti-Siglec 10 antibody , an anti-Siglec 11 antibody and an anti-Siglec 12 antibody. In still other aspects, the ligand / receptor inhibitor comprises a receptor / ligand inhibitor of the CD94 / NKG2 receptor family and the immunomodulatory domain comprises an antibody or antigen-binding fragment selected from an anti-CD94 / NKG2A antibody and an anti-CD94 / NKG2B antibody. In some aspects, the inhibitory ligand / receptor comprises a Leukocyte Ig-like receptor and the immunomodulatory domain comprises an antibody or antigen-binding fragment selected from an anti-LIRB1 antibody, an anti-LIRB2 antibody, an anti-LIRB3 antibody, an anti-LIRB4 antibody. In other aspects, the inhibitory ligand / receptor comprises a Cebenn Ligand / ίζηζ / ε / γίΛΐ Killer Cell Ig-Like Receptor and the immunomodulatory domain comprises the antibody or antigen-binding fragment thereof selected from an anti-KIR 2DL1 antibody, an anti-KIR 2DL2 antibody, an anti-KIR 2DL3 antibody, an anti-KIR antibody 2DL4, an anti-KIR 2DL5A antibody, an anti-KIR 2DL5B antibody, an anti-KIR 3DL1 antibody, an anti-KIR 3DL2 antibody and an anti-KIR 3DL3 antibody. In still other aspects, the inhibitory ligand / receptor comprises an Fc receptor and the immunomodulatory domain comprises an anti-FcyRIIB antibody or antigen-binding fragment. In some aspects, the inhibitory ligand / receptor comprises an adenosine pathway molecule and the immunomodulatory domain comprises an antibody or antigen-binding fragment selected from an anti-CD39 antibody and an anti-CD73 antibody. In other aspects, the inhibitory ligand / receptor comprises a checkpoint inhibitor and the immunomodulatory domain comprises an antibody or antigen-binding fragment selected from an anti-VISTA antibody, an anti-TIM-3 antibody, an anti-LAG-antibody. 3, an anti-CD47 antibody, and an anti-SIRPa antibody. In any of the above aspects, the immunomodulatory domain is operably linked to the collagen-binding domain via a linker. In some aspects, the linker is of sufficient length or mass to reduce uptake of the immunomodulatory domain into collagen fibrils. In some aspects, the linker provides sufficient molecular weight to the fusion protein that it reduces the spreading of a tissue. In some aspects, the linker allows for steric separation of the immunomodulatory domain from collagen fibrils to promote receptor / ligand coupling. In some aspects, the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where 1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400. . In some aspects, the linker is a human serum albumin or fragment thereof. In other aspects, the linker comprises an Fe domain or a mutant Fe domain with reduced FcR interaction. In any of the above aspects, the immunomodulatory fusion protein is of sufficient mass to reduce size-dependent leakage by diffusion or convection upon administration in vivo. In some aspects, the fusion protein is >60 kDa. In some aspects, the immunomodulatory fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing the systemic exposure of the immunomodulatory fusion protein. In some aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) at least one cytokine; (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a Kd < 500 nM, and cefrenn / Lznz / B / YiAi wherein the collagen-binding domain has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100- 500, or 200-400, where the cytokine is operably linked via the linker to the collagen-binding domain, and where the fusion protein is >60 kDa. In some aspects, the Kd of the collagen-binding domain for type I and / or type IV collagen is less than the Kd of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen. In some aspects, the collagen binding domain comprises a human SLRP selected from lumican, decorin, biglycan, fibromodulin, chondroaderin, asporin, PRELP, osteoaderin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen. In some respects, the SLRP is lumican. In some aspects, the lumican comprises the amino acid sequence as set forth in SEQ ID NO: 107. In other aspects, the collagen binding domain is selected from LAIR1, LAIR2, and Glycoprotein IV. In some aspects, the collagen binding domain is LAIR1. In some aspects, the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set forth in SEQ ID NO: 98. In some embodiments, LAIR1 is a variant comprising one or more substitutions, additions or amino acid deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98 In some embodiments, the LAIR1 variant has increased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In still other embodiments, the LAIR1 variant has decreased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In some aspects, the cytokine is a human common chain receptor gamma interleukin selected from IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-15 / IL-15RA, IL-21, and a combination thereof. In some aspects, the cytokine is IL-2. In some aspects, the cytokine is a member of the human IL-12 family selected from IL-12(p35), IL-12(p40), IL-12(p35) / IL-12(p40), IL-23, IL-27, IL-35, and a combination thereof. In some aspects, the cytokine is a single chain IL-12(p35) / IL-12(p40) fusion. In some aspects, the immunomodulatory fusion protein comprises a second cytokine. In some aspects, the second cytokine is IL-2. In other aspects, the cytokine is a human IL-1 family member selected from cebenn / Lznz / B / YiAi from IL-1, IL-18, IL-33, and a combination thereof. In still other aspects, the cytokine is selected from TNFa, INFa, IFN-γ, GM-CSF, FLT3L, G-CSF, M-CSF, and a combination thereof. In some aspects, the linker is of sufficient length or mass to reduce adsorption of the immunomodulatory domain onto collagen fibrils, and / or provides sufficient molecular weight for the fusion protein to reduce diffusion from a tissue and / or allow the steric separation of the immunomodulatory domain from collagen fibrils to promote receptor / ligand coupling. In some aspects, the linker is a human serum albumin or fragment thereof. In other aspects, the linker comprises an Fe domain or a mutant Fe domain with reduced FcR interaction. In some aspects, the fusion protein is of sufficient mass to reduce size-dependent leakage by diffusion or convention upon administration in vivo. In some aspects, the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing the systemic exposure of the immunomodulatory fusion protein. In other aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) at least one chemokine; (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a Kd < 500 nM, and wherein the collagen-binding domain collagen has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100- 500, or 200-400, where the chemokine is operably linked via the linker to the collagen-binding domain, and where the fusion protein is >60 kDa. In some aspects, the KD of the collagen-binding domain for type I and / or type IV collagen is less than the KD of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen. . In some aspects, the collagen binding domain comprises a human SLRP selected from lumican, decorin, biglycan, fibromodulin, chondroaderin, asporin, PRELP, osteoaderin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen. In some respects, the SLRP is lumican. In some aspects, the lumican comprises the amino acid sequence as set forth in SEQ ID NO: 107. In other aspects, the collagen binding domain is selected from LAIR1, LAIR2, and Glycoprotein IV. In some aspects, the collagen binding domain is LAIR1. In some aspects, the collagen-binding domain comprises cefrenn / Lznz / B / YiAi amino acid residues 22-122 of the amino acid sequence as set forth in SEQ ID NO: 98. In some embodiments, LAIR1 is a variant that comprises one or more amino acid substitutions, additions or deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the sequence of amino acids of SEQ ID NO: 98. In some embodiments, the LAIR1 variant has increased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In others In additional embodiments, the LAIR1 variant has decreased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In some aspects, the chemokine is selected from LIF, MIP-2, ΜΙΡ-1α, ΜΙΡ-1β, CXCL1, CXCL9, CXCL10, MCP-1, Eotaxin, RANTES, LIX, and a combination thereof. In some aspects, the chemokine is selected from CCL3, CCL4, CCL5, Eotaxin, and a combination thereof. In some aspects, the linker is of sufficient length or mass to reduce adsorption of the immunomodulatory domain onto collagen fibrils, and / or provides sufficient molecular weight for the fusion protein so that it reduces diffusion into a tissue and / or allows for spherical detachment of the immunomodulatory domain from collagen fibrils to promote receptor / ligand coupling. In some aspects, the linker is a human serum albumin or fragment thereof. In other aspects, the linker comprises an Fe domain or a mutant Fe domain with reduced FcR interaction. In some aspects, the fusion protein is of sufficient mass to reduce size-dependent leakage by diffusion or convention upon administration in vivo. In some aspects, the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing the systemic exposure of the immunomodulatory fusion protein. In still other aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) an agonist antibody that binds to a ligand / receptor comprising an Fe domain or a mutant Fe domain with reduced FcR interaction; and (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a KD < 500 nM, and wherein the collagen-binding domain Collagen binding has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa, wherein the collagen binding domain is operably linked to the C-terminus of the Fe domain or mutant Fe domain. In some aspects, the Kd of the cefrenn / Lznz / B / YiAi collagen-binding domain for collagen type I and / or type IV is less than the KD of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin , osteopontin, tenascin C, or fibrinogen. In some aspects, the collagen binding domain comprises a human SLRP selected from lumican, decorin, biglycan, fibromodulin, chondroaderin, asporin, PRELP, osteoaderin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen. In some respects, the SLRP is lumican. In some aspects, the lumican comprises the amino acid sequence as set forth in SEQ ID NO: 107. In other aspects, the collagen binding domain is selected from LAIR1, LAIR2, and Glycoprotein IV. In some aspects, the collagen binding domain is LAIR1. In some aspects, the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set forth in SEQ ID NO: 98. In some embodiments, LAIR1 is a variant comprising one or more substitutions, additions or amino acid deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98 In some embodiments, the LAIR1 variant has increased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In still other embodiments, the LAIR1 variant has decreased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In some aspects, the agonist antibody is selected from an anti-TNFR1 antibody, an anti-TNFR2 antibody, an anti-CD40 antibody, an anti-4-1BB antibody, and an anti-OX40 antibody. In other aspects, the agonist antibody is selected from an anti-ICOS antibody and an anti-CD28 antibody. In some aspects, the agonist antibody is selected from an anti-CD3y antibody, an anti-CD3ó antibody, a 3ηίί-0ϋ3ζ antibody, and an anti-CD3e antibody. In some aspects, the fusion protein is of sufficient mass to reduce size-dependent leakage by diffusion or convention upon in vivo administration. In some aspects, the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing the systemic exposure of the immunomodulatory fusion protein. In additional aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) an antagonist antibody that binds to an inhibitory ligand / receptor comprising an Fe domain or a mutant Fe domain with reduced FcR interaction; and (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a Kd < 500 nM, and cefrenn / Lznz / Β / γΐΛΐ where the collagen-binding domain has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa, wherein the collagen-binding domain is operably linked to the C-terminus of the Fe domain or domain mutant faith. In some aspects, the Kd of the collagen-binding domain for type I and / or type IV collagen is less than the Kd of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen. In some aspects, the collagen binding domain comprises a human SLRP selected from lumican, decorin, biglycan, fibromodulin, chondroaderin, asporin, PRELP, osteoaderin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen. In some respects, the SLRP is lumican. In some aspects, the lumican comprises the amino acid sequence as set forth in SEQ ID NO: 107. In other aspects, the collagen binding domain is selected from LAIR1, LAIR2, and Glycoprotein IV. In some aspects, the collagen binding domain is LAIR1. In some aspects, the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set forth in SEQ ID NO: 98. In some embodiments, LAIR1 is a variant comprising one or more substitutions, additions or amino acid deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98 In some embodiments, the LAIR1 variant has increased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In still other embodiments, the LAIR1 variant has decreased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In some aspects, the agonist antibody is selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-CTLA4 antibody, an anti-TIGIT antibody, an anti- BTLA, an anti-VISTA antibody, an anti-TIM-3 antibody, an anti-LAG-3 antibody, an anti-CD47 antibody, and an anti-SIRPa antibody. In some aspects, the fusion protein is of sufficient mass to reduce size-dependent leakage by diffusion or convection upon in vivo administration. In some aspects, the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing the systemic exposure of the immunomodulatory fusion protein. In other aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) human IL-2; (ii) human lumican, human LAIR1, or human LAIR1 variant; and cebenn / Lznz / B / YiAi (i¡¡) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, wherein N=1-1000, 10-900, 30-800, 40 -700, 50-600, 100-500, or 200-400, where IL-2 is operably linked via the linker to lumican or LAIR1, and where the fusion protein is >60 kDa. In additional aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) a human IL-12(p35) / IL-12(p40) single chain fusion; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (i¡¡) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, where the single chain IL-12(p35) / IL-12(p40) fusion is operably linked via the linker to lumican or LAIR1, and where the fusion protein is > 60kDa. In still further aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) human CCL-3; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100- 500, or 200-400, where CCL-3 is operably linked via the linker to lumican or LAIR1, and where the fusion protein is >60 kDa. In other aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) human CCL-4; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (i¡¡) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, where CCL-4 is operably linked via the linker to lumican or LAIR1, and where the fusion protein is >60 kDa. In some aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) human CCL-5; (ii) human lumican, human LAIR1, or human LAIR1 variant; and cefrenn / Lznz / B / YiAi (i¡¡) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, wherein N=1-1000, 10-900, 30-800, 40 -700, 50-600, 100-500, or 200-400, where CCL-5 is operably linked via the linker to lumican or LAIR1, and where the fusion protein is >60 kDa. In other aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) Human eotaxin; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (i¡¡) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, where Eotaxin is operably linked via the linker to lumican or LAIR1, and where the fusion protein is >60 kDa. In any of the above aspects, the lumican comprises the amino acid sequence as set forth in SEQ ID NO: 107. In any of the above aspects, LAIR1 comprises the amino acid sequence as set forth in SEQ ID NO: 98. In some embodiments, LAIR1 is a variant comprising one or more amino acid substitutions, additions or deletions, optionally two, three , four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions, or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In some embodiments, the LAIR1 variant has increased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In still other embodiments, the LAIR1 variant has decreased binding affinity to collagen relative to a collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In any of the above aspects, the linker is of sufficient length or mass to reduce adsorption of the immunomodulatory domain onto collagen fibrils, and / or provides sufficient molecular weight to the fusion protein to reduce diffusion into a tissue and / or allow spherical separation of the immunomodulatory domain from collagen fibrils to promote receptor / ligand coupling. In some aspects, the linker is a human serum albumin or fragment thereof. In other aspects, the linker comprises an Fe domain or a mutant Fe domain with reduced FcR interaction. In some aspects, the fusion protein is of sufficient mass to reduce size-dependent leakage by diffusion or convection upon in vivo administration. In some aspects, the fusion protein binds to type I and / or type IV collagen upon cefrenn / ίζηζ / ε / γίΛΐ administration in vivo, thereby reducing the systemic exposure of the immunomodulatory fusion protein. In still other aspects, the disclosure provides an immunomodulatory fusion protein comprising: (i) an agonist antibody comprising an Fe domain or a mutant Fe domain with reduced FcR interaction, wherein the agonist antibody is selected from an anti-CD3 antibody, an anti-4-1-BB antibody, an anti-CD40 antibody and an anti-OX40 antibody; and (ii) human lumican, human LAIR1, or human LAIR1 variant; wherein the lumican or LAIR1 is operably linked to the C-terminus of the Fe domain or mutant Fe domain. In some aspects, the fusion protein is of sufficient mass to reduce size-dependent leakage by diffusion or convection upon in vivo administration. In some aspects, the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing the systemic exposure of the immunomodulatory fusion protein. In some aspects, the disclosure provides a pharmaceutical composition comprising an immunomodulatory fusion protein described herein, and a pharmaceutically acceptable carrier. In other aspects, the disclosure provides a nucleotide sequence encoding an immunomodulatory fusion protein described herein. In some aspects, the disclosure provides an expression vector comprising a nucleic acid described herein. In other aspects, the description provides a cell transformed with an expression vector described herein. In other aspects, the disclosure provides a method of producing an immunomodulatory fusion protein, the method comprising maintaining a cell described herein under conditions that allow expression of the immunomodulatory fusion protein. In additional aspects, the method comprises obtaining the immunomodulatory fusion protein. In other aspects, the disclosure provides a method of activating, enhancing, or promoting a response by an immune cell in a subject, comprising administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein or pharmaceutical composition described at the moment In still further aspects, the disclosure provides a method of inhibiting, reducing, or suppressing a response by an immune cell in a subject, comprising administering to the subject in need thereof, an effective amount of an immunomodulatory fusion protein or a disclosed pharmaceutical composition. at the moment In any of the above aspects, the immune cell is a lymphoid cell selected from innate lymphoid cell, a T cell, a B cell, an NK cell, and a cefrenn / Lznz / B / YiAi combination thereof. In other aspects, the immune cell is a myeloid cell selected from a monocyte, a neutrophil, a granulocyte, a mast cell, a macrophage, a dendritic cell, and a combination thereof. In some aspects, the response by the immune cell comprises cytokine production, antibody production, antigen-specific immune cell production, increased effect function and / or cytotoxicity, and a combination thereof. In some aspects, the immune cell is presented in a tumor microenvironment. In other aspects, the disclosure provides a method of reducing or inhibiting tumor growth, comprising administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein or pharmaceutical composition described herein. In further aspects, the disclosure provides a method of treating cancer in a subject, comprising administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein or pharmaceutical composition described herein. In any of the above aspects, an anti-tumor immune response is induced in the subject after administration of the immunomodulatory fusion protein or pharmaceutical composition. In some aspects, the anti-tumor immune response is a T cell response comprising the production of IFNγ and / or IL-2 by one or both of CD4+ T cells and CD8+ T cells. In any of the above aspects, the infiltration of immune cells into a tumor microenvironment is increased after administration of the immunomodulatory fusion protein or pharmaceutical composition. In any of the above aspects, the number of T regulatory (Treg) cells is reduced in a tumor microenvironment after administration of the immunomodulatory fusion protein or pharmaceutical composition. In any of the above aspects, T cell depletion is reduced in a tumor microenvironment after administration of the immunomodulatory fusion protein or pharmaceutical composition. In any of the above aspects, the immunomodulatory fusion protein or pharmaceutical composition is administered intratumorally. In any of the above aspects, the immunomodulatory fusion protein or pharmaceutical composition is delivered by viral vectors, electroporation, transplantation of cells expressing the immunomodulatory fusion protein, or replicons. In other aspects, the disclosure provides a kit comprising a container comprising an immunomodulatory fusion protein described herein, and an optional pharmaceutically acceptable carrier, or pharmaceutical composition described herein, and a package insert comprising instructions for administration of the cefrenn / Lznz / B / YiAi fusion protein or pharmaceutical composition, to treat or delay the progression of cancer or reduce or inhibit tumor growth in a subject in need thereof. In still further aspects, the disclosure provides a kit comprising a container comprising an immunomodulatory fusion protein described herein, and an optional pharmaceutically acceptable carrier, or pharmaceutical composition described herein, and a package insert comprising instructions. for administration of the antibody or pharmaceutical composition alone or in combination with another agent, to treat or delay the progression of cancer or reduce or inhibit tumor growth in a subject in need thereof. In some aspects, the disclosure provides for the use of an immunomodulatory fusion protein described herein, and an optional pharmaceutically acceptable carrier, or pharmaceutical composition described herein, for the manufacture of a medicament for treating or delaying the progression of cancer. or reduce or inhibit tumor growth in a subject in need thereof. In other aspects, the disclosure provides an immunomodulatory fusion protein described herein, and an optional pharmaceutically acceptable carrier, or a pharmaceutical composition described herein, in the manufacture of a medicament for treating or delaying the progression of cancer or reducing or inhibiting tumor growth in a subject in need thereof. In still further aspects, the disclosure provides an immunomodulatory fusion protein described herein, and an optional pharmaceutically acceptable carrier, or pharmaceutical composition described herein, for use as a medicament. In other aspects, the description provides a method for reducing or inhibiting tumor growth or treating cancer in a subject, the method comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein or pharmaceutical composition described in the present, and an effective amount of a second composition comprising an antibody targeting a tumor antigen, or antigen-binding fragment thereof, thereby reducing or inhibiting tumor growth or treating cancer in the subject. In some aspects, the tumor antigen is a tumor associated antigen (TAA), a tumor specific antigen (TSA), or a tumor neoantigen. In other aspects, the tumor antigen targeting antibody specifically binds to HER-2 / neu, EGFR, VEGFR, CD20, CD33, or CD38. In still other aspects, the disclosure provides a method for reducing or inhibiting tumor growth or treating cancer in a subject, the method comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein or pharmaceutical composition described in herein, and an effective amount cebenn / Lznz / E / YiAi of a second composition comprising a cancer vaccine, thereby reducing or inhibiting tumor growth or treating cancer in the subject. In some aspects, the cancer vaccine is a population of cells immunized in vitro with a tumor antigen and administered to the subject. In other aspects, the cancer vaccine is a peptide comprising one or more tumor associated antigens. In some aspects, the cancer vaccine is an amphiphilic peptide conjugate comprising a tumor associated antigen, a lipid and optionally a linker, wherein the amphiphilic peptide conjugate binds to albumin under physiological conditions. In some aspects, the cancer vaccine further comprises an adjuvant. In some aspects, the description provides a method of reducing or inhibiting tumor growth or treating cancer in a subject, the method comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein or pharmaceutical composition described in the present, and an effective amount of a second composition comprising an immune checkpoint inhibitor, thereby reducing or inhibiting tumor growth or treating cancer in the subject. In some aspects, the immune checkpoint inhibitor comprises an antibody or antigen-binding fragment thereof that binds to PD-1, PD-L1, CTLA-4, LAG3, or TIM3. In additional aspects, the description provides a method for reducing or inhibiting tumor growth or treating cancer in a subject, the method comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein or pharmaceutical composition described in the present, and an effective amount of a second composition comprising a foster cell therapy, thereby reducing or inhibiting tumor growth or treating cancer in the subject. In some aspects, adoptive cell therapy comprises an immune effector cell comprising a chimeric antigen receptor (CAR) molecule that binds to a tumor antigen. In some aspects, the CAR molecule comprises an antigen binding domain, a transmembrane domain, and an intracellular domain comprising a costimulatory domain and / or a primary signaling domain. In some aspects, the antigen-binding domain binds disease-associated tumor antigen. In some aspects, the tumor antigen is selected from CD19, EGFR, Her2 / neu, CD30, and BCMA. In some aspects, the immune effector cell is a T cell, such as a CD8+ T cell. In some aspects, the immune effector cell is a natural killer (NK) cell. In any of the above methods, the immunomodulatory fusion protein or pharmaceutical composition is administered intratumorally. In some aspects, the immunomodulatory fusion protein or pharmaceutical composition and the second composition are administered concurrently or sequentially. In other aspects, the disclosure provides a method of reducing or inhibiting cebenn / Lznz / B / YiAi tumor growth, or treating cancer in a subject, the method comprising administering to a subject in need thereof as an effective amount of the fusion protein immunomodulatory that includes: (i) human IL-2; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (i¡¡) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, where IL-2 is operably linked via the linker to lumican or LAIR1, and where the fusion protein is >60 kDa, thereby reducing or inhibiting tumor growth or treating cancer on the subject. In some aspects, the disclosure provides a method of reducing or inhibiting tumor growth or treating cancer in a subject, the method comprising administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein comprising: (i) a human IL-12(p35) / IL-12(p40) single chain fusion; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100- 500, or 200-400, where the single strand IL-12(p35) / IL-12(p40) fusion is operably linked via the linker to lumican or LAIR1, and where the fusion protein is >60 kDa, thereby reducing or inhibiting tumor growth or treating cancer in the subject. In some aspects, the disclosure provides a method for reducing or inhibiting tumor growth or treating cancer in a subject, the method comprises administering to a subject in need thereof, an effective amount of a first composition comprising an immunomodulatory fusion protein that understands: (i) human IL-2; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, where N=1-1000, 10-900, 30-800, 40-700, 50-600, 100- 500, or 200-400, where IL-2 is operably linked via the linker to lumican or LAIR1, and where the fusion protein is >60 kDa, and a second composition comprises an effective amount of an immunomodulatory fusion protein which includes: (i) a human IL-12(p35) / IL-12(p40) single chain fusion; (ii) human lumican, human LAIR1, or; and cebenn / Lznz / B / YiAi (i¡¡) a linker, wherein the linker is a hydrophilic polypeptide comprising amino acids "N" in length, wherein N=1-1000, 10-900, 30-800, 40 -700, 50-600, 100-500, or 200-400, wherein the single strand IL-12(p35) / IL-12(p40) fusion is operably linked via the linker to lumican or LAIR1, and wherein the fusion protein is >60 kDa, thereby reducing or inhibiting tumor growth or treating cancer in the subject. In some aspects, the method further comprises administering a second (or third, or fourth) composition comprising an effective amount of a tumor antigen-targeting antibody, or antigen-binding fragment thereof. In other aspects, the method further comprises administering a second composition comprising an effective amount of the composition comprising a cancer vaccine. In still other aspects, the method further comprises administering a second composition comprising an effective amount of a second composition comprising an immune checkpoint inhibitor. In some aspects, the immune checkpoint inhibitor comprises an antibody or antigen-binding fragment thereof that binds to PD-1, PD-L1, CTLA-4, LAG3, or TIM3. In other aspects, the method further comprises administering a second composition comprising an effective amount of a second composition comprising an adoptive cell therapy, thereby reducing or inhibiting tumor growth or treating cancer in the subject. In some aspects, Adoptive cell therapy comprises an immune effector cell comprising a chimeric antigen receptor (CAR) molecule that binds to a tumor antigen. In some aspects, the immune effector cell is a T cell, such as a CD8+ T cell or NK cell. In any of the above aspects, the immunomodulatory fusion protein or the pharmaceutical composition is administered intratumorally. In any of the above aspects, the immunomodulatory fusion protein or the pharmaceutical composition or the second composition is administered concurrently or sequentially. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one figure executed in color. Copies of this color figure patent or patent application publication will be furnished by the office upon request and payment of the necessary fees. FIGURE 1A provides a graph showing the binding of Gaussian luciferase alone (Gluc) or fused to collagen-binding polypeptides (Lumican-Gluc, ColG s3a / s3b-Gluc, ColH s3-Gluc) to type I collagen as a function of of concentration. Binding was determined by cpfrpnn / Lznz / E / YiAi by ELISA. FIGURE 1B provides the graph showing the binding of Gaussian luciferase alone (Gluc) or fused to collagen-binding polypeptides (Lumican-Gluc, ColG s3a / s3b-Gluc, ColH s3-Gluc) to type IV collagen as a function of of concentration. Binding was determined by ELISA. FIGURE 1C provides a graph showing the binding of His-tagged murine LAIR-1 (mLAIR1-His) and His-tagged biotinylated lumican (Lwt-HIS-b) to type I collagen as a function of concentration. Binding was determined by ELISA using an anti-HIS antibody with horseradish peroxidase (HRP). FIGURE 1D provides a graph showing competitive binding between His-tagged murine LAIR-1 (mLAIRI) and His-tagged biotinylated lumican to type I collagen as a function of mLAIRI concentration. Lumican binding to type I collagen was determined by competition ELISA in the presence of varying concentrations of mLAIRI using horseradish peroxidase (HRP)-conjugated streptavidin. FIGURE 2A provides a graph quantifying the relative tumor fluorescence over time of fluorescently labeled lumican or lumican-MSA compared to fluorescently labeled MSA after intratumoral injection into B16F10-Trp2KO tumors as determined by indirect fluorescence imaging. alive. FIGURE 2B provides a graph quantifying serum fluorescence from B16F10-Trp2KO tumor-bearing mice injected with fluorescently labeled lumican-MSA or fluorescently labeled MSA as a percentage of injected dose. Serum fluorescence was determined by fluorescent imaging of micro-hematocrit heparin-coated tubes containing mouse blood samples. FIGURE 3A provides a Mantel-Cox survival curve of B16F10 melanoma tumor-bearing mice treated with PBS (control) (i.tu.), MSA-IL2 (¡.tu.), LumicanMSA-IL2 (¡.tu .), or Lumican (¡.tu.). Mice (n=5 or 7 per treatment group) were treated as indicated (arrow) on day 6 and 12. Survival statistics were determined by the Mantel-Cox log-rank test. Significance was indicated with ** (P < 0.002). FIGURE 3B provides a Mantel-Cox survival curve of B16F10 melanoma tumor-bearing mice treated intratumorally with PBS (n = 7, µtu.), anti-TYRP1 antibody (TA99) (i.p.) in combination with MSA- IL2 (n = 17, ¡.tu.), LumicanMSA-IL2 (n = 17, i.tu.), or with Lumican (n = 17, ¡.tu.). Mice were treated as indicated (arrow) on day 6, 12, and 18. Survival statistics were determined by the Mantel-Cox test. Significance was indicated by * (P < 0.03), ** (P < 0.002), *** (P < 0.0002), **** (P < 0.0001), n.s., not significant. FIGURE 3C provides a Mantel-Cox survival curve of B16F10 melanoma tumor-bearing mice treated with PBS (control) (¡.tu.) or with a crfrcnn / Lznz / E / YiAi combination of anti-TYRP1 antibody (TA99). ) (i.p.) and Lumican-MSA-IL2 administered intratumorally (i.tu.), peritoneally (peri.tu) (i.e., adjacent to the tumor), or subsequently near the tail base (s.c. tail base) . Mice were treated as follows (arrow) on day 6, 12, and 18. Survival statistics were determined by the Mantel-Cox log-rank test. Significance was indicated by * (P < 0.03), ** (P < 0.002), *” (P < 0.0002), ”” (P < 0.0001), n.s., not significant. FIGURE 3D provides a Mantel-Cox survival curve of B16F10 melanoma tumor-bearing mice treated with PBS (control) both (i.tu.) and inguinal tumor draining lymph node (i.tdLN), with the antibody anti-TYRP1 (TA99) (i.p) in combination with Lumican-MSA-IL2 (¡.tu.) and PBS (I.tdLN), or with anti-TYRP1 (TA99) antibody (i.p) in combination with Lumican-MSA -IL2 (i.tdLN) and PBS (i.tu). Mice (n=7 per treatment group) were treated as indicated (arrows) on day 6 and day 12. Survival statistics were determined by the Mantel-Cox log-rank test. Significance was indicated with “ (P < 0.002). FIGURE 4 provides a Mantel-Cox survival curve of wild-type (WT) BatF3zo mice bearing B16F10 melanoma tumor treated with PBS (control) (¡.tu.) or anti-TYRP1 (TA99) antibody (i.p.) in combination with Lumican-MSA-IL2 (¡.tu) and immune cell depleting or cytokine neutralizing antibodies as indicated. Mice (n=5 per treatment group) were treated as indicated on days 6, 12, and 18. Survival statistics were determined by the Mantel-Cox log-rank test. Significances were indicated with * (P < 0.03), “ (P < 0.002), *** (P < 0.0002), **** (P < 0.0001), n.s., not significant. FIGURE 5A provides a graph quantifying IFNγ+ cells among live splenocyte-derived CD45+ CD3+ CD8+ T cells, excised on day 10 from mice (treated as described in FIGURE 3B), stimulated with irradiated B16F10 or 4T1 cells for 12 hours in the presence of brefeldin A and subsequently stained for surface markers and intracellular IFNγ (n = 5 mice per treatment group). Data were analyzed by one-way ANOVA with Tukey's multiple comparison test. FIGURE 5B provides a graph quantifying the mean tumor areas of contralateral (untreated) (left panel) and ipsilateral (treated) (middle panel) lesions from treated B16F10 melanoma tumor-bearing mice and percent survival (right panel). ) was monitored over time (n = 7 / group). Mice were inoculated with B16F10 cells on the right (ipsilateral) flank and with B16F10 cells on the left (contralateral) flank on day 0. Intratumoral treatments were administered to the ipsilateral tumor throughout TA99 (i.p.) on day 6 and day 12. Tumor area (mean + S.D.) of contralateral (untreated) and ipsilateral (treated) lesions (left) and cefrenn / Lznz / B / YiAi survival (right) were monitored over time (n = 7 / cluster). For each group, the tumor area was shown until one mouse reached the sacrifice criteria. Survival statistics were determined by the Mantel-Cox log-rank test. Significance was assumed with *, P < 0.03; ”, P < 0.002; P < 0.0002; P < 0.0001; n.s., not significant. FIGURE 6A provides a graph quantifying the weight change of B16F10 melanoma tumor-bearing mice after treatment with PBS (¡.tu.) (n = 6), lumican (¡.tu.) (n = 7) , IL12-MSA (¡.tu.) (n = 7), IL12-MSA-Lumican (¡.tu.) (n = 7), or IL12MSA (i.p.) (n = 7). Mice were treated as indicated (arrows) on day 6 and day 12. FIGURE 6B provides a survival curve for mice inoculated with B16F10 melanoma tumors on day 0 and treated with PBS (control), lumican (i.tu.), IL12-MSA (i.tu), IL12-MSA (i.p.) or IL12-MSA-Lumican (¡.tu) on days 6 and 12. FIGURE 7 provides graphs depicting weight change from baseline (left panel) and corresponding survival over time (right panel) of B16F10 tumor-bearing mice treated with intratumoral (¡.tu.) injections of PBS ( n = 5), MSA-IL2 and IL12-MSA (n = 5), or Lumican-MSA-IL2 and IL12-MSA-Lumican (n = 5) on day 5 and day 11. Arrows indicate treatment time . Survival statistics were determined by the Mantel-Cox log-rank test. Significance was indicated by * (P < 0.03), ” (P < 0.002), “* (P < 0.0002), *”* (P < 0.0001), n.s., not significant. FIGURE 8A provides a Mantel-Cox survival curve of BatF3 / _o wild-type (WT) mice bearing B16F10 melanoma tumor treated with PBS (control) (i.tu.) or Lumican-MSA-IL2 (¡. tu.) in combination with IL12-MSA-Lumican (i.tu.) and immune cell depleting or cytokine neutralizing antibodies as indicated. Mice (n=5 per treatment group) were treated as indicated on days 6, 12, and 18. Survival statistics were determined by the Mantel-Cox log-rank test. Significance was indicated by * (P < 0.03), ** (P < 0.002), *” (P < 0.0002), **** (P < 0.0001), n.s., not significant. FIGURE 8B provides a Mantel-Cox survival curve of B16F10 melanoma tumor-bearing BatF3 / _o wild-type (WT) mice treated with PBS (control) (i.tu.) or Lumican-MSA-IL2 (! .tu.) in combination with IL12-MSA-Lumican (¡.tu.) and immune cell-depleting antibodies as indicated. Mice (n=5 per treatment group) were treated as indicated on days 6, 12, and 18. Survival statistics were determined by the Mantel-Cox log-rank test. Significance was indicated by * (P < 0.03), ** (P < 0.002), *** (P < 0.0002), **** (P < 0.0001), n.s., not significant. FIGURE 8C provides a heat map showing the fold change of immune cells in tumor infiltrates from B16F10 melanoma tumor-bearing mice treated intratumorally with a combination of IL12-MSA-Lumican and LumicanMSA-IL2 (versions of Lumican ) or a combination of IL12-MSA + MSA-IL2 (versions of cefrenn / ίζηζ / Β / γίΛΐ MSA) with respect to treatment with PBS. FIGURES 8D-8E provide graphs quantifying tumor-infiltrating CD8+ T cells isolated from B16F10 melanoma tumor-bearing mice at day 11 post-tumor cell injection (FIGURE 8D) and their corresponding mean fluorescence intensity (MFI) of Surface PD-1 (FIGURE 8E), after treatment as in FIGURE 8C on day 5 post-injection of tumor cells. FIGURE 9 provides graphs depicting the fold change from baseline (left panel) and corresponding survival over time (right panel) of B16F10 melanoma tumor-bearing mice treated with intratumoral (¡.tu.) injections of PBS (n = 5), anti-PD-1 antibody in combination with MSA-IL2 and IL12-MSA (n = 5), or anti-PD-1 antibody in combination with Lumican-MSA-IL2 and IL12-MSA-Lumican (n=5) on day 5 and day 11. Arrows indicate treatment time. Weight change and comparison statistics were determined by one-way ANOVA with Tukey's multiple comparison test. Survival statistics were determined by the Mantel-Cox log-rank test. Significance was indicated by * (P < 0.03), “ (P < 0.002), *** (P < 0.0002), (P < 0.0001), n.s., not significant. FIGURES 10A-10B provide a graph depicting tumor area (left panel) and percent survival (right panel) of mice bearing EMT6 tumor (FIGURE 10A) or mice bearing MC38 tumor (FIGURE 10B) and treated as indicated (arrows) on days 5, 11 and 17 as indicated (arrows). Weight change and comparison statistics were determined by one-way ANOVA with Tukey's multiple comparison test. Survival statistics were determined by the Mantel-Cox log-rank test. Significance was indicated by *, P < 0.03; **, P < 0.002; ***, P < 0.0002; “**, P < 0.0001; n.s., not significant. FIGURE 11 provides graphs depicting the change in weight from baseline (left, mean + S.D.), corresponding tumor area (middle, mean + S.D.), and survival (right) of B16F10 melanoma tumor-bearing mice treated with intratumoral injections. (¡.tu.) of PBS (n = 12) or IL-12 (n = 10 for IL12-MSA; n = 10 for IL12-MSA-Lumican), or cancer vaccine (n = 7) alone, or cancer vaccine and IL12 (n = 7 for IL12-MSA; n = 7 for IL12-MSA-Lumican) on days 5, 11 and 17 as indicated (arrows). Tumor area was shown until one mouse met the sacrifice criteria (>100 mm2). Weight change statistics, shown within the graph, were determined by one-way ANOVA with Tukey's multiple comparison test. Survival statistics, adjacent to the legend, were determined by the Mantel-Cox log-rank test. Significance was assumed with *, P < 0.03; **, P < 0.002; ***, P < 0.0002; P < 0.0001; n.s., not significant. FIGURE 12 provides graphs depicting the weight change from the base cebenn / Lznz / B / YiAi line (left, mean + S.D.), corresponding tumor area (middle, mean + S.D.), and percent survival (right) of mice that with B16F10 melanoma tumor treated with intratumoral (¡.tu.) injections of PBS (n = 11) or IL-12 (n = 9 for IL12-MSA; n = 5 for IL12-MSA-Lumican), or CAR-T (n=11) alone, or CAR-T and IL12 (n=9 for IL12-MSA; n=5 for IL12-MSA-Lumican) on days 5 and 11 as indicated (arrows). Mice were inoculated with B16F10 cells on day 0 and lymphodepleted by total body irradiation on day 4. CAR-T treatments were administered as a single bolus tail vein injection (i.v.) on day 5 The tumor area was shown until one mouse reached the sacrifice criteria (>100 mm2). Weight change statistics, shown within the graph, were determined by one-way ANOVA with Tukey's multiple comparison test. Survival statistics, adjacent to the legend, were determined by the Mantel-Cox log-rank test. Significance was assumed with *, P < 0.03; **, P < 0.002; P < 0.0002; ****, P < 0.0001; n.s., not significant. FIGURE 13 provides graphs depicting change in total body weight during neoadjuvant treatment (left), primary tumor growth, and weight (middle) and survival (right) of treated 4T1 mammary carcinoma tumor-bearing mice. with intratumoral (i.tu.) injections of IL-12 (n = 5 for IL12; n = 5 for IL12-MSA-Lumican) and intraperitoneal (i.p.) injection of anti-PD-1 on day 7 and 13. arrows indicate treatment time and cross indicates surgery time. Mice were inoculated with 4T1-Luc cells in the mammary fat pad on day 0. Neoadjuvant therapy was administered on days 7 and 13 and primary tumors were surgically excised on day 16. Post-operative mice were monitored by in vivo imaging (IVIS) for metastasis. For each group, the tumor area was shown until the primary tumor was excised. Weight change statistics, shown within the graph, were determined by one-way ANOVA with Tukey's multiple comparison test. Survival statistics, adjacent to the legend, were determined by the Mantel-Cox log-rank test. Significance was assumed with *, P < 0.03; **, P < 0.002; ***, P < 0.0002; P < 0.0001; n.s., not significant. FIGURE 14A provides a graph depicting the mean tumor area of ​​4T1 mammary carcinoma tumor-bearing mice treated intratumorally with Lumican-GLuc or a combination of Lumican-CCL3, Lumican-CCL4, and Lumican-CCL on day 7 and day 13. IFNα administration was given intraperitoneally on day 9 and day 15. Tumor growth (mean + SEM) was monitored over time every other day. FIGURE 14B provides a graph depicting the mean tumor area of ​​B16F10 melanoma tumor-bearing mice treated intratumorally with LumicanGLuc or a combination of Lumican-CCL3, Lumican-CCL4, and Lumican-CCL5 on day 7 and day 13. Administration of IFNa intraperitoneally on day 9 and day 15. Cebenn / Lznz / B / YiAi tumor growth (mean + SEM) was monitored over time every other day. FIGURE 14C provides a graph depicting the effect of various concentrations of Lumican-GLuc (Lum GLuc), Lumican-CCL3 (Lum CCL3), Lumican-CCL5 (Lum CCL5) fusion proteins on the proliferation of 4T1 breast tumor cells in vitro. Proliferation was determined by measuring the proliferation reagent WST-1 by absorbance at 450 nm. FIGURE 14D provides a graph depicting the effect of various concentrations of Lumican-GLuc (Lum GLuc), Lumican-CCL3 (Lum CCL3), Lumican-CCL5 (Lum CCL5) fusion proteins on the proliferation of B16F10 melanoma tumor cells in vitro. Proliferation was determined by measuring the WST-1 proliferation reagent by absorbance at 450 nm. FIGURE 15 provides a graph depicting mean tumor areas of tumor lesions in B16F10 melanoma tumor-bearing mice treated with a cancer vaccine administered subcutaneously (s.c.) at the base of the tail with a prime on day 5 and boosters on days 11 and 17 post-injection of tumor cells. The cancer vaccine was administered alone or in combination with CCL11-lumican, TNFo, IFNγ, or Lumican, as indicated, was administered intratumorally on days 11, 17, 23, and 29. Tumor area (mean + SD) it was measured over time every two days. FIGURES 16A-16B provide a graph depicting individual tumor areas of tumor lesions in the B16F10 melanoma tumor-bearing mice treated with a 2.5F-Fc tumor-targeting antibody (i.p.) and MSA-IL2 (i.p.) on days 5, 11 and 17 post-injection of tumor cells in combination with either lumican (Lwt) (¡.tu.) (FIGURE 16B) or CCL11-lumican (11L) (i.tu.) (FIGURE 16A) administered into the days 5 and 11. The tumor area was monitored over time every other day. FIGURE 17A provides a graph showing the binding of agonist antibody to lumican fusion proteins to type I collagen as a function of concentration. Binding was determined by ELISA. FIGURE 17B provides a graph quantifying in vivo fluorescence of a mouse anti-FITC antibody (4420) alone or fused to a fluorescently Alexa-tagged Lumican FluorMR647 after intratumoral injection into mouse 4T1 tumors over time as it is determined by in vivo fluorescence imaging. In vivo fluorescence measurement is given in units of total radiant efficiency (p / s) / (pW / cm2). FIGURE 18A provides a graph showing the binding of a subset of His-tagged lumican-IgG binding fusion proteins, as indicated, to collagen type I (left panel) or collagen IV (right panel) as a function of concentration. Binding was determined by ELISA. cefrenn / Lznz / B / YiAi FIGURE 18B provides a graph depicting the binding of His-tagged lumican-lgG binding fusion proteins to the mouse lgG2a isotype control (Clon C1.18.4) as a function of concentration. Binding was determined by ELISA. Anti-His (Clone ab1187) was used to detect each construct. FIGURE 19 provides 3D microscopy images of mouse omental tissue from OVCA433 human ovarian tumor-bearing mice showing specific accumulation of Alexa Fluor 647-tagged lumican (yellow) around microcolonies of RFP-expressing OVCA433 human ovarian tumor cells ( Red) in mouse omental tissue, with collagen formed on images by SHG microscopy in grey. The labeled lumican was injected intraperitoneally into the tumor-bearing mice. FIGURE 20A provides graphs depicting the expression of IL-12 fusion proteins alone or fused to a fluorescent protein (mCherry), as indicated, of a self-replicating RNA in B16F10 cells as determined by flow cytometry. FIGURE 20B provides a graph depicting the expression of IL-12 fusion proteins alone or fused to a fluorescent protein (mCherry), as indicated, from a self-replicating RNA in B16F10 cells as determined by an IL-12 ELISA. . FIGURE 21A provides a graph showing tumor volume (mean + SD) of tumor-bearing mice treated with either an intratumoral injection of PBS (n=4) or with intratumoral collagen-anchoring cytokines Lumican-MSA-IL2 and IL12. -MSA-Lumican and TA99 and intraperitoneal anti-PD-1 (n = 5) on days 25, 31,37, 43, 49, 55, and 61. For each group, tumor volume was displayed until the mice reached the sacrifice criterion (>1200 mm3). FIGURE 21B provides a Mantel-Cox survival curve of tumor-bearing mice treated with intratumoral PBS (n = 10), with intratumoral Lumican-MSA-IL2 and IL12-MSALumican and intraperitoneal TA99 and anti-PD-1 (n = 14), with intratumoral Lumican-MSA-IL2 and IL12-MSA-Lumican and intraperitoneal anti-PD-1 (n = 10), with intratumoral MSA-IL2 and IL12-MSA and intraperitoneal TA99 and anti-PD-1 (n = 9), or with intratumoral MSA-IL2 and IL12-MSA and intraperitoneal anti-PD-1 (n = 8) on days 25, 31, 37, 43, 49, 55, and 61. Arrowheads indicate times of treatment. The overall survival plot lists mice that succumbed to tumor burden (>1200 mm3) or treatment-related weight loss (>20%); the latter is indicated by a blue for each mouse. Survival was compared by the Mantel-Cox's test. *P < 0.03, “*P < 0.0002, ****P < 0.0001. FIGURE 22A provides a scheme for measuring LAIR binding capacity in B16F10 tumors. FIGURE 22B provides a graph showing the weight of an excised tumor and its extracellular matrix. cefrenn / Lznz / B / YiAi FIGURE 22C provides a graph showing the hydroxyproline content of the B16F10 cell fraction compared to the matrix fraction. FIGURE 22D provides a graph showing the depletion of LAIR fluorescence as a B16F10-derived matrix fraction was placed into 1 mL of AF647-labeled LAIR. FIGURE 22E provides a graph showing the correlation between the hydroxyproline content of matrix fraction and the LAIR binding capacity of the B16F10-derived matrix fraction. FIGURE 23A provides a graph showing the tumor area of ​​B16F10 melanoma tumors (1x106 cells inoculated on day 0) treated with PBS (¡.tu) (n=5) or LAIR-MSA-IL2 (¡.tu) control. ) TA99 (i.p.) (n=7) on days 6 and 13. FIGURE 23B provides a Mantel-Cox survival curve of B16F10 melanoma tumor-bearing mice (1x10 6 cells inoculated on day 0) treated with either PBS (¡.tu) (n=5) or LAIR-MSA-IL2 (¡ .tu) + TA99 (i.p.) (n=7) on days 6 and 13. FIGURE 24A provides a sequence alignment of low affinity collagen binders, LAIR.30.W.A, LAIR.30.W.B, LAIR.30.W.C, and LAIR.30.W.D, compared to wild-type LAIR (LAIR ). FIGURES 24B-24E provide representations of the crystal structures of the wild type LAIR (PDB 4ETY) shown as a gray ribbon, with mutated amino acid residues selected from the low affinity collagen binder, LAIR.30.W.A (FIGURE 24B ), LAIR.30.W.B (FIGURE 24C), LAIR.30.W.C (FIGURE 24D), and LAIR.30.d.D (FIGURE 24E), highlighted as joined spheres. FIGURE 24F provides a graph showing the binding of WT LAIR, WT LAIRMSA, MSA-IL-2 (non-specific binding control), and mutant LAIR-MSA fusions to collagen type 1 in the ELISA assay (n=2). ). Also shown is the binding affinity (Kd) of each LAIR construct, calculated in a non-linear one-site binding fit. FIGURE 25A provides a sequence alignment of low affinity collagen binders, LAIR.30.W.E and LAIR.30.W.F compared to wild-type LAIR. FIGURES 25B-25C provide representations of the crystal structures of the wild type LAIR (PDB 4ETY) shown as a gray ribbon, with mutated amino acid residues selected from low affinity collagen binders, LAIR.30.W.E (FIGURE 25B ) and LAIR.30.W.F (FIGURE 25C), highlighted as joined spheres. FIGURE 25D provides a graph showing the binding of WT LAIR, WT LAIRMSA, MSA-IL-2 (non-specific binding control) and mutant LAIR-MSA fusions to type 1 collagen in an ELISA assay (n=2). Also shown is the binding affinity (Kd) of each LAIR construct, modeled in a non-linear one-site binding fit. FIGURE 26A provides a sequence alignment of the high affinity cefrenn / Lznz / B / YiAi collagen binder, LAIR.30.2.K1.B, compared to wild-type LAIR. FIGURE 26B provides a representation of the crystal structure of the wild type LAIR (PDB 4ETY) shown as a gray ribbon, with selected mutated amino acid residues of the high affinity collagen binder, LAIR.30.2.K1.B, highlighted. as united spheres. FIGURES 26C-26D provide flow cytometric plots showing CRP-XL-biotin binding (Strepravidin-AF647) versus protein expression (goat anti-chicken AF488) of yeast-bearing LAIR wild type (black) or LAIR30.2 .K1 .B (cyan) incubated in either 100 nM (FIGURE 26C) or 0.01 nM (FIGURE 26D) CRP-XL-biotin. FIGURES 26E-26F provide flow cytometry plots showing remaining surface CRP-XL-biotin signal (Streptatividin-AF647) versus protein expression (goat anti-chicken AF488) of LAIR30.2.K1. B bearing yeast (FIGURE 26E) or wild-type LAIR (FIGURE 26F) at different time points (0 hr, 16 hr and 40 hr of competition) after competition with excess non-biotinylated CRP-XL. FIGURE 26G provides a graph showing the mean fluorescence intensity of bound CRP-XL-biotin over time in the kinetic dissociation experiment depicted in FIGURES 26E-26F. Estimated dissociation constants, modeled in a one-phase exponential decay fit, are also shown. DETAILED DESCRIPTION OF THE INVENTION Provided herein are immunomodulatory fusion proteins comprising an immunomodulatory domain operably linked to a collagen binding domain. These fusion proteins localize the immunomodulatory domain (eg, cytokine, antibody), such that it does not spread systemically. Systemic dissemination of an immunomodulatory domain can result in reduced efficacy due to rapid clearance of the site of interest (eg, tumor), and / or toxicity due to effects on non-target cells outside of the tumor. Accordingly, ligation of an immunomodulatory domain to a collagen-binding protein localizes the immunomodulatory domain to prevent systemic dissemination, thereby keeping the immunomodulatory domain at the site of interest and reducing potential off-target effects that could lead to the toxicity. Definitions Terms used in the claims and specifications are defined as set forth below unless otherwise specified. In a case of direct conflict with a term used in a parent provisional patent application, the term used in the present application will control. It should be noted that, as used in the specification and appended claims, the singular forms “a”, “uno / una”, and “el / la” include plural referents unless the cefrenn / ίζηζ / ε / γίΛΐ context so requires. clearly state otherwise. As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some degree depending on the context in which it is used. There are uses of the term that are not clear to ordinary people given the context in which it is used, “approximately shall mean up to plus or minus 10% of the particular value. As used herein, the term "agonist" refers to any molecule (eg, an antibody or antigen-binding fragment thereof) that partially or completely promotes, increases, or activates a biological activity of a described native polypeptide. at the moment. Suitable agonist molecules specifically include agonist antibodies or antibody fragments, amino acid sequence fragments or variants of native polypeptides, peptides, antisense oligonucleotides, small organic molecules, and the like. In some embodiments, activation in the presence of the agonist is observed in a dose-dependent manner. In some embodiments, the measured signal (eg, biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% , at least approximately 35%, at least approximately 40%, at least approximately 45%, at least approximately 50%, at least approximately 55%, at least approximately 60%, at least approximately 65%, at least approximately 70%, at least approximately less about at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% higher than the signal measured with a negative control under conditions comparable. Also described herein are methods for identifying suitable agonists for use in the methods of the disclosure. For example, these methods include, but are not limited to, binding assays such as enzyme-linked immunosorbent assay (ELISA), Forte Bio™ systems, and radioimmunoassay (RIA). These assays determine the ability of an agonist to bind to the polypeptide of interest (eg, a receptor or ligand) and thus indicate the ability of the agonist to promote, increase, or activate the activity of the polypeptide. The efficacy of an agonist can also be determined using functional assays, such as the ability of an agonist to activate or promote polypeptide function. For example, a functional assay may comprise contacting a polypeptide with a candidate agonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide. The potency of an agonist is usually defined by its EC50 value (concentration required to activate 50% of the agonist response). The lower the ECso value, the greater the potency of the agonist and the lower the concentration required to activate the maximal biologic response. cebenn / Lznz / B / YiAi The term "albumin" refers to a protein that has the same, or very similar, three-dimensional structure as human albumin (SEQ ID NO: 42) and that has a long serum half-life. Exemplary albumin proteins include human serum albumin (HSA; SEQ ID NOs: 42 and 43), primate serum albumin (such as chimpanzee serum albumin), gorilla serum albumin or macaque serum albumin, albumin rodent serum albumin (such as hamster serum albumin), guinea pig serum albumin, mouse serum albumin and rat serum albumin, bovine serum albumin (such as cow serum albumin), equine serum albumin (such as horse serum albumin or donkey serum albumin), rabbit serum albumin, goat serum albumin, sheep serum albumin, dog serum albumin, chicken serum albumin, and albumin of pig whey. The term "amprove" refers to any therapeutically beneficial outcome in the treatment of a disease state, eg, cancer, including, prophylaxis, reduction in severity or progression, remission, or cure thereof. "Amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a similar manner to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, for example, hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogues refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., a carbon that is bonded to a hydrogen, a carboxyl group, an amino group, and an R group, for example, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. These analogs have modified R groups (eg, norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a similar manner to a naturally occurring amino acid. Amino acids may be referred to herein by either their commonly known three-letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides can likewise be referred to by their commonly accepted one-letter codes. An "amino acid substitution" refers to the replacement of at least one existing amino acid residue in a predetermined amino acid sequence (a starting polypeptide amino acid sequence) with a different second "replacement" amino acid residue. An "amino acid insertion" refers to the incorporation of at least one additional amino acid into a predetermined amino acid sequence. While the cefrenn / Lznz / B / YiAi insertion usually consists of the insertion of one or two amino acid residues, larger “peptide insertions” can also be made, for example the insertion of about three to about five or even up to about ten, fifteen or twenty amino acid residues. The inserted residues may be naturally occurring or non-naturally occurring as described above. An "amino acid deletion" refers to the removal of at least one amino acid residue from a predetermined amino acid sequence. As used herein, the term "antagonist" refers to any molecule (eg, antibody or antigen-binding fragment thereof) that partially or fully blocks, inhibits, or neutralizes a biological activity of a native polypeptide described in the present. Suitable antagonist molecules specifically include antagonistic antibodies or antibody fragments, amino acid sequence fragments or variants of native polypeptides, peptides, antisense oligonucleotides, small organic molecules, and the like. In some embodiments, inhibition in the presence of the antagonist is observed in a dose-dependent manner. In some embodiments, the measured signal (eg, biological activity) is at least about 5%, at least about 10%, at least about 15% , at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least approximately 100% less than the signal measured with a negative control under comparable conditions. Also described herein are methods for identifying suitable antagonists for use in the methods of the disclosure. For example, these methods include, but are not limited to, binding assays such as enzyme-linked immunosorbent assay (ELISA), Forte Bio® systems, and radioimmunoassays (RIA). These assays determine the ability of an antagonist to bind to the polypeptide of interest (eg, a receptor or ligand) and thus indicate the ability of the antagonist to inhibit, neutralize, or block the activity of the polypeptide. The efficacy of an antagonist can also be determined using functional assays, such as the ability of an antagonist to inhibit polypeptide or agonist function. For example, a functional assay may comprise contacting a polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide. The potency of an antagonist is usually defined by its IC50 value (concentration required to inhibit 50% of the agonist response). The lower the cefrenn / ίζηζ / Β / γίΛΐ value, the greater the potency of the antagonist and the lower the concentration required to inhibit the maximal biological response. As used herein, the term "antibody" refers to a whole antibody comprising two light chain polypeptides and two heavy chain polypeptides. Whole antibodies include different isotypes of antibodies including IgM, IgG, IgA, IgD and IgE antibodies. The term "antibody" includes a polyclonal antibody, a monoclonal antibody, a chimerized or chimeric antibody, a humanized antibody, a primatized antibody, a deimmunized antibody, and a fully human antibody. The antibody can be made in or derived from any of a variety of species, for example, mammals such as humans, non-human primates (for example, orangutans, baboons, or chimpanzees), horses, cattle, pigs, sheep, goats, dogs. , cats, rabbits, guinea pigs, gerbils, hamsters, rats and mice. The antibody can be a purified or recombinant antibody. As used herein, the term "antibody fragment," "antigen-binding fragment," or similar terms refers to a fragment of an antibody that retains the ability to bind to a target antigen(s) and promote, induce and / or increase the activity of the target antigen. These fragments include, for example, a single chain antibody, a single chain Fv fragment (scFv), an Fd fragment, a Fab fragment, a Fab' fragment or an F(ab')2 fragment. An scFv fragment is a single polypeptide chain that includes both the heavy chain and light chain variable regions of the antibody from which the scFv is derived. In addition, intrabodies, minibodies, triabodies, and diabodies are also included in the definition of antibody and are compatible for use in the methods described herein. See, for example, Todorovska et al. (2001) J Immunol Methods 248(1):47-66: Hudson and Kortt (1999) J Immunol Methods 231(1):177-189: Poljak (1994) Structure 2(12) :1121-1123: Rondon and Marasco (1997) Annual Review of Microbiology 51:257-283, the descriptions of each of which are incorporated herein by reference in their entirety. As used herein, the term "antibody fragment" also includes, for example, single domain antibodies such as camelized single domain antibodies. See, for example, Muyldermans et al. (2001) Trends Biochem Sci 26:230-235: Nuttall et al. (2000) Curr Pharm Biotech T253-263; Reichmann et al. (1999) J Immunol Meth 231:25-38: PCT application publication nos. WO 94 / 04678 and WO 94 / 25591; and US Patent No. 6,005,079, all of which are incorporated herein by reference in their entireties. In some embodiments, the disclosure provides single domain antibodies that comprise two VH domains with modifications such that single domain antibodies are formed. The "B7 family" refers to activating ligands and inhibitors. The B7 family comprises cefrenn / Lznz / B / YiAi minus activating ligands B7-1 and B7-2, and inhibitory ligands B7-H1, B7-H2, B7-H3 and B7H4. B7-1 and B7-2 that bind CD28, B7-H1 {ie, PD-L1) that binds PD-1, and B7-H2 that binds ICOS. B7-H3 and B7-H4 bind to unknown receptors. In addition, B7-H3 and B7H4 have been shown to be upregulated in tumor cells and tumor-infiltrating cells. The complete hB7-H3 and hB7-H4 sequence can be found under GenBank Accession Nos. Q5ZPR3 and AAZ17406 (SEQ ID NOs: 49 and 50) respectively. As used herein, the term "chimeric antigen receptor (CAR)" refers to an artificial transmembrane protein receptor comprising (i) an extracellular domain capable of binding to at least one predetermined CAR ligand or antigen, or a predetermined CAR ligand and an antigen, (ii) an intracellular segment comprising one or more cytoplasmic domains derived from signal transduction proteins other than the polypeptide from which the extracellular domain is derived, and (iii) a transmembrane domain. The "chimeric antigen receptor (CAR)" is sometimes called a "chimeric receptor", a "T-body" or a "chimeric immune receptor (CIR)". The phrase "CAR ligand" used interchangeably with "CAR antigen" means any natural or synthetic molecule (eg, small molecule, protein, peptide, lipid, carbohydrate, nucleic acid) or part or fragment thereof that can be specifically bound to a CAR (eg, the extracellular domain of a CAR). In some embodiments, the CAR ligand is a tumor associated antigen, or fragment thereof. In some embodiments, the CAR ligand is a tag. "Intracellular signaling domain" means any oligopeptide or polypeptide domain known to function to convey a signal that causes activation or inhibition of a biological process in a cell, for example, activation of an immune cell such as a T cell or a NK cell. Examples include the ILR chain, CD28 and / or ΟΟ3ζ. As used herein, "cancer antigen" refers to (i) tumor-specific antigens, (ii) tumor-associated antigens, (iii) cells that express tumor-specific antigens, (iv) cells that express tumor-associated antigens. to tumor, (v) embryonic antigens in tumors, (vi) autologous tumor cells, (vii) tumor-specific membrane antigens, (viii) tumor-associated membrane antigens, (ix) growth factor receptors, (x ) growth factor ligands, and (xi) any other type of antigen or antigen-presenting cell or material that is associated with cancer. As used herein, "cancer vaccine" refers to a treatment that induces the immune system to attack cells with one or more tumor-associated antigens. The vaccine can treat existing cancer (eg, therapeutic cancer vaccine) or prevent the development of cancer in certain people (eg, prophylactic cancer vaccine). The vaccine creates memory cells that will recognize Cefrenn / Lznz / B / YiAi tumor cells with the antigen and thus prevent tumor growth. As used herein, the term "chemokine" refers to a member of the family of small cytokines, or signaling proteins, that induce targeted chemotaxis. Chemokines are grouped into four subfamilies: CXC, CC, (X)C, and CX3C. As used herein, the term "collagen" refers to the predominant structural protein located within the extracellular space, and maintains the mechanical integrity of many different tissues. The molecular organization of collagen determines its function. There are more than 20 types of collagen currently identified, with type I being the most common. As used herein, the term "collagen-binding domain" refers to a polypeptide, or portion thereof, that binds to collagen. A collagen binding domain can be part of a larger fusion protein, bioactive agent, or pharmaceutical agent. The binding of a composition, polypeptide or portion thereof, fusion protein, or pharmaceutical or bioactive agent to collagen can be determined by methods known in the art (eg, collagen binding assay; see eg, Turecek et al. , (2002) Semin Thromb Hemost 28(2):149-160). In some embodiments, a collagen binding domain is determined by its ability to compete with a known or reference collagen binding protein to bind collagen. In some embodiments, the collagen binding domains are derived from a naturally occurring collagen binding protein or collagen receptor. Collagen binding proteins and collagen receptors comprising collagen binding domains are known in the art (see for example, Svensson et al., (2001) Osteoarthritis Cartilage 9 Suppl A:S23-28; Leitinger and Hohenester E (2007). ) Matrix Biol 26(3):146-155). In some embodiments, the collagen-binding domain is derived from a procabinote collagen-binding protein. Prokaryotic collagen-binding proteins are known in the art (see, for example, Symersky et al., (1997) Nat Struct Biol 4:833-838). In some embodiments, a collagen-binding domain comprises one or more mutations that increase its affinity for collagen. As used herein, "combination therapy" encompasses the administration of each agent or therapy in a sequential or simultaneous manner in a regimen that will provide beneficial effects of the combination, and co-administration of these agents or therapies in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple separate capsules for each agent. Combination therapy also includes combinations where the individual elements may be administered at different times and / or by different routes but which act in combination to provide a beneficial effect by coercion or pharmacokinetic and pharmacodynamic effect of each cefrenn tumor treatment agent or procedure. / Lznz / B / YiAi of combination therapy. A "co-stimulatory signal", as used herein, refers to a signal, which in combination with a primary signal, such as TCR / CD3 binding, leads to T cell proliferation and / or upregulation or downregulation of key molecules. "Cytotoxic T Lymphocyte Associated Antigen-4 (CTLA-4)" is a T cell surface molecule and is a member of the immunoglobulin superfamily. This protein downregulates the immune system by binding to CD80 and CD86. The term "CTLA-4" as used herein includes human CTLA-4 (hCTLA-4), variants, isoforms, and species homologues of hCTLA-4 and analogs that have at least one common epitope with hCTLA-4. The complete hCTLA-4 sequence can be found under GenBank Accession No. P16410 (SEQ ID NO: 46): A polypeptide or amino acid sequence "derived from" a designated polypeptide or protein refers to the origin of the polypeptide. Preferably, the polypeptide or amino acid sequence that is derived from a particular sequence has an amino acid sequence that is essentially identical to that sequence or a portion thereof, wherein the portion consists of at least 10-20 amino acids, of preferably at least 20-30 amino acids, more preferably at least 30-50 amino acids, or which is otherwise identifiable to one of ordinary skill in the art as being of sequence origin. Polypeptides derived from another peptide may have one or more mutations relative to the parent polypeptide, for example, one or more amino acid residues that have been substituted with another amino acid residue or have one or more amino acid residue insertions or deletions. . A polypeptide can comprise an amino acid sequence that is not naturally occurring. These variants need to have less than 100% sequence identity or similarity to the parent molecule. In certain embodiments, the variant will have an amino acid sequence of from about 75% to less than 100% amino acid sequence identity or similarity to the amino acid sequence of the starting polypeptide, more preferably from about 80% to less than 100%. %, more preferably from about 85% to less than 100%, more preferably from about 90% to less than 100% (for example, 91%, 92%, 93%, 94%, 95%, 96% , 97%, 98%, 99%) and most preferably from about 95% to less than 100%, for example, over the length of the variant molecule. In certain embodiments, an amino acid difference exists between a starting polypeptide sequence and the sequence derived therefrom. Identity or similarity to this sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical (i.e., the same residue) to the starting amino acid residues, after aligning the sequences and introduce the cebenn / Lznz / B / YiAi spaces, if necessary, to achieve the maximum percent sequence identity. In certain embodiments, a polypeptide consists of, consists essentially of, or comprises an amino acid sequence selected from the Sequence Summary Table. In certain embodiments, a polypeptide includes an amino acid sequence of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92 %, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the Sequence Summary Table. In certain embodiments, a polypeptide includes an amino acid sequence contiguous at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a contiguous amino acid sequence selected from the Sequence Summary Table. In certain embodiments, a polypeptide includes an amino acid sequence that is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 , 100, 200, 300, 400, or 500 (or any integer within these numbers) contiguous amino acids of an amino acid sequence selected from the Sequence Summary Table. In certain embodiments, the peptides of the disclosure are encoded by a nucleotide sequence. The nucleotide sequences of the disclosure may be useful for a number of applications, including: cloning, gene therapy, protein expression and purification, mutation introduction, DNA vaccination of a host in need thereof, generation of antibodies to, for example, eg, passive immunization, PCR, generation of primers and probes, and the like. In certain embodiments, the nucleotide sequence of the disclosure comprises, consists of, or consists essentially of, a nucleotide sequence selected from SEQ ID NO: 3, 5, 7, 9, 11, 15, 17, 19, 21, 23 , 25., 27, 29, 31 and 33. In certain embodiments, a nucleotide sequence includes a nucleotide sequence of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% , 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a nucleotide sequence set forth in the Sequence Summary Table . In certain embodiments, a nucleotide sequence includes a nucleotide sequence that is at least 80% contiguous, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a contiguous nucleotide sequence set forth in the Sequence Summary Table. In certain embodiments, a nucleotide sequence includes a nucleotide sequence that is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 , 95, 100, 200, 300, 400, or 500 (or any integer within these numbers) contiguous nucleotides of a nucleotide sequence set forth in the Sequence Summary Table. It will also be understood by one of skill in the art that polypeptides suitable for use in the immunomodulatory fusion proteins described herein can be altered such that they will vary in sequence from the naturally occurring or native sequences from which they were derived, as long as which retain the desirable activity of the native cebenn / Lznz / B / YiAi sequences. For example, nucleotide or amino acid substitutions leading to conservative substitutions or changes in "non-essential" amino acid residues can be made. Mutations can be introduced by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Polypeptides suitable for use in the immunomodulatory fusion proteins described herein may comprise conservative amino acid substitutions at one or more amino acid residues, for example, at essential or non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been identified in the art, including basic side chains (eg, lysine, arginine, histidine), acidic side chains (eg, aspartic acid, glutamic acid), uncharged polar sides (eg, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta branched (eg threonine, valine, isoleucine) and aromatic side chains (eg tyrosine, phenylalanine, tryptophan, histidine). Thus, a non-essential amino acid residue in a binding polypeptide is preferentially replaced with another amino acid residue from the same side chain family. In certain embodiments, an amino acid chain can be replaced with a structurally similar chain that differs in order and / or composition of the side chain family members. Alternatively, in certain embodiments, mutations can be randomly introduced along all or part of a coding sequence, such as by saturation mutagenesis, and the resulting mutants can be incorporated into the disclosure binding polypeptides and sorted. for its ability to join the desired target. As used herein, the term "effector cell" or "effector immune cell" refers to a cell involved in an immune response, eg, in promoting an effector immune response. In some embodiments, the immune effector cells specifically recognize an antigen. Examples of immune effector cells include, but are not limited to, Natural Killer (NK) cells, B cells, monocytes, macrophages, T cells (eg, cytotoxic T lymphocytes (CTLs). In some embodiments, the effector cell is a cell T. As used herein, the term "immune effector function" or "immune effector response" refers to a function or response of an immune effector cell that promotes an immune response to a target. As used herein, the term "Fe region" refers to the portion of a native immunoglobulin formed by the respective Fe domains (or Fe portions) of its cebenn / Lznz / B / YiAi two heavy chains. In some embodiments, the term "Fe domain" refers to a portion of a single immunoglobulin (Ig) heavy chain wherein the Fe domain does not comprise an Fv domain. In some embodiments, the term "Fe domain" refers to a portion of a single immunoglobulin (Ig) heavy chain that also comprises an Fv domain. As such, an Fe domain may also be referred to as "Ig" or "IgG". In certain embodiments, an Fe domain begins in the hinge region just upstream of the papain cleavage site and ends at the C-terminus of the antibody. Accordingly, a complete Fe domain comprises at least one hinge domain, one CH2 domain, and one CH3 domain. In certain embodiments, an Fe domain comprises at least one of: a hinge domain (eg, upper, intermediate, and / or lower hinge region), a CH2 domain, a CH3 domain, a CH4 domain, or a variant, portion, or fragment of them. In certain embodiments, an Fe domain comprises an entire Fe domain (ie, a hinge domain, a CH2 domain, and a CH3 domain). In certain embodiments, an Fe domain comprises a hinge domain (or portion thereof) fused to a CH3 domain (or portion thereof). In certain embodiments, an Fe domain comprises a CH2 domain (or portion thereof) fused to a CH3 domain (or portion thereof). In certain embodiments, an Fe domain consists of a CH3 domain or portion thereof. In certain embodiments, an Fe domain consists of a hinge domain (or portion thereof) and a CH3 domain (or portion thereof). In certain embodiments, an Fe domain consists of a CH2 domain (or portion thereof) and a CH3 domain. In certain embodiments, an Fe domain consists of a hinge domain (or portion thereof) and a CH2 domain (or portion thereof). In certain embodiments, an Fe domain lacks at least a portion of a CH2 domain (eg, all or part of a CH2 domain). An Fe domain refers herein generally to a polypeptide comprising all or part of the Fe domain of an immunoglobulin heavy chain. This includes, but is not limited to, polypeptides comprising the entire CH1, hinge, CH2 and / or CH3 domains, as well as fragments of these peptides comprising only, for example, the hinge, CH2 and CH3 domain. The Fe domain can be derived from an immunoglobulin of any species and / or any subtype, including, but not limited to, a human IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody. A human lgG1 constant region can be found in Uniprot P01857 and SEQ ID NO: 114. The Fe domain of human lgG1 can be found in SEQ ID NO: 115. The Fe domain encompasses native Fe molecules and Fe variants. As with the Fe variants and the native Fc's, the term Fe domain includes molecules in a monomeric or multimeric form, either digested from the whole antibody or produced by other means. The assignment of amino acid residue numbers to an Fe domain is according to the Kabat definitions. See, for example, Sequences of Proteins of Immunological Interest (Table of Contents, Introduction and Constant Region Sequences sections), 5th edition, Bethesda, MD:NIH vol. 1:647-723 (1991); Kabat et al, cefrenn / Lznz / B / YiAi “Introduction” Sequences of Proteins of Immunological Interest, US Dept of Health and Human Services, NIH, 5th edition, Bethesda, MD vol. 1 :xii¡-xcv¡ (1991); Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987); Chothia et al., Nature 342:878-883 (1989), each of which is incorporated herein by reference for all purposes. As set forth herein, it will be understood by one of ordinary skill in the art that any Fc domain can be modified such that it varies in amino acid sequence from the native Fc domain of a naturally occurring immunoglobulin molecule. In certain embodiments, the Fe domain has reduced effector function (eg, binding to FcyR). Fc domains suitable for use in the immunomodulatory fusion proteins described herein can be derived from different immunoglobulin molecules. For example, an Fe domain of a polypeptide may comprise a CH2 and / or CH3 domain derived from an IgG1 molecule and a hinge region derived from an IgG3 molecule. In another example, an Fe domain may comprise a chimeric hinge region derived in part from an IgG1 molecule and in part from an IgG3 molecule. In another example, an Fe domain may comprise a chimeric hinge derived in part from an IgG 1 molecule and in part from an IgG4 molecule. As used herein, the term "gly-ser polypeptide linker" or "glyser linker" refers to a peptide consisting of glycine and serine residues. An exemplary gly-ser polypeptide linker comprises the amino acid sequence Ser(Gly4Ser)n. In certain modalities, n=1. In certain modalities, n=2. In certain embodiments, n=3, ie Ser(Gly4Ser)3. In certain embodiments, n=4, ie Ser(Gly4Ser)4. In certain modalities, n=5. In certain modalities, n=6. In certain modalities, n=7. In certain modalities, n=8. In certain modalities, n=9. In certain modalities, n=10. Another exemplary gly-ser polypeptide linker comprises the amino acid sequence (Gly4Ser)n. In certain modalities, n=1. In certain modalities, n=2. In certain modalities, n=3. In certain modalities, n=4. In certain modalities, n=5. In certain modalities, n=6. Another exemplary gly-ser polypeptide linker comprises the amino acid sequence (GlysSer)n. certain modalities, n=1. In certain modalities, n=2. In certain modalities, n=3. In certain modalities, n=4. In certain modalities, n=5. In certain modalities, n=6. As used herein, the term "human antibody" includes antibodies that have variable and constant regions (if present) of human germ-line immunoglobulin sequences. Human antibodies of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (eg, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo) (see, Lonberg, N. et al. (1994)) Nature 368(6474):856-859); Lonberg, N. (1994) Handbook of Experimental Pharmacology 113:49-101; Lonberg, N. and Huszar, D. (1995) Intern. Rev. Immunol. Vol 13:6593, and Harding, F. and Lonberg, N. (1995) Ann. N.Y. Acad. Sci 764:536-546). However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto the human framework sequences (ie, humanized antibodies). . As used herein, the term a "heterologous antibody" is defined in relation to the non-human transgenic organism that produces this antibody. This term refers to an antibody that has an amino acid sequence or an encoding nucleic acid sequence that corresponds to that found in an organism that does not consist of the transgenic non-human animal, and generally of a different species from that of the non-transgenic animal. transgenic human. As used herein, "immune cell" is a cell of hematopoietic origin and that plays a role in the immune response. Immune cells include lymphocytes (eg, B cells and T cells), naturally-killing cells, and myeloid cells (eg, monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes). As used herein, "immune checkpoint" refers to costimulatory and inhibitory signals that regulate immune cells. In certain embodiments, the immune checkpoint is an inhibitory signal. In certain modalities, the inhibitory signal is the interaction between PD-1 and PD-L1. In certain embodiments, the inhibitory signal is the interaction between CTLA-4 and CD80 or CD86 to displace CD28 binding. In certain embodiments, the inhibitory signal is the interaction between LAG3 and MHC class II molecules. In certain modalities, the inhibitory signal is the interaction between TIM3 and galectin 9. As used herein, "immune checkpoint blocker" refers to a molecule that reduces, inhibits, interferes in whole or in part with, or modulates one or more checkpoint proteins. In certain embodiments, the immune checkpoint blocker prevents the inhibitory signals associated with the immune checkpoint. In certain embodiments, the immune checkpoint blocker is an antibody, or fragment thereof, that disrupts inhibitory signaling associated with the immune checkpoint. In certain embodiments, the immune checkpoint blocker is a small molecule that disrupts inhibitory signaling. In certain embodiments, the immune checkpoint blocker is an antibody, fragment thereof, or antibody mimetic, that prevents interaction between the checkpoint blocker proteins, eg, an antibody or fragment thereof, that prevents the interaction between PD-1 and PD-L1. In certain embodiments, the immune checkpoint blocker is an antibody, or fragment thereof, that prevents the interaction between CTLA-4 and CD80 or CD86. cebenn / Lznz / B / YiAi In certain embodiments, the immune checkpoint blocker is an antibody, or fragment thereof, that prevents the interaction between LAG3 and its ligands, or TIM-3 and its ligands. As used herein, the term "immunomodulatory fusion protein" refers to a polypeptide comprising a collagen-binding domain operably linked to at least one immunomodulatory domain. In some embodiments, the collagen binding domain is operably linked to the immunomodulatory domain via a linker. As used herein, the term "immunomodulatory domain" refers to a polypeptide (eg, cytokine, agonist, or antagonist antibody) that confers an activity that results in the activation or suppression of an immune response (eg, stimulation of CD8+ T cells). In some embodiments, the immunomodulatory domain refers to a polypeptide that binds to its cognate ligand or receptor, thereby resulting in activation or suppression of an immune response. The terms "induce an immune response" and "change an immune response" are used interchangeably and refer to the stimulation of an immune response (ie, either passive or adaptive) to a particular antigen. The term "induces" as used with respect to inducing CDC or ADCC refers to the stimulation of particular direct cell-killing mechanisms. As used herein, a subject "in need of prevention," "in need of treatment," or "in need of" refers to one, and who in the judgment of an appropriate medical professional (eg, a doctor, nurse, or nursing professional in the case of humans; a veterinarian in the case of non-human mammals), would reasonably benefit from a given treatment (such as treatment as a composition comprising a fusion protein described in the present). The term "in vivo" refers to processes that occur in a living organism. As used herein, "interleukin (IL)-2" refers to a pleiotropic cytokine that activates and induces the proliferation of T cells and natural killer (NK) cells. IL-2 signals by binding to its receptor, IL-2R, which is comprised of alpha, beta, and gamma subunits. IL-2 signaling stimulates the proliferation of antigen-activated T cells. As used herein, the term "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities {for example, an isolated antibody that binds immune checkpoint blockers or costimulatory molecules) is substantially free of antibodies that specifically bind to antigens other than the target of interest. An isolated antibody that specifically binds to one epitope may, however, cross-activity to other targets from different species. In addition, an isolated cefrenn / Lznz / B / YiAi antibody is typically substantially free of other cellular material and / or chemicals. As used herein, the term "isolated nucleic acid molecule" refers to nucleic acids encoding fusion proteins, polypeptides, antibodies, or antibody portions described herein, is intended to refer to a nucleic acid molecule in wherein the nucleotide sequences encoding the fusion protein, polypeptide, antibody, or antibody portion are free of other nucleotide sequences, which other sequences may naturally flank nucleic acid in human genomic DNA. As used herein, "isotype" refers to the class of antibody (eg, IgM or IgG1) that is encoded by the heavy chain constant region genes. In some embodiments, an antibody of the disclosure is of the IgG1 isotype. In some embodiments, an antibody of the disclosure is of the IgG2 isotype. In some embodiments, an antibody of the disclosure is of the IgG3 isotype. In some embodiments, an antibody of the disclosure is of the lgG4 isotype. As used herein the term "KD" or "Kd" refers to the equilibrium dissociation constant of a binding reaction between, for example, a ligand and a receptor, an antigen and an antibody, or a binding protein. to collagen and collagen. The Kd value is a numerical representation of the ratio of the binding protein dissociation constant (kd) to the binding protein dissociation constant (ka). The Kd value is inversely related to the binding affinity of the binding protein to its binding partner. The smaller the Kd value, the higher the affinity of the binding protein for its binding partner. Affinity is the resistance of binding of an individual molecule to its binding and is typically measured and reported by the equilibrium dissociation constant (Kd), which is used to assess and classify the order resistances of bimolecular interactions. As used herein, the term "kd" or "kd" (alternatively "koff" or "kOff") is intended to refer to the dissociation rate constant for the dissociation of a binding protein from the protein / protein complex. union partner. The value of kd is a numerical representation of the fraction of complexes that break down or dissociate per second, and is expressed in units of sec-1. As used herein, the term "ka" or "ka" (alternatively "kon" or "kon") is intended to refer to the association constant for the association of a binding protein with a binding partner. The ka value is a numerical representation of the number of antibody / antigen complexes formed per second in a 1 molar (1M) solution of binding partners, and is expressed in M'1sec1 units. As used herein, the terms "linked", "operably linked", "fused" or "fusion" are used interchangeably. These terms refer to the joining together of two or more elements or components or domains, by any means including chemical conjugation, non-covalent complexation, or recombinant means. Chemical conjugation methods (eg, using heterobifunctional crosslinking agents) are known in the art. As used herein, "local administration" or "local delivery" refers to delivery that is not dependent on transport of the composition or agent to its intended target tissue or site through the vascular system. For example, the immunomodulatory fusion protein or composition comprising the fusion protein can be delivered by injection or implantation of the fusion protein or composition, or by injection or implantation of a device containing the fusion protein or composition. Following local administration in the vicinity of a target tissue or site, the composition or agent, or one or more components thereof, can diffuse to the intended target tissue or site. In some embodiments, an immunomodulatory fusion protein is delivered locally by viral vectors, electroporation, cell transplantation expressing the immunomodulatory fusion protein, or replicons. "Lymphocyte Activation Gene-3 (LAG3)" is an inhibitory receptor associated with inhibition of lymphocyte activity by binding to MHC class II molecules. This receptor enhances Treg cell function and inhibits CD8+ effector T cell function. The term "LAG3" as used herein includes human LAG3 (hLAG3), variants, isoforms, and species homologues of hLAG3, and analogs that have at least one common epitope. The complete hLAG3 sequence can be found under GenBank Accession No. P18627 (SEQ ID NO: 47). The term "mammal" or "subject" or "patient" as used herein includes both humans and non-humans and includes, but is not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and pigs. "Nucleic acid" refers to deoxyribonucleotides or ribonucleotides and polymers thereof in any single-stranded or double-stranded form. Unless specifically limited, the term encompasses nucleic acids that contain known analogs of natural nucleosides that have similar binding properties as the reference nucleic acid and are metabolized in a similar manner to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence is also meant to encompass conservatively modified variants thereof (eg, degenerate codon substitutions) and complementary sequences as well as the explicitly stated sequence. Specifically, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected codons (or all) is replaced with mixed base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081, 1991, Ohtsuka et al. Cefren / Lznz / B / YiAi coworkers, Biol. Chem. 260:2605-2608, 1985, and Cassol et al., 1992, Rossolini et al., Mol. Cell. Probes 8:91-98 , 1994). For arginine and leucine, second base modifications can also be conservative. The term nucleic acid is used interchangeably with the gene, cDNA, and mRNA encoded by a gene. The polynucleotides used herein can be composed of any polyribonucleotide or polydeoxyribonucleotide, which can be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is a mixture of single-stranded regions. or double-stranded, hybrid molecules comprising DNA and RNA which may be single-stranded or, more typically, double-stranded or a mixture of single-stranded and double-stranded regions. Furthermore, polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A polynucleotide may contain one or more modified bases or modified DNA or RNA backbones for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA and RNA; thus, "polynucleotide" encompasses chemically, enzymatically, or metabolically modified forms. As used herein, "parenteral administration," "parenterally administered," and other grammatically equivalent phrases, refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, injection and intravenous infusion. , intranasal, infraocular, intramuscular, intra -arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transfrayneal, subcutaneous, sub -basic, intra -articular, subcapsular, subarachnoid, intra -espinal, epidural, intracereneal, intracereneal, intra -corneal, intrach. / intraintestinal, intra -service / intravaginal , and intrasternal The term "percent identity", in the context of two or more nucleic acid or polypeptide sequences, refers to two or more sequences or subsequences that have a specified percentage of nucleotide or amino acid residues that are the same, when compared. and are aligned for maximum match, as measured using one of the sequence comparison algorithms described below (eg, BLASTP and BLASTN or other algorithms available to the skilled person) or by visual inspection. Depending on the application, "percent identity" may exist over a region of the sequence being compared, for example, over a functional domain, or, alternatively, it exists over the full length of the two sequences being compared. For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a Cefrenn / Lznz / B / YiAi sequence comparison algorithm, the test and reference sequences are entered into a computer, designated subsequence coordinate, if necessary, and program parameters of the sequence algorithm are designated . The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. Optimal alignment of sequences for comparison can be driven, for example, by the local homology algorithm of Smith and Waterman, Adv. AppL Math. 2:482 (1981), for the homology alignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443 (1970), by searching by the similarity method of Pearson and Lipman, Proc. Nat'l. Acad. Sel. USA 85:2444 (1988), by computer implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel et al., infra). An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described in Altschul et al., J. Mol. Biol. 215:403-410 (1990). Software for performing BLAST analyzes is publicly available through the National Center for Biotechnology Information website. As generally used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with tissues, organs, and / or bodily fluids of humans and animals if excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. "Polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residues is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as naturally occurring amino acid polymers and non-naturally occurring amino acid polymer. The "Programmed Death-1 (PD-1)" receptor refers to an immuno-inhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds two ligands, PD-LI and PD-L2. The term "PD-1" as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologues of hPD-1, and analogs that have at least one common epitope with hPD-1. 1. The complete hPD-1 sequence can be found under GenBank Accession No. AAC51773 (SEQ ID NO: 44). "Programmed Death Ligand-1 (PD-L1)" is one of two cebenn / ίζηζ / ε / γίΛΐ cell surface glycoprotein ligands for PD-1 (the other is PD-L2) that downregulates the activation of cells and cytokine secretion upon binding to PD-1. The term "PD-L1" as used herein includes human PD-L1 (hPD-LI), variants, isoforms, and species homologues of hPD-LI, and analogs that have at least one common epitope with hPD-LI. LI. The complete hPD-LI sequence can be found under GenBank Accession No. Q9NZQ7 (SEQ ID NO: 45). As used herein, the term "purified" or "isolated" as applied to any of the proteins (fusion proteins, antibodies, or fragments) described herein refers to a polypeptide that has been separated or purified from components (eg, proteins or other naturally occurring biological or organic molecules) that naturally accompany it, eg, other proteins, lipids, and nucleic acid from a prokaryote expressing the protein. Typically, a polypeptide is purified when it constitutes at least 60 (for example, at least 65, 70, 75, 80, 85, 90, 92, 95, 97, or 99) %, by weight, of the total protein in a sample. . As used herein, the terms "binds specifically" and "binds selectively" refer to binding by a collagen-binding domain to collagen, or bound by an antibody to an epitope on a predetermined antigen. In some embodiments, a collagen-binding domain specifically binds or selectively binds collagen based on the Kd for collagen (i.e., the Kd for collagen binding is less than the Kd for at least fibronectin, vitronectin, osteopontin , tenascin C or fibrinogen). The term "sufficient amount" or "sufficient amount to" means an amount sufficient to produce a desired effect, for example, an amount sufficient to reduce the size of a tumor. The term "T cell" refers to a type of white blood cell that can be distinguished from other white blood cells by the presence of a T cell receptor on the cell surface. Various subsets of T cells exist, including, but not limited to, T cells. helper T cells (formerly known as TH cells or CD4+ T cells) and subtypes, including TH1, TH2, TH3, Th17, Th9, and Tfh cells, cytotoxic T cells (formerly known as Te cells, CD8+ T cells, cytotoxic T lymphocytes, killer cells T, killer T cells), memory T cells and subtypes, including core memory T cells (Tcm cells), effector memory T cells (Tem and Temra), and resident memory T cells (Trm cells), regulatory T cells (formerly known as Treg cells or suppressor T cells) and subtypes, including CD4+FOXP3+ Treg cells, CD4+FOXP3-Treg cells, Tr1 cells, Th3 cells, and Treg17 cells, natural killer T cells (formerly known as NKT cells), mucosa-associated invariant T cells (MAITs); and gamma-delta T cells (γδ T cells), including Vy9 / V52 T cells. Any one or more of the above mentioned or non-mentioned T cells may be the target cell type for a cefrenn / Lznz / B / YiAi method as described herein. The term "T cell cytotoxicity" includes any immune response that is mediated by activation of CD8+ T cells. Exemplary immune responses include cytokine production, CD8+ T cell proliferation, granzyme or perforin production, and clearance of an infectious agent. "T-Cell Membrane Protein-3 (TIM3)" is an inhibitory receptor involved in the inhibition of lymphocyte activity by inhibition of the Th1 cell response. Its ligand is galectin 9, which is upregulated in several types of cancers. The term "TIM3" as used herein includes human TIM3 (hTIM3), variants, isoforms, and species homologues of hTIM3, and analogs that have at least one common epitope. The complete hTIM3 sequence can be found under GenBank Accession No. Q8TDQ0 (SEQ ID NO: 48). A "therapeutic antibody" is an antibody, antibody fragment, or construct that is derived from an antibody, and can bind to a cell surface antigen on a target cell to elicit a therapeutic effect. These antibodies can be chimeric, humanized, or fully human antibodies. Methods are known in the art for producing these antibodies. These antibodies include single chain Fe fragments of antibodies, minibodies, and diabodies. Any of the therapeutic antibodies known in the art to be useful for cancer therapy can be used in combination therapy suitable for use in the methods described herein. Therapeutic antibodies can be monoclonal antibodies or polyclonal antibodies. In preferred embodiments, the therapeutic antibodies target cancer. The term "therapeutically effective amount" is an amount that is effective to ameliorate a symptom of a disease. A therapeutically effective amount may be a "prophylactically effective amount" since prophylaxis may be considered therapy. As used herein, the term "vector" is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been ligated. Another type of vector is a "plasmid", which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, where additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (eg, viral vectors that have a bacterial origin of replication and episomal mammalian vectors). Other vectors (eg, non-episomal mammalian vectors) can integrate into the genome of a host cell upon introduction into the host cell, and thus replicate along with the host genome. On the other hand, certain vectors are capable of directing the expression of the genes to which cebenn / Lznz / B / YiAi are operably linked. These vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors"). In general, expression vectors of utility in recombinant DNA techniques are frequently in the form of plasmids. In the present specification, "plasmid" and "vector" may be used interchangeably since plasmid is the most commonly used form of vector. However, the disclosure is intended to include other forms of expression vectors, such as viral vectors (eg, replication-defective retroviruses, adenoviruses, and adeno-associated viruses), which serve equivalent functions. Immunomodulatory fusion protein In some aspects, the disclosure provides an immunomodulatory fusion protein comprising a collagen binding domain operably linked to an immunomodulatory fusion domain. In some embodiments, the immunomodulatory fusion protein further comprises a linker, such that the collagen-binding domain is operably linked to a linker, and the linker is operably linked to the immunomodulatory domain. I. Collagen-binding domains In some embodiments, the disclosure provides immunomodulatory fusion proteins comprising a collagen binding domain. In some embodiments, the collagen-binding domain has an MW of about 5-100 kDa, about 10-80 kDa, about 20-60 kDa, about 30-50 kDa, or about 10 kDa, about 20 kDa, about 30 kDa. , about 40 kDa, about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa, or about 100 kDa. In some embodiments, the collagen-binding domain is about 5 kDa, about 10 kDa, about 20 kDa, about 30 kDa, about 40 kDa, about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa , or approximately 100 kDa. In some embodiments, the collagen binding domain is approximately 30 kDa. In some embodiments, the collagen binding domain is approximately 40 kDa. In some embodiments, the collagen-binding domain is about 10-350, about 10-300, about 10-250, about 10-200, about 10-150, about 10-100, about 10-50, or about 10- 20 amino acids in length. In some embodiments, the collagen binding domain is approximately 10 amino acids in length. In some embodiments, the collagen binding domain is approximately 15 amino acids in length. In some embodiments, the collagen binding domain is approximately 20 amino acids in length. In some embodiments, the collagen binding domain is cebenn / Lznz / B / YiAi approximately 30 amino acids in length. In some embodiments, the collagen binding domain is approximately 40 amino acids in length. In some embodiments, the collagen binding domain is approximately 50 amino acids in length. In some embodiments, the collagen binding domain is approximately 60 amino acids in length. In some embodiments, the collagen binding domain is approximately 70 amino acids in length. In some embodiments, the collagen binding domain is approximately 80 amino acids in length. In some embodiments, the collagen binding domain is approximately 90 amino acids in length. In some embodiments, the collagen binding domain is approximately 100 amino acids in length. In some embodiments, the collagen binding domain is approximately 120 amino acids in length. In some embodiments, the collagen binding domain is approximately 150 amino acids in length. In some embodiments, the collagen binding domain is approximately 200 amino acids in length. In some embodiments, the collagen binding domain is approximately 250 amino acids in length. In some embodiments, the collagen binding domain is approximately 300 amino acids in length. In some embodiments, the collagen binding domain is approximately 350 amino acids in length. A. Isoelectric Point The isoelectric point (pl, pH(l), IEP), is the pH at which a particular molecule (eg, a collagen-binding domain) carries no net electrical charge or is electrically neutral. Table 1 provides the calculated pI for the exemplary collagen binding domains described herein. The Swiss Institute of Bioinformatics ExPASy tool (https: / / web.expasy.org / computej3i / ) was used to calculate the isoelectric points (pl) of the collagen-binding domains shown in Table 1. In some embodiments, the collagen-binding domain has an isoelectric point pl less than (<) about 10, about 8, about 6, about 4, about 2, or about 1. In some embodiments, the collagen-binding domain has a pl isoelectric point of less than (<) 10. In some embodiments, the collagen-binding domain has a pl isoelectric point of less than (<) 10 and a molecular weight (MW) of greater than (>) 5 kDa. Table 1: pl calculated for Exemplary Collagen-Binding Domains cefrenn / ίζηζ / Β / γίΛΐ Collagen binding domain pl calculated SEQ ID NO LAIR1 5.23 98 LAIR2 4.88 99 Glycoprotein IV 7.68 100 Nidogen 5.05 101 Perlecan 6.03 102 Biglican 8.13 103 Decorin 8.76 104 Asporin 6.1 105 Fibromodulin 5.66 106 Lumican 6.17 107 PRELP 9.45 108 Osteoaderin / Osteomodulin 5.22 109 Opticin 5.38 110 Osteoglycine / Mimecan 5.22 111 Chondroaderin 9.14 112 Podcan 6.41 113 Lumican (murine) 6.01 195 cefrenn / Lznz / B / YiAi B. Collagen Type I Collagen is the predominant structural protein located within the extracellular space and type I collagen is the most abundant protein in mammals (Di Lullo et al., (2002) J Biol Chem 277(6):4223-4231). The fundamental structural unit of type I collagen is a long (300-nm), thin (1.5-nm in diameter) protein consisting of three coiled subunits: two a1(l) and one a2(l) chains. Each chain contains 1050 amino acids wound around each other in a characteristic right triple helix. In humans, type I collagen is encoded by the COL1A1 and C0L1A2 genes. The COL1A1 gene encodes the pro-alpha1 chain of type I collagen. The pro-alpha2 chain of the COL1A2 gene of type I collagen, whose triple helix comprises two alpha chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis, and tendon. An exemplary amino acid sequence for the human alpha chain precursor of type I collagen is set forth in SEQ ID NO: 90 (NCBI Reference Sequence: NP_000079.2). An exemplary amino acid sequence for the human alpha2 chain precursor of type I collagen is set forth in SEQ ID NO: 91 (NCBI Reference Sequence: NP 000080.2). C. Type IV Collagen Type IV collagen is comprised of a family of polypeptides and is a major constituent of mammalian basement membranes (Timpl (1989) Eur J Biochem 180:487-502; Paulsson (1992) Crit Rev Biochem Mol Biol 27:93-127 ). The a1(IV) and a2(IV) chains are products of different genes (COL4A1 and COL4A2, respectively) located in pairs in a head-to-head fashion on chromosome 13 in humans (Hudson et al., (1993) J Biol Chem 268:26033-26036). The a3(IV) and a4(IV) chains (encoded by the COL4A3 and COL4A4 genes, respectively) are present in the same orientation on chromosome 2 in humans, and the a5(IV) and a6(IV) chains (encoded by the COL4A5 and COL4A6 genes, respectively) are located on the X chromosome in humans (Hudson et al., (1991) in Pathobiochemistry, ed Kang A. (CRC Press, Boca Raton, FL), pp 17-30). The exemplary amino acid sequence for the human alpha chain of type IV collagen is set forth in SEQ ID NO: 92 (NCBI Reference Sequence: XP_011519350.1). An exemplary amino acid sequence for the human alpha2 chain of type IV collagen is set forth in SEQ ID NO: 93 (NCBI Reference Sequence: NP_001837.2). An exemplary amino acid sequence for the human alpha3 chain of type IV collagen is set forth in SEQ ID NO: 94 (NCBI Reference Sequence: NP 000082.2). An exemplary amino acid sequence for the human alpha4 chain of type IV collagen is set forth in SEQ ID NO: 95 (NCBI Reference Sequence: NP_000083.3). An exemplary amino acid sequence for the human alpha5 chain of type IV collagen is set forth in SEQ ID NO: 96 (NCBI Reference Sequence: XP_011529151.2). An exemplary amino acid sequence for human collagen type IV alpha6 chain is set forth in SEQ ID NO: 97 (NCBI Reference Sequence: XP 006724680.1). Accordingly, in some embodiments, the disclosure provides immunomodulatory fusion proteins comprising a collagen-binding domain that specifically binds collagen. In some embodiments, the collagen-binding domain specifically binds human type I collagen and / or human type IV collagen. In some embodiments, the collagen binding domain binds human type I collagen. In some embodiments, the collagen-binding domain binds to human type IV collagen. In some embodiments, the collagen-binding domain specifically binds human type I collagen and human type IV collagen. In some embodiments, the collagen-binding domain specifically binds to human type I collagen or human type IV collagen. D. Collagen Binding Affinity In some embodiments, the disclosure provides immunomodulatory fusion proteins comprising a collagen-binding domain that specifically binds collagen with an affinity (Kd) of less than about 0.5 nM as determined by a collagen-binding assay. In some embodiments, the disclosure provides immunomodulatory fusion proteins comprising a collagen-binding domain that specifically binds collagen with an affinity (Kd) of less than about 5 nM as determined by a collagen-binding assay. In some embodiments, the cefrenn / Lznz / B / YiAi disclosure provides immunomodulatory fusion proteins comprising a collagen-binding domain that specifically binds to collagen with an affinity (Kd) of less than about 50 nM as determined by an assay. collagen binding. In some embodiments, the disclosure provides immunomodulatory fusion proteins comprising a collagen-binding domain that specifically binds collagen with an affinity (Kd) of less than about 500 nM as determined by a collagen-binding assay. In some embodiments, the collagen-binding domain specifically binds collagen with an affinity (Kd) of approximately 0.5-5 nM, 5-50 nM, or 50-500 nM as determined by a collagen-binding assay. In some embodiments, the collagen-binding domain specifically binds to collagen with an affinity (Kd) of approximately 50-100 nM, 100-200 nM, 200-300 nM, 300-400 nM, or 400-500 nM as determined by a collagen binding assay. In some embodiments, the collagen binding assay determines a binding affinity of the collagen binding domain for collagen. In some embodiments, the collagen binding assay determines a binding affinity of the collagen binding domain for type I collagen. In some embodiments, the collagen binding assay determines a binding affinity for type IV collagen. In some embodiments, the collagen binding assay is an ELISA. Methods and techniques for carrying out a collagen binding ELISA are known in the art (see for example, Smith et al., (2000) J Biol Chem 275:4205-4209). Accordingly, in some embodiments, the disclosure provides an immunomodulatory fusion protein comprising a collagen-binding domain that specifically binds collagen with an affinity (Kd) of less than about 0.5 nM as determined by an ELISA. Accordingly, in some embodiments, the disclosure provides an immunomodulatory fusion protein comprising a collagen-binding domain that specifically binds collagen with an affinity (Kd) of less than about 5 nM as determined by an ELISA. Accordingly, in some embodiments, the disclosure provides an immunomodulatory fusion protein comprising a collagen-binding domain that specifically binds collagen with an affinity (Kd) of less than about 50 nM as determined by an ELISA. Accordingly, in some embodiments, the disclosure provides an immunomodulatory fusion protein comprising a collagen-binding domain that specifically binds collagen with an affinity (Kd) of less than about 500 nM as determined by an ELISA. In some embodiments, the collagen-binding domain specifically binds to collagen with an affinity (Kd) of approximately 0.5-5 nM, 4-40 nM, 50-500 nM as determined by ELISA. In some embodiments, the collagen-binding domain specifically binds to collagen with an affinity (Kd) of approximately 50-100 nM, 100-200 cefrenn / Lznz / B / YiAi nM, 200-300 nM, 300-400 nM, or 400-500 nM as determined by an ELISA. In some embodiments, the collagen binding assay is a surface plasmon resonance (SPR) assay. Methods and techniques for carrying out a collagen binding SPR assay are known in the art (see for example, Saenko et al., (2002) Anal Biochem 302(2):252-262). Accordingly, in some embodiments, the disclosure provides an immunomodulatory fusion protein comprising a collagen-binding domain that specifically binds collagen with an affinity (Kd) of less than about 500 nM as determined by an SPR assay. In some embodiments, the collagen-binding domain specifically binds to collagen with an affinity (Kd) of approximately 50-500 nM as determined by an SPR assay. In some embodiments, the collagen-binding domain specifically binds collagen with an affinity (Kd) of approximately 50-100 nM, 100-200 nM, 200-300 nM, 300-400 nM, or 400-500 nM as is determined by an SPR assay. The phrase "surface plasmon resonance" includes an optical phenomenon that allows analysis of bispecific interactions in real time by detecting alterations in protein concentrations within a biosensor array, for example using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). For additional descriptions, see Jónsson, U., et al. (1993) Ann. Biol. Clin. 51:19-26; Jónsson, U., et al. (1991) Biotechniques 11:620-627; Johnsson, B., et al. (1995) J. Mol. Recognize 8:125-131; and Johnson, B., et al. (1991) Anal. Biochem. 198:268-277. E. Specificity of Collagen Binding In some embodiments, the disclosure provides immunomodulatory fusion proteins comprising a collagen-binding domain that specifically binds collagen and does not specifically bind one or more non-collagenous extracellular matrix (ECM) components including, but not limited to limited to, fibronectin, vitronectin, tenascin C, osteopontin fibrinogen. In some embodiments, the collagen-binding domain binds collagen with a lower KD than one or more non-collagenous ECM components. In some embodiments, the KD of the collagen-binding domain for type I collagen is less than the KD of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen. In some embodiments, the collagen-binding domain is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% bound to collagen. , approximately 99% of KD less than the one or more non-collagen ECM components. In some embodiments, the collagen-binding domain binds to collagen about 2-fold, about 3-fold, about 4-fold, cefrenn / Lznz / B / YiAi about 5-fold, about 10-fold of KD less than one or more ECM components not collagen. In some embodiments, the collagen-binding domain is not a promiscuous binder of the ECM components. In some embodiments, the collagen binding domain does not comprise a heparin binding domain. In some embodiments, the collagen-binding domain is not a growth factor or portion thereof that binds to the extracellular matrix. In some embodiments, the collagen-binding domain binds type I collagen with a lower Kd than type IV collagen. In some embodiments, the collagen-binding domain binds type IV collagen with a lower Kd than type I collagen. In some embodiments, the collagen binding domain competes with a reference collagen binding domain for collagen binding. In some embodiments, the collagen-binding domain competes with a reference collagen-binding domain for binding to type I collagen. In some embodiments, the collagen-binding domain competes with a reference collagen-binding domain for binding to type IV collagen. In some embodiments, the collagen-binding domain competes with a reference collagen-binding domain for binding to collagen type I and collagen type IV. In some embodiments, the collagen-binding domain competes with a reference collagen-binding domain for binding to type I collagen but not to type IV collagen. In some embodiments, the collagen-binding domain competes with a reference collagen-binding domain for binding to type IV collagen but not to type I collagen. In some embodiments, the reference collagen-binding domain comprises one or more (eg, two, three, four, five, six, seven, eight, nine, ten, or more) leucine-rich collagen-binding repeats. . In some embodiments, the reference collagen binding domain comprises a proteoglycan. In some embodiments, the reference collagen-binding domain comprises a proteoglycan, wherein the proteoglycan is selected from the group consisting of: decorin, biglycan, fibromodulin, lumican, chondroaderin, asporin, PRELP, osteoaderin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, nidogen. In some embodiments, the reference collagen-binding domain is lumican. In some embodiments, the reference collagen-binding domain comprises a class I small leucine-rich proteoglycan (SLRP). SLRPs are known to bind collagen (Chen and Birk (2013) FEBS Journal 21202137). In some embodiments, the reference collagen-binding domain comprises a class II SLRP. In some embodiments, the reference collagen-binding domain comprises a class III SLRP. In some embodiments, the reference collagen binding domain comprises a class IV SLRP. In some embodiments, the reference collagen-binding domain comprises a class V SLRP. Further description of the cebenn / Lznz / B / YiAi classes SLRP is described in Schaefer and lozzo (2008) J Biol Chem 283(31):21305-21309, which is incorporated herein by reference in its entirety. In some embodiments, the reference collagen-binding domain comprises leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) protein. In some embodiments, the reference collagen-binding domain comprises leukocyte-associated immunoglobulin-like receptor 2 (LAIR-2) protein. In some embodiments, the reference collagen binding domain comprises Glycoprotein IV. F. Exemplary Collagen-Binding Domains In some embodiments, the collagen-binding domain comprises one or more (eg, two, three, four, five, six, seven, eight, nine, ten, or more) leucine-rich repeats that bind collagen. In some embodiments, the collagen binding domain comprises a proteoglycan. In some embodiments, the collagen binding domain comprises a proteoglycan, wherein the proteoglycan is selected from the group consisting of: decorin, biglycan, testican, bikunin, fibromodulin, lumican, chondroaderin, keratin, ECM2, epiphycan, asporin, PRELP, keratocan, osteoaderin, opticin, osteoglycan, nictalopin, Tsukushi, podocan, podocan-like protein 1 versican, perlecan, nidogen, neurocan, aggrecan, and brevican. In some embodiments, the collagen-binding domain comprises a class I small leucine-rich proteoglycan (SLRP). In some embodiments, the collagen-binding domain comprises a class II SLRP. In some embodiments, the collagen-binding domain comprises a class III SLRP. In some embodiments, the collagen-binding domain comprises a class IV SLRP. In some embodiments, the collagen-binding domain comprises a class V SLRP. Further description of SLRP classes is described in Schaefer and lozzo (2008) J Biol Chem 283(31):21305-21309, which is incorporated herein. for reference in its entirety. In some embodiments, the collagen-binding domain comprises one or more leucine-rich repeats of a human proteoglycan Class II member of the small leucine-rich proteoglycan (SLRP) family. In some embodiments, the SLRP is selected from, decorin, biglycan, fibromodulin, keratin, epiphycan, asporin, and osteoglycin. In some modalities, the SLRP is lumican. In some embodiments, the lumican comprises the amino acid sequence as set forth in SEQ ID NO: 107. lumican Lumican, also known as LUM, is an extracellular matrix protein that, in humans, is encoded by the LUM gene on chromosome 12 (Chakravarti et al., (1995) Genomics 27(3):481-488). Lumican is a Class II proteoglycan member of the small leucine-rich proteoglycan (SLRP) family that includes decorin, biglycan, fibromodulin, keratocan, epiphycan, and osteoglycin (lozzo and Schaefer (2015) Matrix Biology 42:11-55). . cefrenn / ίζηζ / Β / γίΛΐ Similar to the other SLRPs, lumican has a molecular weight of approximately 40 kDa and has four major intramolecular domains: 1) a 16 amino acid residue signal peptide, 2) a negatively charged N-terminal domain containing sulfated tyrosine and binding( es) disulfide, 3) ten tandem leucine-rich repeats that allow lumican to bind to collagen, and 4) a 50 amino acid residue carboxyl-terminal domain containing two residues from 32 separate conserved cisternae. Kao et al., (2006) Experimental Eye Research 82(1):3-4). There are four N-linked sites within the leucine-rich repeat domain of the core protein that can be substituted with keratan sulfate. The lumican core protein (as decorin and fibromodulin) is horseshoe-shaped. This allows collagen molecules to bind to a collagen fibril, thereby helping to keep adjacent fibrils apart Scott (1996) Biochemistry 35(27): 8795-8799. Leukocyte-Associated Immunoglobulin-Like Receptors (LAIR-1 and LAIR-2) Leukocyte-associated Ig-like receptor (LAIR)-1 is a collagen receptor that inhibits the function of immune cells in binding to collagen. Along with LAIR-1, the human genome encodes LAIR-2, a soluble homologue. Human LAIR-1 (h) is expressed on most PBMCs and thymocytes ( Maasho et al., (2005) Mol Immunol 42: 1521-1530 ). Cross-linking of hLAIR-1 by mAbs in vitro delivers a potent inhibitory signal that is capable of inhibiting immune cell function (4, 10-15). Collagens are known to be natural, high affinity ligands for LAIR molecules. The interaction of hLAIR-1 with collagens directly inhibits the activation of immune cells in vitro (Meyaard et al., (1997) Immunity 7:283-290; Poggi (1998) Eur J Immunol 28:2086-2091; Van der Vuurst de Vries et al., (1999) Eur J Immunol 29:3160-3167; Lebbink et al., (2006) J Exp Med 203:1419-1425). In some embodiments, the collagen-binding domain comprises a human type I glycoprotein having an Ig-like domain, or an extracellular portion thereof that binds collagen. In some embodiments, the type I glycoprotein competes with lumican for binding to type I collagen. In some embodiments, the human type I glycoprotein is selected from LAIR1, LAIR2, and Glycoprotein IV. In some embodiments, the human type I glycoprotein is LAIR1. In some embodiments, the human type I glycoprotein is LAIR1 and the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set forth in SEQ ID NO: 98. In some embodiments, the collagen-binding domain is a LAIR1, LAIR2, or Glycoprotein IV variant. In some embodiments, the LAIR1 variant, LAIR2 vanant, or Glycoprotein IV variant comprises one or more amino acid substitutions, additions, or deletions (eg, two, three, four, five, six, seven, eight, nine, ten, or more). with respect to the sequence of LAIR1, LAIR 2 or wild-type Glycoprotein IV proteins. In cebenn / Lznz / B / YiAi some embodiments, the collagen-binding domain is a LAIR1 variant comprising one or more amino acid substitutions, additions, or deletions (for example, two, three, four, five, six, seven, eight , nine, ten or more) with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In some embodiments, the collagen-binding domain is a LAIR1 variant comprising one or more substitutions, additions or deletions of amino acids (eg, two, three, four, five, six, seven, eight, nine, ten or more) in the LAIR1 binding pocket (eg, a LAIR1 binding site comprising one or more E61 residues , S66, Y68, 1102, W109, Y115, R59, E63, R100, E111, and Q112, and combinations thereof) ( Brondijk et al., (2010) Blood 115:13641373 ). In some embodiments, the collagen-binding domain is a LAIR1 variant comprising one or more amino acid substitutions, additions, or deletions (eg, two, three, four, five, six, seven, eight, nine, ten, or more). outside of the bag binding to LAIR1. In some embodiments, the collagen-binding domain is a LAIR1 variant that has increased binding affinity for collagen relative to the collagen-binding affinity of a wild-type LAIR1 protein. In some embodiments, the LAIR1 variant shows an increase in collagen binding affinity relative to the collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. In some embodiments, the LAIR1 variant which has decreased binding affinity to collagen relative to the collagen binding affinity of the wild-type LAIR1 protein. In some embodiments, the LAIR1 variant shows a decrease in collagen binding affinity relative to the collagen binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO: 98. Glycoprotein IV (CD36) In some embodiments, the collagen binding domain comprises Glycoprotein IV (GPIV). Glycoprotein IV binds many ligands including collagen (Tandon (1989) J Biol Chem 264(13): 7576-7583). A multifunctional glycoprotein, GPIV acts as a receptor for a wide range of ligands, including thrombospondin, fibronectin, collagen or amyloid-beta as well as lipid in nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. GPIV is a protein that in humans is encoded by the CD36 gene. The CD36 antigen is an integral membrane protein found on a surface of many cell types in vertebrate animals. It imports fatty acids into cells and is a member of the class B scavenger receptor family of cell surface proteins. In some embodiments, CD36 comprises the amino acid sequence set forth in SEQ ID NO: 100. cefrenn / Lznz / B / YiAi II. Immunomodulatory domain The immunomodulatory fusion proteins described herein comprise at least one immunomodulatory domain operably linked to a collagen-binding domain. In some embodiments, the immunomodulatory fusion protein comprises one, two, three, four, or five immunomodulatory domains. In some embodiments, when more than one immunomodulatory domain is present in the fusion protein, the immunomodulatory domains are the same. In some embodiments, when more than one immunomodulatory domain is present in the fusion protein, the immunomodulatory domains are different. In some embodiments, when more than one immunomodulatory domain is present in the fusion protein, each domain is located at the N-terminus of a collagen-binding domain. In some embodiments, when more than one immunomodulatory domain is present in the fusion protein, each domain is located at the C-terminus of a collagen-binding domain. In some embodiments, when more than one immunomodulatory domain is present in the fusion protein, at least one domain is located at the N-terminus of a collagen-binding domain and at least one domain is located at the C-terminus of the domain. collagen binding. In some embodiments, the immunomodulatory domain activates the activity of an immune system cell. For example, in some embodiments the immunomodulatory domain is a stimulatory immune response, such as, but not limited to, a cytokine, such as an interleukin, a chemokine, a TNF-family member, an agonist antibody, a point blocker. immune control, or a combination thereof. In some embodiments, the immunomodulatory domain enhances an immune response. In some embodiments, enhancement of an immune response includes T cell stimulation, B cell stimulation, B cell stimulation, dendritic cell response cell stimulation, or a combination thereof. In some embodiments, enhancement of an immune response results in the production of cytokines, production of antibodies, production of antigen-specific immune cells (eg, CD8+ T cells or CD4+ T cells), simulation of Type I interferon responses, or combinations thereof. In some embodiments, the immunomodulatory domain comprises a polypeptide that activates, enhances, or promotes a response by an immune cell. In some embodiments, the immunomodulatory domain comprises a polypeptide that inhibits, reduces, or suppresses a response by an immune cell. In some embodiments, the immune cell is a lymphoid cell, including but not limited to T cells, B cells, NK cells, and innate lymphoid cells. In some embodiments, the immune cell is a myeloid cell, including but not limited to monocytes, neutrophils, macrophages, dendritic cells, mast cells, and granulocytes. In some embodiments, the immune cell response is cefrenn / Lznz / B / YiAi cytokine production, antibody production, antigen-specific immune cell production, or a combination thereof. A. Interleukins In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an interleukin (IL). Interleukins are secreted proteins that bind to their specific receptors and play a role in communication between leukocytes. Interleukins suitable for use as an immunomodulatory fusion domain of immunomodulatory fusion proteins include, but are not limited to: IL-2, IL-12, IL-15, IL-15 superagonists (IL15SA), IL-21, IL-6, IL-5, IL-8, IL-7, IL-17, IL-23, IL-18, IL-1, IL-4, IL-3, IL-10, IL-13, and IL -9. In some embodiments, the interleukin suitable for use as an immunomodulatory fusion domain comprises an amino acid sequence selected from SEQ ID NOs: 1-5 and 9-24. In some embodiments, the immunomodulatory domain is an IL-2 polypeptide. In some embodiments, the immunomodulatory domain is an IL-12 polypeptide. In some embodiments, the immunomodulatory domain is an IL-15 polypeptide. In some embodiments, the immunomodulatory domain is an IL-15SA polypeptide. In some embodiments, the immunomodulatory domain is an interleukin polypeptide that binds to a common gamma chain receptor. Interleukins that bind to the common gamma chain receptor include, but are not limited to, IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-15 / IL-15Ra and IL-21. In some embodiments, the immunomodulatory domain is a polypeptide belonging to the IL-12 family. The IL-12 family comprises heterodimeric ligands comprised of a helical α subunit (for example, IL-12p35, IL-23p19, IL-27p28) and a β subunit (for example, IL-12p40, IL-23p40 (which is identical to IL-12p40), EBI3). Exemplary members include IL-12, IL-23, IL-27, and IL-35. In some embodiments, the immunomodulatory domain is a polypeptide belonging to the IL-1 superfamily. The linterleukin-1 (IL-1) family consists of 11 structurally related family members (IL-1a, IL-1-β, IL-1Ra, IL-18, IL-33, and IL-1F5 to IL-1 F10 ), which are among the most potent immune system signaling molecules, acting through a group of closely related receptors. All IL-1 receptors have a similar mode of activation: on ligand binding to the primary receptor subunit (i.e., IL-1R1 for IL-1a and β, IL-18R for IL-18, and ST2 for IL-33). ), a second receptor subunit is recruited (ie IL-1RAP for IL-1a and β, IL-18RAP for IL-18, and IL-1RAP for IL-33) and signaling is initiated through juxtaposition of the receptors. cytoplasmic Toll receptor / IL-1 receptor (TIR) ​​subunit domains. The dimerized TIR domains provide a docking platform for the adapter protein MYD88, which through the recruitment of other intermediates drives the action of the procefrenn / Lznz / B / YiAi inflammatory nuclear factor-κΒ (NF-κΒ) and protein kinase pathways. activated with mitogen (MAPK). Members of the IL-1 family are produced primarily by innate immune cells and act on a variety of cell types during the immune response. Accordingly, in some embodiments the immunomodulatory domain is an IL-18 polypeptide. Interluecin-2 (IL-2) In some embodiments, the immunomodulatory fusion protein comprises a member of the IL-2 family operably linked to a collagen-binding domain, optionally via a linker. In some embodiments, the IL-2 family member is IL-2. Interleukin-2 (IL-2) is a cytokine that induces the proliferation of antigen-activated T cells and stimulates natural killer (NK) cells. The biological activity of IL-2 is mediated through a multisubunit IL-2 receptor (IL-2R) complex of three cell membrane-spanning polypeptide subunits: p55 (IL-2Ra, the alpha subunit, also known as CD25 in humans), p75 (IL-2RP, the beta subunit, also known as CD 122 in humans), and p64 ​​(IL-2Ry, the gamma subunit, also known as CD 132 in humans). The T cell response to IL-2 depends on a variety of factors, including: (1) the concentration of IL-2; (2) the number of IL-2R molecules on the cell surface; and (3) the number of IL-2Rs occupied by IL-2 (ie, the affinity of the binding interaction between IL-2 and IL-2R (Smith, “Cell Growth Signal Transduction is Quantal” In Receptor Activation by Antigens , Cytokines, Hormones, and Growth Factors 766:263-271, 1995)). The IL-2:IL-2R complex is internalized upon ligand binding and the different compounds undergo differential sorting. IL-2Ra is recycled to the cell surface, while IL2 associates with the IL-2:IL-2RPy complex which is routed to the lysosome and degraded. When administered as an intravenous (i.v.) bolus, IL-2 has rapid systemic elimination (an initial elimination phase with a half-life of 12.9 minutes followed by a slower elimination phase with a half-life of 85 minutes) (Konrad et al., Cancer Res. 50:2009-2017, 1990). The results of systemic IL-2 administration in cancer patients are by far ideal. Although 15 to 20 percent of patients objectively responded to high-dose IL-2, the vast majority did not, and many suffered serious, fatal side effects, including nausea, compounded hypotension, and septic shock. The severe toxicity associated with high-dose IL-2 treatment is largely attributable to natural killer (NK) cell activity. NK cells express the intermediate affinity receptor, IL-2RPyc, and are thus stimulated by nanomolar concentrations of IL-2, which do result in patient sera during high-dose IL-2 therapy. Attempts to reduce the serum concentration, and thus selectively stimulate IL-2RaPyc-bearing cells, by reducing the dose and adjusting the cefrenn / ίζηζ / Β / γίΛΐ dosing regimen have been attempted, and although less toxic, these treatments were also less effective. Given the toxicity problems associated with high dose IL-2 anticancer therapy, numerous groups have attempted to improve the anticancer efficacy of IL-2 by simultaneously administering therapeutic antibodies. Still, these efforts have not been largely successful, as they produce no additional or limited clinical benefit compared to IL-2 therapy alone. Accordingly, novel IL2 therapies are needed to more effectively combat various cancers. In some embodiments, ligation of IL-2 to a collagen-binding domain localizes the cytokine to a cell, and thus prevents systemic toxicity. Furthermore, in some embodiments, when administered directly to a tumor or lesion, the collagen-binding domain localizes the cytokine to the tumor or lesion microenvironment, thereby preventing systemic toxicity associated with IL-2 treatment. In some embodiments, the IL-2 is a recombinant human IL-2 such as Proleukin™(aldesleukin). ProleukinMR is a recombinant human interleukin-2 product produced in E. coli. Proleukin™ differs from native interleukin-2 in the following ways: a) it is not glycosylated; b) does not have an N-terminal alanine; and c) has serine substituted for cysteine ​​at amino acid positions 125. ProleukinMRexists as biologically active, non-covalently linked microaggregates with an average size of 27 recombinant interleukin-2 molecules. Proleukin™(aldesleukin) is administered by intravenous infusion. In some embodiments, IL-2 is wild-type IL-2 (eg, human IL-2 in its precursor form or mature IL-2. In some embodiments, IL-2 comprises the amino acid sequence set forth in SEQ ID NO: 1. In certain embodiments, IL-2 is mutated such that it has an altered affinity (eg, higher affinity) for the IL-2R alpha receptor compared to unmodified IL-2. Site-directed mutagenesis can be used to isolate IL-2 mutants that show high affinity binding to CD25, ie, IL-2Ra, as compared to wild-type IL-2. Increasing the affinity of IL-2 for IL-2Ra on the cell surface will increase receptor occupancy within a limited range of IL-2 concentration, as well as raising the local concentration of IL-2 on the cell surface. In some embodiments, the disclosure describes IL-2 mutants, which can be, but need not be, substantially purified and which can function as high affinity CD25 binders. IL-2 is a T cell growth factor that induces antigen-activated T cell proliferation and NK cell stimulation. Exemplary IL-2 mutants that are high affinity binders include those described in WO2013 / 177187A2 (incorporated herein by reference in its entirety). Additional exemplary IL-2 mutants with increased affinity for CD25 are described in US7,569,215, the contents of which are incorporated herein by reference cebenn / Lznz / B / YiAi. In some embodiments, the disclosure describes IL-2 mutants with reduced binding affinity to CD25 relative to wild-type IL-2. In some embodiments, the IL-2 mutant does not bind CD25. In some embodiments, IL-2 mutants comprise an amino acid sequence that is at least 80% identical to SEQ ID NO: 1 that binds to CD25. For example, some embodiments an IL-2 mutant has at least one mutation (for example, a deletion, addition, or substitution of 1,2, 3, 4, 5, 6, 7, 8.9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, or more amino acid residues) that increases the affinity for the high subunit of the IL-2 receptor relative to wild-type IL-2. It is to be understood that the mutations identified in mouse IL-2 can be made at corresponding residues in full-length human IL-2 (nucleic acid sequence (accession: NM000586); amino acid sequence (accession: P60568)). or human IL-2 without the signal peptide. Accordingly, in some embodiments, the IL-2 is human IL-2. In other embodiments, the IL-2 is a mutant human IL-2. In some embodiments, the IL-2 mutants are at least or about 50%, at least or about 65%, at least or about 70%, at least or about 80%, at least or about 85%, at least or about 87 %, at least or about 90%, at least or about 95%, at least or about 97%, at least or about 98%, or at least or about 99% identical in amino acid sequence to IL-2 of wild type (in its parent form or, preferably, the mature form). The mutation may consist of a change in the number or content of amino acid residues. For example, IL-2 mutants may have a greater or fewer number of amino acid residues than wild-type IL-2. Alternatively, or in addition, IL-2 mutants may contain a substitution of one or more amino acid residues that are present from wild-type IL-2. By way of illustration, a polypeptide that includes an amino acid sequence that is at least 95% identical to a reference amino acid sequence of SEQ ID NO: 1 is a polypeptide that includes a sequence that is identical to the reference sequence except for inclusion of up to five alterations to the reference amino acid of SEQ ID NO: 1. For example, up to 5% of the amino acid residues in the reference sequence may be deleted or substituted with another amino acid, or up to a number of amino acids. 5% of the amino acid residues in the reference sequence can be inserted into the reference sequence. These reference sequence alterations can occur at the amino (N-) or carboxy (C-) terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either singly between residues of the reference sequence. reference sequence or in one or more cebenn / Lznz / B / YiAi contiguous clusters within the reference sequence. The substituted amino acid residue(s) can be, but need not be, conservative substitutions, typically including substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. The mutations may be in amino acid residues that contact IL-2Ra. Interleukin-12 (IL-12) In some embodiments, the immunomodulatory fusion protein comprises an IL-12 polypeptide operably linked to a collagen-binding domain, optionally via a linker. Interleukin-12 (IL-12) is a pro-inflammatory cytokine that plays an important role in innate and adaptive immunity. Gately, MK et al., Annu Rev Immunol. 16: 495-521 (1998). IL-12 functions primarily as a 70 kDa heterodimeric protein consisting of two disulfide-linked p35 and p40 subunits. The precursor form of the IL-12 p40 subunit (NM 002187; P29460; also referred to as IL12B, natural killer cell-stimulating factor 2, killer cell maturation factor 2) is 328 amino acids in length, whereas its mature form is 306 amino acids long. The precursor form of the IL-12 p35 subunit (NM_000882; P29459; also referred to as IL-12A, natural killer cell stimulatory factor 1, killer cell maturation factor 1) is 219 amino acids in length and the mature form is 219 amino acids in length. 197 amino acids long. Id. The genes for the IL-12 p35 and p40 subunits reside on different chromosomes and are regulated independently of each other. Gately, MK et al., Annu Rev Immunol. 16: 495-521 (1998). Many different immune cells (eg, dendritic cells, macrophages, monocytes, neutrophils, and B cells) produce IL-12 on antigenic stimuli. The active IL-12 heterodimer is formed after protein synthesis. id Because of its ability to activate both NK cells and cytotoxic T cells, the IL-12 protein has been studied as a promising anticancer therapeutic since 1994. See Nastala, C.L. et al., J Immunol 153: 1697-1706 (1994). But despite high expectations, early clinical studies did not produce satisfactory results. Lasek W. et al., Cancer Immunol Immunother 63: 419-435, 424 (2014). Repeated administration of IL-12, in most patients, led to an adaptive response and a progressive decrease in IL12-induced interferon gamma (IFNy) levels in the blood. Id. On the other hand, while it was recognized that IL-12-induced anticancer activity is largely mediated by secondary IFNγ secretion, the concomitant induction of IFNγ along with other cytokines (eg, TNF-α) or chemokines ( IP-10 or MIG) by IL-12 caused severe toxicity. id In addition to negative feedback and toxicity, the marginal efficacy of crfrcnn / Lznz / E / YiAi IL-12 therapy in clinical settings may be caused by the potent immunosuppressive environment in humans. Id. To minimize IFNγ toxicity and improve the efficacy of IL-12, the scientists tried different procedures, such as different dose and timing protocols for IL-12 therapy. See Sacco, S. et al., Blood 90: 4473-4479 (1997); Leonard, J.P. et al., Blood 90: 2541-2548 (1997); Coughlin, C.M. et al., Cancer Res. 57: 2460-2467 (1997); Asselin-Paturel, C. et al., Cancer 91: 113-122 (2001); and Saudemont, A. et al., Leukemia 16: 1637-1644 (2002). However, these procedures did not significantly impact patient survival. Kang, W.K., et al., Human Gene Therapy 12: 671-684 (2001). Membrane-anchored versions of IL-12 have been studied as a means of reducing toxicity associated with systemic administration, using retroviral and adenoviral vectors for expression in tumor cells. See Pan, W-Y. et al., Mol. ther. 20(5): 927-937 (2012). But, the use of viral vectors presents a potential health risk, since the underlying viruses may act as oncogenes and viral vectors may be immunogenic. Accordingly, in some embodiments, the immunomodulatory fusion proteins described herein comprise an IL-12 polypeptide operably linked to a collagen-binding domain. In some embodiments, ligation of an IL-12 polypeptide to a collagen-binding domain localizes the cytokine in a cell, and therefore prevents systemic toxicity. Furthermore, in some embodiments, when administered directly to a tumor or lesion, the collagen-binding domain localizes the cytokine to the tumor or lesion microenvironment, thereby preventing systemic toxicity. In some embodiments, the IL-12 polypeptide comprises IL-12A (eg, SEQ ID NO: 3). In some embodiments, the IL-12 polypeptide comprises IL-12B (eg, SEQ ID NO: 2). In some embodiments, the IL-12 polypeptide comprises both IL-12A and IL-12B. In some embodiments, IL-12B is located N-terminal to IL-12A in the IL-12 polypeptide. In some embodiments, IL-12A is located N-terminal to IL-12B in the IL-12 polypeptide. The phrase "located N-terminally to" indicates the location in a polypeptide relative to other sequences in the polypeptide relative to the N-terminal polypeptide. For example, IL-12B is "N-terminal to" IL-12A means that IL-12B is located closer to the N-terminus of the IL-12 polypeptide than IL-12A. In some embodiments, the IL-12 polypeptide comprises a single polypeptide chain comprising IL-12B and IL-12A, which are either directly fused together or ligated together by a linker (referred to herein as a "subunit linker"). ”). Non-limiting examples of linkers are described anywhere herein. In some embodiments, the IL-12 polypeptide of the disclosure comprises IL-12A and / or cebenn / ίζηζ / ε / γίΛΐ IL-12B that is a variant, that is a functional fragment, or that contains a substitution, insertion, and / or addition, deletion, and / or covalent modification with respect to an IL-12A or IL-12B sequence nature type. In some embodiments, amino acid residues located in the carboxy, amino terminus, or internal regions of the IL-12 polypeptide are detected, thereby providing fragments. In some embodiments, the IL-12 polypeptide comprises a variant substitution of an IL-12A and / or IL-12B amino acid sequence, which may comprise one, two, three, or more than three substitutions. In some embodiments, the substitution variant may comprise one or more conservative amino acid substitutions. In other embodiments, the variant is an insertion variant. In other embodiments, the variant is a deletion variant. As recognized by those skilled in the art, IL-12 protein fragments, functional protein domains, variants, and homologous (orthologous) proteins are also considered to be within the scope of IL-12 polypeptides of the disclosure. Non-limiting examples of IL-12 polypeptides suitable for use in the immunomodulatory fusion proteins described herein are set forth in SEQ ID NO: 2-3. In some embodiments, the immunomodulatory fusion protein comprises an IL-12 polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the immunomodulatory fusion protein comprises an IL-12 polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the immunomodulatory fusion protein comprises an IL-12 polypeptide comprising the amino acid sequences set forth in SEQ ID NOs: 2 and 3. Interleukin-15 (IL-15) In some embodiments, the immunomodulatory fusion protein comprises an IL-15 polypeptide operably linked to a collagen-binding domain, optionally via a linker. IL-15 is a member of the 4a-helix bundle family of cytokines and plays an important role in the development of an effective immune response. Waldmann, T.A., Cancer ImmunoL Res. 3: 219-227 (2015). IL-15 is essential for proper NK cell development and long-term maintenance of CD8+ memory T cells. The IL-15 gene encodes a 162 amino acid pre-protein that has a 48 amino acid signal peptide, with the mature protein being 114 amino acids in length. Bamford, R.N., et al., Proc. nati. Acad. Sci. USA 93: 2897-2902 (1996). See also, for example, GenBank Accession Numbers NM 000585 for the Homo sapiens IL15 transcript variant 3 mRNA sequence and NP 000576 for the corresponding IL15 isoform 1 pre-proprotein. IL-15 shares some structural similarity to interleukin-2 (IL-2). Similar to IL-2, IL-15 signals through the IL-2 receptor beta chain (CD122) and the common gamma chain (CD132). But unlike IL-2, IL-15 cannot effectively bind to CD122 and CD132 by cefrenn / Lznz / B / YiAi itself. IL-15 first binds to the IL-15 receptor alpha (IL-15Ra) subunit. The IL15Ra gene encodes a 267 amino acid pre-protein having a 30 amino acid signal peptide, with the mature protein being 237 amino acids in length. See, eg, GenBank Accession Numbers NM_002189 for the Homo sapiens IL-15Ra transcript variant 1 mRNA and NP 002180 for the Homo sapiens IL-15Ra isoform 1 precursor amino acid sequence. Human IL-15Ra is predominantly a transmembrane protein that binds IL-15 on the surface of cells such as activated dendritic cells and monocytes. Waldmann, T.A., Cancer Immunol. Res. 3: 219-227 (2015). The IL-15 / IL-15Ra membrane-binding complex then presents IL-15 in trans to the CD122 and CD132 subunits. Consequently, IL-15Ra is an essential component of IL-15 activity. To overcome the short half-life of systemically injected IL-15, precomplexing IL-15 with soluble recombinant IL-15Ra, resulting in the superagonist IL-15 (IL-15SA), has been shown to improve potency. IL-15 systemic injection by ~50-fold, and also increases the serum half-life of the cytokine after systemic injection to ~20 hrs. (Stoklasek et al., J Immunol 177(9):6072, 2006; Dubois et al., J Immunol 180(4);2099, 2008; Rubinstein et al. Proc Nati Acad Sci U SA 103(24):9166, 2006). Accordingly, in some embodiments, the immunomodulatory domain of the immunomodulatory fusion protein is an IL-15 polypeptide. In some embodiments, the IL-15 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the IL-15 polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the IL-15 polypeptide IL-15 is an IL-15 superagonist, comprising IL-15 and IL-15Ra. In some embodiments, the IL-15 superagonist comprises the amino acid sequences set forth in SEQ ID NOs: 4 and 5. B. Interferons In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an interferon (IFN). Interferons comprise a family of secretory proteins induced in response to specific extracellular stimuli through the stimulation of tol-like receptors (TLRs). In some modalities, interferons increase the antiviral defenses of the immune system (eg, antigen presentation). Through high affinity cell surface receptors, IFNs stimulate the genes that signaling molecules use. Interferons suitable for use as an immunomodulatory fusion domain of immunomodulatory fusion proteins include, but are not limited to: IFN-gamma and IFN-alpha. In some embodiments, the immunomodulatory fusion protein comprises a cefrenn / Lznz / B / YiAi IFN-gamma polypeptide operably linked to a collagen binding domain. IFNgamma is produced by a variety of immune cells, such as activated T cells and NK cells. IFN-gamma interacts with a specific receptor on the cell surface and activates signal transduction pathways that produce immunomodulatory effects. Accordingly, in some embodiments, the immunomodulatory domain is an IFNgamma polypeptide. In some embodiments, the IFN-gamma polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the immunomodulatory fusion protein comprises an IFN-alpha polypeptide operably linked to a collagen-binding domain. IFN-alpha is produced by B lymphocytes, null lymphocytes, and macrophages, and activates NK cells, which have antiviral and antitumor activities. Accordingly, in some embodiments, the immunomodulatory domain is an IFN-alpha polypeptide. In some embodiments, the IFN-alpha polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 6. C. Immune Cell Differentiation Stimulating Factors In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an immune cell differentiation-stimulating factor. In some embodiments, immune cell differentiation-stimulating factors activate intracellular signaling pathways that drive the differentiation, development, and proliferation of hematopoietic progenitor cells into specific subtypes of immune cells. Immune cell differentiation-stimulating factors suitable for use in the immunomodulatory fusion proteins described herein include, but are not limited to: GM-CSF (granulocyte-macrophage colony-stimulating factor), G-CSF (granulocyte-macrophage colony-stimulating factor), from granulocyte colonies), and FLT3L (FMS-like tyrosine kinase ligand 3). In some embodiments, the immunomodulatory domain is a GM-CSF polypeptide. GM-CSF is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, NK cells, endothelial cells, and fibroblasts. In addition to having a growth stimulating and differentiating role in hematopoietic precursor cells, GM-CSF has a variety of effects on immune cells that express the GM-CSF receptor. In some embodiments, the GM-CSF polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the immunomodulatory domain is an FLT3L polypeptide. FLT3 is a receptor tyrosine kinase (RTK) that is expressed by immature hematopoietic stem cells. FLT3L is a transmembrane protein or soluble protein and is expressed by a large number of cells, including hematopoietic cells and stromal cells in the bone marrow. In combination with other growth factors, FLT3L stimulates the proliferation and development of various cell types, including myeloid and lymphoid cefrenn / Lznz / B / YiAi precursor cells, dendritic cells, and NK cells. In some embodiments, the FLT3L polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the immunomodulatory domain is a G-CSF polypeptide. In some embodiments, G-CSF regulates the proliferation, differentiation, and functional activation of neutrophilic granulocytes. In some embodiments, the G-CSF polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 29. D. Chemokines In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is a chemokine. In some embodiments, chemokines are proteins that induce targeted chemotaxis of a responsive cell (eg, leukocytes). In general, chemokines are grouped into four subfamilies: CXC, CC, (X)C, and CX3C. In CXC chemokines, an amino acid separates the first two cisternae ("the CXC motif"). ELR+ CXC chemokines are ligands for the chemokine receptors CXCR1 and / or CXCR2, which are G protein-coupled seven transmembrane domain-type receptors that specifically bind ELR+ CXC chemokines. The seven human CXC ELR+ chemokines are human Gro-alpha (also known as CXCL1), human Gro-beta (also known as CXCL2), human Gro-gamma (also known as CXCL3), human ENA-78 (also known as CXCL5) , human GCP-2 (also known as CXCL6), human NAP-2 (also known as CXCL7), and human IL-8 (also known as CXCL8). All ELR+ CXC chemokines bind to the CXCR2 receptor; on the other hand, some CXC ELR+ chemokines bind to both CXCR1 and CXCR2 receptors (ie, CXCL6 and CXCL8), all of which contribute to redundancy in activation pathways. The five murine ELR+ CXC chemokines are keratinocyte (KC) chemoattractants (also known as CXCL1), Macrophage Inflammatory Protein 1 (MIP-2) (also known as CXCL2), dendritic cell inflammatory protein 1 (DCIP-1) (also known as known as CXCL3), lipopolysaccharide (LIX)-induced CXC chemokine (also known as CXCL5), and neutrophil activator peptide-2 (NAP-2) (also known as CXCL7). Chemokines suitable for use in the immunomodulatory fusion protein described herein include, but are not limited to: LIF, M-CSF, MIP-2, MIP-1beta, KP (CXLC1), MIG (CXCL9), IP- 10 (CXCL10), MCP-1, eotaxin, RANTES, LIX, and MIP-1alpha. Amino acids encoding exemplary chemokines suitable for use as an immunomodulatory domain for the immunomodulatory fusion protein described herein are set forth below: cebenn / Lznz / B / YiAi Chemokine Amino acid sequence (SEQ ID NO ) LIF 30 M-CSF 31 MIP-2 32 MIP-1beta 33 KP (CXCL1) 34 MIG (CXCL9) 35 IP-10 (CXCL10) 36 MCP-1 37 Eotaxin 38 RANTES 39 LIX 40 MIP-1 alpha 41 cebenn / lzoz / b / yiai E. Tumor Necrosis Factor (TNF) Superfamily In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an extracellular domain from a member of the tumor necrosis factor (TNF) superfamily. The tumor necrosis factor superfamily of ligands and receptors are a series of structurally homologous cell surface proteins that signal through the formation of trimeric clusters of ligand-receptor complexes. Ligation of activation of TNF superfamily receptors can lead to a wide range of pro-immune responses, including proliferation, enhanced effector function, and chemokine and cytokine production. Some ligands, such as Fas, can lead to the induction of apoptosis and are expressed on the surface of immune cells. Additionally, other ligands function as inhibitory receptors that weaken the immune response. In some embodiments, the extracellular domain is derived from: TNF-alpha, LIGHT, LT-alpha, LT-beta, BTLA, CD160, CD40L, FasL, CD30L, 4-1 BBL, CD27L, OX40L, TWEAK, APRIL, BAFF, RANKL, TRAIL, EDA1, EDA2, or GITRL. The extracellular domain is capable of binding the receptor of the superfamily member selected TNF, thereby inducing or stimulating an immune response. The following table shows the receptor that corresponds to the derived extracellular domain: Ligand Receptor Amino acid sequence of the ligand extracellular domain (SEQ ID NO) TNF-alpha TNFR1, TNFR2 51 LIGHT HEVM, LT-betaR 52 LT-alpha TNFR1, TNFR2, HEVM 53 LT-beta LT-BetaR 54 CD160 HVEM 56 CD40L CD40 57 FasL Fas 58 CD30L CD30 59 4-1 BBL 4-1BB 60 CD27L CD27 61 OX40L 0X40 62 TWEAK Fn14 63 APRIL BCMA, TACI 64 BAFF BCMA, TACI, BAFFR 65 RANKL RANK, OPG 66 TRAIL OPG, TRAIL R1 (DR4), TRAIL R2 (DR5), DcR1, DcR2 67 EDA1 EDAR 68 EDA2 XEDAR 69 GITRL GITR 70 cefrenn / Lznz / B / YiAi F. CD2 Family In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an extracellular domain from a member of the CD28 family. The CD28 family is a family of inhibitory (PD1, CTLA-4) and activation (CD28, ICOS) receptors that bind to members of the B7 family of ligands. CD28 is a costimulatory receptor that provides the second signal required to activate native T cells (along with TCR ligation) and has two natural ligands, CD80 and CD86. CD28 signaling may serve to increase proliferation, effector function, and anti-apoptotic signaling. CD28 signaling has recently been shown to be required in effective PD1 / PDL1 blockade. ICOS (Inducible T Cell Co-stimulatory) is a closely related surface receptor that is expressed on activated T cells and shows similar functions as CD28. Accordingly, in some embodiments, the immunomodulatory domain is an extracellular domain of CD80 (B7-1). In some embodiments, the immunomodulatory domain comprises the amino acid sequence set forth in SEQ ID NO: 71. Accordingly, in some embodiments, the immunomodulatory domain is an extracellular domain of CD86 (B7-2), capable of binding to CD28. In some embodiments, the immunomodulatory domain comprises the amino acid sequence set forth in SEQ ID NO: 72. Accordingly, in some embodiments, the immunomodulatory domain is an extracellular domain of ICOSLG. In some embodiments, the immunomodulatory domain comprises the amino acid sequence set forth in SEQ ID NO: 73. G. Agonist Antibodies In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or an antigen-binding fragment thereof. Agonist antibodies activate their target of interest, in contrast to antagonist antibodies that block their target's function. In some embodiments, agonist antibodies, or antigen-binding fragments thereof, bind to immune activating receptors. In some embodiments, immune activation receptors include, but are not limited to: tumor necrosis factor (TNF) receptors, CD28 family members, T cell receptors (TCRs), Killer Cell Ig-Like receptors (KIRs) , Leukocyte Ig-like receptors (LIRs), CD94 / NKG2 receptors, Fe receptors, signaling lymphocyte activation molecules (SLAMs), and Siglec activation receptors. Tumor Necrosis Factor (TNF) suDerfamily In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to a factor superfamily member receptor. of tumor necrosis (TNF). The TNF superfamily is described supra. For example, in some embodiments, the immunomodulatory domain is an agonist antibody, or antigen-binding fragment, that binds to TNFR1, thereby activating the receptor. The following table provides a list of TNF superfamily member receptor agonist antibodies, or antigen-binding fragments thereof, can be generated to target, suitable for use in the immunomodulatory fusion protein described herein. : cefrenn / Lznz / B / YiAi Ligand Receptor Uniprot KB Receptor TNF-alpha TNFR1 P19438 TNFR2 P20333 LIGHT HEVM Q92956 LT-betaR Q06643 LT-alpha TNFR1 P19438 TNFR2 P20333 HEVM Q92956 LT-beta LT-BetaR Q06643 CD160 HVEM Q 92956 CD40L CD40 P25942 FasL Fas P25445 CD30L CD30 P28908 4-1BBL 4-1BB Q07011 CD27L CD27 P26842 OX40L 0X40 P43489 TWEAK Fn14 Q9NP84 APRIL BCMA Q02223 TACI 014836 BAFF BCMA Q02223 TACI 014836 BAFFR Q96RJ3 RANKL RANK Q9Y6Q6 OPG 000300 TRAIL OPG 000300 TRAIL R1 (DR4) 000220 TRAIL R2 (DR5) 014763 DcR1 014798 DcR2 Q9UBN6 EDA1 EDAR Q9UNE0 EDA2 X WWTP Q9HAV5 GITRL GITR Q9Y5U5 cefrenn / ίζηζ / Β / γίΛΐ In some embodiments, the immunomodulatory domain is an anti-4-1BB agonist antibody. In some embodiments, the immunomodulatory domain is an anti-0X40 agonist antibody. In some embodiments, the immunomodulatory domain is a CD40 agonist antibody. CD28 Receptor Superfamily In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to a CD28 superfamily receptor. The CD28 superfamily is described supra. For example, in some embodiments, the immunomodulatory domain is an agonist antibody, or antigen-binding fragment, that binds to CD28, thereby activating the receptor. The following table provides a list of CD28 superfamily member receptors, agonist antibodies, or antigen-binding fragments thereof, which can be generated to the target, suitable for use in the immunomodulatory fusion protein described herein: Ligand Receptor Uniprot KB receptor CD80 (B7-1) CD28 P10747 CD86 (B7-2) CD28 P10747 ICOSLG ICOS Q9Y6W8 T-Cell Receptor (TCR) Complex In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to a T-Cell Receptor (TCR) complex. . The T Cell Receptor (TCR) is the cell surface receptor responsible for imparting antigenic specificity to T cells. Each TCR is specific for a particular peptide presented by either MHC Class I (for CD8+ T cells) or MHC Class II (for CD4+ T cells). For naïve T cells, TCR ligation provides the first of two signals required to activate the T cell. TCR ligation of CD8+ T cells leads to death of the cell displaying the cognate pMHC (and potentially cells). transients) through the release of soluble factors, such as perforin and granzyme B, as well as upregulation of apoptosis-inducing ligands, such as Fas ligand. For CD4+ helper T cells, ligation of the TCR to its cognate pMHC results in the release of cytokines. Accordingly, in some embodiments, the immunomodulatory domain is an agonist antibody, or antigen-binding fragment thereof, that binds to a TCR. For example, in some embodiments, the immunomodulatory domain is an agonist antibody, or antigen-binding fragment, that binds to CD3y, thereby activating the receptor. The following table provides a list of members of the TCR complexes, agonist antibodies, or antigen-binding fragments thereof, which can be generated to the target, suitable for use in the immunomodulatory fusion protein described herein: cefrenn / ίζηζ / Β / γίΛΐ TCR Binder TCR Complex Member KB Uniprot Member pMHC CD3y P09693 pMHC CD35 P04234 pMHC CD3C P20963 pMHC CD3s P07766 Killer Cell-Like Receptor (KIR) In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to a Killer Cell Ig-Like Receptor ( KIR). Killer cell immunoglobulin-like receptor (KIR) is a family of receptors expressed primarily on NK cells and some subsets of T cells. These receptors are primarily responsible through receptor recognition (and thus function). inhibitory), by binding to MHC class I molecules (HLA-A, HLA-B, and HLA-C). These receptors can be either activating or inhibitory, depending on the length of the cytoplasmic tail. Inhibitory receptors have a longer tail and contain an ITIM domain. Activation KIRs have a shorter cytoplasmic domain and associate with DAP12 to mediate signaling. Activation KIRs are provided in the following table, in which agonist antibodies, or antigen-binding fragments thereof, can be generated to the target, suitable for use in the immunomodulatory fusion protein described herein: cefrenn / ίζηζ / Β / γίΛΐ Ligand Receptor Uniprot KB Receptor HLA KIR 2DS1 Molecules Q14954 HLA KIR 2DS2 Molecules P43631 HLA KIR 2DS3 Molecules Q14952 HLA KIR 2DS4 Molecules P43632 HLA KIR 2DS5 Molecules Q14953 HLA KIR3DS1 Q14943 Molecules Leukocyte-Like Receptor (LIR) In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to a leukocyte Ig-like receptor (LIR). . LIR receptors are a class of immune receptors expressed primarily on innate immune cells. Its main ligand is MHC Class I molecules and they largely show inhibitory functions, although some have activation functions. LIRA2, for example, acts as an innate sensor for immunoglobulin fragments that have been cleaved by microbial proteases. In some embodiments, the immunomodulatory domain is an agonist antibody, or an antigen-binding fragment thereof, that binds to LIRA2. In some embodiments, antibodies capable of binding to LIRA2 can be generated based on Uniprot ID Q8N149. CD94 / NKG2 Receptor Family In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to a CD94 / NKG2 receptor. CD94 / NKG2 are heterodimeric C-type lectin receptors that are expressed on the surface of NK cells and some subsets of CD8 T cells. They bind to HLA-E molecules (non-classical MHC Class I molecules), and can transmit both inhibitory and activation signals to NK cells. Inhibitory receptors contain ITIM domains in their cytoplasmic tails, while activating receptors associate with DAP12 and DAP10 containing ITAM domains. The activating CD94 / NKG2 receptors are provided in the table below, in which agonist antibodies, or antigen-binding fragments thereof, can be generated to the target, suitable for use in the immunomodulatory fusion protein described in the table below. present. In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an extracellular domain of a CD94 / NKG2 ligand. The following table shows the receptor that corresponds to the derived extracellular domain. cebenn / ίζηζ / Β / γίΛΐ Ligand Receptor Uniprot KB Receptor Amino acid sequence of the ligand extracellular domain (SEQ ID NO) MICA CD94 Q13241 74 NKG2D P26718 MICB CD94 Q13241 75 NKG2D P26718 ULBP1 CD94 Q13241 76 NKG2D P26718 ULBP2 CD94 Q132 41 77 NKG2D P26718 ULBP3 CD94 Q13241 78 NKG2D P26718 ULBP4 CD94 Q13241 79 NKG2D P26718 ULBP5, isoform 1 CD94 Q13241 80 NKG2D P26718 ULBP5, isoform 2 CD94 Q13241 81 NKG2D P26718 ULBP6 NKG2D P26718 82 NKG2C P26717 NKG2E Q 07444 NKG2H 043908 CD94 Q13241 Faith Receivers In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to an Fe receptor. Fe receptors are receptors for immune cells expressed primarily in innate immune cells that bind to the constant region of antibodies and induce a wide range of functions. Fe receptors are almost exclusively activated (except for FcyRIIB, which transmits inhibitory signals). Fe receptor ligation can lead to ADCC, phagocytosis, degranulation, and transmission of activation signals that increase effector function. cefrenn / lzoz / b / yiai The following table provides a list of F receptor agonist antibodies, or antigen-binding fragments thereof, can be generated to target, suitable for use in the immunomodulatory fusion protein described herein: Ligand Receptor Uniprot KB Receptor igG FcyRI P12314 igG FcyRIIC P31995 igG FcyRI HA P12318 igG FcyRIHB P31994 igE FceRI P30273 igE FceRH P06734 igA FcaR P24071 IgA / lgM FcpR Q8WWV6 Signaling Lymphocyte Activation Molecules (SLAM) In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to a signaling lymphocyte activation molecule receptor ( SLAM). SLAM receptors are a series of molecules that function both as receptors and ligands. SLAM molecules interact with each other in adjacent cells to send either activation or inhibitory signals. SLAM molecules that contain immunoreceptor tyrosine-based switch motifs in their cytoplasmic tails allow them to associate with both activating and inhibitory signaling molecules intracellularly. The following table provides a list of SLAM receptors that agonist antibodies, or antigen-binding fragments thereof, can be generated to target, suitable for use in the immunomodulatory fusion protein described herein. In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an extracellular domain of a SLAM ligand. The following table shows the receptor that corresponds to the derived extracellular domain. Ligand Receptor Uniprot KB Receptor Amino acid sequence of the ligand extracellular domain (SEQ ID NO) SLAMF1 SLAMF1 Q13291 83 SLAMF2 SLAMF2 P09326 84 SLAMF3 SLAMF3 Q9HBG7 85 SLAMF4 SLAMF4 Q9BZW8 86 SLAMF5 SLAMF5 Q9UIB8 87 SLAMF6 SLAMF 6 Q96DU3 88 SLAMF7 SLAMF7 Q9NQ25 89 cefrenn / lzoz / b / yiai Siglec Family Receptors In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an agonist antibody, or antigen-binding fragment thereof, that binds to a receptor from a Siglec family. Siglecs are a family of surface receptors found primarily on immune cells that are part of the lectin (sugar binding protein) family. These receptors bind to ligands containing sialic acid. These receptors function primarily as inhibitory receptors on a wide range of immune cell types, although some (siglec 14, 15, and 16) contain an ITAM activation domain. Activating Siglec receptors are provided in the following table, in which agonistic antibodies, or antigen-binding fragments thereof, can be generated to the target, suitable for use in the immunomodulatory fusion protein described herein: Receiver KB Uniprot Receiver Siglec 14 Q08ET2 Siglec 15 Q6ZMC9 Siglec 16 A6NMB1 H. Antagonistic Antibodies In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof. Antagonistic antibodies block the function of their target. In some embodiments, the antagonistic antibodies, or antigen-binding fragments thereof, bind to inhibitory immune receptors, thereby allowing the induction of an immune response. In some embodiments, the antagonistic antibodies, or antigen-binding fragments thereof, bind to the immune inhibitory ligands, thereby allowing the induction of an immune response. In some embodiments, immune inhibitory receptors and ligands include, but are not limited to: CD28 receptors, tumor necrosis factor (TNF) superfamily receptors, Siglec receptors, CD94 / NKG2 receptors, Leukocyte Ig-like receptors (LIRs ), Killer Cell Ig-like receptors (KIRs), Fe receptors, adenosine pathway molecules, other checkpoint inhibitors, and LAIR1. CD28 molecules In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds to a CD28 molecule. As described supra, the CD28 family includes both activating and inhibitory molecules. Accordingly, in some embodiments, antagonism of inhibitory molecules results in induction or stimulation of immune responses. The following table provides a list of CD28 molecules that antagonistic antibodies, or antigen-binding fragments thereof, can be generated to target, suitable for use in the immunomodulatory fusion protein described herein. cebenn / Lznz / B / YiAi Molecule Molecule Uniprot KB PD1 Q15116 PDL1 Q9NZQ7 PDL2 Q9BQ51 CTLA-4 P16410 B7-H4 Q7Z7D3 B7-H3 Q5ZPR3 In some embodiments, the immunomodulatory domain is an antagonistic antibody, or antigen-binding fragment thereof, that binds PD-1. In some embodiments, the immunomodulatory domain is an antagonistic antibody, or antigen-binding fragment thereof, that binds PD-L1. In some embodiments, the immunomodulatory domain is an antagonistic antibody, or antigen-binding fragment thereof, that binds CTLA-4. Molecules of the TNF Superfamily In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds to a member of the TNF superfamily. As described supra, the TNF superfamily includes both activating and inhibitory molecules. Accordingly, in some embodiments, antagonism of inhibitory molecules results in induction or stimulation of immune responses. The following table provides a list of TNF superfamily molecules that can be targeted by antagonistic antibodies, or antigen-binding fragments thereof, suitable for use in the immunomodulatory fusion protein described herein. cefrenn / ίζηζ / Β / γίΛΐ Molecule Molecule Uniprot KB TIGIT Q495A1 BTLA Q7Z6A9 Siglec Receivers In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds to a Siglec receptor. As described supra, the Siglec family includes both activating and inhibitory molecules. Accordingly, in some embodiments, antagonism of inhibitory molecules results in induction or stimulation of immune responses. The following table provides a list of Siglec receptor antagonist antibodies, or antigen-binding fragments thereof, can be generated to target, suitable for use in the immunomodulatory fusion protein described herein. Receiver Receiver Uniprot KB Siglec 1 (siualaddition) Q9BZZ2 Siglec 2 (CD22) P20273 Siglec 3 (CD33) P20138 Siglec 4a (MAG) P20916 Siglec 5 015389 Siglec 6 043699 Siglec 7 Q9Y286 Siglec 8 Q9NYZ 4 Siglec 9 Q9Y336 Siglec 10 Q96LC7 Siglec 11 Q96RL6 Siglec 12 Q96PQ1 CD94 / NKG2 receptors In some embodiments, the immunomodulatory domain suitable for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds CD94 / NKG2 receptors. As described supra, the CD94 / NKG2 family includes both activating and inhibitory molecules. Accordingly, in some embodiments, antagonism of inhibitory molecules results in induction or stimulation of immune responses. Accordingly, in some embodiments, the immunomodulatory domain is an antagonistic antibody, or antigen-binding fragment thereof, that binds CD94 / NKG2A. In some embodiments, these antibodies are generated based on UniProt ID P26715. In some embodiments, the immunomodulatory domain is an antagonistic antibody, or antigen-binding fragment thereof, that binds CD94 / NKG2B. In some embodiments, these antibodies are generated based on UniProt ID Q13241. Leukocyte / q-Like Receptors (LIRs) In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds to Leukocyte Ig-Like Receptors (LIRs). As described supra, the LIR family includes both activating and inhibitory molecules. Accordingly, in some embodiments, antagonism of inhibitory molecules results in induction or stimulation of immune responses. The following table provides a list of LIRs that antagonistic antibodies, or antigen-binding fragments thereof, can be generated to target, suitable for use in the immunomodulatory fusion protein described herein. cebenn / Lznz / B / YiAi Receiver KB Uniprot Receiver LIRB1 Q8NHL6 LIRB2 Q8N423 LIRB3 075022 LIRB4 Q8NHJ6 Killer Cell / q-Like Receptors (KIRs) In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds to a Killer Cell Ig-Like Receptor (KIR). ). As described supra, the KIR family includes both activating and inhibitory molecules. Accordingly, in some embodiments, antagonism of inhibitory molecules results in induction or stimulation of immune responses. The following table provides a list of KIRs that antagonistic antibodies, or antigen-binding fragments thereof, can be generated to target, suitable for use in the immunomodulatory fusion protein described herein. cefrenn / Lznz / B / YiAi Receiver KB Uniprot Receiver KIR2DL1 P43626 KIR 2DL2 P43627 KIR 2DL3 P43628 KIR 2DL4 Q99706 KIR 2DL5A Q8N109 KIR2DL5B Q8NHK3 KIR3DL1 P43629 KIR3DL2 P43630 KIR3DL3 Q8N743 Faith receptors In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds to an Fe receptor. As described supra, the The Fe family of receptors includes both activating and inhibitory molecules. Accordingly, in some embodiments, antagonism of inhibitory molecules results in induction or stimulation of immune responses. In some embodiments, the inhibitory Fc receptor is FcyRIlB. In some embodiments, the immunomodulatory domain is an antagonistic antibody, or antigen-binding fragment thereof, that binds FcyRIlB. In some embodiments, these antibodies are generated based on UniProt ID P31994. Molecules of the Adenosine Pathway In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds to a member of the adenosine pathway. For example, CD39 and CD73 are enzymes expressed on the cell surface that catalyze the conversion of ATP to adenosine. Extracellular ATP is a dangerous molecule that elicits an immune response, while adenosine is immunosuppressive. These molecules contribute to an immunosuppressive environment locally by generating adenosine. Accordingly, in some embodiments, the immunomodulatory domain is an antagonistic antibody, or antigen-binding fragment thereof, that binds CD39. In some embodiments, these antibodies are generated based on UniProt ID P49961. In some embodiments, the immunomodulatory domain is an antagonistic antibody, or antigen-binding fragment thereof, that binds CD73. In some embodiments, these antibodies are generated based on UniProt ID P21589. Other Checkpoint Inhibitors In some embodiments, the suitable immunomodulatory domain for use in the immunomodulatory fusion proteins of the present disclosure is an antagonistic antibody, or antigen-binding fragment thereof, that binds to an immune checkpoint inhibitor. In some embodiments, by antagonizing these immune checkpoint inhibitors, an immune response is induced or stimulated. The following table provides a list of immune checkpoint inhibitors that antagonistic antibodies, or antigen-binding fragments thereof, can be generated to target, suitable for use in the immunomodulatory fusion protein described herein. cefrenn / lzoz / b / yiai Molecule Molecule Uniprot KB VISTA Q9H7M9 TIM-3 Q8TDQ0 LAG-3 P18627 CD47 Q08722 SIRPa P78324 III Liquators In some embodiments, the immunomodulatory fusion protein comprises an immunomodulatory domain operably linked to a collagen binding protein through a linker. In some embodiments, the linker between the immunomodulatory domain and the collagen binding protein provides steric separation such that the immunomodulatory domain retains its activity (eg, promotes receptor / ligand coupling). In some embodiments, the linker between the immunomodulatory domain and the collagen binding protein is of sufficient length or mass to reduce adsorption of the immunomodulatory domain to collagen fibrils. Methods for measuring adsorption are known to those of skill in the art. For example, adsorption can be measured by ellipsometry (ELM), surface plasmon resonance (SPR), optical waveguide light mode spectroscopy (OWLS), attenuated total internal infrared reflectance (ATR-IR) spectroscopy. circular dichroism (CD), total internal infrared reflectance (TIRF) spectroscopy, and other high-resolution microscopy techniques. In some embodiments, these methods show the spatial arrangement between domains of the immunomodulatory fusion protein. In some embodiments, the linker between the immunomodulatory domain and the collagen binding protein provides sufficient molecular weight to slow or reduce tissue diffusion. Methods for measuring tissue diffusion are known to those of skill in the art. For example, diffusion can be measured by in vivo imaging, or through microscopy of tissue sections over time. Exemplary methods are described in at least Schmidt and Wittrup, Mol Cañe Ther. 2009' and Wittrup et al. Methods in Enzymol 2012, each of which is incorporated herein by reference in its entirety. In some embodiments, the linker is a hydrophilic peptide comprising amino acids "N" in length, where N=1-1000, 50-800, 100-600, or 200-500. A. Serum Albumin In some embodiments, the linker is a serum albumin, or fragments thereof. Methods for using serum albumin to proteins are described, for example, US2010 / 0144599, US2007 / 0048282 and US2011 / 0020345, which are incorporated herein by reference in their entirety. In some embodiments, the linker is human serum albumin (HSA), or variants or fragments thereof, such as those described in US 5,876,969, WO 2011 / 124718, WO 2013 / 075066 and WO 2011 / 0514789. Albumins suitable for use in immunomodulatory fusion proteins can be from human, primate, rodent, bovine, equine, donkey, rabbit, goat, sheep, dog, chicken, or pig. In some embodiments, the albumin is serum albumin, eg, a human serum albumin (SEQ ID NO: 42, primate serum albumin (eg, chimpanzee serum albumin, gorilla serum albumin), rodent serum (for example, hamster serum albumin), guinea pig serum albumin, mouse serum albumin, and rat serum albumin), bovine serum albumin, equine serum albumin, donkey, rabbit serum albumin, goat serum albumin, sheep serum albumin, dog serum albumin, chicken serum albumin and pig serum albumin. In some embodiments, the albumin, or variant or fragment thereof, has a sequence identity to the wild-type HSA sequence as set forth in SEQ ID NO: 42 of at least 50%, such as at least 60%, at least 70%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, the number of alterations, eg substitutions, insertions or deletions, in albumin variants is 1-20, eg 1-10 and 1-5, such as 1, 2, 3, 4, 5 , 6, 7, 8, 9, or 10 alterations compared to corresponding cefrenn / Lznz / B / YiAi wild-type albumin (eg, HSA). In some embodiments, albumin fragments, or variant fragments thereof, are suitable for use in immunomodulatory fusion proteins. Exemplary albumin fragments are described in WO 2011 / 124718. In some embodiments, an albumin fragment (eg, an HSA fragment) is at least 20 amino acids in length, such as at least 40 amino acids, at least 60 amino acids, at least 80 amino acids, at least 100 acidic amino acids, at least 150 amino acids, at least 200 amino acids, at least 300 amino acids, at least 400 amino acids, or at least 500 amino acids in length. In some embodiments, an albumin fragment may comprise at least an entire albumin subdomain. HSA domains have been expressed as recombinant proteins (Dockal et al. JBC 1999;274:9303-10), where domain I was defined as consisting of amino acids 1-197 (SEQ ID NO: 116), domain II was was defined as consisting of amino acids 189-385 (SEQ ID NO: 117), and domain III was defined as consisting of amino acids 381-585 (SEQ ID NO: 118) of HSA (SEQ ID NO: 42). The overlap of the domains occurs because of the extended ot-helix structure (h10-h1) that exists between domains I and II, and between domains II and III (Peters, 1996, op. cit, Table 2-4 ). HSA also comprises six subdomains (IA, IB, NA, NB, INA, and NIB subdomains). The IA subdomain comprises amino acids 6-105, the IB subdomain comprises amino acids 120-177, the NA subdomain comprises amino acids 200-291, the NB subdomain comprises amino acids 316-369, the INA subdomain comprises amino acids 392-491 and the NIB subdomain comprises amino acids 512-583 of SEQ ID NO: 42. In some embodiments, a fragment comprises all or part of one or more domains or subdomains as defined above, or any combination of those domains and / or subdomains. In some embodiments, an albumin fragment comprises at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% of an albumin or albumin domain, or a variant or fragment of it. B. Faith Domains In some embodiments, the suitable linker for use in the immunomodulatory fusion protein described herein is an Fc domain. In some embodiments, the Fc domain is a component of the agonist or antagonist antibodies described supra, and thus an Fc domain. Separate faith is not necessary. In certain embodiments, the Fe domain comprises the amino acid sequence set forth in SEQ ID NO: 115. In some embodiments, the Fe domain does not contain an antigen-binding variable region. In some embodiments, the Fe domain contains a variable region that binds antigen. Suitable Fe domains for the immunomodulatory cefrenn / Lznz / B / YiAi fusion proteins described herein can be obtained from a variety of different sources. In certain embodiments, an Fe domain is derived from a human immunoglobulin. In certain embodiments, the Fe domain is from a human IgG1 constant region. The Fe domain of human IgG1 is set forth in SEQ ID NO: 115. It is understood, however, that the Fe domain may be derived from an immunoglobulin from another mammalian species, including, for example, a rodent (eg, a mouse). , rat, rabbit, guinea pig) or non-human primate species (eg, chimpanzee, macaque). Moreover, the Fe domain or portion thereof can be derived from any of the immunoglobulin class, including IgM, IgG, IgD, IgA, and IgE, and any immunoglobulin isotype, including IgG1, IgG2, IgG3, and igG4. In some embodiments, the immunomodulatory fusion protein comprises a mutant Fc domain. In some embodiments, the immunomodulatory fusion protein comprises a mutant, IgG1 Fe domain. In some embodiments, a mutant Fe domain comprises one or more mutations in the hinge, CH2, and / or CH3 domains. In some aspects, a mutant Fe domain includes a D265A mutation. A variety of Fc domain gene sequences (eg, mouse and human constant region gene sequences) are available in the form of publicly accessible repositories. Constant region domains comprising an Fc domain sequence lacking a particular effector function and / or with a particular modification to reduce immunogenicity may be selected. Many sequences of antibodies and antibody-coding genes have been published and suitable Fe domain sequences (eg, hinge, CH2, and / or CH3 sequences, or portions thereof) can be derived from these sequences using art-recognized techniques. field. Genetic material obtained using any of the above methods can then be altered or synthesized to obtain polypeptides suitable for use in the methods described herein. It will further be appreciated that the scope of this disclosure encompasses alleles, variants, and mutations of the constant region DNA sequences. Fe domain sequences can be cloned, for example, using the polymerase chain reaction and primers that are selected to amplify the domain of interest. To clone an Fc domain sequence of an antibody, mRNA can be isolated from hybridoma, spleen, or lymphatic cells, reverse transcribed into DNA, and antibody genes amplified by PCR. PCR amplification methods are described in detail in US Patent Nos. 4,683,195; 4,683,202; 4,800,159; 4,965,188; and in, for example, "PCR Protocols: A Guide to Methods and Applications" Innis et al., eds., Academic Press, Diego, Calif. (1990); Ho and collaborators. 1989. Gene 77:51; Horton et al. 1993. Methods Enzymol. 217:270. PCR can be initiated by the consensus constant region primers or by more specific primers based on the published cebenn / Lznz / B / YiAi heavy and light chain DNA and amino acid sequences. As discussed above, PCR can also be used to isolate DNA clones encoding antibody heavy and light chains. In this case, libraries can be sorted by consensus primers or larger homologous probes, such as mouse constant region probes. Numerous primer sets suitable for amplification of antibody genes are known in the art (eg, 5' primers based on the N-terminal sequence of purified antibodies (Benhar and Pastan. 1994. Protein Engineering 7:1509). Rapid amplification of cDNA ends (Ruberti, F. et al. 1994. J. Immunol. Methods 173:33) Antibody leader sequences (Larrick et al. Biochem Biophys Res Commun 1989; 160:1250). antibody sequences are further described by Newman et al. US Patent No. 5,658,570, filed January 25, 1995, which is incorporated herein by reference. In some embodiments, the disclosed immunomodulatory fusion protein comprises one or more Fe domains (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more Fe domains). In certain embodiments, the Fe domains may be of different types. In certain embodiments, at least one Fc domain present in the immunomodulatory fusion protein comprises a hinge domain or portion thereof. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain comprising at least one CH2 domain or portion thereof. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain comprising at least one CH3 domain or portion thereof. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain comprising at least one CH4 domain or portion thereof. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fc domain comprising at least one hinge domain or portion thereof and at least one CH2 domain or portion thereof (eg, in the hinge-CH2 orientation). In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain comprising at least one CH2 domain or portion thereof and at least one CH3 domain or portion thereof (eg, in the CH2-CH3 orientation). In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain comprising at least one hinge domain or portion thereof, at least one CH2 domain or portion thereof, and at least one CH3 domain or portion thereof, for example in the Hinge-CH2-CH3, HingeCH3-CH2 or CH2-CH3-Hinge orientation. In certain embodiments, the immunomodulatory fusion protein comprises at least one full-length Fc region derived from one or more immunoglobulin heavy chains (for example, an Fc domain that includes the hinge, CH2, and CH3 domains, although these need not be derived therefrom). antibody). In certain embodiments, the immunomodulatory cefrenn / ίζηζ / Β / γίΛΐ fusion protein comprises at least two complete Fc domains derived from one or more immunoglobulin heavy chains. In certain embodiments, the entire Fe domain is derived from a human IgG immunoglobulin heavy chain (eg, human IgG1). In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain that comprises a complete CH3 domain. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain that comprises a complete CH2 domain. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain comprising at least one CH3 domain, and at least one of a hinge region, and a CH2 domain. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain comprising a hinge and CH3 domain. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain comprising a hinge, CH2 and CH3 domain. In certain embodiments, the Fe domain is derived from a human IgG immunoglobulin heavy chain (eg, human IgG1). The constant region domains or portions thereof that constitute an F domain of the immunomodulatory fusion protein can be derived from different immunoglobulin molecules. For example, a polypeptide suitable for use in the immunomodulatory fusion proteins described herein may comprise a CH2 domain or portion thereof derived from an IgG1 molecule and a CH3 region or portion thereof derived from an IgG3 molecule. In some embodiments, the immunomodulatory fusion protein comprises an Fc domain comprising a hinge domain derived in part from an IgG1 molecule and in part from an IgG3 molecule. As set forth herein, it will be understood by one of ordinary skill in the art that an Fc domain can be altered such that the amino acid sequence of a naturally occurring antibody molecule varies. In certain embodiments, the immunomodulatory fusion protein lacks one or more constant region domains of a complete Fc region, ie, they are partially or completely deleted. In certain embodiments, the immunomodulatory fusion protein lacks a complete CH2 domain. In certain embodiments, the immunomodulatory fusion protein comprises CH2 domain-deleted F regions derived from a vector (eg, from IDEC Pharmaceuticals, San Diego) encoding a human lgG1 constant region domain (see, eg, WO02 / 060955A2 and WO02 / 096948A2). This exemplary vector is modified to delete the CH2 domain and provide a synthetic vector expressing a domain-deleted IgG1 constant region. It will be noted that these exemplary constructs are preferentially modified to fuse a CH3 binding domain directly to a hinge region of the respective Fe domain. In other constructs, it may be desirable to provide a peptide spacer between cebenn / Lznz / B / YiAi one or more constituent Fe domains. For example, a peptide spacer can be placed between a hinge region and a CH2 domain and / or between a CH2 and CH3 domain. For example, compatible constructs can be expressed where the CH2 domain has been deleted and the remaining CH3 domain (synthetic or non-synthetic) is attached to the hinge region with a 1-20, 1-10 or 1-peptide spacer. 5 amino acids. This peptide spacer can be added, for example, to ensure that the regulatory elements of the constant region domain remain free and accessible or that the hinge region remains flexible. Preferably, any compatible linker peptides used in the present disclosure will be relatively non-immunogenic and will not prevent proper folding of Fe. In certain embodiments, an Fc domain employed in the immunomodulatory fusion protein is altered or modified, eg, by amino acid mutation (eg, addition, deletion, or substitution). As used herein, the term "Fe domain variant" refers to an Fe domain that has at least one amino acid modification, such as amino acid substitution, compared to the wild-type Fe from which the Fe domain is derived. For example, where the Fe domain is derived from a human IgG1 antibody, a variant comprises at least one amino acid mutation (eg, substitution) compared to a wild-type amino acid at the corresponding position of the human IgG1 Fe region. . In certain embodiments, the Fe variant comprises a substitution at an amino acid position located in a hinge domain or portion thereof. In certain embodiments, the Fe variant comprises a substitution at an amino acid position located in a CH2 domain or portion thereof. In certain embodiments, the Fe variant comprises a substitution at an amino acid position located in a CH3 domain or portion thereof. In certain embodiments, the Fe variant comprises a substitution at an amino acid position located in a CH4 domain or portion thereof. In certain embodiments, the immunomodulatory fusion protein comprises an Fe variant comprising more than one amino acid substitution. The immunomodulatory fusion protein may comprise, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions in the Fe domain. Preferably, the amino acid substitutions are spatially positioned between yes by a range of at least 1 amino acid position or more, eg, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid positions or more. More preferably, the modified amino acids are spatially positioned apart from each other by a range of at least 5, 10, 15, 20 or 25 amino acid positions or more. In some embodiments, an Fe domain includes changes in the region between amino acids 234-238, including the LLGGP sequence at the start of the CH2 domain. In some crfrcnn / Lznz / E / YiAi modalities, an Fe variant alters Fe-mediated effector function, particularly ADCC, and / or decreases binding avidity for Fe receptors. In some aspects, sequence changes closer to the CH2-CH3 binding, at positions such as K322 or P331 can abolish complement-mediated cytotoxicity and / or impair avidity for FcR binding. In some embodiments, an Fe domain incorporates changes at residues P238 and P331, eg, changes the wild-type prolines at these positions to serine. In some embodiments, alterations in the hinge region in one or more of the three hinge cisternae, encoding CCC, SCO, SSC, SCS, or SSS at these residues may also affect FcR binding and molecular homogeneity, for example, by the removal of mismatched cisternae that can destabilize the folded protein. Other amino acid mutations in the Fe domain are contemplated to reduce binding to the Fe gamma receptor and the Fe gamma receptor subtypes. For example, mutations at positions 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 279, 280, 283, 285, 298, 289, 290, 292, 293, 294, 295, 296, 298, 301,303, 305, 307, 312, 315, 322, 324, 327, 329, 330, 331,333, 334, 335, 337, 338, 340, 356, 360, 373, 376, 378, 379, 382, ​​388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438, or 439 of the Fe region can alter binding as described in US Patent No. 6,737,056, issued May 18. May 2004, incorporated herein by reference in its entirety. This patent reported that the change of Pro331 in lgG3 to Ser resulted in a six-fold lower affinity compared to wild-type lgG3, indicating the involvement of Pro331 in Rl binding of Fe gamma. In addition, amino acid modifications at positions 234, 235, 236, and 237, 297, 318, 320, and 322 are described as potentially altering receptor binding affinity in U.S. 5,624,821, issued April 29, 1997 and incorporated herein by reference in its entirety. Additional mutations contemplated for use include, for example, those described in US Patent Application Publication No. 2006 / 0235208, published October 19, 2006 and incorporated herein by reference in its entirety. Additionally, the mutations described in US Patent Application Publication No. 2006 / 0235208, incorporated herein by reference in its entirety, are contemplated for use. The L234A / L235A mutant is described, for example, in US Patent Application Publication No. 2003 / 0108548, published June 12, 2003 and incorporated herein by reference in its entirety. In embodiments, the described modifications are included either individually or in combination. In certain embodiments, the mutation is D265A in human IgG 1. In certain embodiments, the immunomodulatory fusion protein comprises an Fc variant comprising an amino acid substitution that alters the antigen-dependent effector functions of the polypeptide, in particular ADCC or complement activation, cebenn / Lznz / B / YiAi for example, compared to the wild-type Fe region. This immunomodulatory fusion protein shows decreased binding to FcR gamma when compared to wild-type polypeptides and therefore mediates reduced elector function. Fe variants with decreased FcR gamma binding affinity are expected to reduce effector function, and these molecules are also useful, for example, for the treatment of conditions in which destruction of target cells is undesirable, for example, where cells normal cells may express target molecules, or where chronic administration of the polypeptide could result in unwanted immune system activation. In certain embodiments, the immunomodulatory fusion protein exhibits altered binding to an activating FcyR (eg, Fcyl, Fcylla, or FcyRIIIa). In certain embodiments, the immunomodulatory fusion protein displays altered binding affinity to an inhibitory FcyR (eg, FcyRIIb). Exemplary amino acid substitutions that alter FcR or complement binding activity are described in International PCT Publication No. WO05 / 063815 which is incorporated by reference herein. In some embodiments, the immunomodulatory fusion protein comprises an amino acid substitution that alters glycosylation of the fusion protein. For example, in some embodiments, the Fe domain comprises a mutation that leads to reduced glycosylation (eg, N- or O-linked glycosylation) or comprises an altered glycoform of the wild-type Fe domain (eg, a low-fucose or low-fucose glycan). fucose free). In certain embodiments, the immunomodulatory fusion protein has an amino acid substitution near or within a glycosylation motif, eg, an N-linked glycosylation motif containing the NXT or NXS amino acid sequence. Exemplary amino acid substitutions that reduce or alter glycosylation are described in WO05 / 018572 and US2007 / 0111281, the contents of which are incorporated by reference herein. In certain embodiments, the immunomodulatory fusion protein comprises at least one Fe domain having a modified cysteine ​​residue or analog thereof that is positioned on the solvent exposed surface. In certain embodiments, the immunomodulatory fusion protein comprises an Fc domain comprising at least one modified free cysteine ​​residue or analog thereof that is substantially free of disulfide bonding with a second cysteine ​​residue. Any of the above modified cysteine ​​residues or analogs thereof can subsequently be conjugated to a functional domain using art-recognized techniques (eg, conjugated with a thiol-reactive heterobifunctional linker). In certain embodiments, the immunomodulatory fusion protein comprises a genetically fused Fc domain having two or more of its constituent Fc domains independently selected from the Fc domains described herein. In certain cefrenn / Lznz / B / YiAi modalities, the Fe domains are the same. In certain embodiments, at least two of the Fe domains are different. For example, Fe domains comprise the same number of amino acid residues or may differ in length by one more amino acid residue (eg, by approximately 5 amino acid residues (eg, 1, 2, 3, 4, or 5 amino acid residues). of amino acids), about 10 residues, about 15 residues, about 20 residues, about 30 residues, about 40 residues, or about 50 residues). In certain embodiments, the Fe domains differ in sequence at one or more amino acid positions. For example, at least two of the Fe domains may differ by about 5 amino acid positions (eg, 1, 2, 3, 4, or 5 amino acid positions), about 10 positions, about 15 positions, about 20 positions, about 30 positions, approximately 40 positions, or approximately 50 positions). C. Additional Ligators In some embodiments, the suitable linker for use in the immunomodulatory fusion protein described herein is a polyethylene glycol (PEG) domain. PEG is a well known, water soluble polymer that is commercially available or can be prepared by ring-opened polymerization of ethylene glycol according to methods well known in the art (Sandler and Karo, Polimer Synthesis, Academic Press, New York, Vol. 3, pages 138-161). The term "PEG" is widely used to encompass any polyethylene glycol molecule, and can be represented by the formula: X—OÍCHgCHsOjn-iCHsCHgOH, where n is 20 to 2300 and X is H or a terminal modification, for example, a C1 alkyl -4. In certain embodiments, PEG suitable for use in the methods described herein is terminated at one end with hydroxy or methoxy, ie, X is H or CH3 ("PEG methoxy"). PEG may contain additional chemical groups that are necessary for binding reactions; that results from the chemical synthesis of the molecule; or that it is a spacer for the optimal distance of the parts of the molecule. Furthermore, this PEG may consist of one or more PEG side chains that are ligated together. PEGs with more than one PEG chain are called multiarmed or branched PEGs. Branched PEGs can be prepared, for example, by addition of polyethylene oxide to various polyols, including glycerol, pentaerythritol, and sorbitol. For example, four-armed branched PEG can be prepared from pentaerythritol and ethylene oxide. Branched PEG is described in, for example, EP-A 0 473 084 and US5, 932,462, both of which are hereby incorporated by reference. One form of PEGs includes two PEG side chains (PEG2) linked through the primary amino groups of a lysine (Monfardini et al., Bioconjugate Chem 1995;6:62-9). In certain embodiments, PEG is conjugated to a cysteine ​​moiety at the N- or C-terminus of immunomodulatory fusion protein domains (eg, the cebenn / Lznz / B / YiAi immunomodulatory domain and collagen-binding domain). . A portion of PEG can also be bound by other chemicals, including by conjugation to amines. Conjugation of PEG to peptides or proteins generally involves activation of PEG and coupling of the activated PEG intermediates directly to the target proteins / peptides or to a linker, which is subsequently activated and coupled to the target proteins / peptides ( see Abuchowski et al., JBC 1977;252:3571 and JBC 1977;252:3582, and Harris et al., in: Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (J. M. Harris ed.) Plenum Press: New York, 1992 ; Chap. 21 and 22). A variety of molecular mass forms of PEG can be selected, for example, from about 1,000 Daltons (Da) to 100,000 Da (n is 20 to 2300). The number of repeat units "n" in the PEG is approximated for the molecular mass described in Daltons. One skilled in the art can select a suitable molecular mass for PEG, eg, based on at least the molecular mass of the immunomodulatory fusion protein without PEG. In certain embodiments, PEG molecules can be activated to react with amino groups in domains such as lysines (Bencham C.O. et al. Anal. Biochem., 131, 25 (1983); Veronese, F.M. et al., Appl. Biochem., 11, 141 (1985); Zalipsky, S. et al., Polimeric Drugs and Drug Delivery Systems, adrs 9-110 ACS Symposium Series 469 (1999); Zalipsky, S. et al., Europ. Polim. J. , 19, 11771183 (1983); Delgado, C. et al., Biotechnology and Applied Biochemistry, 12, 119128 (1990)). In certain embodiments, PEG carbonate esters are used to conjugate PEG. Ν,Ν'-Disuccinimidylcarbonate (DSC) can be used in reaction with PEG to form the active mixed PEG-succinimidyl carbonate that can be subsequently reacted with a nucleophilic group of a linker or an amino group of IL-2 (see US Patent No. 5,281,698 and US Patent No. 5,932,462). In a similar type of reaction, 1,1'-(dibenzotriazolyl)carbonate and di-(2-pyridyl)carbonate can be reacted with PEG to form PEG-benzotriazolyl and carbonate mixed with PEG-pyridyl (US Patent No. 5,382,657) , respectively. Pegylation can be carried out according to methods of the state of the art, for example by reaction of IL-2 with electrophilically active PEGs (Shearwater Corp., USA, www.shearwatercorp.com). Preferred PEG reagents suitable for use in the methods described herein are, for example, N-hydroxysuccinimidyl propionates (PEG-SPA), butanoates (PEG-SBA), PEG-succinimidyl propionate or branched N-hydroxysuccinimides such as mPEG2-NHS (Monfardini, C, et al., Bioconjugate Chem. 6 (1995) 62-69). In some embodiments, the suitable linker for use in the immunomodulatory cefrenn / Lznz / E / YiAi fusion protein described herein is transferrin, as described in US 7,176,278 and US 8,158,579, which are incorporated herein by reference. In its whole. In some embodiments, the suitable linker for use in the immunomodulatory fusion protein described herein is a serum immunoglobulin binding protein such as those described in US2007 / 0178082, which is incorporated herein by reference in its whole. In some embodiments, the suitable linker for use in the immunomodulatory fusion protein described herein is a globulin such as thyroxine-binding globulin, an α2-macroglobulin, or haptoglobulin. In some embodiments, the suitable linker for use in the immunomodulatory fusion protein described herein is a fibronectin (Fn)-based scaffolding domain protein, such as those described in US2012 / 0094909, which is incorporated herein. for reference in its entirety. Methods for making fibronectin-based scaffold domain proteins are also described in US2012 / 0094909. A non-limiting example of an extended PK group based on Fn3 is Fn3(HSA). D. Other Linkers In some embodiments, the immunomodulatory domain is operably linked to a collagen-binding domain via a linker, eg, a gly-ser linker. In some embodiments, the immunomodulatory domain is operably linked to a collagen-binding domain via a linker (eg, serum albumin), wherein the linker is ligated to the collagen-binding domain and the immunomodulatory domain via additional linkers (eg gly-ser linker). Suitable linkers for fusing the collagen-binding domain and the immunomodulatory domain, or for fusing the collagen-binding domain, the immunomodulatory domain, and the linker (eg, serum albumin) are well known in the art, and are widely used. described in, for example, US2010 / 0210511, US2010 / 0179094, and US2012 / 0094909, which is incorporated herein by reference in its entirety. Exemplary linkers include gly-ser polypeptide linkers, glycine-proline polypeptide linkers, and proline-alanine polypeptide linkers. In certain embodiments, the linker is a gly-ser polypeptide linker, ie, a peptide consisting of glycine and serine residues. Exemplary gly-ser polypeptide linkers comprise the amino acid sequence Ser(Gly4Ser)n. In certain modalities, n=L In certain modalities, n=2. In certain embodiments, n=3, ie Ser(Gly4Ser)3. In certain embodiments, n=4, ie Ser(Gly4Ser)4. In certain modalities, n=5. In certain modalities, n=6. In certain modalities, n=7. In certain modalities, n=8. In certain modalities, n=9. In certain modalities, n=10. Other exemplary gly-ser polypeptide linkers include the amino acid sequence Ser(Gly4Ser)n. In certain modalities, n=l. In certain cefrenn / Lznz / B / YiAi modalities, n=2. In certain modalities, n=3. In certain modalities, n=4. In certain modalities, n=5. In certain modalities, n=6. Another exemplary gly-ser polypeptide linker comprises (Gly4Ser)n. In certain modalities, n=l. In certain modalities, n=2. In certain modalities, n=3. In certain modalities, n=4. In certain modalities, n=5. In certain modalities, n=6. Another exemplary gly-ser polypeptide linker comprises (GlysSer)n. In certain modalities, n=l. In certain modalities, n=2. In certain modalities, n=3. In certain modalities, n=4. In certain modalities, n=5. In certain modalities n=6. Other linkers that are suitable for use in immunomodulatory fusion proteins are known in the art, for example, the serine-rich linkers described in US 5,525,491, the helix-forming peptide linkers (for example, A(EAAAK)nA ( n=2-5)) described in Arai et al., Protein Eng 2001;14:529-32, and the stable linkers described in Chen et al., Mol Pharm 2011;8:457-65, i.e., the dipeptide linker LE, a thrombin-sensitive disulfide cyclopeptide linker, and the alpha-helix-forming linker LEA(EAAAK)4ALEA(EAAAK)4ALE (SEQ ID NO: 119). Other exemplary linkers include GS linkers (ie, (GS)n), GGSG linkers (ie, (GGSG)n), GSAT linkers, SEG linkers, and GGS linkers (ie, (GGSGGS)n), where n is a positive integer (for example, 1, 2, 3, 4, or 5). Other suitable linkers for use in the hybrid nuclease-albumin molecules can be found using publicly available databases, such as the Linker Database (ibi.vu.nl / programs / linkerdbwww). The Linker Database is a database of inter-domain linkers in multifunctional enzymes that serve as potential linkers in novel fusion proteins (see, for example, George et al., Protein Engineering 2002;15:871 - 9). It will be understood that variant forms of these exemplary polypeptide linkers can be created by introducing one or more nucleotide substitutions, additions, or deletions into the nucleotide sequence encoding a polypeptide linker such that one or more amino acid substitutions, additions, or deletions they are introduced into the polypeptide linker. Mutations can be introduced by standard techniques, such as site-directed mutagenesis and POR-mediated mutagenesis. The polypeptide linkers of the disclosure are at least one amino acid in length and may be of varying lengths. In one embodiment, a polypeptide linker of the disclosure is from about 1 to about 50 amino acids in length. As used in this context, the term "about" indicates + / - two amino acid residues. Since the length of the linker can be a positive integer, length from about 1 to about 50 amino acids in length, means length from 1 to 48-52 amino acids in length. In another embodiment, a polypeptide linker of the disclosure is about 10-20 amino acids in length. In cefrenn / Lznz / B / YiAi another embodiment, a polypeptide linker of the disclosure is from about 15 to about 50 amino acids in length. In another embodiment, a polypeptide linker of the disclosure is from about 20 to about 45 amino acids in length. In another embodiment, a polypeptide linker of the disclosure is about 15 to about 25 amino acids in length. In another embodiment, a polypeptide linker of the description is 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or 61 or more amino acids in length. Polypeptide linkers can be introduced into polypeptide sequences using techniques known in the art. The modifications can be confirmed by DNA sequence analysis. The plasmid DNA can be used to transform host cells for stable production of the produced polypeptides. IV Exemplary Immunomodulatory Fusion Proteins The disclosure provides immunomodulatory fusion proteins comprising an immunomodulatory fusion domain and a collagen-binding domain, optionally a linker, wherein the immunomodulatory domain is operably linked with or without the linker to the collagen-binding domain. The immunomodulatory fusion proteins of the disclosure are modular and can be configured to incorporate several individual domains. A. IL-2 Fusion Proteins In some embodiments, the immunomodulatory fusion protein comprises IL-2 and lumican, wherein IL-2 is operably linked to lumican. In some embodiments, IL-2 is operably linked to lumican with albumin. In some embodiments, IL-2 is operably linked to the N-terminus of lumican. In some embodiments, IL-2 is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises the human IL-2 sequence set forth in SEQ ID NO: 1 operably linked to the human lumican sequence set forth in SEQ ID NO: 107. In some embodiments, the immunomodulatory fusion protein comprises the human IL-2 sequence set forth in SEQ ID NO: 1 operably linked to the human lumican sequence set forth in SEQ ID NO: 107 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. In some embodiments, the immunomodulatory fusion protein comprises IL-2 and LAIR-1, wherein IL-2 is operably linked to LAIR-1. In some embodiments, IL-2 is operably linked to LAIR-1 with albumin. In some embodiments, IL-2 is operably linked to the N-terminus of LAIR-1. In some embodiments, IL-2 is operably linked to the C-terminus of LAIR-1. In some embodiments, the immunomodulatory fusion protein comprises the cefrenn / Lznz / B / YiAi human IL-2 sequence set forth in SEQ ID NO: 1 operably linked to the human LAIR1 sequence set forth in SEQ ID NO: 98. In some embodiments, the immunomodulatory fusion protein comprises the human IL-2 sequence set forth in SEQ ID NO: 1 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. B. IL-12 Fusion Proteins In some embodiments, the immunomodulatory fusion protein comprises IL-12 and lumican, wherein IL-12 is operably linked to lumican. In some embodiments, IL-12 is operably linked to lumican with albumin. In some embodiments, IL-12 is operably linked to the N-terminus of lumican. In some embodiments, IL-12 is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises the human IL-12 sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3 operably linked to the human lumican sequence set forth in SEQ ID NO: 107. In some embodiments, the immunomodulatory fusion protein comprises the human IL-12 sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3 operably linked to the human lumican sequence set forth in SEQ ID NO: 107 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. In some embodiments, the immunomodulatory fusion protein comprises IL-12 and LAIR-1, wherein IL-12 is operably linked to LAIR-1. In some embodiments, IL-12 is operably linked to LAIR-1 with albumin. In some embodiments, IL-12 is operably linked to the N-terminus of LAIR-1. In some embodiments, IL-12 is operably linked to the C-terminus of LAIR-1. In some embodiments, the immunomodulatory fusion protein comprises the human IL-12 sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98. In some embodiments , the immunomodulatory fusion protein comprises the human IL-12 sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. C. CCL-3 Fusion Proteins In some embodiments, the immunomodulatory fusion protein comprises CCL-3 and lumican, wherein CCL-3 is operably linked to lumican. In some embodiments, CCL-3 is operably linked to lumican with albumin. In some embodiments, CCL-3 is operably linked to the N-terminus of lumican. In some embodiments, CCL-3 is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises the cefrenn / ίζηζ / Ε / γίΛΐ human CCL-3 sequence set forth in SEQ ID NO: 41 operably linked to the human lumican sequence set forth in SEQ ID NO: 107. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-3 sequence set forth in SEQ ID NO: 41 operably linked to the human lumican sequence set forth in SEQ ID NO: 107 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. In some embodiments, the immunomodulatory fusion protein comprises CCL-3 and LAIR-1, wherein CCL-3 is operably linked to LAIR-1. In some embodiments, CCL-3 is operably linked to LAIR-1 with albumin. In some embodiments, CCL-3 is operably linked to the N-terminus of LAIR-1. In some embodiments, CCL-3 is operably linked to the C-terminus of LAIR-1. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-3 sequence set forth in SEQ ID NO: 41 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-3 sequence set forth in SEQ ID NO: 41 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43 D. CCL-4 Fusion Proteins In some embodiments, the immunomodulatory fusion protein comprises CCL-4 and lumican, wherein CCL-4 is operably linked to lumican. In some embodiments, CCL-4 is operably linked to lumican with albumin. In some embodiments, CCL-4 is operably linked to the N-terminus of lumican. In some embodiments, CCL-4 is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-4 sequence set forth in SEQ ID NO: 33 operably linked to the human lumican sequence set forth in SEQ ID NO: 107. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-4 sequence set forth in SEQ ID NO: 33 operably linked to the human lumican sequence set forth in SEQ ID NO: 107 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. In some embodiments, the immunomodulatory fusion protein comprises CCL-4 and LAIR-1, wherein CCL-4 is operably linked to LAIR-1. In some embodiments, CCL-4 is operably linked to LAIR-1 with albumin. In some embodiments, CCL-4 is operably linked to the N-terminus of LAIR-1. In some embodiments, CCL-4 is operably linked to the C-terminus of LAIR-1. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-4 sequence set forth in SEQ ID NO: 33 operably linked to the cebenn / Lznz / E / YiAi sequence. 100 human LAIR-1 set forth in SEQ ID NO: 98. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-4 sequence set forth in SEQ ID NO: 33 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. E. CCL-5 Fusion Proteins In some embodiments, the immunomodulatory fusion protein comprises CCL-5 and lumican, wherein CCL-5 is operably linked to lumican. In some embodiments, CCL-5 is operably linked to lumican with albumin. In some embodiments, CCL-5 is operably linked to the N-terminus of lumican. In some embodiments, CCL-5 is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-5 sequence set forth in SEQ ID NO: 39 operably linked to the human lumican sequence set forth in SEQ ID NO: 107. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-5 sequence set forth in SEQ ID NO: 39 operably linked to the human lumican sequence set forth in SEQ ID NO: 107 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. In some embodiments, the immunomodulatory fusion protein comprises CCL-5 and LAIR-1, wherein CCL-5 is operably linked to LAIR-1. In some embodiments, CCL-5 is operably linked to LAIR-1 with albumin. In some embodiments, CCL-5 is operably linked to the N-terminus of LAIR-1. In some embodiments, CCL-5 is operably linked to the C-terminus of LAIR-1. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-5 sequence set forth in SEQ ID NO: 39 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98. In some embodiments, the immunomodulatory fusion protein comprises the human CCL-5 sequence set forth in SEQ ID NO: 39 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43 . F. Eotaxin Fusion Proteins In some embodiments, the immunomodulatory fusion protein comprises Eotaxin and lumican, wherein Eotaxin is operably linked to lumican. In some embodiments, Eotaxin is operably linked to lumican with albumin. In some embodiments, Eotaxin is operably linked to the N-terminus of lumican. In some embodiments, Eotaxin is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises the human Eotaxin sequence set forth in SEQ ID NO: 38 operably linked to the human lumican sequence set forth in SEQ ID NO: 107. In some embodiments, the cefrenn / Lznz / E / YiAi 101 immunomodulatory fusion protein comprises the human Eotaxin sequence set forth in SEQ ID NO: 38 operably linked to the human lumican sequence set forth in SEQ ID NO: 107 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. In some embodiments, the immunomodulatory fusion protein comprises Eotaxin and LAIR-1, wherein Eotaxin is operably linked to LAIR-1. In some embodiments, Eotaxin is operably linked to LAIR-1 with albumin. In some embodiments, Eotaxin is operably linked to the N-terminus of LAIR-1. In some embodiments, Eotaxin is operably linked to the C-terminus of LAIR-1. In some embodiments, the immunomodulatory fusion protein comprises the human Eotaxin sequence set forth in SEQ ID NO: 38 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98. In some embodiments, the immunomodulatory fusion protein comprises the human Eotaxin sequence set forth in SEQ ID NO: 38 operably linked to the human LAIR-1 sequence set forth in SEQ ID NO: 98 with a human serum albumin sequence selected from SEQ ID NO: 42 and SEQ ID NO: 43. G. Antibody Fusion Proteins In some embodiments, the immunomodulatory fusion protein comprises an anti-CD3 antibody and lumican, wherein the anti-CD3 antibody is operably linked to lumican. In some embodiments, the anti-CD3 antibody is operably linked to the N-terminus of lumican. In some embodiments, the anti-CD3 antibody is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises an anti-CD3 antibody and LAIR-1, wherein the anti-CD3 antibody is operably linked to LAIR1. In some embodiments, the anti-CD3 antibody is operably linked to the N-terminus of LAIR-1. In some embodiments, the anti-CD3 antibody is operably linked to the C-terminus of LAIR-1. In some embodiments, the immunomodulatory fusion protein comprises an anti-4-1-BB antibody and lumican, wherein the anti-4-1-BB antibody is operably linked to lumican. In some embodiments, the anti-4-1-BB antibody is operably linked to the N-terminus of lumican. In some embodiments, the anti-4-1-BB antibody is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises an anti-4-1-BB antibody and LAIR-1, wherein the anti-4-1-BB antibody is operably linked to LAIR-1. In some embodiments, the anti-4-1-BB antibody is operably linked to the N-terminus of LAIR-1. In some embodiments, the anti-4-1-BB antibody is operably linked to the C-terminus of LAIR-1. cebenn / Lznz / E / YiAi 102 In some embodiments, the immunomodulatory fusion protein comprises an anti-CD40 antibody and lumican, wherein the anti-CD40 antibody is operably linked to lumican. In some embodiments, the anti-CD40 antibody is operably linked to the N-terminus of lumican. In some embodiments, the anti-CD40 antibody is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises an anti-CD40 antibody and LAIR-1, wherein the anti-CD40 antibody is operably linked to LAIR-1. In some embodiments, the anti-CD40 antibody is operably linked to the N-terminus of LAIR-1. In some embodiments, the anti-CD40 antibody is operably linked to the C-terminus of LAIR-1. In some embodiments, the immunomodulatory fusion protein comprises the anti-OX40 antibody and lumican, wherein the anti-OX40 antibody is operably linked to lumican. In some embodiments, the anti-OX40 antibody is operably linked to the N-terminus of lumican. In some embodiments, the anti-OX40 antibody is operably linked to the C-terminus of lumican. In some embodiments, the immunomodulatory fusion protein comprises the anti-OX40 antibody and LAIR-1, wherein the anti-OX40 antibody is operably linked to LAIR-1. In some embodiments, the anti-OX40 antibody is operably linked to the N-terminus of LAIR-1. In some embodiments, the anti-OX40 antibody is operably linked to the C-terminus of LAIR-1. V Methods for making Immunomodulatory Fusion Proteins In some aspects, the polypeptides described herein (eg, collagen-binding domains, cytokines, antibodies) are made in transformed host cells using recombinant DNA techniques. To do so, a recombinant DNA molecule encoding the peptide is prepared. Methods for preparing these DNA molecules are well known in the art. For example, the coding sequences for the peptides could be excised from the DNA using suitable restriction enzymes. Alternatively, the DNA molecule could be synthesized using chemical synthesis techniques, such as the phosphoramidate method. A combination of these techniques could be used. Methods for making the polypeptides also include a vector capable of expressing the peptides in an appropriate host. The vector comprises the DNA molecule encoding the peptides operably linked to the appropriate expression control sequences. Methods for carrying out this operative ligation, either before or after the DNA molecule is inserted into the vector, are well known. Expression control sequences include promoters, activators, enhancers, operators, ribosomal nuclease domains, start signals, stop signals, termination signals, cefrenn / Lznz / B / YiAi signals 103 polyadenylation, and other signals involved with the control of transcription or translation. The resulting vector having the DNA molecule thereon is used to transform an appropriate host. This transformation can be carried out using methods well known in the field. Any of a large number of available and well-known host cells may be suitable for use in the methods described herein. The selection of a particular host is dependent on a number of factors recognized in the art. These include, for example, compatibility with the chosen expression vector, toxicity of the modified peptides to the DNA molecule, speed of transformation, ease of recovery of the peptides, expression characteristics, biosafety, and cost. A balance of these factors must be achieved with the understanding that not all hosts may be equally efficient for the expression of a particular DNA sequence. Within these general guidelines, useful microbial hosts include bacteria (such as E. coli sp.), yeast (such as Saccharomyces sp.) and other fungi, insects, plants, mammalian (including human) cells in culture, or other hosts known in the art. The transformed host cell is then cultured and purified. Host cells can be grown under standard fermentation conditions so that the desired compounds are expressed. These fermentation conditions are well known in the art. Finally, the peptides are purified from the culture by methods well known in the art. Composites can also be made by synthetic methods. For example, solid phase synthesis techniques can be used. Suitable techniques are well known in the art, and include those described in Merrifield (1973), Chem. Polypeptides, pp. 335-61 (Katsoyannis and Panayotis eds.); Merrifield (1963), J. Am. Chem. Soc. 85: 2149; Davis et al. (1985), Biochem. Intl. 10: 394-414; Stewart and Young (1969), Solid Phase Peptide Synthesis; US Patent No. 3,941,763; Finn et al. (1976), The Proteins (3rd ed.) 2: 105-253; and Erickson et al. (1976), The Proteins (3rd ed.) 2: 257-527. Solid phase synthesis in the art is the preferred technique for making individual peptides since it is the most economical method for making small peptides. Peptides containing derivative peptides or containing non-peptide groups could be synthesized by well known organic chemistry techniques. Other methods are molecule expression / synthesis which are generally known in the art to one of ordinary skill. The nucleic acid molecules described above may be contained within a vector that is capable of directing their expression in, for example, a cell that has been transduced with the vector. Therefore, in addition to polypeptide mutants, expression vectors containing a nucleic acid molecule encoding a cefrenn / Lznz / B / YiAi mutant 104 and cells transfected with these vectors are among others the certain modalities. Vectors suitable for use include T7-based vectors for use in bacteria (see, for example, Rosenberg et al., Gene 56: 125, 1987), the pMSXND expression vector for use in mammalian cells (Lee and Nathans , J. Biol. Chem. 263:3521, 1988), and baculovirus-derived vectors (eg, the pBacPAKS expression vector from Clontech, Palo Alto, Calif.) for use in insect cells. Nucleic acid bugs, encoding the polypeptide of interest in these vectors, can be operably linked to a promoter, which is selected based on, for example, the cell type in which expression is sought. For example, a T7 promoter can be used in bacteria, a polyhedrin promoter can be used in insect cells, and a cytomegalovirus or metallothionein promoter can be used in mammalian cells. Also, in the case of higher eukaryotes, tissue-specific and cell-type-specific promoters are widely available. These promoters are so named because of their ability to direct the expression of a nucleic acid molecule in a given tissue or cell type within the body. Skilled artisans are well aware of numerous promoters and other regulatory elements that can be used to direct expression of nucleic acids. In addition to the sequences that facilitate transcription of the inserted nucleic acid molecule, the vectors may contain origins of replication, and other genes that encode a selectable marker. For example, the neomycin resistance gene (neor) imparts G418 resistance to cells in which it is expressed, and thus allows phenotypic selection of transfected cells. Those of skill in the art can readily determine whether a given regulatory element or selectable marker is suitable for use in a particular experimental context. Viral vectors that are suitable for use include, for example, retroviral, adenoviral, and adeno-associated vectors, herpes viruses, simian virus 40 (SV40), and bovine papillomavirus vectors (see, for example, Gluzman (Ed.), Eukaryotic Viral Vectors, CSH Laboratory Press, Cold Spring Harbor, N.Y.). Eukaryotic and prokaryotic cells that contain and express a nucleic acid molecule encoding a polypeptide mutant are also suitable for use. A cell is a transfected cell, ie, a cell into which a nucleic acid molecule, for example a nucleic acid molecule encoding a mutant polypeptide, has been introduced by means of recombinant DNA techniques. Progeny from this cell are also considered suitable for use in the methods described herein. The precise components of the expression system are not critical. For example, a polypeptide mutant can be produced in a prokaryotic host, such as E. coli bacterium, or in a eukaryotic host, such as an insect cell (for example, a crfrcnn / Lznz / E / YiAi cell). 105 Sf21), or mammalian cells (eg, COS cells, NIH 3T3 cells, or HeLa cells). These cells are available from many sources, including the American Type Culture Collection (Manassas, Va.). When selecting an expression system, it matters only that the components are compatible with each other. Artificers or ordinary experience are capable of making this determination. In addition, if guidance is required in the selection of an expression system, skilled designers may consult Ausubel et al. (Current Protocols in Molecular Biology, John Wiley and Sons, New York, N.Y., 1993) and Pouwels et al. (Cloning Vectors : A Laboratory Manual, 1985 Suppl. 1987). Expressed polypeptides can be purified from the expression system using routine biochemical procedures, and used, for example, as therapeutic agents, as described herein. Pharmaceutical Compositions and Administration Modes In certain embodiments, the disclosure provides for a pharmaceutical composition comprising an immunomodulatory fusion protein with a pharmaceutically acceptable diluent, carrier, solubilizer, emulsifier, preservative, and / or adjuvant. In certain embodiments, the acceptable formulation materials are preferably non-toxic to the containers at the dosages and concentrations employed. In certain embodiments, the formulation material(s) are for s.c. and / or LV. In certain embodiments, the formulation materials are for local administration, eg, intratumoral administration. In certain embodiments, the pharmaceutical composition may contain formulation materials to modify, maintain, or preserve, for example, pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or composition penetration. In certain embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobials; antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen sulfite); buffer solutions (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose, or dextrins); proteins (such as serum albumin, gelatin, or immunoglobulins); coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerin, propylene glycol, or polyethylene glycol); sugar alcohols cefrenn / lzaz / b / yiai 106 (such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal); stability-enhancing agents (such as sucrose and sorbitol); tonicity-enhancing agents (such as alkali metal halides, preferably sodium or potassium chloride, mannitol sorbitol); supply vehicles; diluents; pharmaceutical excipients and / or adjuvants. (Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company (1995). In certain embodiments, the formulation comprises PBS; 20 mM NaOAC, pH 5.2, 50 mM NaCI; and / or 10 mM NAOAC, pH 5.2 , 9% sucrose In certain embodiments, the optimal pharmaceutical composition will be determined by one of skill in the art depending on, for example, the route of administration and proposal, delivery format, and desired dosage, eg, Remington's Pharmaceutical Sciences, supra In certain embodiments, these compositions can factor in the physical state, stability, in vivo release rate, and in vivo clearance rate of the immunomodulatory fusion protein. In some embodiments, formulations comprising an immunomodulatory fusion protein described herein are at 4°C to 37°C when administered to a subject. In certain embodiments, the primary vehicle or carrier in a pharmaceutical composition may be either aqueous or non-aqueous in nature. For example, in certain embodiments, a suitable vehicle or carrier may be water for injection, physiological saline, or artificial cerebrospinal fluid, possibly supplemented by other materials common in compositions for parenteral administration. In certain embodiments, the saline solution comprises isotonic phosphate buffered saline. In certain embodiments, neutral buffered saline or saline mixed with serum albumin are additional exemplary vehicles. In certain embodiments, the pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which may further include sorbitol or a suitable substitute thereof. In certain embodiments, a composition comprising an immunomodulatory fusion protein is prepared for storage by mixing the selected composition having the desired degree of purity with optional formulating agents (Remington's Pharmaceutical Sciences, supra) in the form of a lyophilized cake or a aqueous solution. Furthermore, in certain embodiments, a composition comprising an immunomodulatory fusion protein is formulated as a lyophilisate using appropriate excipients such as sucrose. In certain embodiments, the pharmaceutical composition is selected for parenteral delivery. In certain embodiments, the compositions are selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of these cebenn / ίζηζ / ε / γίΛΐ 107 pharmaceutically acceptable compositions is within the ability of one skilled in the art. In certain embodiments, the components of the formulation are present in concentrations that are acceptable to the site of administration. In certain embodiments, buffer solutions are used to maintain the physiological pH composition at or slightly lower than pH, typically within a pH range of about 5 to about 8. In certain embodiments, when parenteral administration is contemplated, a therapeutic composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising an immunomodulatory fusion protein, in a pharmaceutically acceptable carrier. In certain embodiments, a vehicle for parenteral injection is sterile distilled water in which the immunomodulatory fusion protein is formulated as an appropriately preserved, sterile, isotonic solution. In certain embodiments, the preparation may involve formulation of the desired molecule with an agent, such as injectable microspheres, bioerodible particles, polymeric compounds, (such as polylactic acid or polyglycolic acid), granules, or liposomes that can provide controlled or sustained release. of the product which can then be supplied via a depot injection. In certain modalities, implantable hyaluronic acid may also be used, and may have the effect of promoting sustained duration in the circulation. In certain embodiments, implantable drug delivery devices can be used to deliver the desired molecule. In certain embodiments, a pharmaceutical composition is formulated for inhalation. In certain embodiments, an immunomodulatory fusion protein is formulated as a dry powder for inhalation. In certain embodiments, an inhalation solution comprises an immunomodulatory fusion protein that is formulated with a propellant for aerosol delivery. In certain embodiments, solutions can be nebulized. Pulmonary delivery is further described in PCT Application No. PCT / US94 / 001875, which describes the pulmonary delivery of chemically modified proteins. In certain embodiments, it is contemplated that the formulations be administered orally. In certain embodiments, an immunomodulatory fusion protein that is administered in this form is formulated with or without those carriers suitably utilized in the compounding of solid dosage forms such as tablets and capsules. In certain embodiments, the capsule is designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. In certain embodiments, at least one additional agent is included to facilitate uptake of the immunomodulatory fusion protein. In certain embodiments, diluents, flavorings, low melting point waxes, vegetable oils, lubricants, cefrenn / Lznz / B / YiAi 108 suspending agents, tablet disintegrating agents, and binders may also be employed. In certain embodiments, a pharmaceutical composition comprises an effective amount of the immunomodulatory fusion protein in admixture with non-toxic excipients that are suitable for tableting. In certain embodiments, by dissolving the tablets in sterile water, or other appropriate vehicle, solutions are prepared in unit dosage form. In certain embodiments, suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc. Additional pharmaceutical compositions will be apparent to those skilled in the art, including formulations involving an immunomodulatory fusion protein, in sustained or controlled delivery formulations. In certain embodiments, techniques for formulating a variety of other sustained or controlled delivery means, such as liposome carriers, bioerodible microparticles or porous pellets and depot injections, are also known to those skilled in the art. See, for example, PCT Application No. PCT / US93 / 00829 which describes the controlled release of porous polymeric microparticles for the delivery of pharmaceutical compositions. In certain embodiments, sustained release preparations can include semipermeable polymer matrices in the form of shaped articles, eg, films or microcapsules. Sustained release matrices can include polyesters, hydrogels, polylactides (US Patent No. 3,773,919 and EP 058,481), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al. Biopolimers, 22:547-556 (1983) ), poly(2-hydroxyethyl-methacrylate) (Langer et al. J. Biomed. Mater. Res., 15:167-277 (1981) and Langer, Chem. Tech., 12:98- 105 (1982)), ethylene vinyl acetate (Langer et al. supra) or poly-D(-)-3-hydroxybutyric acid (EP 133,988). In certain embodiments, sustained release compositions include liposomes, which can be prepared by any of a number of methods known in the art. See, for example, Eppstein et al. Proc. nati. Acad. Sci. USA, 82:3688-3692 (1985); EP 036,676; EP 088,046 and EP 143,949. The pharmaceutical composition that is used for administration in vivo is typically sterile. In certain embodiments, this is accomplished by filtration through sterile filtration membranes. In certain embodiments, where the composition is lyophilized, sterilization using this method is conducted either before or after lyophilization and reconstitution. In certain embodiments, the composition for parenteral administration can be stored in lyophilized form or in a solution. In certain embodiments, parenteral compositions are generally placed in a container having a sterile access port, for example, a cebenn / Lznz / B / YiAi 109 intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle. In certain embodiments, once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. In certain embodiments, these formulations can be stored either in a ready-to-use form or in a form (eg, lyophilized) that is reconstituted prior to administration. In certain embodiments, kits are provided for producing a single dose delivery unit. In certain embodiments, the kit may contain both a first container holding a dry protein and a second container holding an aqueous formulation. In certain embodiments, kits containing single and multi-chamber prefilled syringes (eg, liquid syringes and lyso-syringes) are included. In certain embodiments, the effective amount of a pharmaceutical composition containing the immunomodulatory fusion protein that is employed therapeutically will depend, for example, on the therapeutic context and objectives. One skilled in the art will appreciate that dosage levels appropriate for treatment, according to certain modalities, will thus vary depending, in part, on the molecule delivered, the indication for which the immunomodulatory fusion protein is being used, the route of administration, and the size (body weight, body surface area, or organ size) and / or condition (the age and general health) of the patient. In certain embodiments, the physician may titrate the dosage and modify the route of administration to obtain the optimal therapeutic effect. In certain embodiments, the dosing frequency will take into account the pharmacokinetic parameters of the immunomodulatory fusion protein in the formulation used. In certain embodiments, a physician will administer the composition until a dosage that achieves the desired effect is reached. In certain embodiments, the composition can therefore be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion through a implantation device or catheter. Further refinement of the proper dosage is routinely done by those of ordinary skill in the art and is within the scope of tasks customarily performed by them. In certain modalities, appropriate dosing can be assessed through the use of appropriate dose-response data. In certain embodiments, the route of administration of the pharmaceutical composition is according to known methods, for example, orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, subcutaneous, infraocular, intra-arterial, cebenn / Lznz / B / YiAi 110 intraportal, or intralesional; or sustained release systems or by implantation devices. In certain embodiments, the compositions can be administered by bolus injection or continuously by infusion, or by implantation device. In certain modalities, the individual elements of the combination therapy may be administered by different routes. In certain embodiments, the composition can be administered locally through implantation of a membrane, sponge, or other appropriate material into which the desired molecule has been absorbed or encapsulated. In certain embodiments, when an implantation device is used, the device can be implanted in suitable tissue or organ, and delivery of the desired molecule can be through diffusion, timed-release bolus, or continuous administration. In certain embodiments, it may be desirable to use a pharmaceutical composition comprising an immunomodulatory fusion protein in an ex vivo manner. In these cases, the cells, tissues and / or organs that are removed from the patient are exposed to a pharmaceutical composition comprising the immunomodulatory fusion protein after which the cells, tissues and / or organs are subsequently implanted back into the patient. In certain embodiments, an immunomodulatory fusion protein is delivered by implanting certain cells that have been genetically modified, using methods such as those described herein, to express and secrete the polypeptides. In certain embodiments, these cells may be animal or human cells, and may be autologous, heterologous, or xenogeneic. In certain embodiments, cells can be immortalized. In certain embodiments, in order to decrease the likelihood of an immune response, the cells may be encapsulated to prevent infiltration of surrounding tissues. In certain embodiments, the encapsulation materials are typically biocompatible, semipermeable polymeric encasements or membranes that allow release of the protein product(s) but prevent destruction of the cells by the patient's immune system or other tissue damaging factors. surrounding. Treatment Methods The immunomodulatory fusion proteins and / or nucleic acids expressing them, described herein, are useful for treating a disorder associated with abnormal apoptosis or differentiation process (for example, cell proliferative disorders (for example, hyperproliferative disorders) or disorders cell differentiation, such as cancer). Non-limiting examples of cancers that are suitable for treatment with the methods of the present disclosure are described below. Examples of cell proliferative and / or differentiation disorders include cancer (eg, carcinoma, sarcoma, metastatic disorders or hematopoietic neoplastic disorders, eg, leukemias). A metastatic tumor can arise from a multitude cefrenn / ίζηζ / Β / γίΛΐ 111 primary tumor types, including but not limited to those of the prostate, colon, lung, breast, and liver. Accordingly, the compositions used herein, eg comprising, immunomodulatory fusion protein, can be administered to a patient who has cancer. As used herein, the terms "cancer" (or "cancerous"), "hyperproliferative" and "neoplastic" refer to cells that have the capacity for autonomous growth (i.e., an abnormal state or condition characterized by cell growth that proliferates rapidly). Hyperproliferative and neoplastic disease states can be categorized as pathological (i.e., characterizing or constituting a disease state), or they can be categorized as non-pathological (i.e., deviating from normal but associated with disease state). ). The terms are intended to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues or organs, regardless of the type or histopathological stage of invasion. "Pathological hyperproliferative" cells occur in disease states characterized by malignant tumor growth, examples of non-pathological hyperproliferative cells include cell proliferation associated with wound repair. The terms "cancer" or "neoplasm" are used to refer to malignant neoplasms of various organ systems, including those involving the lungs, breast, thyroid, lymph glands and lymphatic tissue, gastrointestinal organs, and the genitourinary tract, as well as adenocarcinomas. which are generally considered to include malignancies such as most colon cancers, renal cell carcinoma, prostate and / or testicular tumors, non-small cell carcinoma of the lung, small bowel cancer, and esophageal cancer. The term "carcinoma" is recognized in the field and refers to malignant conditions of epithelial or endocrine tissues including carcinomas of the respiratory system, carcinomas of the gastrointestinal system, carcinomas of the genitourinary system, testicular carcinomas, breast carcinomas, prostatic carcinomas, carcinomas of the endocrine system and melanomas. Immunomodulatory fusion proteins can be used to treat patients who have, are suspected of having, or may be at high risk of developing any type of cancer, including renal cell carcinoma or melanoma, or any viral disease. Exemplary carcinomas include those that form from tissue of the cervix, lung, prostate, breast, head and neck, colon, and ovary. The term also includes carcinosarcomas, which include malignant tumors composed of carcinomatous and sarcomatous tissues. An "adenocarcinoma" refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures. Additional examples of proliferative disorders include cefrenn / Lznz / B / YiAi neoplastic disorders 112 hematopoietic. As used herein, the term "hematopoietic neoplastic disorders" includes diseases involving hyperplastic / neoplastic cells of hematopoietic origin, eg, arising from myeloid, lymphoid, or erythroid lineages, or precursor cells thereof. Preferably, the diseases arise from poorly differentiated acute leukemias (eg, erythroblastic leukemia and acute megakaryoblastic leukemia). Additional exemplary myeloid disorders include, but are not limited to, acute pro-myeloid leukemia (APML), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML) (reviewed in Vaickus, L. (1991) Crit. Rev. in Oncol. / Hemotol.11:267-97); Lymphoid malignancies include, but are not limited to, acute lymphoblastic leukemia (ALL) including B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL), and macroglobulinemia from Waldenstrom (WM). Additional forms of malignant lymphomas include, but are not limited to non-Hodgkin lymphoma and variants thereof, peripheral T-cell lymphomas, adult T-cell leukemia / lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), granular lymphocytic leukemia large (LGF), Hodgkin's disease, and Reed-Sternberg's disease. It will be appreciated by those skilled in the art that amounts of an immunomodulatory fusion protein sufficient to reduce tumor growth and size, or a therapeutically effective amount, will vary not only in the particular compounds or compositions selected, but also in the route of delivery. administration, the nature of the condition being treated, and the age and condition of the patient, and is ultimately given at the discretion of the physician or pharmaceutical person. The duration of time during which the compounds used in the present method will be given varies on an individual basis. It will be appreciated by those skilled in the art that the B16 melanoma model used herein is a generalized model for solid tumors. That is, the efficacy of treatments in this model is also predictive of the efficacy of treatments in other non-melanoma solid tumors. For example, as described in Baird et al. (J Immunology 2013;190:469-78; Epub Dec 7, 2012), the efficacy of cps, a parasite strain that induces an adaptive immune response, in mediating antitumor immunity against B16F10 tumors have been found to be generalisable to other solid tumors, including models of lung carcinoma and ovarian cancer. In another example, the results of a search line on VEGF-targeting lymphocytes also show that the results in B16F10 tumors were generalizable to the other tumor types studied (Chinnasamy et al. JCI 2010;120:3953-68; Chinnasamy and strainers Clin Cancer Res 2012; 18:1672-83). In yet another example, immunotherapy involving LAG-3 and PD-1 led to a reduced tumor burden, with generalizable results in colonic fidrosarcoma and adenocarcinoma cell lines (Woo and cefrenn / Lznz / B / YiAi 113 collaborators Cancer Res 2012; 72:917-27). In certain embodiments, the immunomodulatory fusion proteins described herein are used to treat cancer. In certain embodiments, the immunomodulatory fusion proteins described herein are used to treat melanoma, leukemia, lung cancer, breast cancer, prostate cancer, ovarian cancer, colon cancer, and brain cancer. In certain embodiments, the immunomodulatory fusion proteins described herein inhibit the growth and / or proliferation of tumor cells. In certain embodiments, the immunomodulatory fusion proteins described herein reduce tumor size. In certain embodiments, the immunomodulatory fusion proteins described herein inhibit metastasis of a primary tumor. It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as treatment of the observed cancers and symptoms. Combination Therapy In some modalities, immunomodulatory fusion proteins are used in combination with other therapies. For example, in some modalities immunomodulatory fusion proteins are used in combination with other immunotherapy. Exemplary immunotherapies include, but are not limited to, chimeric antigen receptor (CAR) T-cell therapy, antibodies targeting tumor-associated antigens, immune checkpoint inhibitors, and cancer vaccines. I. Chimeric Antigen Receptor (CAR) Effector Cells In some aspects, the disclosure provides immunomodulatory fusion proteins that are used or carried out in conjunction with chimeric antigen receptor (CAR) effector cell (eg, CAR T cell) therapy. Chimeric antigen receptors (CARs) are genetically engineered, artificial transmembrane receptors that confer arbitrary specificity for a ligand on an immune effector cell (eg, a T cell, natural killer cell, or other immune cell) and result in the activation of the effector cell in the recognition and binding of the ligand. Typically, these receptors are used to impart the antigen specificity of a monoclonal antibody on a T cell. In some embodiments, CARs contain three domains: 1) an ectodomain typically comprising a signal peptide, a ligand or antigen recognition region (eg scFv) and a flexible spacer; 2) a transmembrane (TM) domain; 3) an endodomain (alternatively known as an "activation domain") typically comprising one or more intracellular signaling domains. The CAR ectodomain resides outside the cell and is exposed to the extracellular space, whereby it is accessible to cefrenn / Lznz / B / YiAi. 114 interaction with its cognate ligand. The TM domain allows the CAR to anchor to the cell membrane of the effector cell. The third endodomain (also known as the "activation domain") aids in the activation of effector cells upon the binding of CAR to its specific ligand. In some embodiments, activation of effector cells comprises induction of cytokine and chemokine production, as well as activation of the cells' cytolytic activity. In some modalities, CARs redirect cytotoxicity towards tumor cells. In some embodiments, CARs comprise a ligand- or antigen-specific recognition domain that binds to a specific targeting ligand or antigen (also referred to as a binding domain). In some embodiments, the binding domain is a single chain antibody variable fragment (scFv), a tethered ligand, or coreceptor extracellular domain, fused to a transmembrane domain, which in turn ligates to a signaling domain. . In some embodiments, the signaling domain is derived from the CD3ζ or FcRy. In some embodiments, the CAR comprises one or more costimulatory domains derived from a protein such as CD28, CD137 (also known as 4-1BB), CD134 (also known as 0X40), and CD278 (also known as ICOS). Mating of the CAR antigen-binding domain with its target antigen on the surface of a target cell results in the clustering of the CAR and provides an activation stimulus to the CAR-containing cell. In some modalities, the main feature of CARs is their ability to redirect the specificity of immune effector cells, thereby triggering proliferation, cytokine production, phagocytosis, or production of molecules that can mediate cell death of the cell expressing the CAR. Target antigen in a major histocompatibility (MHC) dependent manner that exploits the cell-specific targeting capabilities of cell-specific monoclonal antibodies, soluble ligands, or co-receptors. Although scFv-based CARs modified to contain a CD3C or FcRy signaling domain have been shown to deliver a potent signal for T cell activation and effector function, they are not sufficient to induce signals that promote T cell survival and expansion in the absence of a concomitant costimulatory signal. A new generation of CARs containing a binding domain, a hinge domain, a transmembrane domain, and the signaling domain derived from CD3ζ or FcRy together with one or more costimulatory signaling domains (for example, CD28-derived intracellular costimulatory domains, CD137, CD134, and CD278) have been shown to have more direct effective antitumor activity, as well as increased cytokine secretion, lytic activity, survival, and proliferation of CAR-expressing T cells in vitro, in animal models and cancer patients (Milone et al. collaborators, Molecular cebenn / Lznz / B / YiAi 115 Therapy, 2009; 17:1453-1464; Zhong et al., Molecular Therapy, 2010; 18:413-420; Carpenito et al., PNAS, 2009; 106:3360-3365). In some embodiments, chimeric antigen receptor-expressing donor cells (eg, CAR-T cells) are cells that are derived from a patient with a disease or condition and are genetically engineered in vitro to express at least one CAR with a arbitrary specificity to a ligand. The cells carry out at least one effector function (eg, cytokine induction) that is stimulated or induced by specific ligand binding to CAR and that is useful for treatment of the same disease or condition of the patient. The effector cells can be T cells (eg, cytotoxic T cells or helper T cells). One of skill in the art would understand that other cell types (eg, a natural killer cell or stem cell) may express the CARs and that a chimeric antigen receptor effector cell may comprise an effector cell other than a T cell. In some embodiments, the effector cell is a T cell (eg, a cytotoxic T cell) that exerts its effector function (eg, a cytotoxic T cell response) on a target cell when it comes into contact with or in proximity to the target cell. target or target cell (eg a cancer cell) (see eg Chang and Chen (2017) Trends Mol Med 23(5):430-450). Prolonged exposure of T cells to their cognate antigen may result in depletion of effector functions, allowing the persistence of infected or transformed cells. Recently developed strategies to stimulate or rejuvenate host effector function using agents that induce immune checkpoint blockade have resulted in success towards the treatment of various cancers. Evidence has always suggested that T cell depletion may also represent a significant impediment in sustaining long-term antitumor activity by chimeric antigen receptor-expressing T cells (CAR-T cells. In some modalities, the differentiation status of the T cells collected from the patient prior to CAR-transduction and the conditioning regimen a patient undergoes prior to reintroduction of CAR-T cells (eg, addition or exclusion of alkylating agents, fludarabine, total body irradiation ) can profoundly affect the persistence and cytotoxic potential of CAR-T cells.In vitro culture conditions that stimulate (via anti-CD3 / CD28 or stimulatory cells) and expand (via cytokines, such as IL- 2) T cell populations can also alter the differentiation status and effector function of CAR-T cells (Ghoneim et al., (2016) Trends in Molecular Medicine 22(12):1000-1011). In some modalities, particularly for the treatment of ALL and / or NHL, suitable CARs target CD19 or CD20. Non-limiting examples include CARs comprising a structure: (i) an anti-CD19 scFv, a CD8 H / TM domain, a 4-1BB cefrenn / Lznz / B / YiAi domain 116 CS and a ΟΟ3ζ TCR signaling domain; (ii) an anti-CD19 scFv, a CD28 hinge and transmembrane domain, a CD28 co-stimulatory domain and a Οϋ3ζ TCR signaling domain; and (iii) an anti-CD20 scFv, an IgG hinge and transmembrane domain, a CD28 / 4-1BB costimulatory domain, and a ΰϋ3ζ TCR signaling domain. In some embodiments, a suitable CAR effector cell for combination with the combinations and methods described herein target CD19 or CD20, including but not limited to Kymriah™(tisagenlecleucel; Novartis; formerly CTL019) and Yescarta™(axicabtagene ciloleucel; Kite Pharma ). A. Re-Oriented CAR T Cells In some embodiments, the suitable CAR-T therapy for use in combination with immunomodulatory fusion proteins is a retargeted CAR-T cell. In some embodiments, effector cells (eg, T cells) modified to express a CAR that binds to a universal immune receptor, a tag, a switch, or an Fc region on an immunoglobulin are suitable for the methods described herein. In some embodiments, effector cells (eg, T cells) are modified to express a universal immune receptor or UnivIR. One type of UnivIR is a biotin-bindin...

Claims

1. An immunomodulatory fusion protein, characterized in that it comprises: (i) an immunomodulatory fusion domain; (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a Kd < 500 nM, and wherein the collagen-binding domain has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa; and (iii) optionally, a linker, wherein the immunomodulatory domain is operably linked with or without the linker to the collagen-binding domain.

2. The immunomodulatory fusion protein according to claim 1, characterized in that the Kd of the collagen-binding domain for type I and / or type IV collagen is less than the Kd of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen.

3. The immunomodulatory fusion protein according to any of claims 1-2, characterized in that the collagen-binding domain has an MW of approximately 5-100 kDa, approximately 10-80 kDa, approximately 20-60 kDa, approximately 30-50 kDa, or approximately 10 kDa, approximately 20 kDa, approximately 30 kDa, approximately 40 kDa, approximately 50 kDa, approximately 60 kDa, approximately 70 kDa, approximately 80 kDa, approximately 90 kDa or approximately 100 kDa.

4. The immunomodulatory fusion protein according to any of claims 1-3, characterized in that the collagen-binding domain comprises one or more leucine-rich repeats that bind to collagen.

5. The immunomodulatory fusion protein according to claim 4, characterized in that the collagen-binding domain comprises two, three, four, five, six, seven, eight, nine or ten collagen-binding leucine-rich repeats.

6. The immunomodulatory fusion protein according to any of claims 1-5, characterized in that the collagen-binding domain comprises one or more leucine-rich repeats of a human class II proteoglycan member of the small leucine-rich proteoglycan (SLRP) family.

7. The immunomodulatory fusion protein according to claim 6, characterized in that the SLRP is selected from lumican, decorin, biglican, fibromodulin, cefrenn / ίζηζ / Β / γίΛΐ 252 chondroadherin, asporin, PRELP, osteoadherin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen.

8. The immunomodulatory fusion protein according to claim 7, characterized in that the SLRP is lumican.

9. The immunomodulatory fusion protein according to any of claims 1-5, characterized in that the collagen-binding domain comprises human SLRP.

10. The immunomodulatory fusion protein according to claim 9, characterized in that the SLRP is selected from lumican, decorin, biglican, fibromodulin, chondroadherin, asporin, PRELP, osteoadherin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen.

11. The immunomodulatory fusion protein according to claim 10, characterized in that the SLRP is lumican.

12. The immunomodulatory fusion protein according to claim 11, characterized in that the lumican comprises the amino acid sequence as set out in SEQ ID NO:

107.

13. The immunomodulatory fusion protein according to any of claims 1-3, characterized in that the collagen-binding domain comprises a human type I glycoprotein having an Ig-like domain, or an extracellular portion thereof that binds to collagen.

14. The immunomodulatory fusion protein according to claim 13, characterized in that the type I glycoprotein competes with lumican for binding to type I collagen.

15. The immunomodulatory fusion protein according to any of claims 13-14, characterized in that the human type I glycoprotein is selected from LAIR1, LAIR2, and Glycoprotein IV.

16. The immunomodulatory fusion protein according to claim 14, characterized in that the human type I glycoprotein is LAIR1.

17. The immunomodulatory fusion protein according to claim 13, characterized in that the human type I glycoprotein is LAIR1 and the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set out in SEQ ID NO:

98.

18. The immunomodulatory fusion protein according to any of claims 1-3, characterized in that the collagen-binding domain comprises a LAIR1 variant comprising one or more amino acid substitutions, additions or deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein which comprises the amino acid sequence of SEQ ID NO:

98.

19. The immunomodulatory fusion protein according to any of claims 1-3, characterized in that the collagen-binding domain comprises a LAIR1 variant having increased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

20. The immunomodulatory fusion protein according to any of claims 1-3, characterized in that the collagen-binding domain comprises a LAIR1 variant having decreased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

21. The immunomodulatory fusion protein according to any of claims 1-20, characterized in that the immunomodulatory domain comprises a polypeptide that activates, enhances or promotes a response by an immune cell.

22. The immunomodulatory fusion protein according to any of claims 1-20, characterized in that the immunomodulatory domain comprises a polypeptide that inhibits, reduces or suppresses a response by an immune cell.

23. The immunomodulatory fusion protein according to any of claims 21-22, characterized in that the immune cell is a lymphoid cell selected from an innate lymphoid cell, a T cell, a B cell, an NK cell, and a combination thereof.

24. The immunomodulatory fusion protein according to any of claims 21-23, characterized in that the immune cell is a myeloid cell selected from a monocyte, a neutrophil, a granulocyte, a mast cell, a macrophage, a dendritic cell, and a combination thereof.

25. The immunomodulatory fusion protein according to any of claims 21-24, characterized in that the immune cell response comprises cytokine production, antibody production, antigen-specific immune cell production, increased effector function and / or cytotoxicity, and a combination thereof.

26. The immunomodulatory fusion protein according to any of claims 21-25, characterized in that the immunomodulatory domain comprises one or more selected from a cytokine, a chemokine, an activating ligand / receptor, an inhibitory ligand / receptor, or a combination thereof.

27. The immunomodulatory fusion protein according to claim 26, characterized in that the immunomodulatory domain comprises one or more cytokines.

28. The immunomodulatory fusion protein according to claim cefrenn / Lznz / B / YiAi 254 27, characterized in that the cytokine is a human gamma common chain receptor interleukin selected from IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-15 / IL-15RA, IL-21, and a combination thereof.

29. The immunomodulatory fusion protein according to claim 28, characterized in that the cytokine is IL-2.

30. The immunomodulatory fusion protein according to claim 27, characterized in that the cytokine is a member of the human IL-12 family selected from IL-12(p35), IL-12(p40), IL-12(p35) / IL-12(p40), IL-23, IL-27, IL-35, and a combination thereof.

31. The immunomodulatory fusion protein according to claim 30, characterized in that the cytokine is a single-chain fusion of IL-12(p35) / IL12(p40).

32. The immunomodulatory fusion protein according to claim 27, characterized in that the cytokine is a member of the human IL-1 family selected from IL-1, IL-18, IL-33, and a combination thereof.

33. The immunomodulatory fusion protein according to claim 32, characterized in that the cytokine is IL-18.

34. The immunomodulatory fusion protein according to claim 27, characterized in that the cytokine is selected from TNFα, INFα, IFN-γ, GM-CSF, FLT3L, G-CSF, M-CSF, and a combination thereof.

35. The immunomodulatory fusion protein according to claim 26, characterized in that the immunomodulatory domain comprises one or more chemokines.

36. The immunomodulatory fusion protein according to claim 35, characterized in that the chemokine is selected from LIF, MIP-2, MIR-1α, MIR-1β, CXCL1, CXCL9, CXCL10, MCP-1, Eotaxin, RANTES, LIX and a combination thereof.

37. The immunomodulatory fusion protein according to claim 35, characterized in that the chemokine is selected from CCL3, CCL4, CCL5, Eotaxin and a combination thereof.

38. The immunomodulatory fusion protein according to claim 26, characterized in that the immunomodulatory domain comprises one or more activating ligand / receptors.

39. The immunomodulatory fusion protein according to claim 38, characterized in that the activating ligand / receptor is selected from a TNF superfamily, a CD28 receptor superfamily, a B7 ligand family, and a T cell receptor.

40. The immunomodulatory fusion protein according to claim 39, characterized in that the activation ligand / receptor is a ligand of the cebenn / Lznz / B / YiAi 255 TNF superfamily selected from TNF-alpha, CD40L, 4-1BBL, 0X40, and a combination thereof.

41. The immunomodulatory fusion protein according to claim 39, characterized in that the activation ligand / receptor is a receptor of the TNF superfamily and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from an anti-TNFR1 antibody, an anti-TNFR2 antibody, an anti-CD40 antibody, an anti-4-1BB antibody and an anti-QX40 antibody.

42. The immunomodulatory fusion protein according to claim 39, characterized in that the activating ligand / receptor is a member of the CD28 superfamily or a member of the B7 family selected from ICOS ligand, CD80, and CD86, and a combination thereof.

43. The immunomodulatory fusion protein according to claim 39, characterized in that the activation ligand / receptor is a member of the CD28 superfamily and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from an anti-ICOS antibody and an anti-CD28 antibody.

44. The immunomodulatory fusion protein according to claim 39, characterized in that the activation ligand / receptor is a T cell receptor and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from an anti-CD3y antibody, an anti-CD3o antibody, an anti-Oϋ3ζ antibody, and an anti-CD3e antibody.

45. The immunomodulatory fusion protein according to claim 26, characterized in that the immunomodulatory domain comprises one or more inhibitory ligands / receptors.

46. ​​The immunomodulatory fusion protein according to claim 45, characterized in that the inhibitory ligand / receptor is selected from a CD28 receptor superfamily, a TNF superfamily, and a checkpoint inhibitor.

47. The immunomodulatory fusion protein according to claim 46, characterized in that the inhibitory ligand / receptor is a member of the CD28 superfamily and the immunomodulatory domain comprises an antibody or antigen-binding fragment thereof selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-CTLA4 antibody.

48. The immunomodulatory fusion protein according to claim 46, characterized in that the inhibitory ligand / receptor is a member of the TNF superfamily and the immunomodulatory domain comprises an antibody or antigen-binding fragment selected from an anti-TIGIT antibody and an anti-BTLA antibody.

49. The immunomodulatory fusion protein according to claim 46, characterized in that the inhibitory ligand / receptor is a checkpoint inhibitor and the immunomodulatory domain comprises an antibody or antigen-binding fragment cefrenn / Lznz / B / γALA 256 selected from an anti-VISTA antibody, an anti-TIM-3 antibody, an anti-LAG3 antibody, an anti-CD47 antibody, and an anti-SIRPa antibody.

50. The immunomodulatory fusion protein according to any of claims 1-49, characterized in that the immunomodulatory domain is operably linked to the collagen-binding domain via a linker.

51. The immunomodulatory fusion protein according to claim 50, characterized in that the linker is of sufficient length or mass to reduce the adsorption of the immunomodulatory domain onto collagen fibrils.

52. The immunomodulatory fusion protein according to claim 50, characterized in that the linker provides a sufficient molecular weight to the fusion protein to reduce diffusion from a tissue.

53. The immunomodulatory fusion protein according to claim 50, characterized in that the ligand allows steric separation of the immunomodulatory domain from collagen fibrils to promote receptor / ligand docking.

54. The immunomodulatory fusion protein according to any of claims 51-53, characterized in that the linker is a hydrophilic polypeptide comprising “N” amino acids in length, wherein 1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400.

55. The immunomodulatory fusion protein according to claim 50, characterized in that the binder is a human serum albumin or a fragment thereof.

56. The immunomodulatory fusion protein according to claim 50, characterized in that the linker comprises an Fe domain or a mutant Fe domain with reduced FcR interaction.

57. The immunomodulatory fusion protein according to any of claims 1-56, characterized in that the fusion protein is of sufficient mass to reduce size-dependent escape by diffusion or convection upon in vivo administration.

58. The immunomodulatory fusion protein according to claim 50, characterized in that the fusion protein is > 60 kDa.

59. The immunomodulatory fusion protein according to claim 50, characterized in that the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing systemic exposure of the immunomodulatory fusion protein.

60. An immunomodulatory fusion protein, characterized in that it comprises: (i) at least one cytokine; (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a KD < 500 nM, and wherein the collagen-binding domain has an isoelectric point < 10 and a molecular weight (MW) of > 5 kDa; and (i) a linker, wherein the linker is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein the cytokine is operably bound via the linker to the collagen-binding domain, and wherein the fusion protein is > 60 kDa.

61. The immunomodulatory fusion protein according to claim 60, characterized in that the Kd of the collagen-binding domain for type I and / or type IV collagen is less than the Kd of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen.

62. The immunomodulatory fusion protein according to any of claims 60-61, characterized in that the collagen-binding domain comprises a human SLRP selected from lumican, decorin, biglican, fibromodulin, chondroadherin, asporin, PRELP, osteoadherin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen.

63. The immunomodulatory fusion protein according to claim 62, characterized in that the SLRP is lumican.

64. The immunomodulatory fusion protein according to claim 63, characterized in that the lumican comprises the amino acid sequence as set out in SEQ ID NO:

107.

65. The immunomodulatory fusion protein according to any of claims 60-61, characterized in that the collagen-binding domain is selected from LAIR1, LAIR2, and Glycoprotein IV.

66. The immunomodulatory fusion protein according to claim 65, characterized in that the collagen-binding domain is LAIR1.

67. The immunomodulatory fusion protein according to claim 66, characterized in that the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set out in SEQ ID NO:

98.

68. The immunomodulatory fusion protein according to claim 66, characterized in that the collagen-binding domain comprises a LAIR1 variant comprising one or more amino acid substitutions, additions, or deletions, optionally two, three, four, five, six, seven, eight, nine, ten, or more amino acid substitutions, additions, or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98. cefrenn / Lznz / B / YiAi 258 69. The immunomodulatory fusion protein according to claim 66, characterized in that the collagen-binding domain comprises a LAIR1 variant having an increased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

70. The immunomodulatory fusion protein according to claim 66, characterized in that the collagen-binding domain comprises a LAIR1 variant having decreased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

71. The immunomodulatory fusion protein according to any of claims 60-70, characterized in that the cytokine is a human gamma common chain receptor interleukin selected from IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, IL-15 / IL15RA, IL-21, and a combination thereof.

72. The immunomodulatory fusion protein according to claim 71, characterized in that the cytokine is IL-2.

73. The immunomodulatory fusion protein according to any of claims 60-70, characterized in that the cytokine is a member of the human IL-12 family selected from IL-12(p35), IL-12(p40), IL-12(p35) / IL-12(p40), IL-23, IL-27, IL-35, and a combination thereof.

74. The immunomodulatory fusion protein according to claim 73, characterized in that the cytokine is a single-chain fusion of IL-12(p35) / IL12(p40).

75. The immunomodulatory fusion protein according to claim 74 characterized in that it comprises a second cytokine, wherein the second cytokine is IL-2.

76. The immunomodulatory fusion protein according to any of claims 60-70, characterized in that the cytokine is a member of the human IL-1 family selected from IL-1, IL-18, IL-33, and a combination thereof. The immunomodulatory fusion protein according to any of claims 60-70, characterized in that the cytokine is selected from TNFα, INFα, IFN-γ, GM-CSF, FLT3L, G-CSF, M-CSF, and a combination thereof.

78. The immunomodulatory fusion protein according to any of claims 60-77, characterized in that the ligand is of sufficient length or mass to reduce the adsorption of the immunomodulatory domain on collagen fibrils, and / or provides sufficient molecular weight to the fusion protein to reduce diffusion from a tissue and / or allows spherical separation of the immunomodulatory domain from collagen fibrils to promote receptor / ligand docking.

79. The immunomodulatory fusion protein according to any of claims 60-77, characterized in that the binder is a human serum albumin or a fragment thereof.

80. The immunomodulatory fusion protein according to any of claims 60-77, characterized in that the linker comprises an Fe domain or a mutant Fe domain with reduced FcR interaction.

81. The immunomodulatory fusion protein according to any of claims 60-80, characterized in that the fusion protein is of sufficient mass to reduce size-dependent escape by diffusion or convection upon in vivo administration.

82. The immunomodulatory fusion protein according to any of claims 60-80, characterized in that the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing systemic exposure of the immunomodulatory fusion protein.

83. An immunomodulatory fusion protein characterized in that it comprises: (i) at least one chemokine; (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a Kd < 500 nM, and wherein the collagen-binding domain has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N = 1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein the chemokine is operably bound via the linker to the collagen-binding domain, and wherein the fusion protein is > 60 kDa.

84. The immunomodulatory fusion protein according to claim 83, characterized in that the KD of the collagen-binding domain for type I and / or type IV collagen is less than the KD of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen.

85. The immunomodulatory fusion protein according to any of claims 83-84, characterized in that the collagen-binding domain comprises a human SLRP selected from lumican, decorin, biglican, fibromodulin, chondroadherin, asporin, PRELP, osteoadherin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen.

86. The immunomodulatory fusion protein according to claim cefrenn / Lznz / B / YiAi 260 85, characterized in that the SLRP is lumican.

87. The immunomodulatory fusion protein according to claim 86, characterized in that the lumican comprises the amino acid sequence as set out in SEQ ID NO:

107.

88. The immunomodulatory fusion protein according to any of claims 83-84, characterized in that the collagen-binding domain is selected from LAIR1, LAIR2, and Glycoprotein IV.

89. The immunomodulatory fusion protein according to claim 88, characterized in that the collagen-binding domain is LAIR1.

90. The immunomodulatory fusion protein according to claim 89, characterized in that the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set out in SEQ ID NO:

98.

91. The immunomodulatory fusion protein according to claim 89, characterized in that the collagen-binding domain comprises a LAIR1 variant comprising one or more amino acid substitutions, additions or deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

92. The immunomodulatory fusion protein according to claim 89, characterized in that the collagen-binding domain comprises a LAIR1 variant having increased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

93. The immunomodulatory fusion protein according to claim 89, characterized in that the collagen-binding domain comprises a LAIR1 variant having decreased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

94. The immunomodulatory fusion protein according to any of claims 83-93, characterized in that the chemokine is selected from LIF, MIP-2, MIP1α, MIP-1β, CXCL1, CXCL9, CXCL10, MCP-1, Eotaxin, RANTES, LIX, and a combination thereof.

95. The immunomodulatory fusion protein according to claim 83-93, characterized in that the chemokine is selected from CCL3, CCL4, CCL5, Eotaxin and a combination thereof.

96. The immunomodulatory fusion protein according to any of claims 83-95, characterized in that the ligand is of sufficient length or mass to reduce the adsorption of the immunomodulatory domain on collagen fibrils, and / or provides sufficient molecular weight to the fusion protein to reduce diffusion from a tissue and / or allows spherical separation of the immunomodulatory domain from collagen fibrils to promote receptor / ligand docking.

97. The immunomodulatory fusion protein according to any of claims 83-95, characterized in that the binder is a human serum albumin or a fragment thereof.

98. The immunomodulatory fusion protein according to any of claims 83-95, characterized in that the linker comprises an Fe domain or a mutant Fe domain with reduced FcR interaction.

99. The immunomodulatory fusion protein according to any of claims 83-98, characterized in that the fusion protein is of sufficient mass to reduce size-dependent escape by diffusion or convection upon in vivo administration.

100. The immunomodulatory fusion protein according to any of claims 83-98, characterized in that the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing systemic exposure of the immunomodulatory fusion protein.

101. An immunomodulatory fusion protein, characterized in that it comprises: (i) an agonist antibody that binds to a ligand / receptor comprising an Fe domain or a mutant Fe domain with reduced FcR interaction; and (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a Kd < 500 nM, and wherein the collagen-binding domain has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa, wherein the collagen-binding domain is operably ligated to the C-terminus of the Fe domain or mutant Fe domain.

102. The immunomodulatory fusion protein according to claim 101, characterized in that the KD of the collagen-binding domain for type I and / or type IV collagen is less than the Kd of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen.

103. The immunomodulatory fusion protein according to any of claims 101-102, characterized in that the collagen-binding domain comprises a human SLRP selected from lumican, decorin, biglican, fibromodulin, chondroadherin, asporin, PRELP, osteoadherin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen. cefrenn / Lznz / B / YiAi 262 104. The immunomodulatory fusion protein according to claim 103, characterized in that the SLRP is lumican.

105. The immunomodulatory fusion protein according to claim 104, characterized in that the lumican comprises the amino acid sequence as set out in SEQ ID NO:

107.

106. The immunomodulatory fusion protein according to any of claims 101-102, characterized in that the collagen-binding domain is selected from LAIR1, LAIR2, and Glycoprotein IV.

107. The immunomodulatory fusion protein according to claim 106, characterized in that the collagen-binding domain is LAIR1.

108. The immunomodulatory fusion protein according to claim 107, characterized in that the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set out in SEQ ID NO:

98.

109. The immunomodulatory fusion protein according to claim 107, characterized in that the collagen-binding domain comprises a LAIR1 variant comprising one or more amino acid substitutions, additions or deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

110. The immunomodulatory fusion protein according to claim 107, characterized in that the collagen-binding domain comprises a LAIR1 variant having a higher collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

111. The immunomodulatory fusion protein according to claim 107, characterized in that the collagen-binding domain comprises a variant having decreased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

112. The immunomodulatory fusion protein according to any of claims 101-111, characterized in that the agonist antibody is selected from an anti-TNFR1 antibody, an anti-TNFR2 antibody, an anti-CD40 antibody, an anti-4-1BB antibody, and an anti-OX40 antibody.

113. The immunomodulatory fusion protein according to any of claims 101-111, characterized in that the agonist antibody is selected from an anti-ICOS antibody and an anti-CD28 antibody.

114. The immunomodulatory fusion protein according to any of claims 101-111, characterized in that the antibody is selected from an anti-CD3y antibody, an anti-CD3o antibody, a 3ηύ-Oϋ3ζ antibody, and an anti-CD3s antibody. cefrenn / Lznz / B / γΐΛΐ 263 115. The immunomodulatory fusion protein according to any of claims 101-114, characterized in that the fusion protein is of sufficient mass to reduce size-dependent escape by diffusion or convection upon in vivo administration.

116. The immunomodulatory fusion protein according to any of claims 101-114, characterized in that the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing systemic exposure of the immunomodulatory fusion protein.

117. An immunomodulatory fusion protein, characterized in that it comprises: (i) an antagonistic antibody that binds to an inhibitory ligand / receptor comprising an Fe domain or a mutant Fe domain with reduced FcR interaction; and (ii) a collagen-binding domain, wherein the collagen-binding domain specifically binds type I and / or type IV collagen and binds type I collagen with a Kd < 500 nM, and wherein the collagen-binding domain has an isoelectric point pl < 10 and a molecular weight (MW) of > 5 kDa, wherein the collagen-binding domain is operably ligated to the C-terminus of the Fe domain or mutant Fe domain.

118. The immunomodulatory fusion protein according to claim 117, characterized in that the Kd of the collagen-binding domain for type I and / or type IV collagen is less than the Kd of the collagen-binding domain for an extracellular matrix component selected from fibronectin, vitronectin, osteopontin, tenascin C, or fibrinogen.

119. The immunomodulatory fusion protein according to any of claims 117-118, characterized in that the collagen-binding domain comprises a human SLRP selected from lumican, decorin, biglican, fibromodulin, chondroadherin, asporin, PRELP, osteoadherin / osteomodulin, opticin, osteoglycin / mimecan, podocan, perlecan, and nidogen.

120. The immunomodulatory fusion protein according to claim 119, characterized in that the SLRP is lumican.

121. The immunomodulatory fusion protein according to claim 120, characterized in that the lumican comprises the amino acid sequence as set out in SEQ ID NO:

107.

122. The immunomodulatory fusion protein according to any of claims 117-118, characterized in that the collagen-binding domain is selected from LAIR1, LAIR2, and Glycoprotein IV.

123. The immunomodulatory fusion protein according to claim 122, characterized in that the collagen-binding domain is LAIR1. cefrenn / Lznz / B / YiAi 264 124. The immunomodulatory fusion protein according to claim 111, characterized in that the collagen-binding domain comprises amino acid residues 22-122 of the amino acid sequence as set out in SEQ ID NO:

98.

125. The immunomodulatory fusion protein according to claim 123, characterized in that the collagen-binding domain comprises a LAIR1 variant comprising one or more amino acid substitutions, additions or deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

126. The immunomodulatory fusion protein according to claim 123, characterized in that the collagen-binding domain comprises a LAIR1 variant having increased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

127. The immunomodulatory fusion protein according to claim 123, characterized in that the collagen-binding domain comprises a LAIR1 variant having decreased collagen-binding affinity with respect to a collagen-binding affinity of a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

128. The immunomodulatory fusion protein according to any of claims 117-127, characterized in that the agonist antibody is selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-CTLA4 antibody, an anti-TIGIT antibody, an anti-BTLA antibody, an anti-VISTA antibody, an anti-TIM-3 antibody, an anti-LAG-3 antibody, an anti-CD47 antibody, and an anti-SIRPa antibody.

129. The immunomodulatory fusion protein according to any of claims 117-128, characterized in that the fusion protein is of sufficient mass to reduce size-dependent escape by diffusion or convection upon in vivo administration.

130. The immunomodulatory fusion protein according to any of claims 117-128, characterized in that the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing systemic exposure of the immunomodulatory fusion protein.

131. An immunomodulatory fusion protein, characterized in that it comprises: (i) human IL-2; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising cebenn / Lznz / B / YiAi 265 amino acids “N” in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein IL-2 is operably linked through the linker to lumican or LAIR1, and wherein the fusion protein is > 60 kDa.

132. An immunomodulatory fusion protein, characterized in that it comprises: (i) a human IL-12(p35) / IL-12(p40) single-chain fusion; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein the IL-12(p35) / IL-12(p40) single-chain fusion is operably linked through the linker to lumican or LAIR1, and wherein the fusion protein is > 60 kDa.

133. An immunomodulatory fusion protein, characterized in that it comprises: (i) human CCL-3; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein CCL-3 is operably linked through the linker to lumican or LAIR1, and wherein the fusion protein is > 60 kDa.

134. An immunomodulatory fusion protein, characterized in that it comprises: (i) human CCL-4; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein CCL-4 is operably linked through the linker to lumican or LAIR1, and wherein the fusion protein is > 60 kDa.

135. An immunomodulatory fusion protein, characterized in that it comprises: (i) human CCL-5; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising “N” amino acids in length, where N = 1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein CCL-5 is operably linked via the linker to lumican or LAIR1, and wherein the fusion protein is > 60 kDa. cefrenn / Lznz / B / YiAi 266 136. An immunomodulatory fusion protein, characterized in that it comprises: (i) human eotaxin; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a linker, wherein the linker is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein Eotaxin is operably linked through the linker to lumican or LAIR1, and wherein the fusion protein is > 60 kDa.

137. The immunomodulatory fusion protein according to any of claims 131-136, characterized in that the lumican comprises the amino acid sequence as set out in SEQ ID NO:

107.

138. The immunomodulatory fusion protein according to any of claims 131-136, characterized in that LAIR1 comprises the amino acid sequence as set forth in SEQ ID NO: 98, or comprises one or more amino acid substitutions, additions or deletions, optionally two, three, four, five, six, seven, eight, nine, ten or more amino acid substitutions, additions or deletions with respect to a LAIR1 protein comprising the amino acid sequence of SEQ ID NO:

98.

139. The immunomodulatory fusion protein according to any of claims 131-138, characterized in that the ligand is of sufficient length or mass to reduce the adsorption of the immunomodulatory domain onto collagen fibrils, and / or provides sufficient molecular weight to the fusion protein to reduce diffusion from a tissue and / or allows steric separation of the immunomodulatory domain from collagen fibrils to promote receptor / ligand docking.

140. The immunomodulatory fusion protein according to any of claims 131-138, characterized in that the binder is a human serum albumin or a fragment thereof.

141. The immunomodulatory fusion protein according to any of claims 131-138, characterized in that the linker comprises an Fe domain or a mutant Fe domain with reduced FcR interaction.

142. The immunomodulatory fusion protein according to any of claims 131-141, characterized in that the fusion protein is of sufficient mass to reduce size-dependent escape by diffusion or convection upon in vivo administration.

143. The immunomodulatory fusion protein according to any of claims 131-142, characterized in that the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing systemic exposure of the immunomodulatory fusion protein. cefrenn / ίζηζ / ε / γίΛΐ 267 144. An immunomodulatory fusion protein, characterized in that it comprises: (i) an agonist antibody comprising an Fe domain or a mutant Fe domain with reduced FcR interaction, wherein the agonist antibody is selected from an anti-CD3 antibody, an anti-4-1-BB antibody, an anti-CD40 antibody, and an anti-OX40 antibody; and (ii) human lumican, human LAIR1, or human LAIR1 variant; wherein lumican or LAIR1 is operably ligated to the C-terminal of the Fe domain or mutant Fe domain.

145. The immunomodulatory fusion protein according to claim 144, characterized in that the fusion protein is of sufficient mass to reduce size-dependent escape by diffusion or convection upon in vivo administration.

146. The immunomodulatory fusion protein according to any of claims 144-145, characterized in that the fusion protein binds to type I and / or type IV collagen upon in vivo administration, thereby reducing systemic exposure of the immunomodulatory fusion protein.

147. A pharmaceutical composition, characterized in that it comprises an immunomodulatory fusion protein according to any of the preceding claims, and a pharmaceutically acceptable carrier.

148. A nucleic acid, characterized in that it comprises a nucleotide sequence encoding an immunomodulatory fusion protein according to any of claims 1-146.

149. An expression vector, characterized in that it comprises the nucleic acid according to claim 148.

150. A cell, characterized in that it is transformed with an expression vector in accordance with claim 149.

151. A method for producing an immunomodulatory fusion protein, the method being characterized in that it comprises maintaining a cell according to claim 150 under conditions that permit expression of the immunomodulatory fusion protein.

152. The method according to claim 151, further characterized in that it comprises obtaining the immunomodulatory fusion protein.

153. A method for activating, enhancing, or promoting a response by means of an immune cell in a subject, characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein in accordance with any of claims 1-146, or the pharmaceutical composition of claim 147.

154. A method for inhibiting, reducing, or suppressing an immune cell response in a subject, characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein of cefrenn / Lznz / B / YiAi 268 in accordance with any of claims 1-146, or the pharmaceutical composition of claim 147.

155. The method according to any of claims 153-154, characterized in that the T cell is a lymphoid cell selected from an innate lymphoid cell, a T cell, a B cell, an NK cell, and combinations thereof.

156. The method according to any of claims 153-154, characterized in that the immune cell is a myeloid cell selected from a monocyte, a neutrophil, a granulocyte, a mast cell, a macrophage, a dendritic cell, and a combination thereof.

157. The method according to any of claims 153-156, characterized in that the immune cell response comprises cytokine production, antibody production, production of antigen-specific immune cells, increased effector function and / or cytotoxicity, and a combination thereof.

158. The method according to any of claims 153-157, characterized in that the immune cell response is presented by a tumor microenvironment.

159. A method for reducing or inhibiting tumor growth, characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein in accordance with claims 1-146, or the pharmaceutical composition of claim 147.

160. A method for treating cancer in a subject, characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein in accordance with claims 1-146, or the pharmaceutical composition of claim 147.

161. The method according to any of claims 159-160, characterized in that the antitumor immune response is induced in the subject after administration of the immunomodulatory fusion protein or pharmaceutical composition.

162. The method according to claim 161, characterized in that the antitumor immune response is a T cell response comprising the production of IFNγ and / or IL-2 by one or both CD4+ T cells and CD8+ T cells.

163. The method according to any of claims 159-162, characterized in that the infiltration of immune cells into a tumor microenvironment is increased after administration of the immunomodulatory fusion protein or pharmaceutical composition.

164. The method according to any of claims 159-163, characterized in that the number of regulatory T cells (Treg) is reduced in a tumor microenvironment or T cell depletion is reduced in a tumor microenvironment cefrenn / Lznz / B / YiAi 269 after administration of the immunomodulatory fusion protein or pharmaceutical composition.

165. The method according to any of claims 153-164, characterized in that the immunomodulatory fusion protein or pharmaceutical composition is administered intratumorally.

166. A kit, characterized in that it comprises a container comprising an immunomodulatory fusion protein according to any of claims 1-146, and an optional pharmaceutically acceptable carrier, or a pharmaceutical composition of claim 147, and a package insert comprising instructions for administering the fusion protein or pharmaceutical composition, to treat or delay the progression of cancer or reduce or inhibit tumor growth in a subject in need thereof.

167. A kit, characterized in that it comprises a container comprising an immunomodulatory fusion protein in accordance with any of claim 1146, and an optional pharmaceutically acceptable carrier, or a pharmaceutical composition of claim 147, and a package insert comprising instructions for the administration of the antibody or pharmaceutical composition alone or in combination with another agent, to treat or delay the progression of cancer or reduce or inhibit tumor growth in a subject in need thereof.

168. Use of an immunomodulatory fusion protein according to any of claims 1-146, and an optional pharmaceutically acceptable carrier, or a pharmaceutical composition of claim 147, for the manufacture of a medicament to treat or delay the progression of cancer or reduce or inhibit tumor growth in a subject in need thereof.

169. An immunomodulatory fusion protein according to any of claims 1-146, characterized in that it includes an optional pharmaceutically acceptable carrier, or a pharmaceutical composition of claim 147, in the manufacture of a medicament for treating or delaying the progression of cancer or reducing or inhibiting tumor growth in a subject in need thereof.

170. An immunomodulatory fusion protein conforming to any of claims 1-146, and an optional pharmaceutically acceptable carrier, or a pharmaceutical composition of claim 147, characterized in that it is for use as a medicament.

171. A method for reducing or inhibiting tumor growth or treating cancer in a subject, the method being characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein in accordance with any of claims 1-146, or the pharmaceutical composition of claim cefrenn / Lznz / B / YiAi 270 147, and an effective amount of a second composition comprising a tumor antigen-targeting antibody, or antigen-binding fragment thereof, thereby reducing or inhibiting tumor growth or treating cancer in the subject.

172. The method according to claim 156, characterized in that the tumor antigen is a tumor-associated antigen (TAA), a tumor-specific antigen (TSA), or a tumor neoantigen.

173. The method according to any of claims 171-172, characterized in that the tumor antigen targeting antibody binds specifically to human HER-2 / neu, EGFR, VEGFR, CD20, CD33, or CD38.

174. A method for reducing or inhibiting tumor growth or treating cancer in a subject, the method being characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein in accordance with any of claim 146, or the pharmaceutical composition of claim 147, and an effective amount of a second composition comprising a cancer vaccine, thereby reducing or inhibiting tumor growth or treating cancer in the subject.

175. The method according to claim 174, characterized in that the cancer vaccine is a population of cells immunized in vitro with a tumor antigen and is administered to the subject.

176. The method according to claim 174, characterized in that the cancer vaccine is a peptide comprising one or more tumor-associated antigens.

177. The method according to claim 174, characterized in that the cancer vaccine is an amphiphilic peptide conjugate comprising a tumor-associated antigen, a lipid, and optionally a ligand, wherein the amphiphilic peptide conjugate binds to albumin under physiological conditions.

178. The method according to any of claims 174-177, characterized in that the cancer vaccine further comprises an adjuvant.

179. A method for reducing or inhibiting tumor growth or treating cancer in a subject, the method being characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein in accordance with any of claims 1-146, or the pharmaceutical composition of claim 147, and an effective amount of a second composition comprising an immune checkpoint inhibitor, thereby reducing or inhibiting tumor growth or treating cancer in the subject.

180. The method according to claim 179, characterized in that the immune checkpoint inhibitor comprises an antibody or antigen-binding fragment thereof that binds to PD-1, PD-L1, CTLA-4, LAG3, or TIM3. cefrenn / Lznz / B / YiAi 271 181. A method for reducing or inhibiting tumor growth or treating cancer in a subject, the method being characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein in accordance with any of claims 1-146, or the pharmaceutical composition of claim 147, and an effective amount of a second composition comprising an adoptive cell therapy, thereby reducing or inhibiting tumor growth or treating cancer in the subject.

182. The method according to claim 181, characterized in that the adoptive cell therapy comprises an immune effector cell comprising a chimeric antigen receptor (CAR) molecule that binds to a tumor antigen.

183. The method according to any of claims 181-182, characterized in that the CAR molecule comprises an antigen-binding domain, a transmembrane domain, and an intracellular domain comprising a co-stimulatory domain and / or a primary signaling domain.

184. The method according to claim 183, characterized in that the antigen-binding domain binds to the disease-associated tumor antigen.

185. The method according to claim 183, characterized in that the tumor antigen is selected from CD19, EGFR, Her2 / neu, CD30 and BCMA.

186. The method according to any of claims 182-185, characterized in that the immune effector cell is a T cell, such as a CD8+ T cell.

187. The method according to any of claims 182-185, characterized in that the immune effector cell is a natural killer (NK) cell.

188. The method according to any of claims 182-185, characterized in that the immunomodulatory fusion protein or pharmaceutical composition is administered intratumorally.

189. The method according to any of claims 171-188, characterized in that the immunomodulatory fusion protein or pharmaceutical composition and the second composition are administered concurrently or sequentially.

190. A method for reducing or inhibiting tumor growth or treating cancer in a subject, the method being characterized in that it comprises administering to a subject in need thereof, an effective amount of the immunomodulatory fusion protein comprising: (i) human IL-2; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a ligand, wherein the ligand is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein IL-2 is operably ligated through the ligand to lumican or LAIR1, and wherein the fusion protein is > 60 kDa, thereby reducing or inhibiting tumor growth or treating cancer in the subject.

191. A method for reducing or inhibiting tumor growth or treating cancer in a subject, the method being characterized in that it comprises administering to a subject in need thereof, an effective amount of an immunomodulatory fusion protein comprising: (i) a single-chain fusion of human IL-12(p35) / IL-12(p40); (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a ligand, wherein the ligand is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein the single-chain fusion of IL-12(p35) / IL-12(p40) is operably ligated through the ligand to lumican or LAIR1, and wherein the fusion protein is > 60 kDa, thereby reducing or inhibiting tumor growth or treating cancer in the subject.

192. The method according to claim 190, further characterized in that it comprises administering a second composition comprising an effective amount of an immunomodulatory fusion protein comprising: (i) a human IL-12(p35) / IL-12(p40) single-chain fusion; (ii) human lumican, human LAIR1, or human LAIR1 variant; and (iii) a ligand, wherein the ligand is a hydrophilic polypeptide comprising “N” amino acids in length, wherein N=1-1000, 10-900, 30-800, 40-700, 50-600, 100-500, or 200-400, wherein the IL-12(p35) / IL-12(p40) single-chain fusion is operably ligated through the ligand to lumican or LAIR1, and wherein the fusion protein is > 60 kDa.

193. The method according to any of claims 190-192, further characterized in that it comprises administering a second composition comprising an effective amount of a tumor antigen-targeting antibody, or antigen-binding fragment thereof.

194. The method according to any of claims 190-193, further characterized in that it comprises administering a second composition comprising an effective amount of the composition comprising a cancer vaccine.

195. The method according to any of claims 190-194, further characterized in that it comprises administering a second composition comprising an effective amount of a second composition comprising an immune checkpoint inhibitor.

196. The method according to claim 195, characterized in that the immune checkpoint inhibitor comprises an antibody or antigen-binding fragment thereof that binds PD-1, PD-L1, CTLA-4, LAG3, or TIM3.

197. The method according to any of claims 190-196, further characterized in that it comprises administering a second composition comprising an effective amount of a second composition comprising an adoptive cell therapy, thereby reducing or inhibiting tumor growth or treating cancer in the subject.

198. The method according to claim 197, characterized in that the adoptive cell therapy comprises an immune effector cell comprising a chimeric antigen receptor (CAR) molecule that binds to a tumor antigen.

199. The method according to claim 198, characterized in that the immune effector cell is a T cell, such as a CD8+ T cell or an NK cell.

200. The method according to any of claims 190-199, characterized in that the immunomodulatory fusion protein or pharmaceutical composition is administered intratumorally.

201. The method according to any of claims 190-200, characterized in that the immunomodulatory fusion protein or pharmaceutical composition and the second composition are administered concurrently or sequentially.