Bispecific signaling agents and uses thereof

Abstract

The present invention relates, in part, to bispecific chimeric proteins that find use in various immunotherapies based on various properties, including, for example, a dual immune cell recruitment and immune signal delivery function.

Description

BISPECIFIC SIGNALING AGENTS AND USES THEREOF FIELD The present invention relates, in part, to chimeric proteins that can recruit effector cells and deliver signaling to provide beneficial effects. DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY The contents of the text file submitted electronically herewith: A computer readable format copy of the Sequence Listing (filename: ORN-009PC_Sequence_listing; date recorded: February 3, 2017; file size: 386 KB). BACKGROUND Cancer is a global health challenge that causes nearly 7 million deaths each year worldwide and which has, to date, proven largely untreatable despite major advances in medicine. Frustratingly, cancers appear to develop strategies to evade immune detection and destruction thereby sidestepping the body's main protection against disease. Many recent immunotherapies have been developed to re-direct the body's immune system towards cancers. Immunotherapy provides the advantage of cell specificity that other treatment modalities, such as chemotherapy and radiation, lack. As such, methods for enhancing the efficacy of immune based therapies can be clinically beneficial. For example, costimulatory and coinhibitory molecules play a central role in the regulation of T cell immune responses. However, despite impressive patient responses to agents targeting these costimulatory and coinhibitory molecules, including, for example, clinical trials that led to the approval of YERVOY, KEYTRUDA, and OPDIVO, checkpoint inhibition therapy still fails in the overwhelming majority of patients. Further, most cancer treatments, including immunotherapies, require complex regimens of various agents - each typically bringing a complex pattern of side effects that narrows a patient's therapeutic window for treatment and makes the patient more susceptible to other diseases. Therefore, there remains a need for improved immunotherapeutic agents, including those that can effectively modulate the immune system in a multifunctional manner. SUMMARY In some aspects, the present invention relates to chimeric proteins which find use in various targeted cell methods. In some aspects, the present invention relates to chimeric proteins having two or more targeting moieties which have recognition domains (e.g. antigen recognition domains, including without limitation various antibody formats, inclusive of single-domain antibodies) which specifically bind to a target (e.g. antigen, receptor) of interest. The chimeric protein further comprises a modified (e.g. mutant) signaling agent (for instance, an immune-modulating agent), the modified (e.g. mutant) signaling agent having one or more modifications (e.g. mutations) that provide improved safety as compared to an unmodified (e.g. wild type) signaling agent. The targeting moieties and the modified (e.g. mutant) signaling agent are optionally connected by one or more linkers. In various embodiments, the targeting moieties having recognition domains that specifically bind to a target (e.g. antigen, receptor) of interest, including those found on one or more immune cells, which can include, without limitation, T cells, cytotoxic T lymphocytes, T helper cells, natural killer (NK) cells, natural killer T (NKT) cells, anti-tumor macrophages (e.g. M1 macrophages), neutrophils, B cells, and dendritic cells. In some embodiments, the recognition domains specifically bind to a target (e.g. antigen, receptor) of interest and effectively recruit one of more immune cells. In some embodiments, the targets (e.g. antigens, receptors) of interest can be found on one or more tumor cells. In these embodiments, the present chimeric proteins may recruit an immune cell, e.g. an immune cell that can kill and / or suppress a tumor cell, to a site of action (such as, by way of non-limiting example, the tumor microenvironment). Furthermore, not only can the present chimeric proteins directly or indirectly recruit cells that increase the likelihood of a beneficial effect, e.g. an anti-tumor effect, but also the present chimeric proteins may deliver important signaling to the cells via signaling agents (e.g. via one or more of an interferon, interleukin, TNF, EPO, etc.). Further, such signaling agents may be mutated such that the signaling is controlled and provides improved safety (e.g. does not come at the cost of systemic toxicity). Further still, in various embodiments, the present invention provides for various mutations to the signaling agents that can, for example, temper activity at a site of therapeutic action (e.g. at a therapeutic receptor) and also reduce or eliminate off-target binding at a non- therapeutic receptor. That is, in some embodiments, the signaling agents have reduced receptor promiscuity and controlled on-target action. In various embodiments, the signaling agent can modulate one or more cells that are targeted by the targeting moieties (e.g. recruited cells, such as disease cells and / or effector cells). For instance, the signaling agent can modulate one or both of the targeted cells (and the targeted cells can be effector and / or disease cells), depending on whether the targeted cells express a receptor for the signaling agent. In various embodiments, the present chimeric proteins find use in the treatment of various diseases or disorders such as cancer, infections, immune disorders, anemia, autoimmune diseases, cardiovascular diseases, wound healing, ischemia-related diseases, neurodegenerative diseases, metabolic diseases and many other diseases and disorders, and the present invention encompasses various methods of treatment. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows, in panel A, C57BL / 6 mice were inoculated subcutaneously (50 μl) with 6x10<com:Sup>5< / com:Sup> B16mCD20cl1 melanoma tumor cells. Perilesional treatment with 120 µg of an anti-PD-L1 VHH (120 µl) or a fusion of an anti- PD-L1 VHH to human IFNalpha, Q124R mutant was started when tumors reached a size of <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> 10 mm<com:Sup>2< / com:Sup> as measured by caliper. The curves are in the same order (top to bottom) as in the figure legend identifying the treatment types (e.g. PBS is the top curve, anti-PD-L1 is the middle curve, and the bottom curve is the fusion of an anti-PD-L1 VHH to human IFNalpha, Q124R mutant). In panel B: C57BL / 6 littermates were inoculated subcutaneously (50 μl) with 6x10<com:Sup>5< / com:Sup> B16mCD20cl1 melanoma tumor cells. Perilesional treatment with 30 μg of the indicated constructs (100 µl) was started when tumors reached a size of ± 10 mm<com:Sup>2< / com:Sup> as measured by caliper. Black arrows indicate the treatment-schedule. The curves are in the same order (top to bottom) as in the figure legend identifying the treatment types (e.g. top curve is PBS, middle curve is a fusion of an anti-CD20 VHH to human IFNalpha, Q124R mutant, and the bottom curve is a bi-specific construct: anti-CD20 VHH-human IFNalpha, Q124R mutant-anti-PD-L1 VHH). FIG. 2 shows an experiment in which C57BL / 6 mice were inoculated subcutaneously (50 μl) with 6x10<com:Sup>5< / com:Sup> B16mCD20cl1 melanoma tumor cells. Perilesional treatment with 30 μg of the indicated chimeras (100 μl) was started when tumors reached a size of <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> 10 mm<com:Sup>2< / com:Sup> as measured by caliper. Top row of arrows indicate the treatment-schedule. Bottom row of arrows indicate perilesional injection of 120 µg of anti-PD-L1 VHH (120 µl). The curves are in the same order (top to bottom) as in the figure legend identifying the treatment types. "PD-L1 Q124R" is a fusion of an anti-PD-L1 VHH to human IFNalpha, Q124R mutant; "Clec9A-Q124R" is a fusion of an anti-Clec9A VHH to human IFNalpha, Q124R mutant; and "Clec9A-Q124R-PD-L1" is a bi-specific construct: anti- Clec9A VHH-human IFNalpha, Q124R mutant-anti-PD-L1 VHH. FIG. 3 shows various safety parameters of the bi-specific mCD20-Q124R-PD-L1 chimera. FIG. 3A shows tumor weight over time when PBS, mCD20-Q124R, or mCD20-Q124R-PD-L1 is administered. In panels B-G, the order of histograms is, left to right, PBS, "CD20-Q124R," a fusion of an anti-CD20 VHH to human IFNalpha Q124R mutant, and a bi-specific of anti-CD20 VHH-human IFNalpha, Q124R mutant-anti-PD-L1 VHH ("CD20-Q124R- PD-L1"). FIG. 4 shows various safety parameters of the bi-specific Clec9A-Q124R-PD-L1 chimera. FIG. 4A shows tumor weight over time when PBS, anti-PD-L1, CLEC9A-Q124R, CLEC9A-Q124R-PD-L1, or PD-L1-Q124R is administered. In panels B-G, the order of histograms is, left to right, PBS, anti-PD-L1, "Clec9A-Q124R," a fusion of an anti-Clec9A VHH to human IFNalpha Q124R mutant, a bi-specific of anti-Clec9A VHH-human IFNalpha, Q124R mutant-anti-PD-L1 VHH ("Clec9A-Q124R-PD-L1"), and "PD-L1-Q124R," a fusion of an anti-PD-L1 VHH to human IFNalpha Q124R mutant. FIG. 5 shows a mouse tumor growth study in which C57BL / 6 mice were inoculated subcutaneously (50 µl) with 6x10<com:Sup>5< / com:Sup> B16 melanoma tumor cells. Perilesional treatment with 30 μg of the indicated treatment agents (100 μl) was started when tumors reached a size of <com:Math><semantics>±<annotation encoding="application / x-tex">\pm< / annotation>< / semantics>< / com:Math> 10 mm<com:Sup>2< / com:Sup> as measured by caliper. Graph shows the evolution of tumor size over the indicated time. FIG. 6 shows a mouse tumor growth study in which C57BL / 6 mice were inoculated subcutaneously with B16 melanoma tumor cells. Perilesional treatment with the indicated treatment agents was started when tumors reached certain size as measured by caliper. Graph shows the evolution of tumor size over the indicated time. FIG. 7 shows a mouse tumor growth study in which Batf3 knockout mice that lack cross-presenting dendritic cells were inoculated subcutaneously with B16 melanoma tumor cells. Perilesional treatment with the indicated treatment agents was started when tumors reached certain size as measured by caliper. Graph shows the evolution of tumor size over the indicated time. FIG. 8, panels A-C, show a mouse tumor growth study in which mice were inoculated with 4T1 mammary tumor cells. The mice were treated with the indicated agents. Graphs show the evolution of tumor size over the indicated time. FIG. 9 shows a mouse tumor growth study in which mice were inoculated with either B16 melanoma tumor cells (panel A) or 4T1 mammary tumor cells (panels B and C). The mice were then treated with the indicated agents with or without doxorubicin. Graphs show the evolution of tumor size over the indicated time. FIG. 10 shows a mouse tumor growth study in which mice were inoculated with 4T1 mammary tumor cells. Tumor free mice from Fig. 9, panel B were rechallenged with 10<com:Sup>5< / com:Sup> 4T1 cells, and tumor growth was monitored. Graph shows the evolution of tumor size over the indicated time. FIG. 11 shows the efficacy of bispecific chimeras using an experimental autoimmune encephalomyelitis (EAE) model. Panel A shows a schematic of the experimental design. Panel B shows the clinical score of mice treated with 100 IU of the indicated agents. Panel C shows the clinical score of mice treated with 1000 IU of the indicated agents. Panel D shows that the Clec9A-CD20-hIFNa2-Q124R bispecific chimera was safe and did not induce lymphopenia. The histogram bars represent, from left to right, treatment with PBS, a monospecific fusion of anti-Clec9A to modified human IFN alpha Q124R, a monospecific fusion of anti-mCD20 to modified human IFN alpha Q124R, a monospecific fusion of anti-Bcll10 to modified human IFN alpha Q124R, wild type IFN, a combination of the monospecific fusion of anti-Clec9A to modified human IFN alpha Q124R and the monospecific fusion of anti-mCD20 to modified human IFN alpha Q124R, the Clec9A-hIFNa2-Q124R-CD20 bispecific chimera, and the Clec9A-CD20-hIFNa2-Q124R bispecific chimera. Panel E compares the efficacy of the Clec9A-hIFNa2-Q124R-CD20 bispecific chimera at 100 IU and 1000 IU dosages. Panel F compares the efficacy of the Clec9A-CD20-hIFNa2-Q124R bispecific chimera at 100 IU and 1000 IU dosages. FIG. 12 shows the efficacy of the Clec9A-CD20-hIFNa2-Q124R bispecific chimera at the 5000 IU dosage. Panel A shows the effect of the bispecific chimera on clinical score. Panel B shows the effect of the bispecific chimera on weight. Panel C shows the effect of the bispecific chimera on the incidence and onset of disease. FIG. 13 shows an evaluation of tumor-antigen specific CD8<com:Sup>+< / com:Sup> T cell proliferation and activation both in tumor- draining lymph nodes (panels A and B) as well as in spleen (panels C and D), two prime organs in the induction of anti-tumor immunity. B16-OVA bearing mice were injected once with PBS, bispecific chimera of anti-Clec9A VHH / anti-PD-L1 VHH / human IFN Q124R or the same bispecific chimera in combination with doxorubicin one day after adoptive transfer of CFSE-labeled CD8<com:Sup>+< / com:Sup> OT-l cells carrying a CD8 TCR recognizing the model antigen ovalbumin (OVA), present on B16-OVA tumor cells. Proliferation and activation of CFSE-labeled CD8+ OT-I cells was evaluated 4 days later by flow cytometry, showing enhanced proliferation and activation status of the proliferated cells in mice receiving the bispecific chimera of anti-Clec9A VHH / anti-PD-L1 VHH / human IFN Q124R or the same bispecific chimera in combination with doxorubicin as compared to perilesional injection with PBS (panels A and C). Data show the percentage of OT-I CD8+ cells having undergone at least one division. One representative flow cytometric profile is included. In addition, as shown in panels B and D, flow cytometric analysis of CD44 and CD62L expression was performed on CD8+ CFSE+ T cells showing activated and memory T cell phenotype upon delivery of bispecific chimera of anti-Clec9A VHH / anti-PD-L1 VHH / human IFN Q124R either alone or in combination with doxorubicin. * P<0.05, ** P<0.01, *** P<0.001 and **** P<0.0001 compared with PBS treated animals by one-way ANOVA with Dunnett's multiple comparison test. FIG. 14 shows B16 cells stimulated with 100 ng / ml chimeras (or were left unstimulated) and stained for phospho STAT1. Data are plotted as mean fluorescent intensities. Chimeras analyzed are: anti-Sirp1<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> VHH / anti-PD-L1 VHH / human IFN Q124R, anti-DNAM VHH / anti-PD-L1 VHH / human IFN Q124R; and a monospecific fusion of anti-Bcll10 VHH to modified human IFN alpha Q124R (non-specific control). FIG. 15 shows, in panels A, B, and C, human CD8 targeting of mono-specific chimeras (anti-human CD8 VHH / human IFN R149A). Zebra-plot of CD8 versus pSTAT1 staining of stimulated PBMCs is shown in panel A. Panels B and C: mean fluorescent intensities (MFI) of pSTAT1 staining of CD8-positive (panel B) or CD8- negative (panel C) cells are plotted. FIG. 15 shows, in panels D, E, and F human CD8 targeting of bi-specific chimeras (anti-human CD8 VHH / anti-human PD-L1 VHH / human IFN R149A). FIG. 16 shows an experiment in which MDA-MB-321 cells were stimulated with a serial dilution of chimeras and stained for phospho STAT1. Data are plotted as mean fluorescent intensities (MFI). Chimeras studied were anti- human PD-L1 VHH / human IFN R149A; anti-human PD-L1 VHH / human IFN R33A / E120R; anti-human Clec9A VHH / anti-human PD-L1 VHH / human IFN R149A; anti-human Clec9A VHH / anti-human PD-L1 VHH / human IFN R33A / E120R; and anti-human Bcl10 VHH / human IFN R149A. For reference, this is the order of the constructs in FIG. 16, from top to bottom, when viewing the 4 ng / ml point on the X axis. FIG. 17 shows, Daudi, Jurkat and Wish cells were stimulated with a serial dilution scFv chimeras and stained for phospho STAT1. Data are plotted as mean fluorescent intensities (MFI). Chimeras studied were anti-human CD20 scFv / anti-human CD3 scFv / IFN R149A. When viewing the graphs at point 1000 on the x axis, the order of the curves is Jurkat, Daudi, and Wish cells. FIG. 18 shows the antitumor effects of an anti-human Clec9a VHH / anti-human PDL1 VHH / human IFN-R149A bi- specific chimera on a human tumor (RL) grown in humanized mice. With reference to day 18 on the X axis, the constructs studied were, from top to bottom: PBS (control); anti-human Clec9a VHH / anti-human PDL1 VHH / human IFN-R149A bi-specific chimera; and anti-human Clec9a VHH / anti-human PDL1 VHH / human IFN- R149A bi-specific chimera plus FMS-like tyrosine kinase 3 ligand (FLT3L). FIG. 19 shows a human dendritic cell pSTAT1 signaling assay. Chimeras studied were anti-human Clec9A VHH / anti-human PD-L1 VHH / human IFN R149A and anti-human Clec9A VHH / anti-human PD-L1 VHH / human IFN R33A / E120R. Two doses of the agents were studied: 100 ng / ml and 500 ng / ml. PBS was the control and the data are expressed as a fold change of the percentage of pSTAT1* dendritic cells (data is an average of a triplicate data set). DETAILED DESCRIPTION The present invention is based, in part, on the surprising discovery that bi-specific chimeric proteins with signaling agents bearing therapeutically beneficial mutations provide beneficial therapeutic properties and reduced side effects. In various embodiments, these chimeric proteins may recruit the appropriate cells (e.g. immune cells) to site of in need of therapeutic action (e.g. a tumor cell) via the dual targeting moieties and, in addition, delivery one or more important signals to effect a therapeutic signal (e.g. via one or more modified signaling agents). The present invention provides pharmaceutical compositions comprising the chimeric proteins and their use in the treatment of various diseases. Administration of the chimeric proteins and pharmaceutical compositions of the invention achieves significantly reduced side effects compared to the wild type soluble agent. Chimeric Proteins In various embodiments, the present invention relates to a bi-specific or multifunctional chimeric protein having two or more targeting moieties having recognition domains that specifically bind to a target (e.g. antigen, receptor) of interest, which optionally, and directly or indirectly, recruit cells of relevance and / or modulate the function of the recruited cells, and a modified signaling agent, which bears one or more mutations that render the signaling agent suitable for pharmaceutical use with minimal side effects (e.g. minimal cytokine storm-like effects, flu-like symptoms, suicidal thoughts, off-target side effects, among others). In various embodiments, the chimeric protein, among other features, directly or indirectly recruits one or more effector cells to a disease cell, e.g. via the targeting moieties, and further delivers a signal to the effector cell to modulate the disease cell in a therapeutically-relevant manner. In various embodiments, the chimeric protein, among other features, directly or indirectly recruits one or more effector cells to a disease cell, e.g. via the targeting moieties, and further delivers a signal to the disease cell to modulate the effector cell in a therapeutically-relevant manner. In various embodiments, the chimeric protein, among other features, directly or indirectly recruits one or more effector cells to a disease cell, e.g. via the targeting moieties, and further delivers a signal to the effector cell to modulate the effector cell in a therapeutically-relevant manner. In various embodiments, the chimeric protein, among other features, directly or indirectly recruits one or more effector cells to a disease cell, e.g. via the targeting moieties, and further delivers a signal to the disease cell to modulate the disease cell in a therapeutically-relevant manner. In some embodiments, the signaling agent effects effector cell and / or the disease cell. In various embodiments, the present chimeric protein provides at least two therapeutic benefits when used pharmaceutically. For instance, the present chimeric protein may effectively recruit proper cells to a site of required therapy (by way of non-limiting example, immune effector cells to a tumor, e.g. the tumor microenvironment) and deliver one or more signals to the cells - e.g. immune effector cells and / or tumor cells - to promote a cancer reducing or eliminating effect (e.g. provide immune cell stimulation from the signaling agent, provide immune co-stimulatory signals via the targeting domains, provide reduction or silencing of immune co- inhibitory signals via the targeting domains, etc.). Accordingly, as described herein, the present chimeric protein provides a platform of therapeutically-relevant options for the effective treatment of diseases via the immune system, including, without limitation, the treatment of cancer. Furthermore, the present chimeric protein, in various embodiments, has pharmacodynamic and pharmacokinetic properties that make it particularly suited for use in therapies. For example, in various embodiments, including embodiments in which smaller antibody-based formats are used for targeting (as described elsewhere herein), the present chimeric protein has a molecular weight that allows avoidance of renal excretion to allow for therapeutic effects at a low dose (e.g. without loss of the therapeutic via the kidney). For instance, the present chimeric protein, in various embodiments, is engineered to have a molecular mass of about 50 KDa, or about 60 KDa, or about 70 KDa, or about 80 KDa, or about 90 KDa, or about 100 KDa. In various embodiments, the present constructs evade kidney filtration such that they do not require external methods of half-life extension. In various embodiments, each of the individual chimeric proteins may by conjugated and / or fused with another agent to extend half-life or otherwise improve pharmacodynamic and pharmacokinetic properties. In some embodiments, the chimeric proteins may be fused or conjugated with one or more of PEG, XTEN (e.g., as rPEG), polysialic acid (POLYXEN), albumin (e.g., human serum albumin or HAS), elastin-like protein (ELP), PAS, HAP, GLK, CTP, transferrin, and the like. In some embodiments, the chimeric protein may be fused or conjugated with an antibody or an antibody fragment such as an Fc fragment. For example, the chimeric protein may be fused to either the N-terminus or the C-terminus of the Fc domain of human immunoglobulin (Ig) G. In various embodiments, each of the individual chimeric proteins is fused to one or more of the agents described in BioDrugs (2015) 29:215–239. As described herein, the present chimeric protein may have improved safety due to one of more modifications, e.g. mutations. In various embodiments, improved safety means that the present chimeric protein provides lower toxicity (e.g. systemic toxicity and / or tissue / organ-associated toxicities); and / or lessened or substantially eliminated side effects; and / or increased tolerability, lessened or substantially eliminated adverse events; and / or reduced or substantially eliminated off-target effects; and / or an increased therapeutic window. In some embodiments, the present chimeric protein increases the therapeutic index (e.g., by about 2-fold, about 5-fold, about 10-fold, about 25-fold, about 50-fold, about 100-fold, about 200-fold, or more) of any protein therapeutic (e.g., based on a naturally occurring or engineered protein or fragment thereof) by reducing the general toxicity of the protein and maintaining or increasing the selective effect of the protein on target cells or tissues. For instance, this increase in therapeutic index (e.g., by about 2-fold, about 5-fold, about 10-fold, about 25-fold, about 50-fold, about 100-fold, about 200-fold, or more) may be of the modified signaling agent (e.g. relative to the wild type signaling agent, or relative to a wild type signaling agent in the context of a fusion protein with a single targeting moiety, or relative to a wild type signaling agent in the context of a fusion protein with more than one targeting moieties). In some embodiments, the present chimeric protein allows for efficient binding of the targeting moieties and the signaling agent to their receptors. For instance, in some embodiments, the chimeric protein allows for efficient binding of one of the targeting moieties and the signaling agent to receptors on the same cell (e.g., different receptors) as well as the efficient binding of the other targeting moiety to another cell. As described elsewhere herein, in various embodiments, the signaling agent is mutated to provide attenuated activity, and the binding of the targeting moiety and the signaling agent to receptors on the same cell is sequential, e.g. targeting moiety / receptor binding preceding signaling agent / receptor binding. For instance, in some embodiments the signaling agent by itself is significantly less active in its mutated form (e.g. relative to wild type) because it cannot efficiently bind to its receptor(s). Accordingly, chimeric proteins of the invention are useful to avoid unwanted side effects caused by the signaling agent binding to its natural receptor on non-target cells. However, the signaling agent is active on target cells because the targeting moiety(ies) compensates for the missing / insufficient binding (e.g., without limitation and / or avidity) required for substantial activation. In various embodiments, the chimeric proteins of the present invention have a modified (e.g. mutant) signaling agent which causes the signaling agent to be inactive en route to the site of therapeutic activity (e.g. in contact with a target cell, including a tumor cell) through the body and to have its effect substantially on specifically targeted cell types which greatly reduces undesired side effects In various embodiments, the present chimeric proteins have selective bioactivity, e.g. therapeutically-relevant bioactivity, towards targeted cells (e.g. tumor cells), but not towards cells that are not targeted (e.g. normal, non- tumor cells). In various embodiments, the present chimeric proteins provide synergistic activity and / or therapeutic effects. In such embodiments, the activity and / or therapeutic effects of the chimeric proteins have improved therapeutic effects, e.g. synergistically greater, than the therapeutic effects of the individual components (i.e., the targeting moieties and the signaling agent) administered alone or in combination via co-administration. In various embodiments, the present chimeric proteins have two or more targeting moieties and the signaling agent connected together via different configurations. In an embodiment, one of the targeting moieties is linked to the amino-terminus of the signaling agent and the other targeting moiety is linked to the carboxy-terminus of the signaling agent. In another embodiment, both targeting moieties are linked to the amino-terminus of the signaling agent. For example, the amino-terminus of the signaling agent may be linked to the carboxy-terminus of one of the targeting moieties, which in turn is linked to the other targeting moiety (e.g., via its amino-terminus). In a further embodiment, both targeting moieties are linked to the carboxy-terminus of the signaling agent. For example, the carboxy-terminus of the signaling agent may be linked to the amino-terminus of one of the targeting moieties, which in turn is linked to the other targeting moiety (e.g., via its carboxy-terminus). In various embodiments, the present chimeric proteins are in the form of a fusion protein having the components described herein. In various embodiments, the present chimeric proteins have two or more targeting moieties that target different antigens or receptors, and one targeting moiety may be attenuated for its antigen or receptor, e.g. the targeting moiety binds its antigen or receptor with a low affinity or avidity (including, for example, at an affinity or avidity that is less than the affinity or avidity the other targeting moiety has for its for its antigen or receptor, for instance the difference between the binding affinities may be about 10-fold, or 25-fold, or 50-fold, or 100-fold, or 300-fold, or 500-fold, or 1000-fold, or 5000-fold; for instance the lower affinity or avidity targeting moiety may bind its antigen or receptor at a K<com:Sub>D< / com:Sub> in the mid- to high-nM or low- to mid-µM range while the higher affinity or avidity targeting moiety may bind its antigen or receptor at a K<com:Sub>D< / com:Sub> in the mid- to high-pM or low- to mid-nM range). For instance, in some embodiments, the present chimera comprises an attenuated targeting moiety that is directed against a promiscuous antigen or receptor, which may improve targeting to a cell of interest (e.g. via the other targeting moiety) and prevent effects across multiple types of cells, including those not being targeted for therapy (e.g. by binding promiscuous antigen or receptor at a higher affinity than what is provided in these embodiments). In various embodiments, the present invention provides for an isolated nucleic acid encoding a chimeric protein as described herein. Targeting Moiety Cellular Recruitment In various embodiments, the chimeric proteins of the present invention have targeting moieties having recognition domains which specifically bind to a target (e.g. antigen, receptor) of interest. In various embodiments, the chimeric proteins of the present invention have one or more targeting moieties which target different cells (e.g. to make a synapse) or the same cell (e.g. to get a more concentrated signaling agent or therapeutic effect). The target (e.g. antigen, receptor) of interest can be found on one or more immune cells, which can include, without limitation, T cells, cytotoxic T lymphocytes, T helper cells, natural killer (NK) cells, natural killer T (NKT) cells, anti-tumor macrophages (e.g. M1 macrophages), B cells, dendritic cells, or subsets thereof. In some embodiments, the recognition domains specifically bind to a target (e.g. antigen, receptor) of interest and effectively, directly or indirectly, recruit one of more immune cells. In some embodiments, the target (e.g. antigen, receptor) of interest can be found on one or more tumor cells. In these embodiments, the present chimeric proteins may directly or indirectly recruit an immune cell, e.g., in some embodiments, to a therapeutic site (e.g. a locus with one or more disease cell or cell to be modulated for a therapeutic effect). In some embodiments, the present chimeric proteins may directly or indirectly recruit an immune cell, e.g. an immune cell that can kill and / or suppress a tumor cell, to a site of action (such as, by way of non-limiting example, the tumor microenvironment). In various embodiments, the chimeric proteins have targeting moieties having recognition domains which specifically bind to a target (e.g. antigen, receptor) which is part of a non-cellular structure. In some embodiments, the antigen or receptor is not an integral component of an intact cell or cellular structure. In some embodiments, the antigen or receptor is an extracellular antigen or receptor. In some embodiments, the target is a non-proteinaceous, non-cellular marker, including, without limitation, nucleic acids, inclusive of DNA or RNA, such as, for example, DNA released from necrotic tumor cells or extracellular deposits such as cholesterol. In some embodiments, the target (e.g. antigen, receptor) of interest is part of the non-cellular component of the stroma or the extracellular matrix (ECM) or the markers associated therewith. As used herein, stroma refers to the connective and supportive framework of a tissue or organ. Stroma may include a compilation of cells such as fibroblasts / myofibroblasts, glial, epithelia, fat, immune, vascular, smooth muscle, and immune cells along with the extracellular matrix (ECM) and extracellular molecules. In various embodiments, the target (e.g. antigen, receptor) of interest is part of the non-cellular component of the stroma such as the extracellular matrix and extracellular molecules. As used herein, the ECM refers to the non-cellular components present within all tissues and organs. The ECM is composed of a large collection of biochemically distinct components including, without limitation, proteins, glycoproteins, proteoglycans, and polysaccharides. These components of the ECM are usually produced by adjacent cells and secreted into the ECM via exocytosis. Once secreted, the ECM components often aggregate to form a complex network of macromolecules. In various embodiments, the chimeric protein of the invention comprises a targeting moiety that recognizes a target (e.g., an antigen or receptor or non-proteinaceous molecule) located on any component of the ECM. Illustrative components of the ECM include, without limitation, the proteoglycans, the non-proteoglycan polysaccharides, fibers, and other ECM proteins or ECM non-proteins, e.g. polysaccharides and / or lipids, or ECM associated molecules (e.g. proteins or non-proteins, e.g. polysaccharides, nucleic acids and / or lipids). In some embodiments, the targeting moiety recognizes a target (e.g. antigen, receptor) on ECM proteoglycans. Proteoglycans are glycosylated proteins. The basic proteoglycan unit includes a core protein with one or more covalently attached glycosaminoglycan (GAG) chains. Proteoglycans have a net negative charge that attracts positively charged sodium ions (Na+), which attracts water molecules via osmosis, keeping the ECM and resident cells hydrated. Proteoglycans may also help to trap and store growth factors within the ECM. Illustrative proteoglycans that may be targeted by the chimeric proteins of the invention include, but are not limited to, heparan sulfate, chondroitin sulfate, and keratan sulfate. In an embodiment, the targeting moiety recognizes a target (e.g. antigen, receptor) on non-proteoglycan polysaccharides such as hyaluronic acid. In some embodiments, the targeting moiety recognizes a target (e.g. antigen, receptor) on ECM fibers. ECM fibers include collagen fibers and elastin fibers. In some embodiments, the targeting moiety recognizes one or more epitopes on collagens or collagen fibers. Collagens are the most abundant proteins in the ECM. Collagens are present in the ECM as fibrillar proteins and provide structural support to resident cells. In one or more embodiments, the targeting moiety recognizes and binds to various types of collagens present within the ECM including, without limitation, fibrillar collagens (types I, II, III, V, XI), facit collagens (types IX, XII, XIV), short chain collagens (types VIII, X), basement membrane collagens (type IV), and / or collagen types VI, VII, or XIII. Elastin fibers provide elasticity to tissues, allowing them to stretch when needed and then return to their original state. In some embodiments, the target moiety recognizes one or more epitopes on elastins or elastin fibers. In some embodiments, the targeting moiety recognizes one or more ECM proteins including, but not limited to, a tenascin, a fibronectin, a fibrin, a laminin, or a nidogen / entactin. In an embodiment, the targeting moiety recognizes and binds to tenascin. The tenascin (TN) family of glycoproteins includes at least four members, tenascin-C, tenascin-R, tenascin-X, and tenascin W. The primary structures of tenascin proteins include several common motifs ordered in the same consecutive sequence: amino-terminal heptad repeats, epidermal growth factor (EGF)-like repeats, fibronectin type III domain repeats, and a carboxyl-terminal fibrinogen-like globular domain. Each protein member is associated with typical variations in the number and nature of EGF-like and fibronectin type III repeats. Isoform variants also exist particularly with respect to tenascin-C. Over 27 splice variants and / or isoforms of tenascin-C are known. In a particular embodiment, the targeting moiety recognizes and binds to tenascin-CA1. Similarly, tenascin-R also has various splice variants and isoforms. Tenascin-R usually exists as dimers or trimers. Tenascin-X is the largest member of the tenascin family and is known to exist as trimers. Tenascin-W exists as trimers. In some embodiments, the targeting moiety recognizes one or more epitopes on a tenascin protein. In some embodiments, the targeting moiety recognizes the monomeric and / or the dimeric and / or the trimeric and / or the hexameric forms of a tenascin protein. In an embodiment, the targeting moieties recognize and bind to fibronectin. Fibronectins are glycoproteins that connect cells with collagen fibers in the ECM, allowing cells to move through the ECM. Upon binding to integrins, fibronectins unfolds to form functional dimers. In some embodiments, the targeting moiety recognizes the monomeric and / or the dimeric forms of fibronectin. In some embodiments, the targeting moiety recognizes one or more epitopes on fibronectin. In illustrative embodiments, the targeting moiety recognizes fibronectin extracellular domain A (EDA) or fibronectin extracellular domain B (EDB). Elevated levels of EDA are associated with various diseases and disorders including psoriasis, rheumatoid arthritis, diabetes, and cancer. In some embodiments, the targeting moiety recognizes fibronectin that contains the EDA isoform and may be utilized to target the chimeric protein to diseased cells including cancer cells. In some embodiments, the targeting moiety recognizes fibronectin that contains the EDB isoform. In various embodiments, such targeting moieties may be utilized to target the chimeric protein to tumor cells including the tumor neovasculature. In an embodiment, the targeting moiety recognizes and binds to fibrin. Fibrin is another protein substance often found in the matrix network of the ECM. Fibrin is formed by the action of the protease thrombin on fibrinogen which causes the fibrin to polymerize. In some embodiments, the targeting moiety recognizes one or more epitopes on fibrin. In some embodiments, the targeting moiety recognizes the monomeric as well as the polymerized forms of fibrin. In an embodiment, the targeting moiety recognizes and binds to laminin. Laminin is a major component of the basal lamina, which is a protein network foundation for cells and organs. Laminins are heterotrimeric proteins that contain an <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>-chain, a <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-chain, and a <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>-chain. In some embodiments, the targeting moiety recognizes one or more epitopes on laminin. In some embodiments, the targeting moiety recognizes the monomeric, the dimeric as well as the trimeric forms of laminin. In an embodiment, the targeting moiety recognizes and binds to a nidogen or entactin. Nidogens / entactins are a family of highly conserved, sulfated glycoproteins. They make up the major structural component of the basement membranes and function to link laminin and collagen IV networks in basement membranes. Members of this family include nidogen-1 and nidogen-2. In various embodiments, the targeting moiety recognizes an epitope on nidogen-1 and / or nidogen-2. In various embodiments, the targeting moiety comprises an antigen recognition domain that recognizes an epitope present on any of the targets (e.g., ECM proteins) described herein. In an embodiment, the antigen- recognition domain recognizes one or more linear epitopes present on the protein. As used herein, a linear epitope refers to any continuous sequence of amino acids present on the protein. In another embodiment, the antigen-recognition domain recognizes one or more conformational epitopes present on the protein. As used herein, a conformation epitope refers to one or more sections of amino acids (which may be discontinuous) which form a three-dimensional surface with features and / or shapes and / or tertiary structures capable of being recognized by an antigen recognition domain. In various embodiments, the targeting moiety may bind to the full-length and / or mature forms and / or isoforms and / or splice variants and / or fragments and / or any other naturally occurring or synthetic analogs, variants, or mutants of any of the targets (e.g., ECM proteins) described herein. In various embodiments, the targeting moiety may bind to any forms of the proteins described herein, including monomeric, dimeric, trimeric, tetrameric, heterodimeric, multimeric and associated forms. In various embodiments, the targeting moiety may bind to any post-translationally modified forms of the proteins described herein, such as glycosylated and / or phosphorylated forms. In various embodiments, the targeting moiety comprises an antigen recognition domain that recognizes extracellular molecules such as DNA. In some embodiments, the targeting moiety comprises an antigen recognition domain that recognizes DNA. In an embodiment, the DNA is shed into the extracellular space from necrotic or apoptotic tumor cells or other diseased cells. In various embodiments, the targeting moiety comprises an antigen recognition domain that recognizes one or more non-cellular structures associated with atherosclerotic plaques. Two types of atherosclerotic plaques are known. The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries. Beneath the endothelium there is a fibrous cap covering the atheromatous core of the plaque. The core includes lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger foamy cells and capillaries. A fibrous plaque is also localized under the intima, within the wall of the artery resulting in thickening and expansion of the wall and, sometimes, spotty localized narrowing of the lumen with some atrophy of the muscular layer. The fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic) and lipid-laden cells. In some embodiments, the targeting moiety recognizes and binds to one or more of the non-cellular components of these plaques such as the fibrin, proteoglycans, collagen, elastin, cellular debris, and calcium or other mineral deposits or precipitates. In some embodiments, the cellular debris is a nucleic acid, e.g. DNA or RNA, released from dead cells. In various embodiments, the targeting moiety comprises an antigen recognition domain that recognizes one or more non-cellular structures found in the brain plaques associated with neurodegenerative diseases. In some embodiments, the targeting moiety recognizes and binds to one or more non-cellular structures located in the amyloid plaques found in the brains of patients with Alzheimer's disease. For example, the targeting moiety may recognize and bind to the peptide amyloid beta, which is a major component of the amyloid plaques. In some embodiments, the targeting moiety recognizes and binds to one or more non-cellular structures located in the brains plaques found in patients with Huntington's disease. In various embodiments, the targeting moiety recognizes and binds to one or more non-cellular structures found in plaques associated with other neurodegenerative or musculoskeletal diseases such as Lewy body dementia and inclusion body myositis. In some embodiments, the chimeric proteins of the invention may have two or more targeting moieties that bind to non-cellular structures. In some embodiments, there are two targeting moieties and one targets a cell while the other targets a non-cellular structure. In various embodiments, the targeting moieties can directly or indirectly recruit cells, such as disease cells and / or effector cells. In various embodiments, the signaling agent can modulate one or more cells that are targeted by the targeting moieties (e.g. recruited cells, such as disease cells and / or effector cells). For instance, the signaling agent can modulate one or both of the targeted cells (and the targeted cells can be effector and / or disease cells), depending on whether the targeted cells express a receptor for the signaling agent. In some embodiments, the present chimeric proteins are capable of, or find use in methods involving, shifting the balance of immune cells in favor of immune attack of a tumor. For instance, the present chimeric proteins can shift the ratio of immune cells at a site of clinical importance in favor of cells that can kill and / or suppress a tumor (e.g. T cells, cytotoxic T lymphocytes, T helper cells, natural killer (NK) cells, natural killer T (NKT) cells, anti- tumor macrophages (e.g. M1 macrophages), B cells, dendritic cells, or subsets thereof) and in opposition to cells that protect tumors (e.g. myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs); tumor associated neutrophils (TANs), M2 macrophages, tumor associated macrophages (TAMs), or subsets thereof). In some embodiments, the present chimeric protein is capable of increasing a ratio of effector T cells to regulatory T cells. For example, in some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with T cells. In some embodiments, the targeting moiety comprises an antigen recognition domain that directly or indirectly recruits T cells. In an embodiment, the targeting moiety comprises an antigen recognition domain that specifically binds to effector T cells. In some embodiments, the targeting moiety comprises an antigen recognition domain that directly or indirectly recruits effector T cells, e.g., in some embodiments, to a therapeutic site (e.g. a locus with one or more disease cell or cell to be modulated for a therapeutic effect). Illustrative effector T cells include cytotoxic T cells (e.g. αβ TCR, CD3+, CD8+, CD45RO+); CD4+ effector T cells (e.g. αβ TCR, CD3+, CD4+, CCR7+, CD62Lhi, IL-7R / CD127+); CD8+ effector T cells (e.g. αβ TCR, CD3+, CD8+, CCR7+, CD62Lhi, IL-7R / CD127+); effector memory T cells (e.g. CD62Llow, CD44<com:Sup>+< / com:Sup>, TCR, CD3<com:Sup>+< / com:Sup>, IL<com:Sup>-< / com:Sup>7R / CD127<com:Sup>+< / com:Sup>, IL-15R<com:Sup>+< / com:Sup>, CCR7low); central memory T cells (e.g. CCR7<com:Sup>+< / com:Sup>, CD62L<com:Sup>+< / com:Sup>, CD27+; or CCR7hi, CD44+, CD62Lhi, TCR, CD3+, IL-7R / CD127+, IL-15R+); CD62L+ effector T cells; CD8+ effector memory T cells (TEM) including early effector memory T cells (CD27* CD62L-) and late effector memory T cells (CD27<com:Sup>-< / com:Sup> CD62L<com:Sup>-< / com:Sup>) (TemE and TemL, respectively); CD127(*)CD25(low / -) effector T cells; CD127(-)CD25(-) effector T cells; CD8<com:Sup>+< / com:Sup> stem cell memory effector cells (TSCM) (e.g. CD44(low)CD62L(high)CD122(high)sca(<com:Sup>+< / com:Sup>)); TH1 effector T-cells (e.g. CXCR3+, CXCR6+ and CCR5+; or αβ TCR, CD3+, CD4+, IL-12R+, IFNγR+, CXCR3+), TH2 effector T cells (e.g. CCR3<com:Sup>+< / com:Sup>, CCR4<com:Sup>+< / com:Sup> and CCR8<com:Sup>+< / com:Sup>; or αβ TCR, CD3<com:Sup>+< / com:Sup>, CD4<com:Sup>+< / com:Sup>, IL-4R<com:Sup>+< / com:Sup>, IL-33R<com:Sup>+< / com:Sup>, CCR4<com:Sup>+< / com:Sup>, IL-17RB<com:Sup>+< / com:Sup>, CRTH2+); TH9 effector T cells (e.g. αβ TCR, CD3+, CD4+); TH17 effector T cells (e.g. αβ TCR, CD3+, CD4+, IL- 23R<com:Sup>+< / com:Sup>, CCR6<com:Sup>+< / com:Sup>, IL-1R<com:Sup>+< / com:Sup>); CD4<com:Sup>+< / com:Sup>CD45RO<com:Sup>+< / com:Sup>CCR7<com:Sup>+< / com:Sup> effector T cells, ICOS<com:Sup>+< / com:Sup> effector T cells; CD4<com:Sup>+< / com:Sup>CD45RO<com:Sup>+< / com:Sup>CCR7(<com:Sup>-< / com:Sup>) effector T cells; and effector T cells secreting IL-2, IL-4 and / or IFN-γ. Illustrative T cell antigens of interest include, for example (and inclusive of the extracellular domains, where applicable): CD8, CD3, SLAMF4, IL-2Rα, 4-1BB / TNFRSF9, IL-2 R β, ALCAM, B7-1, IL-4 R, B7-H3, BLAME / SLAMFS, CEACAM1, IL-6 R, CCR3, IL-7 Rα, CCR4, CXCRI / IL-S RA, CCR5, CCR6, IL-10R α, CCR 7, IL-I 0 R β, CCRS, IL-12 R β 1, CCR9, IL-12 R β 2, CD2, IL-13 R α 1, IL-13, CD3, CD4, ILT2 / CDS5j, ILT3 / CDS5k, ILT4 / CDS5d, ILT5 / CDS5a, lutegrin a 4 / CD49d, CDS, Integrin a E / CD103, CD6, Integrin a M / CD 11 b, CDS, Integrin a X / CD11c, Integrin \( \beta \) 2 / CDIS, KIR / CD15S, CD27 / TNFRSF7, KIR2DL1, CD2S, KIR2DL3, CD30 / TNFRSFS, KIR2DL4 / CD15Sd, CD31 / PECAM-1, KIR2DS4, CD40 Ligand / TNFSF5, LAG-3, CD43, LAIR1, CD45, LAIR2, CDS3, Leukotriene B4-R1, CDS4 / SLAMF5, NCAM-L1, CD94, NKG2A, CD97, NKG2C, CD229 / SLAMF3, NKG2D, CD2F-10 / SLAMF9, NT-4, CD69, NTB-A / SLAMF6, Common y Chain / IL-2 R y, Osteopontin, CRACC / SLAMF7, SLAMF7 (CS1), PD-1, CRTAM, PSGL-1, CTLA-4, RANK / TNFRSF11A, CX3CR1, CX3CL1, L-Selectin, CXCR3, SIRP β 1, CXCR4, SLAM, CXCR6, TCCR / WSX-1, DNAM-1, Thymopoietin, EMMPRIN / CD147, TIM-1, EphB6, TIM-2, Fas / TNFRSF6, TIM-3, Fas Ligand / TNFSF6, TIM-4, Fcy RIII / CD16, TIM-6, TNFR1 / TNFRSF1A, Granulysin, TNF RIII / TNFRSF1B, TRAIL RI / TNFRSF1OA, ICAM-1 / CD54, TRAIL R2 / TNFRSF10B, ICAM-2 / CD102, TRAILR3 / TNFRSF10C,IFN-yR1, TRAILR4 / TNFRSF10D, IFN-y R2, TSLP, IL-1 R1 and TSLP R. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these illustrative T cell antigens. In an exemplary embodiment, the present chimeric protein comprises a targeting moiety directed against CD8. In various embodiments, the targeting moiety directed against CD8 is a protein-based agent capable of specific binding to CD8 without functional modulation (e.g. partial or complete neutralization) of CD8. CD8 is a heterodimeric type I transmembrane glycoprotein, whose <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> chains are both composed of an immunoglobulin (lg)-like extracellular domain connected by an extended O-glycosylated stalk to a single-pass transmembrane domain and a short cytoplasmic tail (Li et al., 2013). The cytoplasmic region of the α-chain contains two cysteine motifs that serve as a docking site for src tyrosine kinase p56lck (Lck). In contrast, this Lck binding domain appears to be absent from the <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> chain, suggesting that the CD8 <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> chain is not involved in downstream signaling (Artyomov et al., 2010). CD8 functions as a co-receptor for the T-cell receptor with its principle role being the recruitment of Lck to the TCR-pMHC complex following co-receptor binding to MHC (Turner et al., 1990, Veillette et al., 1988). The increase in the local concentration of this kinase activates a signaling cascade that recruits and activates ζ-chain-associated protein kinase 70 (ZAP-70), subsequently leading to the amplification or enhancement of T-cell activation signals (Purbhoo et al., 2001, Laugel et al., 2007a). In various embodiments, the chimeric protein of the invention comprises a targeting moiety having an antigen recognition domain that recognizes an epitope present on the CD8 α and / or β chains. In an embodiment, the antigen-recognition domain recognizes one or more linear epitopes on the CD8 <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> and / or <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> chains. As used herein, a linear epitope refers to any continuous sequence of amino acids present on the CD8 α and / or β chains. In another embodiment, the antigen-recognition domain recognizes one or more conformational epitopes present on the CD8 <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> and / or <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> chains. As used herein, a conformation epitope refers to one or more sections of amino acids (which may be discontinuous) which form a three-dimensional surface with features and / or shapes and / or tertiary structures capable of being recognized by an antigen recognition domain. In various embodiments, the present chimeric protein may comprise a targeting moiety that may bind to the full- length and / or mature forms and / or isoforms and / or splice variants and / or fragments and / or any other naturally occurring or synthetic analogs, variants, or mutants of human CD8 α and / or β chains. In various embodiments, the targeting moiety directed against CD8 may bind to any forms of the human CD8 α and / or β chains, including monomeric, dimeric, heterodimeric, multimeric and associated forms. In an embodiment, the targeting moiety directed against CD8 may bind to the monomeric form of CD8 α chain or CD8 β chain. In another embodiment, the targeting moiety directed against CD8 may bind to a homodimeric form comprised of two CD8 a chains or two CD8 β chains. In a further embodiment, the targeting moiety directed against CD8 may bind to a heterodimeric form comprised of one CD8 α chain and one CD8 β chain. In an embodiment, the present chimeric protein comprises a targeting moiety with an antigen recognition domain that recognizes one or more epitopes present on the human CD8 α chain. In an embodiment, the human CD8 α chain comprises the amino acid sequence of: Isoform 1 (SEQ ID NO: 1) MALPVTALLLPLALLLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPT SGCSWLFQPRGAAASPTFLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLT LSDFRRENEGYYFCSALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIA SQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLY CNHRNRRRVCKCPRPVVKSGDKPSLSARYV. In an embodiment, the human CD8 a chain comprises the amino acid sequence of: Isoform 2 (SEQ ID NO: 2) MALPVTALLLPLALLLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPT SGCSWLFQPRGAAASPTFLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLT LSDFRRENEGYYFCSALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIA SQPLSLRPEACRPAAGGAGNRRRVCKCPRPVVKSGDKPSLSARYV. In an embodiment, the human CD8 a chain comprises the amino acid sequence of: Isoform 3 (SEQ ID NO: 3) MRNQAPGRPKGATFPPRRPTGSRAPPLAPELRAKQRPGERVMALPVTALL LPLALLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPTSGCSWLFQ PRGAAASPTFLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLTLSDFRRENE GYYFCSALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPE ACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRR VCKCPRPVVKSGDKPSLSARYV. In an embodiment, the present chimeric protein comprises a targeting moiety with an antigen recognition domain that recognizes one or more epitopes present on the human CD8 β chain. In an embodiment, the human CD8 β chain comprises the amino acid sequence of: Isoform 1 (SEQ ID NO: 4) MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMR IYWLRQRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNL TSVKPEDSGIYFCMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVC RLPRPETQKGPLCSPITLGLLVAGVLVLLVSLGVAIHLCCRRRRARLRFMKQ FYK. In an embodiment, the human CD8 β chain comprises the amino acid sequence of: Isoform 2 (SEQ ID NO: 5) MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMR IYWLRQRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNL TSVKPEDSGIYFCMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVC RLPRPETQKGPLCSPITLGLLVAGVLVLLVSLGVAIHLCCRRRRARLRFMKQ LRLHPLEKCSRMDY. In an embodiment, the human CD8 β chain comprises the amino acid sequence of: Isoform 3 (SEQ ID NO: 6) MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMR IYWLRQRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNL TSVKPEDSGIYFCMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVC RLPRPETQKGRRRRARLRFMKQPQGEGISGTFVPQCLHGYYSNTTTSQKL LNPWILKT. In an embodiment, the human CD8 β chain comprises the amino acid sequence of: Isoform 4 (SEQ ID NO: 7) MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMR IYWLRQRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNL TSVKPEDSGIYFCMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVC RLPRPETQKGPLCSPITLGLLVAGVLVLLVSLGVAIHLCCRRRRARLRFMKQ KFNIVCLKISGFTTCCCFQILQISREYGFGVLLQKDIGQ. In an embodiment, the human CD8 β chain comprises the amino acid sequence of: Isoform 5 (SEQ ID NO: 8) MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMR IYWLRQRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNL TSVKPEDSGIYFCMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVC RLPRPETQKGPLCSPITLGLLVAGVLVLLVSLGVAIHLCCRRRRARLRFMKQ PQGEGISGTFVPQCLHGYYSNTTTSQKLLNPWILKT. In an embodiment, the human CD8 β chain comprises the amino acid sequence of: Isoform 6 (SEQ ID NO: 9) MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMR IYWLRQRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNL TSVKPEDSGIYFCMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVC RLPRPETQKGRRRRARLRFMKQFYK. In an embodiment, the human CD8 β chain comprises the amino acid sequence of: Isoform 7 (SEQ ID NO: 10) MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMR IYWLRQRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNL TSVKPEDSGIYFCMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVC RLPRPETQKDFTNKQRIGFWCPATKRHRSVMSTMWKNERRDTFNPGEFN GC. In an embodiment, the human CD8 β chain comprises the amino acid sequence of: Isoform 8 (SEQ ID NO: 11) MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMR IYWLRQRQAPSSDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNL TSVKPEDSGIYFCMIVGSPELTFGKGTQLSVVDFLPTTAQPTKKSTLKKRVC RLPRPETQKGLKGKVYQEPLSPNACMDTTAILQPHRSCLTHGS. In various embodiments, the present chimeric protein comprises a targeting moiety capable of specific binding. In various embodiments, the chimeric protein comprises a targeting moiety having an antigen recognition domain such as an antibody or derivatives thereof. In an embodiment, the CD8 binding agent comprises a targeting moiety which is an antibody. In various embodiments, the antibody is a full-length multimeric protein that includes two heavy chains and two light chains as described elsewhere herein. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the present chimeric protein comprises a targeting moiety directed against CD8 which is a single-domain antibody, such as a VHH. The VHH may be derived from, for example, an organism that produces VHH antibody such as a camelid, a shark, or the VHH may be a designed VHH. VHHs are antibody- derived therapeutic proteins that contain the unique structural and functional properties of naturally-occurring heavy-chain antibodies. VHH technology is based on fully functional antibodies from camelids that lack light chains. These heavy-chain antibodies contain a single variable domain (V<com:Sub>H< / com:Sub>H) and two constant domains (CH2 and CH3). VHHs are commercially available under the trademark of NANOBODY or NANOBODIES. In an embodiment, the present chimeric protein comprises a VHH. In some embodiments, the present chimeric protein comprises a targeting moiety directed against CD8 which is a VHH comprising a single amino acid chain having four "framework regions" or FRs and three "complementary determining regions" or CDRs. As used herein, "framework region" or "FR" refers to a region in the variable domain which is located between the CDRs. As used herein, "complementary determining region" or "CDR" refers to variable regions in VHHs that contains the amino acid sequences capable of specifically binding to antigenic targets. In various embodiments, the targeting moiety directed against CD8 comprises a VHH having a variable domain comprising at least one CDR1, CDR2, and / or CDR3 sequences. In some embodiments, the CDR1 sequence is selected from: GFTFDDYAMS (SEQ ID NO:12) or GFTFDDYAIG (SEQ ID NO:13). In some embodiments, the CDR2 sequence is selected from: TINWNGGSAEYAEPVKG (SEQ ID NO:14) or CIRVSDGSTYYADPVKG (SEQ ID NO:15). In some embodiments, the CDR3 sequence is selected from: KDADLVWYNLS (SEQ ID NO:16) or KDADLVWYNLR (SEQ ID NO:17) or AGSLYTCVQSIVVVPARPYYDMDY (SEQ ID NO:18). In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:12, SEQ ID NO:14, and SEQ ID NO:16. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:12, SEQ ID NO:14, and SEQ ID NO:17. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:12, SEQ ID NO:14, and SEQ ID NO:18. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:12, SEQ ID NO:15, and SEQ ID NO:16. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:12, SEQ ID NO:15, and SEQ ID NO:17. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:12, SEQ ID NO:15, and SEQ ID NO:18. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:16. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:17. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:13, SEQ ID NO:14, and SEQ ID NO:18. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:13, SEQ ID NO:15, and SEQ ID NO:16. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:13, SEQ ID NO:15, and SEQ ID NO:17. In various embodiments, the CD8 targeting moiety comprises SEQ ID NO:13, SEQ ID NO:15, and SEQ ID NO:18. In various embodiments, the CD8 targeting moiety comprises an amino acid sequence selected from the following sequences: R3HCD27 (SEQ ID NO:19) QVQLQESGGSVQPGGSLRLSCAASGFTFDDYAMSWVRQVPGKGLEWV STINWNGGSAEYAEPVKGRFTISRDNAKNTVYLQMNSLKLEDTAVYYCAK DADLVWYNLSTGQGTQVTVSSAAAYPYDVPDYGS or R3HCD129 (SEQ ID NO:20) QVQLQESGGLVQPGGSLRLSCAASGFTFDDYAMSWVRQVPGKGLEWV STINWNGGSAEYAEPVKGRFTISRDNAKNTVYLQMNSLKLEDTAVYYCAK DADLVWYNLRTGQGTQVTVSSAAAYPYDVPDYGS or R2HCD26 (SEQ ID NO:21) QVQLQESGGGLVQAGGSLRLSCAASGFTFDDYAIGWFRQAPGKEREGVS CIRVSDGSTYYADPVKGRFTISSDNAKNTVYLQMNSLKPEDAAVYYCAAGS LYTCVQSIVVVPARPYYDMDYWGKGTQVTVSSAAAYPYDVPDYGS. In various embodiments, the targeting moiety comprises an amino acid sequence described in US Patent Publication No. 2014 / 0271462. In various embodiments, the the CD8 targeting moiety comprises an amino acid sequence described in Table 0.1, Table 0.2, Table 0.3, and / or Figures 1A-12I of US Patent Publication No. 2014 / 0271462. In various embodiments, the the CD8 targeting moiety comprises a HCDR1 of a HCDR1 of SEQ ID NO: 22 or 23 and / or a HCDR2 of HCDR1 of SEQ ID NO: 22 or 23 and / or a HCDR3 of HCDR1 of SEQ ID NO: 22 or 23 and / or a LCDR1 of LCDR1 of SEQ ID NO: 24 and / or a LCDR2 of LCDR1 of SEQ ID NO: 24 and / or a LCDR3 of LCDR1 of SEQ ID NO: 24, as provided below. SEQ ID NO: 22: Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Asp Pro Ala Asn Asp Asn Thr Leu Tyr Ala Ser Lys Phe Gln Gly Arg Ala Thr lle Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Gly Arg Gly Tyr Gly Tyr Tyr Val Phe Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser. SEQ ID NO: 23: Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Asp Pro Ala Asn Asp Asn Thr Leu Tyr Ala Ser Lys Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Gly Tyr Tyr Val Phe Asp His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser. SEQ ID NO: 24: Asp Val Gln Ile Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Arg Ser Ile Ser Gln Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile Tyr Ser Gly Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln His Asn Glu Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu lle Lys. In various embodiments, the present invention contemplates the use of any natural or synthetic analogs, mutants, variants, alleles, homologs and orthologs (herein collectively referred to as "analogs") of the targeting moiety directed against CD8 as described herein. In various embodiments, the amino acid sequence of the targeting moiety that targets CD8 further includes an amino acid analog, an amino acid derivative, or other non- classical amino acids. In various embodiments, the targeting moiety of the invention may comprise an amino acid sequence that targets CD8 which is at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical with any one of the sequences disclosed herein (e.g. about 60%, or about 61%, or about 62%, or about 63%, or about 64%, or about 65%, or about 66%, or about 67%, or about 68%, or about 69%, or about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, about 99% or about 100% sequence identity with any one of the sequences disclosed herein). In various embodiments, the targeting moiety of the invention comprises one or more mutations that do not substantially reduce the present CD8 targeting moiety's capability to specifically bind to CD8. In various embodiments, the mutations do not substantially reduce the targeting moiety's capability to specifically bind to CD8 without functionally modulating CD8. In various embodiments, the binding affinity of the CD8 targeting moiety for the full-length and / or mature forms and / or isoforms and / or splice variants and / or fragments and / or any other naturally occurring or synthetic analogs, variants, or mutants (including monomeric, dimeric, heterodimeric, multimeric and / or associated forms) of human CD8 α and / or β chains may be described by the equilibrium dissociation constant (K<com:Sub>D< / com:Sub>). In various embodiments, the present chimeric protein comprises a targeting moiety that binds to the full-length and / or mature forms and / or isoforms and / or splice variants and / or fragments and / or any other naturally occurring or synthetic analogs, variants, or mutants (including monomeric, dimeric, heterodimeric, multimeric and / or associated forms) of human CD8 α and / or β chains with a K<com:Sub>D< / com:Sub> of less than about 1 uM, about 900 nM, about 800 nM, about 700 nM, about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, about 10 nM, or about 5 nM, or about 1 nM. In various embodiments, the present chimeric protein comprises a targeting moiety that binds but does not functionally modulate the antigen of interest, i.e., CD8. For instance, in various embodiments, the targeting moiety simply targets the antigen but does not substantially functionally modulate the antigen, e.g.it does not substantially inhibit, reduce or neutralize a biological effect that the antigen has. In various embodiments, the targeting moiety agent binds an epitope that is physically separate from an antigen site that is important for its biological activity (e.g. an antigen's active site). Such non-functionally modulating (e.g. non-neutralizing) binding finds use in various embodiments of the present invention, including methods in which the present chimeric protein is used to directly or indirectly recruit active immune cells to a site of need via an effector antigen. For example, in various embodiments, the present chimeric protein may be used to directly or indirectly recruit cytotoxic T cells via CD8 to a tumor cell in a method of reducing or eliminating a tumor (e.g. the chimeric protein may comprise a targeting moiety having an anti-CD8 antigen recognition domain and a targeting moiety having a recognition domain (e.g. an antigen recognition domain) directed against a tumor antigen or receptor). In such embodiments, it is desirable to directly or indirectly recruit CD8-expressing cytotoxic T cells but not to neutralize the CD8 activity. In these embodiments, CD8 signaling is an important piece of the tumor reducing or eliminating effect. By way of non-limiting example, in various embodiments, the present chimeric protein has a targeting moiety directed against a checkpoint marker expressed on a T cell, e.g. one or more of PD-1, CD28, CTLA4, ICOS, BTLA, KIR, LAG3, CD137, OX40, CD27, CD40L, TIM3, and A2aR. For example, in some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with B cells. In some embodiments, the recognition domains directly or indirectly recruit B cells, e.g., in some embodiments, to a therapeutic site (e.g. a locus with one or more disease cell or cell to be modulated for a therapeutic effect). Illustrative B cell antigens of interest include, for example, CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD38, CD39, CD40, CD70, CD72, CD73, CD74, CDw75, CDw76, CD77, CD78, CD79a / b, CD80, CD81, CD82, CD83, CD84, CD85, CD86, CD89, CD98, CD126, CD127, CDw130, CD138, CDw150, and B-cell maturation antigen (BCMA). In various embodiments, a targeting moiety of the chimeric protein binds one or more of these illustrative B cell antigens. By way of further example, in some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with Natural Killer cells. In some embodiments, the recognition domains directly or indirectly recruit Natural Killer cells, e.g., in some embodiments, to a therapeutic site (e.g. a locus with one or more disease cell or cell to be modulated for a therapeutic effect). Illustrative Natural Killer cell antigens of interest include, for example TIGIT, 2B4 / SLAMF4, KIR2DS4, CD155 / PVR, KIR3DL1, CD94, LMIR1 / CD300A, CD69, LMIR2 / CD300c, CRACC / SLAMF7, LMIR3 / CD300LF, Kir1alpha, DNAM-1, LMIR5 / CD300LB, Fc-epsilon RII, LMIR6 / CD300LE, Fc-y RI / CD64, MICA, Fc-y RIIB / CD32b, MICB, Fc-y RIIC / CD32c, MULT-1, Fc-y RIIA / CD32a, Nectin-2 / CD112, Fc-y RIII / CD16, NKG2A, FcRH1 / IRTA5, NKG2C, FcRH2 / IRTA4, NKG2D, FcRH4 / IRTA1, NKp30, FcRH5 / IRTA2, NKp44, Fc- Receptor-like 3 / CD16-2, NKp46 / NCR1, NKp80 / KLRF1, NTB-A / SLAMF6, Rae-1, Rae-1 α, Rae-1 β, Rae-1 delta, H60, Rae-1 epsilon, ILT2 / CD85j, Rae-1 γ, ILT3 / CD85k, TREM-1, ILT4 / CD85d, TREM-2, ILT5 / CD85a, TREM-3, KIR / CD158, TREML1 / TLT-1, KIR2DL1, ULBP-1, KIR2DL3, ULBP-2, KIR2DL4 / CD158d and ULBP-3. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these illustrative NK cell antigens. Also, in some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with macrophages / monocytes. In some embodiments, the recognition domains directly or indirectly recruit macrophages / monocytes, e.g., in some embodiments, to a therapeutic site (e.g. a locus with one or more disease cell or cell to be modulated for a therapeutic effect). Illustrative macrophages / monocyte antigens of interest include, for example SIRP1a, B7-1 / CD80, ILT4 / CD85d, B7-H1, ILT5 / CD85a, Common β Chain, Integrin α 4 / CD49d, BLAME / SLAMF8, Integrin α X / CDIIc, CCL6 / C10, Integrin β 2 / CD18, CD155 / PVR, Integrin β 3 / CD61, CD31 / PECAM-1, Latexin, CD36 / SR-B3, Leukotriene B4 R1, CD40 / TNFRSF5, LIMPIIISR-B2, CD43, LMIR1 / CD300A, CD45, LMIR2 / CD300c, CD68, LMIR3 / CD300LF, CD84 / SLAMF5, LMIR5 / CD300LB, CD97, LMIR6 / CD300LE, CD163, LRP-1, CD2F-10 / SLAMF9, MARCO, CRACC / SLAMF7, MD-1, ECF-L, MD-2, EMMPRIN / CD147, MGL2, Endoglin / CD105, Osteoactivin / GPNMB, Fc-y RI / CD64, Osteopontin, Fc-y RIIB / CD32b, PD-L2, Fc-y RIIC / CD32c, Siglec-3 / CD33, Fc-y RIIA / CD32a, SIGNR1 / CD209, Fc-γ RIII / CD16, SLAM, GM-CSF R α, TCCR / WSX-1, ICAM-2 / CD102, TLR3, IFN-γ RI, TLR4, IFN-ganna R2, TREM-I, IL-I RII, TREM-2, ILT2 / CD85j, TREM-3, ILT3 / CD85k, TREML1 / TLT-1, 2B4 / SLAMF 4, IL-10 R α, ALCAM, IL-10 R β, AminopeptidaseN / ANPEP, ILT2 / CD85j, Common β Chain, ILT3 / CD85k, Clq R1 / CD93, ILT4 / CD85d, CCR1, ILT5 / CD85a, CCR2, Integrin a 4 / CD49d, CCR5, Integrin a M / CDII b, CCR8, Integrin a X / CDIIc, CD155 / PVR, Integrin β 2 / CD18, CD14, Integrin β 3 / CD61, CD36 / SR-B3, LAIR1, CD43, LAIR2, CD45, Leukotriene B4-R1, CD68, LIMPIIISR-B2, CD84 / SLAMF5, LMIR1 / CD300A, CD97, LMIR2 / CD300c, CD163, LMIR3 / CD300LF, Coagulation Factor III / Tissue Factor, LMIR5 / CD300LB, CX3CR1, CX3CL1, LMIR6 / CD300LE, CXCR4, LRP-1, CXCR6, M-CSF R, DEP-1 / CD148, MD-1, DNAM-1, MD-2, EMMPRIN / CD147, MMR, Endoglin / CD105, NCAM-L1, Fc-y RI / CD64, PSGL-1, Fc-y RIIIICD16, RP105, G-CSF R, L-Selectin, GM-CSF R a, Siglec-3 / CD33, HVEM / TNFRSF14, SLAM, ICAM-1 / CD54, TCCR / WSX-1, ICAM- 2 / CD102, TREM-I, IL-6 R, TREM-2, CXCRI / IL-8 RA, TREM-3 and TREMLI / TLT-1. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these illustrative macrophage / monocyte antigens. Also, in some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with dendritic cells. In some embodiments, the recognition domains directly or indirectly recruit dendritic cells, e.g., in some embodiments, to a therapeutic site (e.g. a locus with one or more disease cell or cell to be modulated for a therapeutic effect). Illustrative dendritic cell antigens of interest include, for example, CLEC9A, XCR1, RANK, CD36 / SRB3, LOX-1 / SR-E1, CD68, MARCO, CD163, SR-A1 / MSR, CD5L, SREC-1, CL-PI / COLEC12, SREC-II, LIMPIIISRB2, RP105, TLR4, TLR1, TLR5, TLR2, TLR6, TLR3, TLR9, 4-IBB Ligand / TNFSF9, IL-12 / IL-23 p40, 4-Amino-1,8-naphthalimide, ILT2 / CD85j, CCL21 / 6Ckine, ILT3 / CD85k, 8-oxo-dG, ILT4 / CD85d, 8D6A, ILT5 / CD85a, A2B5, lutegrin α 4 / CD49d, Aag, Integrin β 2 / CD18, AMICA, Langerin, B7-2 / CD86, Leukotriene B4 RI, B7-H3, LMIR1 / CD300A, BLAME / SLAMF8, LMIR2 / CD300c, Clq R1 / CD93, LMIR3 / CD300LF, CCR6, LMIR5 / CD300LB CCR7, LMIR6 / CD300LE, CD40 / TNFRSF5, MAG / Siglec-4-a, CD43, MCAM, CD45, MD-1, CD68, MD-2, CD83, MDL-1 / CLEC5A, CD84 / SLAMF5, MMR, CD97, NCAMLI, CD2F-10 / SLAMF9, Osteoactivin GPNMB, Chern 23, PD-L2, CLEC-1, RP105, CLEC-2, CLEC-8, Siglec-2 / CD22, CRACC / SLAMF7, Siglec-3 / CD33, DC-SIGN, Siglec-5, DC-SIGNR / CD299, Siglec-6, DCAR, Siglec-7, DCIR / CLEC4A, Siglec-9, DEC-205, Siglec-10, Dectin-1 / CLEC7A, Siglec-F, Dectin-2 / CLEC6A, SIGNR1 / CD209, DEP-1 / CD148, SIGNR4, DLEC, SLAM, EMMPRIN / CD147, TCCR / WSX-1, Fc-y R1 / CD64, TLR3, Fc-y RIIB / CD32b, TREM-1, Fc-y RIIC / CD32c, TREM-2, Fc-y RIIA / CD32a, TREM-3, Fc-y RIII / CD16, TREML1 / TLT-1, ICAM-2 / CD102, DEC205, and Vanilloid R1. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these illustrative DC antigens. In an exemplary embodiment, the present chimeric protein comprises a targeting moiety directed against Clec9A. In various embodiments, the targeting moiety directed against Clec9A is a protein-based agent capable of specific binding to Clec9A. In various embodiments, the targeting moiety is a protein-based agent capable of specific binding to Clec9A without neutralization of Clec9A. Clec9A is a group V C-type lectin-like receptor (CTLR) expressed on the surface of a subset of dendritic cells (i.e., BDCA<com:Sub>3< / com:Sub>+ dendritic cells) specialized for the uptake and processing of materials from dead cells. Clec9A recognizes a conserved component within nucleated and nonnucleated cells, exposed when cell membranes are damaged. CLEC9A is expressed at the cell surface as a glycosylated dimer and can mediate endocytosis, but not phagocytosis. CLEC9A possesses a cytoplasmic immunoreceptor tyrosine-based activation-like motif that can recruit Syk kinase and induce proinflammatory cytokine production (see Huysamen et al. (2008), JBC, 283:16693-701). In various embodiments, the present chimeric protein comprises a targeting moiety having an antigen recognition domain that recognizes an epitope present on Clec9A. In an embodiment, the antigen-recognition domain recognizes one or more linear epitopes present on Clec9A. As used herein, a linear epitope refers to any continuous sequence of amino acids present on Clec9A. In another embodiment, the antigen-recognition domain recognizes one or more conformational epitopes present on Clec9A. As used herein, a conformation epitope refers to one or more sections of amino acids (which may be discontinuous) which form a three-dimensional surface with features and / or shapes and / or tertiary structures capable of being recognized by an antigen recognition domain. In various embodiments, the present chimeric protein comprises a targeting moiety that may bind to the full- length and / or mature forms and / or isoforms and / or splice variants and / or fragments and / or any other naturally occurring or synthetic analogs, variants, or mutants of human Clec9A. In various embodiments, the targeting moiety may bind to any forms of the human Clec9A, including monomeric, dimeric, heterodimeric, multimeric and associated forms. In an embodiment, the targeting moiety binds to the monomeric form of Clec9A. In another embodiment, the targeting moiety binds to a dimeric form of Clec9A. In a further embodiment, the targeting moiety binds to glycosylated form of Clec9A, which may be either monomeric or dimeric. In an embodiment, the present chimeric protein comprises a targeting moiety with an antigen recognition domain that recognizes one or more epitopes present on human Clec9A. In an embodiment, the human Clec9A comprises the amino acid sequence of: MHEEEIYTSLQWDSPAPDTYQKCLSSNKCSGACCLVMVISCVFCMGLLTA SIFLGVKLLQVSTIAMQQQEKLIQQERALLNFTEWKRSCALQMKYCQAFMQ NSLSSAHNSSPCPNNWIQNRESCYYVSEIWSIWHTSQENCLKEGSTLLQIE SKEEMDFITGSLRKIKGSYDYWVGLSQDGHSGRWLWQDGSSPSPGLLPA ERSQSANQVCGYVKSNSLLSSNCSTWKYFICEKYALRSSV (SEQ ID NO: 25). In various embodiments, the present chimeric protein comprises a targeting moiety capable of specific binding. In various embodiments, the chimeric protein comprises a targeting moiety having an antigen recognition domain such as an antibody or derivatives thereof. In an embodiment, the chimeric protein comprises a targeting moiety which is an antibody. In various embodiments, the antibody is a full-length multimeric protein that includes two heavy chains and two light chains as described elsewhere herein. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the present chimeric protein comprises a targeting moiety which is a single-domain antibody, such as a VHH (which is commercially available under the trademark of NANOBODIES) as described elsewhere herein. In an embodiment, the present chimeric protein comprises a VHH. In some embodiments, the present chimeric protein comprises a targeting moiety which is a VHH comprising a single amino acid chain having four "framework regions" or FRs and three "complementary determining regions" or CDRs. As used herein, "framework region" or "FR" refers to a region in the variable domain which is located between the CDRs. As used herein, "complementary determining region" or "CDR" refers to variable regions in VHHs that contains the amino acid sequences capable of specifically binding to antigenic targets. In various embodiments, the present chimeric protein comprises a VHH having a variable domain comprising at least one CDR1, CDR2, and / or CDR3 sequences. In some embodiments, the CDR1 sequence is selected from: GSISSINVMG (SEQ ID NO: 26); GSFSSINVMG (SEQ ID NO: 27); GSISSINIMG (SEQ ID NO: 28); GSISSINIMG (SEQ ID NO: 29); VSIFSINAMG (SEQ ID NO: 30); GSIFSLNAMG (SEQ ID NO: 31); GRTISNYDMA (SEQ ID NO: 32); GRTFTTSLMQ (SEQ ID NO: 33); ERNLRIYDMA (SEQ ID NO: 34); ERNLRSYDMA (SEQ ID NO: 35); GLTFSNYHMG (SEQ ID NO: 36); GLTFSSYHMG (SEQ ID NO: 37); GLTFSRYHMG (SEQ ID NO: 38); GLTLSSYYIA (SEQ ID NO: 39); GLTFSSYYTG (SEQ ID NO: 40); GLTLSSYHMG (SEQ ID NO: 41); GRTSSPYVTG (SEQ ID NO: 42); GFTFSGYVMS (SEQ ID NO: 43); GFTFSGYVMT (SEQ ID NO: 44); or GFTFSGYLMS (SEQ ID NO: 45). In some embodiments, the CDR2 sequence is selected from: RITNLGLPNYADWLKD (SEQ ID NO: 46); RITNLGLPNYADSVTG (SEQ ID NO: 47); RITNIGLPNYADSVKG (SEQ ID NO: 48); RITNLGLPNYADSVEG (SEQ ID NO: 49); AITSGGRVVYSDSVKG (SEQ ID NO: 50); AITSGGRTAYADSVKG (SEQ ID NO: 51); HITSDGRIVYADPVKG (SEQ ID NO: 52); RISGSGDRTDYADSVKG (SEQ ID NO: 53); SITWSTGNTHYADSVKG (SEQ ID NO: 54); VISSSGDSTHYSDFVKG (SEQ ID NO: 55); VITSSGDSTHYSDFVKG (SEQ ID NO: 56); QITWSDASIYYAGSVKG (SEQ ID NO: 57); QITWSDTSIYYAGSVKG (SEQ ID NO: 58); QITWSDGTTYYPGSVKG (SEQ ID NO: 59); QIRWSDDSTYYPGSVKG (SEQ ID NO: 60); QISWSDDSTYYADSVKG (SEQ ID NO: 61); TVSWGGVTYYADSVKG (SEQ ID NO: 62); SIGSGGGYPSYTDSVEG (SEQ ID NO: 63); SIGSGGGYPSYTGSVEG (SEQ ID NO: 64); HIGSGGGYPSYTDSVQG (SEQ ID NO: 65); HIGSGGGHATYTDSVEG (SEQ ID NO: 66); or TIGSGGGITSYADSVKG (SEQ ID NO: 67). In some embodiments, the CDR3 sequence is selected from: VALSAEY (SEQ ID NO: 68); VALKAEY (SEQ ID NO: 69); VGLKAEY (SEQ ID NO: 70); KTKSAVLFGGMDY (SEQ ID NO: 71); YIRGEDY (SEQ ID NO: 72); KHYASNY (SEQ ID NO: 73); QDFGSPSF (SEQ ID NO: 74); QDFRSPDF (SEQ ID NO: 75); QIFGSPNF (SEQ ID NO: 76); LAIHGDY (SEQ ID NO: 77); NQIRQWP (SEQ ID NO: 78); NSIRQWP (SEQ ID NO: 79); NAIRQWP (SEQ ID NO: 80); RKVGGPDY (SEQ ID NO: 81); NTFGNVY (SEQ ID NO: 82); LGR; or VIK. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:26, SEQ ID NO:46, and SEQ ID NO:68. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:27, SEQ ID NO:47, and SEQ ID NO:69. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:28, SEQ ID NO:48, and SEQ ID NO:69. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:26, SEQ ID NO:49, and SEQ ID NO:70. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:29, SEQ ID NO:50, and SEQ ID NO:71. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:30, SEQ ID NO:51, and SEQ ID NO:72. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:31, SEQ ID NO:52, and SEQ ID NO:73. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:32, SEQ ID NO:53, and SEQ ID NO:74. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:32, SEQ ID NO:53, and SEQ ID NO:75. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:32, SEQ ID NO:53, and SEQ ID NO:76. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:33, SEQ ID NO:54, and SEQ ID NO:77. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:34, SEQ ID NO:55, and SEQ ID NO:78. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:34, SEQ ID NO:55, and SEQ ID NO:79. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:35, SEQ ID NO:56, and SEQ ID NO:80. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:36, SEQ ID NO:57, and SEQ ID NO:81. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:37, SEQ ID NO:58, and SEQ ID NO:81. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:38, SEQ ID NO:59, and SEQ ID NO:81. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:39, SEQ ID NO:60, and SEQ ID NO:81. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:40, SEQ ID NO:61, and SEQ ID NO:81. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:41, SEQ ID NO:61, and SEQ ID NO:81. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:42, SEQ ID NO:62, and SEQ ID NO:82. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:43, SEQ ID NO:63, and LGR. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:43, SEQ ID NO:64, and LGR. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:43, SEQ ID NO:65, and LGR. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:44, SEQ ID NO:66, and LGR. In some embodiments, the Clec9A targeting moiety comprises SEQ ID NO:45, SEQ ID NO:67, andVIK. In various embodiments, the Clec9A targeting moiety comprises an amino acid sequence selected from the following sequences: R2CHCL8 (SEQ ID NO: 83) QVQLVESGGGLVHPGGSLRLSCAASGSISSINVMGWYRQAPGKERELVAR ITNLGLPNYADWLKDRFTISRDNAKNTVYLQMNSLKPEDTAVYYCYLVALS AEYWGQGTQVTVSS; R1CHCL50 (SEQ ID NO: 84) QVQLVESGGGLVHPGGSLRLSCAASGSFSSINVMGWYRQAPGKERELVA RITNLGLPNYADSVTGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCYLVALK AEYWGQGTQVTVSS; R1CHCL21 (SEQ ID NO: 85) QVQLVESGGGLVHRGGSLRLSCAASGSISSINIMGWYRQAPGKERELVARI TNIGLPNYADSVKGRFTISRDNAKSTVYLQMNSLNAEDTAVYYCYLVALKA EYWGQGTQVTVSS; R2CHCL87 (SEQ ID NO: 86) QVQLVESGGGLVQPGGSLRLSCAASGSISSINVMGWYRQAPGKERELVA RITNLGLPNYADSVEGRFTISRDKDENTVYLEMNTLKPEDTAVYYCYLVGLK AEYWGQGTQVTVSS; R2CHCL24 (SEQ ID NO: 87) QVQLVESGGGLVQPGGSLRLSCAASGSSDSINAMGWYRQAPGKERELVA AITSGGRVVYSDSVKGRGTISRDNAKNTVYLQIASLKPEDTAVYYCNVKTK SAVLFGGMDYWGKGTQVTVSS; R2CHCL38 (SEQ ID NO: 88) QVQLVESGGGLVQPGGSLRLSCAASVSIFSINAMGWYRQAPGKERELVAA ITSGGRTAYADSVKGRFTISRDNSKNTVYLQMDSLKPEDTDVYYCKAYIRG EDYWGKGTQVTVSS; R1CHCL16 (SEQ ID NO: 89) DVQLVESGGGLVQPGGSLRLSCAASGSIFSLNAMGWYRQAPGKERELVA HITSDGRIVYADPVKGRFTISRVDGKNMVTLQMNSLKPEDTAVYYCNAKHY ASNYWGQGTQVTVSS; R2CHCL10 (SEQ ID NO: 90) QVQLVESGGGSVQAGGSLRLSCAASGRTISNYDMAWSRQAPGKEREFVA RISGSGDRTDYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCQIQD FGSPSFSGQGTQVTVSS; R1CHCL34 (SEQ ID NO: 91) DVQLVESGGGSVQAGGSLRLSCAASGRTISNYDMAWSRQAPGKEREFVA RISGSGDRTDYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCQIQD FRSPDFWSQGTQVTVSS; R1CHCL82 (SEQ ID NO: 92) QVQLVESGGESVQAGGSLRLSCAASGRTISNYDMAWSRQAPGKEREFVA RISGSGDRTDYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYNCQTQI FGSPNFSGQGTQVTVSS; R2CHCL3 (SEQ ID NO: 93) QVQLVESGGGLVQAGDSLRLSCAASGRTFTTSLMQWHRQAPGKEREFVA SITWSTGNTHYADSVKGRFTISRDNARNTVYLQMNSLKPEDTAIYTCRVLAI HGDYWGQGTQVTVSS; R2CHCL69 (SEQ ID NO: 94) DVQLVESGGGLVQAGDSLRLSCAASERNLRIYDMAWYRQAPGKEREYVA VISSSGDSTHYSDFVKGRFTISRDNAKNTVSLQMDSLKPEDTAFYYCNVNQ IRQWPWGQGTQVTVSS; R1CHCL56 (SEQ ID NO: 95) QVQLVESGGGLVQAGDSLRLSCAASERNLRIYDMAWYRQAPGKEREYVA VISSSGDSTHYSDFVKGRFTISRDNAKNTVSLQMDSLKPEDTAFYYCNVNS IRQWPWGQGTQVTVSS; R2CHCL32 (SEQ ID NO: 96) QVQLVESGGGLVQAGDSLRLSCTASERNLRSYDMAWWRQAPGKEREYV AVITSSGDSTHYSDFVKGRFTISRDNAKNTVSLQMDSLKPEDTASYYCNVN AIRQWPWGQGTQVTVSS; R2CHCL49 (SEQ ID NO: 97) DVQLVESGGGSVQAGGSLRLSCAISGLTFSNYHMGWYRQAPGREREFVA QITWSDASIYYAGSVKGRFTISRDNVKNIVYLQIDNLKPEDTAIYYCDARKVG GPDYWGQGTQVTVSS; R2CHCL53 (SEQ ID NO: 98) QVQLVESGGGLVQAGGSLTLSCAISGLTFSSYHMGWYRQAPGREREFVA QITWSDTSIYYAGSVKGRFTISRDNVKNIVYLQIDNLKPEDTAIYYCDARKVG GPDYWGQGTQVTVSS; R2CHCL22 (SEQ ID NO: 99) DVQLVESGGGLVQAGGSLRLSCAISGLTFSRYHMGWYRQAPGREREFVA QITWSDGTTYYPGSVKGRFTISRDNARNTVYLQIDNLKPEDTAIYYCDARKV GGPDYWGQGTQVTVSS; R2CHCL25 (SEQ ID NO: 100) QVQLVESGGGLVQAGGSLRLSCATSGLTLSSYYIAWYRQAPGREREFVAQ IRWSDDSTYYPGSVKGRFTISRDNARNTVYLRMDNLKPEDTARYYCDARK VGGPDYWGQGTQVTVSS; R2CHCL18 (SEQ ID NO: 101) DVQLVESGGGLVQAGGSLRLSCATSGLTFSSYYTGWYRQAPGREREFVA QISWSDDSTYYADSVKGRFTISRDNARNTVYLQMNNLKPGDTAIYYCDARK VGGPDYWGQGTQVTVSS; R1CHCL23 (SEQ ID NO: 102) DVQLVESGGGLVQAGGSLRLSCATSGLTLSSYHMGWYRQAPGREREFVA QISWSDDSTYYADSVKGRFTISRDNARNTVYLQMNNLKPEDTAIYYCDARK VGGPDYWGQGTQVTVSS; R1CHCL27 (SEQ ID NO: 103) DVQLVESGGGLVQAGGSLRLSCAASGRTSSPYVTGWYRQTPGKEREPVA TVSWGGVTYYADSVKGRFTISRDNAKNTVYLQMNALKPEDTAIYYCNVNTF GNVYWGQGTQVTVSS; R2CHCL13 (SEQ ID NO: 104) QVQLVESGGGLVQPGGSLRLSCAASGFTFSGYVMSWVRQAPGKGLEWV ASIGSGGGYPSYTDSVEGRFTISRDNAKNTLYLLMDNLKPDDTAVYYCEML GRRGQGTQVTVSS; R2CHCL14 (SEQ ID NO: 105) QVQLVESGGGLVQPGGSLRLSCAASGFTFSGYVMSWVRQAPGKGLEWV ASIGSGGGYPSYTDSVEGRFTISRDNAKNTLYLQMNNLKPDDTAVYYCEM LGRRGQGTQVTVSS; R2CHCL42 (SEQ ID NO: 106) QVQLVESGGGLVQPGGSLRLSCAASGFTFSGYVMSWVRQAPGKGLEWV ASIGSGGGYPSYTGSVEGRFTISRDNAKNTLYLLMNNLKPDDTAVYYCEML GRRGQGTQVTVSS; R2CHCL41 (SEQ ID NO: 107) QVQLVESGGGLVQPGGSLRLSCAASGFTFSGYVMSWVRQAPGKGLEWV AHIGSGGGYPSYTDSVQGRFTISRDNAKNTLYLQMNNLKPEDTAVYYCEM LGRRGQGTQVTVSS; R2CHCL94 (SEQ ID NO: 108) QVQLVESGGGLVQPGGSLRLSCAASGFTFSGYVMTWVRQAPGKGLEWV AHIGSGGGHATYTDSVEGRFTISRDNAKNTLYLQMNNLKAEDTAVYYCEFL GRRGQGTQVTVSS; or R2CHCL27(SEQ ID NO: 109) QVQLVESGGGLVQPGGSLRLSCAASGFTFSGYLMSWVRQAPGKGLEWV ATIGSGGGITSYADSVKGRFTISRDNAKNTLYLQMNNLKHEDTAVYYCETVI KRGQGTQVTVSS. In various embodiments, the present invention contemplates the use of any natural or synthetic analogs, mutants, variants, alleles, homologs and orthologs (herein collectively referred to as "analogs") of the targeting moiety directed against Clec9A as described herein. In various embodiments, the amino acid sequence of the targeting moiety directed against Clec9A further includes an amino acid analog, an amino acid derivative, or other non-classical amino acids. In various embodiments, the present chimeric protein comprises a targeting moiety comprising an amino acid sequence that is at least 60% identical to any one of the sequences disclosed herein. For example, the chimeric protein may comprise a targeting moiety comprising an amino acid sequence that is at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to any one of the sequences discloses herein (e.g. about 60%, or about 61%, or about 62%, or about 63%, or about 64%, or about 65%, or about 66%, or about 67%, or about 68%, or about 69%, or about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, about 99% or about 100% sequence identity to any one of the sequences disclosed herein). In various embodiments, the targeting moiety of the invention comprises one or more mutations that do not substantially reduce the Clec9A targeting moiety's capability to specifically bind to Clec9A. In various embodiments, the mutations do not substantially reduce the targeting moiety's capability to specifically bind to Clec9A without neutralizing Clec9A. In various embodiments, the binding affinity of the Clec9A targeting moiety for the full-length and / or mature forms and / or isoforms and / or splice variants and / or fragments and / or monomeric and / or dimeric forms and / or any other naturally occurring or synthetic analogs, variants, or mutants (including monomeric and / or dimeric forms) of human Clec9A may be described by the equilibrium dissociation constant (KD). In various embodiments, the present chimeric protein comprises a targeting moiety that binds to the full-length and / or mature forms and / or isoforms and / or splice variants and / or fragments and / or any other naturally occurring or synthetic analogs, variants, or mutants (including monomeric and / or dimeric forms) of human Clec9A with a K<com:Sub>D< / com:Sub> of less than about 1 uM, about 900 nM, about 800 nM, about 700 nM, about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, about 10 nM, or about 5 nM, or about 1 nM. In various embodiments, the present chimeric protein comprises a targeting moiety that binds but does not functionally modulate the antigen of interest, e.g., Clec9A. For instance, in various embodiments, the Clec9A targeting moiety simply targets the antigen but does not substantially functionally modulate (e.g. substantially inhibit, reduce or neutralize) a biological effect that the antigen has. In various embodiments, the Clec9A targeting moiety binds an epitope that is physically separate from an antigen site that is important for its biological activity (e.g. an antigen's active site). Such binding without significant function modulation finds use in various embodiments of the present invention, including methods in which the present chimeric protein is used to directly or indirectly recruit active immune cells to a site of need via an effector antigen. For example, in various embodiments, the present chimeric protein may be used to directly or indirectly recruit dendritic cells via Clec9A to a tumor cell in a method of reducing or eliminating a tumor (e.g. the chimeric protein may comprise a targeting moiety having an anti-Clec9A antigen recognition domain and a targeting moiety having a recognition domain (e.g. antigen recognition domain) directed against a tumor antigen or receptor). In such embodiments, it is desirable to directly or indirectly recruit dendritic cells but not to functionally modulate the Clec9A activity. In these embodiments, Clec9A signaling is an important piece of the tumor reducing or eliminating effect. In some embodiments, the present chimeric protein enhances antigen-presentation by dendritic cells. For example, in various embodiments, the present chimeric protein may directly or indirectly recruits dendritic cells via Clec9A to a tumor cell, where tumor antigens are subsequently endocytosed and presented on the dendritic cell for induction of potent humoral and cytotoxic T cell responses. In some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) on immune cells selected from, but not limited to, megakaryocytes, thrombocytes, erythrocytes, mast cells, basophils, neutrophils, eosinophils, or subsets thereof. In some embodiments, the recognition domains directly or indirectly recruit megakaryocytes, thrombocytes, erythrocytes, mast cells, basophils, neutrophils, eosinophils, or subsets thereof, e.g., in some embodiments, to a therapeutic site (e.g. a locus with one or more disease cell or cell to be modulated for a therapeutic effect). In some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with megakaryocytes and / or thrombocytes. Illustrative megakaryocyte and / or thrombocyte antigens of interest include, for example, GP IIb / IIIa, GPIb, vWF, PF4, and TSP. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these illustrative megakaryocyte and / or thrombocyte antigens. In some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with erythrocytes. Illustrative erythrocyte antigens of interest include, for example, CD34, CD36, CD38, CD41a (platelet glycoprotein IIb / IIIa), CD41b (GPIIb), CD71 (transferrin receptor), CD105, glycophorin A, glycophorin C, c-kit, HLA-DR, H2 (MHC-II), and Rhesus antigens. In In various embodiments, a targeting moiety of the chimeric protein binds one or more of these illustrative erythrocyte antigens. In some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with mast cells. Illustrative mast cells antigens of interest include, for example, SCFR / CD117, Fc<com:Sub>E< / com:Sub>RI, CD2, CD25, CD35, CD88, CD203c, C5R1, CMAI, FCERIA, FCER2, TPSABI. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these mast cell antigens. In some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with basophils. Illustrative basophils antigens of interest include, for example, Fc<com:Sub>e< / com:Sub>RI, CD203c, CD123, CD13, CD107a, CD107b, and CD164. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these basophil antigens. In some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with neutrophils. Illustrative neutrophils antigens of interest include, for example, 7D5, CD10 / CALLA, CD13, CD16 (FcRIII), CD18 proteins (LFA-1, CR3, and p150, 95), CD45, CD67, and CD177. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these neutrophil antigens. In some embodiments, the targeting moiety comprises an antigen recognition domain that specifically binds to a target (e.g. antigen, receptor) associated with eosinophils. Illustrative eosinophils antigens of interest include, for example, CD35, CD44 and CD69. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these eosinophil antigens. In various embodiments, the targeting moiety may comprise an antigen recognition domain may bind to any appropriate target, antigen, receptor, or cell surface markers known by the skilled artisan. In some embodiments, the antigen or cell surface marker is a tissue-specific marker. Illustrative tissue-specific markers include, but are not limited to, endothelial cell surface markers such as ACE, CD14, CD34, CDH5, ENG, ICAM2, MCAM, NOS3, PECAMI, PROCR, SELE, SELP, TEK, THBD, VCAMI, VWF; smooth muscle cell surface markers such as ACTA2, MYHIO, MYHI 1, MYH9, MYOCD; fibroblast (stromal) cell surface markers such as ALCAM, CD34, COLIAI, COL1A2, COL3A1, FAP, PH-4; epithelial cell surface markers such as CDID, K6IRS2, KRTIO, KRT13, KRT17, KRT18, KRT19, KRT4, KRT5, KRT8, MUCI, TACSTDI; neovasculature markers such as CD13, TFNA, Alpha-v beta-3 (<com:Math><semantics>αVβ3<annotation encoding="application / x-tex">\alpha_{V}\beta_{3}< / annotation>< / semantics>< / com:Math>), E-selectin; and adipocyte surface markers such as ADIPOQ, FABP4, and RETN. In various embodiments, a targeting moiety of the chimeric protein binds one or more of these antigens. In various embodiments, a targeting moiety of the chimeric protein binds one or more of cells having these antigens. In some embodiments, the recognition domains specifically bind to a target (e.g. antigen, receptor) associated with tumor cells. In some embodiments, the recognition domains directly or indirectly recruit tumor cells. For instance, in some embodiments, the direct or indirect recruitment of the tumor cell is to one or more effector cell (e.g. an immune cell as described herein) that can kill and / or suppress the tumor cell. Tumor cells, or cancer cells refer to an uncontrolled growth of cells or tissues and / or an abnormal increased in cell survival and / or inhibition of apoptosis which interferes with the normal functioning of bodily organs and systems. For example, tumor cells include benign and malignant cancers, polyps, hyperplasia, as well as dormant tumors or micrometastases. Illustrative tumor cells include, but are not limited to cells of: basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra- epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (e.g. that associated with brain tumors), and Meigs' syndrome. Tumor cells, or cancer cells also include, but are not limited to, carcinomas, e.g. various subtypes, including, for example, adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma), sarcomas (including, for example, bone and soft tissue), leukemias (including, for example, acute myeloid, acute lymphoblastic, chronic myeloid, chronic lymphocytic, and hairy cell), lymphomas and myelomas (including, for example, Hodgkin and non-Hodgkin lymphomas, light chain, non-secretory, MGUS, and plasmacytomas), and central nervous system cancers (including, for example, brain (e.g. gliomas (e.g. astrocytoma, oligodendroglioma, and ependymoma), meningioma, pituitary adenoma, and neuromas, and spinal cord tumors (e.g. meningiomas and neurofibroma). Illustrative tumor antigens include, but are not limited to, MART-1 / Melan-A, gp100, Dipeptidyl peptidase IV (DPPIV), adenosine deaminase-binding protein (ADAbp), cyclophilin b, Colorectal associated antigen (CRC)- 0017-1A / GA733, Carcinoembryonic Antigen (CEA) and its immunogenic epitopes CAP-1 and CAP-2, etv6, aml1, Prostate Specific Antigen (PSA) and its immunogenic epitopes PSA-1, PSA-2, and PSA-3, prostate-specific membrane antigen (PSMA), T-cell receptor / CD3-zeta chain, MAGE-family of tumor antigens (e.g., MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE- A11, MAGE-A12, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1, MAGE- C2, MAGE-C3, MAGE-C4, MAGE-C5), GAGE-family of tumor antigens (e.g., GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, GAGE-9), BAGE, RAGE, LAGE-1, NAG, GnT-V, MUM-1, CDK4, tyrosinase, p53, MUC family, HER2 / neu, p21ras, RCAS1, α-fetoprotein, E-cadherin, α-catenin, β-catenin and γ-catenin, p120ctn, gp100 Pmel117, PRAME, NY-ESO-1, cdc27, adenomatous polyposis coli protein (APC), fodrin, Connexin 37, Ig-idiotype, p15, gp75, GM2 and GD2 gangliosides, viral products such as human papilloma virus proteins, Smad family of tumor antigens, Imp-1, NA, EBV-encoded nuclear antigen (EBNA)-1, brain glycogen phosphorylase, SSX-1, SSX-2 (HOM-MEL-40), SSX-1, SSX-4, SSX-5, SCP-1 CT-7, c-erbB-2, CD19, CD20, CD22, CD30, CD33, CD37, CD56, CD70, CD74, CD138, AGS16, MUC1, GPNMB, Ep-CAM, PD-L1, PD- L2, PMSA, and BCMA (TNFRSF17). In various embodiments, a targeting moiety of the chimeric protein binds one or more of these tumor antigens. In some embodiments, the present chimeric protein has (i) one or more of the targeting moieties which is directed against an immune cell selected from a T cell, a B cell, a dendritic cell, a macrophage, a NK cell, or subsets thereof and (ii) one or more of the targeting moieties which is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a T cell (including, without limitation an effector T cell) and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a B cell and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a dendritic cell and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a macrophage and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a NK cell and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. By way of non-limiting example, in various embodiments, the present chimeric protein has (i) a targeting moiety directed against a T cell, for example, mediated by targeting to CD8, SLAMF4, IL-2 R a, 4-1BB / TNFRSF9, IL-2 R β, ALCAM, B7-1, IL-4 R, B7-H3, BLAME / SLAMFS, CEACAM1, IL-6 R, CCR3, IL-7 Rα, CCR4, CXCRI / IL-S RA, CCR5, CCR6, IL-10R a, CCR 7, IL-1 0 R \( \beta \), CCRS, IL-12 R \( \beta \) 1, CCR9, IL-12 R \( \beta \) 2, CD2, IL-13 R \( \alpha \) 1, IL-13, CD3, CD4, ILT2 / CDS5j, ILT3 / CDS5k, ILT4 / CDS5d, ILT5 / CDS5a, lutegrin α 4 / CD49d, CDS, Integrin α E / CD103, CD6, Integrin a M / CD 11 b, CDS, Integrin a X / CD11c, Integrin B 2 / CDIS, KIR / CD15S, CD27 / TNFRSF7, KIR2DL1, CD2S, KIR2DL3, CD30 / TNFRSFS, KIR2DL4 / CD15Sd, CD31 / PECAM-1, KIR2DS4, CD40 Ligand / TNFSF5, LAG-3, CD43, LAIR1, CD45, LAIR2, CDS3, Leukotriene B4-R1, CDS4 / SLAMF5, NCAM-L1, CD94, NKG2A, CD97, NKG2C, CD229 / SLAMF3, NKG2D, CD2F-10 / SLAMF9, NT-4, CD69, NTB-A / SLAMF6, Common y Chain / IL-2 R y, Osteopontin, CRACC / SLAMF7, PD-1, CRTAM, PSGL-1, CTLA-4, RANK / TNFRSF11A, CX3CR1, CX3CL1, L-Selectin, CXCR3, SIRP β 1, CXCR4, SLAM, CXCR6, TCCR / WSX-1, DNAM-1, Thymopoietin, EMMPRIN / CD147, TIM-1, EphB6, TIM-2, Fas / TNFRSF6, TIM-3, Fas Ligand / TNFSF6, TIM-4, Fcy RIII / CD16, TIM-6, TNFR1 / TNFRSF1A, Granulysin, TNF RIII / TNFRSF1B, TRAIL RI / TNFRSFIOA, ICAM-1 / CD54, TRAIL R2 / TNFRSF10B, ICAM-2 / CD102, TRAILR3 / TNFRSF10C,IFN-yR1, TRAILR4 / TNFRSF10D, IFN-γ R2, TSLP, IL-1 R1, or TSLP R; and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. By way of non-limiting example, in various embodiments, the present chimeric protein has a targeting moiety directed against (i) a checkpoint marker expressed on a T cell, e.g. one or more of PD-1, CD28, CTLA4, ICOS, BTLA, KIR, LAG3, CD137, OX40, CD27, CD40L, TIM3, and A2aR and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In various embodiments, the present chimeric protein has one or more targeting moieties directed against PD-1. In some embodiments, the chimeric protein has one or more targeting moieties which selectively bind a PD-1 polypeptide. In some embodiments, the chimeric protein comprises one or more antibodies, antibody derivatives or formats, peptides or polypeptides, or fusion proteins that selectively bind a PD-1 polypeptide. In an embodiment, the targeting moiety comprises the anti-PD-1 antibody pembrolizumab (aka MK-3475, KEYTRUDA), or fragments thereof. Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in Hamid, et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8,354,509, and WO 2009 / 114335. In illustrative embodiments, pembrolizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising the amino acid sequence of: QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 110); and / or a light chain comprising the amino acid sequence of: EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 111). In an embodiment, the targeting moiety comprises the anti-PD-1 antibody, nivolumab (aka BMS-936558, MDX- 1106, ONO-4538, OPDIVO), or fragments thereof. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449 and WO 2006 / 121168. In illustrative embodiments, nivolumab or an antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of: [Image disponible dans le document PDF, Image available in the PDF document] and / or a light chain comprising the amino acid sequence of: [Image disponible dans le document PDF, Image available in the PDF document] In an embodiment, the targeting moiety comprises the anti-PD-1 antibody pidilizumab (aka CT-011, hBAT or hBAT-1), or fragments thereof. Pidilizumab and other humanized anti-PD-I monoclonal antibodies are disclosed in US 2008 / 0025980 and WO 2009 / 101611. In illustrative embodiments, the anti-PD-1 antibody or an antigen- binding fragment thereof for use in the methods provided herein comprises a light chain variable regions comprising an amino acid sequence selected from SEQ ID NOS: 15-18 of US 2008 / 0025980: SEQ ID No: 15 of US 2008 / 0025980 (SEQ ID NO: 114): EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWYQQKPGKAPKLLIYRTSNLASGVPSR FSGSGSGTDFTLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIK; SEQ ID No: 16 of US 2008 / 0025980 (SEQ ID NO: 115): EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSR FSGSGSGTDYTLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIK; SEQ ID No: 17 of US 2008 / 0025980 (SEQ ID NO: 116): EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSR FSGSGSGTDYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIK; SEQ ID No: 18 of US 2008 / 0025980 (SEQ ID NO: 117): EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSR FSGSGSGTSYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIK; and / or a heavy chain comprising an amino acid sequence selected from SEQ ID NOS: 20-24 of US 2008 / 0025980: SEQ ID No: 20 of US 2008 / 0025980 (SEQ ID NO: 118): QVQLVQSGSELKKPGASVKISCKASGYSFSNYGMNWVRQAPGQGLQWMGWINTDSGESTY AEEFKGRFVFSLDTSVSTAYLQITSLTAEDTGMYFCAKVGYDALDYWGQGTLVTVSS; SEQ ID No: 21 of US 2008 / 0025980 (SEQ ID NO: 119): QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTY AEEFKGRFVFSLDTSVSTAYLQITSLTAEDTGMYFCAKVGYDALDYWGQGTLVTVSS; SEQ ID No: 22 of US 2008 / 0025980 (SEQ ID NO: 120): QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTY AEEFKGRFVFSLDTSVNTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSS; SEQ ID No: 23 of US 2008 / 0025980 (SEQ ID NO: 121): QIQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTY AEEFKGRFVFSLDTSVNTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSS; SEQ ID No: 24 of US 2008 / 0025980 (SEQ ID NO: 122): QIQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTDSGESTY AEEFKGRFAFSLDTSVNTAYLQITSLNAEDTGMYFCVRVGYDALDYWGQGTLVTVSS. In an embodiment, the targeting moiety comprises a light chain comprising SEQ ID NO:18 of US 2008 / 0025980 and a heavy chain comprising SEQ ID NO:22 of US 2008 / 0025980. In an embodiment, the targeting moiety comprises AMP-514 (aka MEDI-0680). In an embodiment, the targeting moiety comprises the PD-L2-Fc fusion protein AMP-224, which is disclosed in WO2010 / 027827 and WO 2011 / 066342. In such an embodiment, the targeting moiety may include a targeting domain which comprises SEQ ID NO:4 of WO2010 / 027827 (SEQ ID NO: 123): LFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITASLQKVENDTSPHRERATLLEEQ LPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKYLTLKVKASYRKINTHILKVPETDEV ELTCQATGYPLAEVSWPNVSVPANTSHSRTPEGLYQVTSVLRLKPPPGRNFSCVFWNTHV RELTLASIDLQSQMEPRTHPTWLLHIFIPFCIIAFIFIATVIALRKQLCQKLYSSKDTTK RPVTTTKREVNSAI and / or the B7-DC fusion protein which comprises SEQ ID NO:83 of WO2010 / 027827 (SEQ ID NO: 124): MIFLLLMLSLELQLHQIAALFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITASLQ KVENDTSPHRERATLLEEQLPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKYLTLKVK ASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPANTSHSRTPEGLYQVTSVL RLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPTWEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK. In an embodiment, the targeting moiety comprises the peptide AUNP 12 or any of the other peptides disclosed in US 2011 / 0318373 or 8,907,053. For example, the targeting moiety may comprise AUNP 12 (i.e., Compound 8 or SEQ ID NO:49 of US 2011 / 0318373) which has the sequence of SEQ ID NO: 125: SNTSESFK (SNTSESF) FRVTQLAPKAQIKE-NH2 [Image disponible dans le document PDF, Image available in the PDF document] In an embodiment, the targeting moiety comprises the anti-PD-1 antibody 1E3, or fragments thereof, as disclosed in US 2014 / 0044738. In illustrative embodiments, 1E3 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVQLQQSGPV LVKPGASVKM SCKASGYTFT DYYMNWVKQS HGKSLEWIGN INPYNGGTTY NQKFKGKATL TVDKSSRTAY MEINSLTSED SAVYYCARGR IYDGSLDYWG QGTALTVSS (SEQ ID NO: 126); and / or a light chain variable region comprising the amino acid sequence of: DIQMTQFPSS LCASQGGKVT VTCKASQDIN NYMAWYQHKP GKGPRLLIHY TSTLLSGIPS RFSGSGSGRD YSFSISNLEP EDIATYYCLQ YDNLWTFGGG TKLEIK (SEQ ID NO: 127). In an embodiment, the targeting moiety comprises the anti-PD-1 antibody 1E8, or fragments thereof, as disclosed in US 2014 / 0044738. In illustrative embodiments, 1E8 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLQQSGAE LAKPGASVRL SCKASGYTFT NYWMHWVKQR PGQGLEWIGH INPSSGFTTY NQNFKDKATL TADKSSNTAY MQLSSLTYED SAVYFCARED YDVDYWGQGT TLTVSS (SEQ ID NO: 128); and / or a light chain variable region comprising the amino acid sequence of: DIVMTQSQKF MSTSVGDRVS VTCKASQSVD TNVAWYQQKP GQSPKALIFS ASYRYSGVPD RFTGSGSGTD FTLTINSVQS EDLAEYFCQQ YNSYPYTFGS GTKLEIK (SEQ ID NO: 129). In an embodiment, the targeting moiety comprises the anti-PD-1 antibody 1H3, or fragments thereof, as disclosed in US 2014 / 0044738. In illustrative embodiments, 1H3 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVOLVESGGG LVKPGGSLKL SCAASGFTFS DYGMHWVRQA PEKGLEWVAY ISSGSYTIYY TDTVKGRFTI SRDNAKNTLF LQMTSLRSED TAMYYCARRG YGSFYEYYFD YWGQGTTLTV SS (SEQ ID NO: 130; and / or light chain variable region comprising the amino acid sequence of: QIVLTQSPAL MSASPGEKVT MTCSASSSVS YMYWYQQKPR SSPKPWIYLT SNLASGVPAR FSGSGSGTSY SLTISSMEAE DAATYYCQQW SSNPFTFGSG TKLEIK (SEQ ID NO: 131). In an embodiment, the targeting moiety comprises a VHH directed against PD-1 as disclosed, for example, in US 8,907,065 and WO 2008 / 071447. In illustrative embodiments, the VHHs against PD-1 comprise SEQ ID NOS: 347-351 of US 8,907,065: SEQ ID No: 347 of US 8,907,065 (SEQ ID NO: 132): EVQLVESGGGLVQAGKSLRLSCAASGSIFSIHAMGWFRQAPGKEREFVAA ITWSGGITYYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADR AESSWYDYWGQGTQVTVSS; SEQ ID No: 348 of US 8,907,065 (SEQ ID NO: 133): EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV ITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDK HQSSWYDYWGQGTQVTVSS; SEQ ID No: 349 of US 8,907,065 (SEQ ID NO: 134): EVQLVESGGGLVQAGGSLRLSCAASGSISSIHAMGWFRQAPGKEREFVAA ITWSGGITYYADSLKGRFTISRDNAKNTGYLQMNSLKPEDTAIYYCAADR AQSSWYDYWGQGTQVTVSS; SEQ ID No: 350 of US 8,907,065 (SEQ ID NO: 135): EVQLVESGGGLVQAGGSLGLSCAASGSIFSINAMAWFRQAPGKEREFVAL ISWSGGSTYYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADR VDSNWYDYWGQGTQVTVSS; SEQ ID No: 351 of US 8,907,065 (SEQ ID NO: 136): EVQLVESGGGLVQAGGSLRLSCAASGRAFSSGTMGWFRRAPGKEREFVA SIPWSGGRIYYADSVKGRFTISRDNAQNTVYLQMNSLKPEDTAVYYCAVK ERSTGWDFASWGQCTQVTVSS. In an embodiment, the targeting moiety comprises any one of the anti-PD-1 antibodies, or fragments thereof, as disclosed in US2011 / 0271358 and WO2010 / 036959. In illustrative embodiments, the antibody or an antigen- binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID NOS: 25-29 of US2011 / 0271358: SEQ ID No: 25 of US2011 / 0271358 (SEQ ID NO: 137): QVQLVQSGAELKQPGASVKMSCKASGYSFTSSWIHWVKQAPGQGLEWIGYIYPSTGFTEY NQKFKDRATLTADKSTSTAYMELSSLRSEDSAVYYCARWRDSSGYHAMDYWGQGTSVTVS S; SEQ ID No: 26 of US2011 / 0271358 (SEQ ID NO: 138): QVQLVQSGAEVKQPGASVKMSCKASGYSFTSSWIHWVKQAPGQGLEWIGYIYPSTGFTEY NQKFKDRATLTADKSTSTAYMELSSLRSEDTAVYY3 / d10CARWRDSSGYHAMDYWGQGTSVTVS S; SEQ ID No: 27 of US2011 / 0271358 (SEQ ID NO: 139): QVQLVQSGHEVKQPGASVKMSCKASGYSFTSSWIHWVKQAPGQGLEWIGYIYPSTGFTEY NQKFKDRATLTADKSTSTAYMELSSLRSEDTAVYYCARWRDSSGYHAMDYWGQGTLVTVS S; SEQ ID No: 28 of US2011 / 0271358 (SEQ ID NO: 140): QVQLVQSGHEVKQPGASVKMSCKASGYSFTSSWIHWVRQAPGQGLEWIGYIYPSTGFTEY NQKFKDRATLTADKSTSTAYMELSSLRSEDTAVYYCARWRDSSGYHAMDYWGQGTLVTVS S; SEQ ID No: 29 of US2011 / 0271358 (SEQ ID NO: 141): QVQLVQSGHEVKQPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGYIYPSTGFTEY NQKFKDRATITADKSTSTAYMELSSLRSEDTAVYYCARWRDSSGYHAMDYWGQGTLVTVS S; and / or a light chain comprising an amino acid sequence selected from SEQ ID NOS: 30-33 of US2011 / 0271358: SEQ ID No: 30 of US2011 / 0271358 (SEQ ID NO: 142): DIVLTQSPASLTLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLES GIPARFSGSGSGTDFTLTISSLEEEDFATYYCQHSWEIPYTFGQGTKLEIK; SEQ ID No: 31 of US2011 / 0271358 (SEQ ID NO: 143): DIVLTQSPATLSLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLES GIPARFSGSGSGTDFTLTISSLEPEDFATYYCQHSWEIPYTFGQGTKLEIK; SEQ ID No: 32 of US2011 / 0271358 (SEQ ID NO: 144): EIVLTQSPATLSLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLES GIPARFSGSGSGTDFTLTISSLEPEDFATYYCQHSWEIPYTFGQGTKLEIK; SEQ ID No: 33 of US2011 / 0271358 (SEQ ID NO: 145): DIVLTQSPATLSLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLES GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSWEIPYTFGQGTKLEIK. In various embodiments, the present chimeric protein comprises one or more antibodies directed against PD-1, or antibody fragments thereof, selected from TSR-042 (Tesaro, Inc.), REGN2810 (Regeneron Pharmaceuticals, Inc.), PDR001 (Novartis Pharmaceuticals), and BGB-A317 (BeiGene Ltd.) In various embodiments, the present chimeric protein has one or more targeting moieties directed against PD-L1. In some embodiments, the chimeric protein has one or more targeting moieties which selectively bind a PD-L1 polypeptide. In some embodiments, the chimeric protein comprises one or more antibodies, antibody derivatives or formats, peptides or polypeptides, or fusion proteins that selectively bind a PD-L1 polypeptide. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody MEDI4736 (aka durvalumab), or fragments thereof. MEDI4736 is selective for PD-L1 and blocks the binding of PD-L1 to the PD-1 and CD80 receptors. MEDI4736 and antigen-binding fragments thereof for use in the methods provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. The sequence of MEDI4736 is disclosed in WO / 2016 / 06272. In illustrative embodiments, MEDI4736 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising the amino acid sequence of: EVQLVESGGG LVQPGGSLRL SCAASGFTFS RYWMSWVRQA PGKGLEWVAN IKQDGSEKYY VDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAREG GWFGELAFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPEFEG GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPASIEKTI SKAKGQPREP QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K (SEQ ID NO: 146); and / or a light chain comprising the amino acid sequence of: EIVLTQSPGT LSLSPGERAT LSCRASQRVS SSYLAWYQQK PGQAPRLLIY DASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYGSLPWTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC (SEQ ID NO: 147). In illustrative embodiments, the MEDI4736 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4 of WO / 2016 / 06272 (SEQ ID NO: 148): EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYY VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS S; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO:3 of WO / 2016 / 06272 (SEQ ID NO: 149): EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody atezolizumab (aka MPDL3280A, RG7446), or fragments thereof. In illustrative embodiments, atezolizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising the amino acid sequence of: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRF TISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 150); and / or a light chain comprising the amino acid sequence of: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSG TDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC (SEQ ID NO: 151). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody avelumab (aka MSB0010718C), or fragments thereof. In illustrative embodiments, avelumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising the amino acid sequence of: EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYIMMWVRQA PGKGLEWVSS IYPSGGITFY ADTVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARIK LGTVTTVDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 152); and / or a light chain comprising the amino acid sequence of: QSALTQPASV SGSPGQSITI SCTGTSSDVG GYNYVSWYQQ HPGKAPKLMI YDVSNRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYYC SSYTSSSTRV FGTGTKVTVL GQPKANPTVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADGSPVK AGVETTKPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS (SEQ ID NO: 153). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody BMS-936559 (aka 12A4, MDX-1105), or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, BMS- 936559 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMGGIIPIFGKAHY AQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVT VSS (SEQ ID NO: 154); and / or a light chain variable region comprising the amino acid sequence of: EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK (SEQ ID NO: 155). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 3G10, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 3G10 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGFSWVRQAPGQGLEWMGWITAYNGNTNY AQKLQGRVTMTTDTSTSTVYMELRSLRSDDTAVYYCARDYFYGMDVWGQGTTVTVSS (SEQ ID NO: 156); and / or a light chain variable region comprising the amino acid sequence of: EIVLTQSPATLSLSPGERATLSCRASQSVSSYLVWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKVEIK (SEQ ID NO: 157). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 10A5, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 10A5 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDVHWVRQAPGQRLEWMGWLHADTGITKF SQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARERIQLWFDYWGQGTLVTVSS (SEQ ID NO: 158); and / or a light chain variable region comprising the amino acid sequence of: DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ ID NO: 159). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 5F8, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 5F8 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKVSGGIFSTYAINWVRQAPGQGLEWMGGIIPIFGTANH AQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDQGIAAALFDYWGQGTLVTVSS (SEQID NO: 160); and / or a light chain variable region comprising the amino acid sequence of: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 161). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 10H10, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 10H10 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVQLVESGGGLVQPGRSLRLSCAVSGFTFDDYVVHWVRQAPGKGLEWVSGISGNSGNIGY ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAVPFDYWGQGTLVTVSS (SEQ ID NO: 162); and / or a light chain variable region comprising the amino acid sequence of: DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK (SEQ ID NO: 163). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 1B12, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 1B12 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSSYAISWVRQAPGQGLEWMGGIIPIFGRAHY AQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVT VSS (SEQ ID NO: 164); and / or a light chain variable region comprising the amino acid sequence of: EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK (SEQ ID NO: 165). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 7H1, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 7H1 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKTSGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGKAHY AQKFQGRVTITADESTTTAYMELSSLRSEDTAVYYCARKYDYVSGSPFGMDVWGQGTTVT VSS (SEQ ID NO: 166); and / or a light chain variable region comprising the amino acid sequence of: EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK (SEQ ID NO: 167). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 11E6, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 11E6 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAINWVRQAPGQGLEWMGGIIPIFGSANY AQKFQDRVTITADESTSAAYMELSSLRSEDTAVYYCARDSSGWSRYYMDVWGQGTTVTVS s (SEQ ID NO: 168); and / or a light chain variable region comprising the amino acid sequence of: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPFGGGTKVEIK (SEQ ID NO: 169). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 12B7, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 12B7 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKEPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGGIIPLFGIAHY AQKFQGRVTITADESTNTAYMDLSSLRSEDTAVYYCARKYSYVSGSPFGMDVWGQGTTVT VSS (SEQ ID NO: 170); and / or a light chain variable region comprising the amino acid sequence of: EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTRLEIK (SEQ ID NO: 171). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 13G4, or fragments thereof, as disclosed in US 2013 / 0309250 and WO2007 / 005874. In illustrative embodiments, 13G4 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVQLVESGGGLVQPGRSLRLSCAASGITFDDYGMHWVRQAPGKGLEWVSGISWNRGRIEY ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGRFRYFDWFLDYWGQGTLVTVS s (SEQ ID NO: 172); and / or a light chain variable region comprising the amino acid sequence of: AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK (SEQ ID NO: 173). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 1E12, or fragments thereof, as disclosed in US 2014 / 0044738. In illustrative embodiments, 1E12 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVKLQESGPS LVKPSQTLSL TCSVTGYSIT SDYWNWIRKF PGNKLEYVGY ISYTGSTYYN PSLKSRISIT RDTSKNQYYL QLNSVTSEDT ATYYCARYGG WLSPFDYWGQ GTTLTVSS (SEQ ID NO: 174); and / or a light chain variable region comprising the amino acid sequence of: DIVMTQSHKL MSTSVGDRVS ITCKASQDVG TAVAWYQQKP GQSPKLLIYW ASTRHTGVPD RFTGSGSGTD FTLTISNVQS EDLADYFCQQ DSSYPLTFGA GTKVELK (SEQ ID NO: 175). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 1F4, or fragments thereof, as disclosed in US 2014 / 0044738. In illustrative embodiments, 1F4 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVQLQESGPG LVAPSQSLSI TCTVSGFSLT TYSINWIRQP PGKGLEWLGV MWAGGGTNSN SVLKSRLIIS KDNSKSQVFL KMNSLQTDDT ARYYCARYYG NSPYYAIDYW GQGTSVTVSS (SEQ ID NO: 176); and / or a light chain variable region comprising the amino acid sequence of: DIVTTQSHKL MSTSVGDRVS ITCKASQDVG TAVAWYQQKP GQSPKLLIYW ASTRHTGVPD RFTGSGSGTD FTLTISNVQS EDLADYFCQQ DSSYPLTFGA GTKVELK (SEQ ID NO: 177). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 2G11, or fragments thereof, as disclosed in US 2014 / 0044738. In illustrative embodiments, 2G11 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVKLQESGPS LVKPSQTLSL TCSVTGYSII SDYWNWIRKF PGNKLEYLGY ISYTGSTYYN PSLKSRISIT RDTSKNQYYL QLNSVTTEDT ATYYCARRGG WLLPFDYWGQ GTTLTVSS (SEQ ID NO: 178); and / or a light chain variable region comprising the amino acid sequence of: DIVMTQSPSS LAVSVGEKVS MGCKSSQSLL YSSNQKNSLA WYQQKPGQSP KLLIDWASTR ESGVPDRFTG SGSGTDFTLT ISSVKAEDLA VYYCOOYYGY PLTFGAGTKL ELK (SEQ ID NO: 179). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 3B6, or fragments thereof, as disclosed in US 2014 / 0044738. In illustrative embodiments, 3B6 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVKLQESGPS LVKPGASVKL SCKASGYTFT SYDINWVKQR PGQGLEWIGW IFPRDNNTKY NENFKGKATL TVDTSSTTAY MELHSLTSED SAVYFCTKEN WVGDFDYWGQ GTTLTLSS (SEQ ID NO: 180); and / or a light chain variable region comprising the amino acid sequence of: DIVMTQSPAI MSASPGEKVT MTCSASSSIR YMHWYQQKPG TSPKRWISDT SKLTSGVPAR FSGSGSGTSY ALTISSMEAE DAATYYCHQR SSYPWTFGGG TKLEIK (SEQ ID NO: 181). In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 3D10, or fragments thereof, as disclosed in US 2014 / 0044738 and WO2012 / 145493. In illustrative embodiments, 3D10 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: EVQLQQSGPD LVTPGASVRI SCQASGYTFP DYYMNWVKQS HGKSLEWIGD IDPNYGGTTY NQKFKGKAIL TVDRSSSTAY MELRSLTSED SAVYYCARGA LTDWGQGTSL TVSS (SEQ ID NO: 182); and / or a light chain variable region comprising the amino acid sequence of: QIVLSQSPAI LSASPGEKVT MTCRASSSVS YIYWFQQKPG SSPKPWIYAT FNLASGVPAR FSGSGSGTSY SLTISRVETE DAATYYCQQW SNNPLTFGAG TKLELK (SEQ ID NO: 183). In an embodiment, the targeting moiety comprises any one of the anti-PD-L1 antibodies disclosed in US2011 / 0271358 and WO2010 / 036959. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 34-38 of US2011 / 0271358: SEQ ID No: 34 of US2011 / 0271358 (SEQ ID NO: 184): EVQLVQSGPELKKPGASVKMSCKASGYTFTSYVMHWVKQAPGQRLEWIGYVNPFNDGTKY NEMFKGRATLTSDKSTSTAYMELSSLRSEDSAVYYCARQAWGYPWGQGTLVTVSS; SEQ ID No: 35 of US2011 / 0271358 (SEQ ID NO: 185): EVQLVQSGAEVKKPGASVKMSCKASGYTFTSYVMHWVKQAPGQRLEWIGYVNPFNDGTKY NEMFKGRATLTSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS; SEQ ID No: 36 of US2011 / 0271358 (SEQ ID NO: 186): EVQLVQSGAEVKKPGASVKMSCKASGYTFTSYVMHWVRQAPGQRLEWIGYVNPFNDGTKY NEMFKGRATLTSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS; SEQ ID No: 37 of US2011 / 0271358 (SEQ ID NO: 187): EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWIGYVNPFNDGTKY NEMFKGRATLTSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS; SEQ ID No: 38 of US2011 / 0271358 (SEQ ID NO: 188): EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWIGYVNPFNDGTKY NEMFKGRATITSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID Nos: 39-42 of US2011 / 0271358: SEQ ID No: 39 of US2011 / 0271358 (SEQ ID NO: 189): DIVLTQSPASLALSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDS GVPSRFSGSGSGTDFTLTINSLEEEDAAMYFCQQSRRVPYTFGQGTKLEIK; SEQ ID No: 40 of US2011 / 0271358 (SEQ ID NO: 190): DIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDS GVPSRFSGSGSGTDFTLTINSLEAEDAAMYFCQQSRRVPYTFGQGTKLEIK; SEQ ID No: 41 of US2011 / 0271358 (SEQ ID NO: 191): EIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDS GVPSRFSGSGSGTDFTLTINSLEAEDAAMYFCQQSRRVPYTFGQGTKLEIK; SEQ ID No: 42 of US2011 / 0271358 (SEQ ID NO: 192): DIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDS GVPSRFSGSGSGTDFTLTINSLEAEDAATYFCQQSRRVPYTFGQGTKLEIK. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 2.7A4, or fragments thereof, as disclosed in WO 2011 / 066389, US8,779,108, and US2014 / 0356353. In illustrative embodiments, 2.7A4 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: SEQ ID No: 2 of WO 2011 / 066389 (SEQ ID NO: 193): EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISSSGDYIYY ADSVKGRFTISRDNAKNSLFLQMNSLKAEDTAVYYCARDLVTSMVAFDYWGQGTLVTVSS; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 7 of WO 2011 / 066389 (SEQ ID NO: 194): SYELTQPPSVSVSPGQAARITCSGDALPQKYVFWYQQKSGQAPVLVIYEDSKRPSGIPER FSGSSSGTMATLTISGAQVEDEADYYCYSTDRSGNHRVFGGGTRLTVL. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 2.9D10, or fragments thereof, as disclosed in WO 2011 / 066389, US8,779,108, and US2014 / 0356353. In illustrative embodiments, 2.9D10 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: SEQ ID No: 12 of WO 2011 / 066389 (SEQ ID NO: 195): EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGGEQYY VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDWNYGYYDMDVWGQGTTVTVSS; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 17 of WO 2011 / 066389 (SEQ ID NO: 196): EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLAWFQQKPGQAPRLLIFGTSSRATGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSIFTFGPGTKVDIK. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 2.14H9, or fragments thereof, as disclosed in WO 2011 / 066389, US8,779,108, and US2014 / 0356353. In illustrative embodiments, 2.14H9 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: SEQ ID No: 22 of WO 2011 / 066389 (SEQ ID NO: 197): EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYY VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS S; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 27 of WO 2011 / 066389 (SEQ ID NO: 198): EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTEVEIK. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 2.20A8, or fragments thereof, as disclosed in WO 2011 / 066389, US8,779,108, and US2014 / 0356353. In illustrative embodiments, 2.20A8 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: SEQ ID No: 32 of WO 2011 / 066389 (SEQ ID NO: 199): EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAIRGSGGSTYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDLHYDSSGYLDYWGQGTLVTVS S; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 37 of WO 2011 / 066389 (SEQ ID NO: 200): DIQMTQSPSSVSASVGDRVTITCRASQGIRSWLAWYQQKPGKAPKLLIYAISRLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPLTFGGGTKVEIK. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 3.15G8, or fragments thereof, as disclosed in WO 2011 / 066389, US8,779,108, and US2014 / 0356353. In illustrative embodiments, 3.15G8 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: SEQ ID No: 42 of WO 2011 / 066389 (SEQ ID NO: 201): EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGGEKYY VDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCARVQLYSDYFDYWGQGTLVTVSS; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 47 of WO 2011 / 066389 (SEQ ID NO: 202): DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKSGKAPKLLIYAASGLQSGVPS RFSGSGSGTDFTLTISSLQPEDLATYYCQQSHSLPPTFGQGTKVEIK. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 3.18G1, or fragments thereof, as disclosed in WO 2011 / 066389, US8,779,108, and US2014 / 0356353. In illustrative embodiments, 3.18G1 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: SEQ ID No: 52 of WO 2011 / 066389 (SEQ ID NO: 203): EVQLLESGGDLVQPGGSLRLSCAASGFTFNSYAMSWVRQAPGKGLEWVSTISGSGGFTFS ADSVKGRFTISRDNSKNTLFLQMNSLRVEDSAVYSCAKVLVGFNNGCWDYWGQGTLVTVS S; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 57 of WO 2011 / 066389 (SEQ ID NO: 204): SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPER FSGSNSGNTATLTISRVEAGDEADYYCQVWDSSNDHVVFGGGTKLTVL. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 2.7A4OPT, or fragments thereof, as disclosed in WO 2011 / 066389, US8,779,108, and US2014 / 0356353, and US2014 / 0356353. In illustrative embodiments, 2.7A4OPT or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: SEQ ID No: 62 of WO 2011 / 066389 (SEQ ID NO: 205): EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISSSGDYIYY ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLVTSMVAFDYWGQGTLVTVSS; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 67 of WO 2011 / 066389 (SEQ ID NO: 206): SYELTQPPSVSVSPGQTARITCSGDALPQKYVFWYQQKSGQAPVLVIYEDSKRPSGIPER FSGSSSGTMATLTISGAQVEDEADYYCYSTDRSGNHRVFGGGTKLTVL. In an embodiment, the targeting moiety comprises the anti-PD-L1 antibody 2.14H9OPT, or fragments thereof, as disclosed in WO 2011 / 066389, US8,779,108, and US2014 / 0356353. In illustrative embodiments, 2.14H9OPT or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: SEQ ID No: 72 of WO 2011 / 066389 (SEQ ID NO: 207): EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYY VDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS S; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 77 of WO 2011 / 066389 (SEQ ID NO: 208): EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIP DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK. In an embodiment, the targeting moiety comprises any one of the anti-PD-L1 antibodies disclosed in WO2016 / 061142. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 18, 30, 38, 46, 50, 54, 62, 70, and 78 of WO2016 / 061142: SEQ ID No: 18 of WO2016 / 061142 (SEQ ID NO: 209): QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKY NEKFKNRFTISRDDSKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS; SEQ ID No: 30 of WO2016 / 061142 (SEQ ID NO: 210): EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKY NEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS; SEQ ID No: 38 of WO2016 / 061142 (SEQ ID NO: 211): EVQLVQSGAEVKKPGESLRISCKGSGYTFTSYWMYWVRQAPGQGLEWMGRIDPNSGSTKY NEKFKNRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYRKGLYAMDYWGQGTTVTVSS; SEQ ID No: 46 of WO2016 / 061142 (SEQ ID NO: 212): EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWIRQSPSRGLEWLGRIDPNSGSTKY NEKFKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDYRKGLYAMDYWGQGTTVTVSS; SEQ ID No: 50 of WO2016 / 061142 (SEQ ID NO: 213): EVQLVQSGAEVKKPGESLRISCKGSGYTFTSYWMYWIRQPPGKGLEWIGRIDPNSGSTKY NEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS; SEQ ID No: 54 of WO2016 / 061142 (SEQ ID NO: 214): QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMYWIRQSPSRGLEWLGRIDPNSGSTKY NEKFKNRFTISRDDSKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS; SEQ ID No: 62 of WO2016 / 061142: (SEQ ID NO: 215) EVQLVQSGAEVKKPGESLRISCKGSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKY NEKFKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDYRKGLYAMDYWGQGTTVTVSS; SEQ ID No: 70 of WO2016 / 061142 (SEQ ID NO: 216): QITLKESGPTLVKPTQTLTLTCTFSGYTFTSYWMYWVRQAPGKGLEWVSRIDPNSGSTKY NEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS; SEQ ID No: 78 of WO2016 / 061142 (SEQ ID NO: 217): EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKY NEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID Nos: 22, 26, 34, 42, 58, 66, 74, 82, and 86 of WO2016 / 061142: SEQ ID No: 22 of WO2016 / 061142 (SEQ ID NO: 218): DIVMTQTPLSLPVTPGEPASISCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGIPA RFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNSYPLTFGQGTKVEIK; SEQ ID No: 26 of WO2016 / 061142 (SEQ ID NO: 219): DIQMTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGQGTKVEIK; SEQ ID No: 34 of WO2016 / 061142 (SEQ ID NO: 220): EIVLTQSPDFQSVTPKEKVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCQQYNSYPLTFGQGTKVEIK; SEQ ID No: 42 of WO2016 / 061142 (SEQ ID NO: 221): EIVLTQSPDFQSVTPKEKVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPS RFSGSGSGTDFTFTISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIK. SEQ ID No: 58 of WO2016 / 061142 (SEQ ID NO: 222): EIVLTQSPATLSLSPGERATLSCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGIPP RFSGSGYGTDFTLTINNIESEDAAYYFCQQYNSYPLTFGQGTKVEIK; SEQ ID No: 66 of WO2016 / 061142 (SEQ ID NO: 223): DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK; SEQ ID No: 74 of WO2016 / 061142 (SEQ ID NO: 224): DIQMTQSPSSLSASVGDRVTITCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPS RFSGSGSGTDFTFTISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIK; SEQ ID No: 82 of WO2016 / 061142 (SEQ ID NO: 225): AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK; SEQ ID No: 86 of WO2016 / 061142 (SEQ ID NO: 226): EIVLTQSPDFQSVTPKEKVTITCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK. In an embodiment, the targeting moiety comprises any one of the anti-PD-L1 antibodies disclosed in WO2016 / 022630. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, and 46 of WO2016 / 022630: SEQ ID No: 2 of WO2016 / 022630 (SEQ ID NO: 227): EVKLVESGGGLVKPGGSLKLSCAASGFIFRSYGMSWVRQTPEKRLEWVASISSGGSTYYP DSVKGRFTISRDNARNILYLQMSSLRSEDTAMYDCARGYDSGFAYWGQGTLVTVSE; SEQ ID No: 6 of WO2016 / 022630 (SEQ ID NO: 228): EVKLVESGGGLVKPGGSLKLSCAASGFTFRSYGMSWVRQTPEKRLEWVASISSGGTTYYP DSVKGRFIISRDNARNILYLQMSSLRSEDTAMYYCAKGYDSGFAYWGQGTLVIVSA; SEQ ID No: 10 of WO2016 / 022630 (SEQ ID NO: 229): QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWRGVTTDYN AAFMSRLTITKDNSKSQVFFKMNSLQANDTAIYYCARLGFYAMDYWGQGTSVTVSS; SEQ ID No: 14 of WO2016 / 022630 (SEQ ID NO: 230): QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWSGGVTDYN AAFISRLSISKDNSKSQVFFKMNSLQANDTAIYYCARLGFYAMDYWGQGTSVTVSS; SEQ ID No: 18 of WO2016 / 022630 (SEQ ID NO: 231): EVKLFESGGGLVQPGGSLKLSCVASGFDFSTYWMHWVRQAPGQGLEWIGQINPDSTTINY APSLKDRFIISRDNAKNTLFLQMSKVRSEDTALYYCAKPGDYGYDFDCWGQGTTLTVSS; SEQ ID No: 22 of WO2016 / 022630 (SEQ ID NO: 232): EVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWNWIRKFPGNKLEYMGYISYSGSTYYN PSLKSRISITRDTSKNQYYLQLNSVTTEDTATYYCARSLLWFSTGFAYWGQGTLVTVSA; SEQ ID No: 26 of WO2016 / 022630 (SEQ ID NO: 233): QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWSGGITDYN AAFKSRLSISKDNSKSQVFFKMNSLQANDTAIYFCARLGFYAMDYWGQGTSVTVSS; SEQ ID No: 30 of WO2016 / 022630 (SEQ ID NO: 234): EVKLVESGGGLVKPGGSLKLSCAASGFTFRSYGMSWARQIPEKRLEWVASISSGGTTYYL GSVQGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYDAGFAYWGQGTLVSVSE; SEQ ID No: 34 of WO2016 / 022630 (SEQ ID NO: 235): EVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWTWIRKFPGNKLEYMGYISYTGSTYYN PSLKSRISISRDTSKSQYYLQLNSVTTEDTATYYCARQRDWLGFAYWGQGTLVTVSA; SEQ ID No: 38 of WO2016 / 022630 (SEQ ID NO: 236): EEKLVESGGGLVKPGGSLKLSCAASGFSFSSYGMSWVRQTPEKRLEWVASISSGGSIYYP DSVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYDAGFAFWGQGTLVTASA; SEQ ID No: 42 of WO2016 / 022630 (SEQ ID NO: 237): QITLKESGPTLVKPTQTLTLTCTVSGFSLSTYGVHWIRQPPGKALEWLGVIWRGVTTDYN AAFMSRLTITKDNSKNQVVLTMNNMDPVDTATYYCARLGFYAMDYWGQGTLVTVSS; SEQ ID No: 46 of WO2016 / 022630 (SEQ ID NO: 238): EVQLVESGGGLVKPGGSLRLSCAASGFIFRSYGMSWVRQAPGKGLEWVASISSGGSTYYP DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYDCARGYDSGFAYWGQGTLVTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID Nos: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 of WO2016 / 022630: SEQ ID No: 4 of WO2016 / 022630 (SEQ ID NO: 239): DIVLTQSPASLAVSLGQRATISCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASNLES GVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIKR; SEQ ID No: 8 of WO2016 / 022630 (SEQ ID NO: 240): DIVLTQSPPSLAVSLGQRATISCRASQSVSTSSSSYMHWYQQKPGQPPKLLIKYASNLES GVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIK; SEQ ID No: 12 of WO2016 / 022630 (SEQ ID NO: 241): SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLIYYAANRYTGVPD RFTGSGYGTDFTFTISIVQAEDLAVYFCQQDYTSPYTFGGGTKLEIK; SEQ ID No: 16 of WO2016 / 022630 (SEQ ID NO: 242): SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVGWYQQKPGQSPKLLIYYASNRYSGVPD RFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYTSPYTFGGGTKLEIK; SEQ ID No: 20 of WO2016 / 022630 (SEQ ID NO: 243): DVLMTQTPLYLPVSLGDQASISCRSSQIIVHSNANTYLEWFLQKPGQSPKLLIYKVSNRF SGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK; SEQ ID No: 24 of WO2016 / 022630 (SEQ ID NO: 244): QIVLTQSPAIMSASPGEKVTLTCSASSSVSSSYLYWNQQKPGSSPKVWIYNTSNLASGVP ARFSGSGSGTSYSLTISSMEAEDAASYFCHQWRSYPPTLGAGTKLELK; SEQ ID No: 28 of WO2016 / 022630 (SEQ ID NO: 245): QIVLTQSPAIMSASPGEKVTMTCSANSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPAR FSGSGSGTSYSLTISSMGAEDAATYYCQQWSSNPWTFGGGTKLEIK; SEQ ID No: 32 of WO2016 / 022630 (SEQ ID NO: 246): DIVLTQSPASLAVSLGQRATISCRASQSVSTSSYSYMHWYQQKPGQPPKLLIKYASNLES GVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQNSWEIPYTFGGGTKLEIK; SEQ ID No: 36 of WO2016 / 022630 (SEQ ID NO: 247): DIVMTQTPSSLAVSLGEKVTMSCKSSQSLLYSSNQKNSLAWYQQKPGQSPKLLIYWASNR ESGVPDRFTGSSSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK; SEQ ID No: 40 of WO2016 / 022630 (SEQ ID NO: 248): DIVLTQSPASLAVSLGQRATISCRASQSVSTSSYSYVHWYQQKPGQPPKLLIKYASNLES GVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIK; SEQ ID No: 44 of WO2016 / 022630 (SEQ ID NO: 249): DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYAANRYTGVPD RFSGSGYGTDFTFTISSLQPEDIATYFCQQDYTSPYTFGQGTKLEIK; SEQ ID No: 48 of WO2016 / 022630 (SEQ ID NO: 250): DIVLTQSPASLAVSPGQRATITCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASNLES GVPARFSGSGSGTDFTLTINPVEANDTANYYCQHSWEIPYTFGQGTKLEIK. In an embodiment, the targeting moiety comprises any one of the anti-PD-L1 antibodies disclosed in WO2015 / 112900. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 38, 50, 82, and 86 of WO 2015 / 112900: SEQ ID No: 38 of WO2015 / 112900 (SEQ ID NO: 251): EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNF DEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS; SEQ ID No: 50 of WO 2015 / 112900 (SEQ ID NO: 252): EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNF DEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS; SEQ ID No: 82 of WO 2015 / 112900 (SEQ ID NO: 253): QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNF DEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS; SEQ ID No: 86 of WO 2015 / 112900 (SEQ ID NO: 254): EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQAPGQGLEWMGNIYPGTGGSNF DEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID Nos: 42, 46, 54, 58, 62, 66, 70, 74, and 78 of WO 2015 / 112900: SEQ ID No: 42 of WO2015 / 112900 (SEQ ID NO: 255): EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR ESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQNDYSYPYTFGQGTKVEIK; SEQ ID No: 46 of WO 2015 / 112900 (SEQ ID NO: 256): DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR ESGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQNDYSYPYTFGQGTKVEIK; SEQ ID No: 54 of WO 2015 / 112900 (SEQ ID NO: 257): EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIK; SEQ ID No: 58 of WO 2015 / 112900 (SEQ ID NO: 258): DIVMTQTPLSLPVTPGEPASISCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK; SEQ ID No: 62 of WO 2015 / 112900 (SEQ ID NO: 259): EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK; SEQ ID No: 66 of WO 2015 / 112900 (SEQ ID NO: 260): EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK; SEQ ID No: 70 of WO 2015 / 112900 (SEQ ID NO: 261): EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK; SEQ ID No: 74 of WO 2015 / 112900 (SEQ ID NO: 262): DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYLQKPGQSPQLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK; SEQ ID No: 78 of WO 2015 / 112900 (SEQ ID NO: 263): DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK. In an embodiment, the targeting moiety comprises any one of the anti-PD-L1 antibodies disclosed in WO 2010 / 077634 and US 8,217,149. In illustrative embodiments, the anti-PD-L1 antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain region comprising the amino acid sequence of: SEQ ID No: 20 of WO 2010 / 077634 (SEQ ID NO: 264): EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYY ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA; and / or a light chain variable region comprising the amino acid sequence of: SEQ ID No: 21 of WO 2010 / 077634 (SEQ ID NO: 265): DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR. In an embodiment, the targeting moiety comprises any one of the anti-PD-L1 antibodies obtainable from the hybridoma accessible under CNCM deposit numbers CNCM I-4122, CNCM I-4080 and CNCM I-4081 as disclosed in US 20120039906. In an embodiment, the targeting moiety comprises a VHH directed against PD-L1 as disclosed, for example, in US 8,907,065 and WO 2008 / 071447. In illustrative embodiments, the VHHs against PD-L1 comprise SEQ ID NOS: 394-399 of US 8,907,065: SEQ ID No: 394 of US 8,907,065 (SEQ ID NO: 266): EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREWASS ISSSDGSTYYADSVKGRFTISRDNAKNTVFLQMNSLKPEDTAVYSCAASQ APITIATMMKPFYDYWGQGTQVTVSS; SEQ ID No: 395 of US 8,907,065 (SEQ ID NO: 267): EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAKCWFRQAPGKEREWVSC ISSSDGSTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYFCAARH GGPLTVEYFFDYWGQGTQVTVSS: SEQ ID No: 396 of US 8,907,065 (SEQ ID NO: 268): EVQLVESGGGLVQPGGSLRLSCAASGFTFDYYAIGWFRQAPGKAREGVSC ISGGDNSTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCATGG WKYCSGYDPEYIYWGQGTQVTVSS; SEQ ID No: 397 of US 8,907,065 (SEQ ID NO: 269): EVQLVESGGGLVQAGGSLRLSCAASGSTFSQYDVGWYRQAPGKQRELVA FSSSGGRTIYPDSVKGRFTFSRDNTKNTVYLQMTSLKPEDTAVYYCKIDW YLNSYWGQGTQVTVSS; SEQ ID No: 398 of US 8,907,065 (SEQ ID NO: 270): EVQLVESGGGLVQAGGSLRLSCAASGVDASNSAMGWYRQAPGKQREWVAR ITGGGLIAYTDSVKGRFTISRDNAKSTVYLQMNSLEPEDTAVYYCNTINS RDGWGQGTQVTVSS; SEQ ID No: 399 of US 8,907,065 (SEQ ID NO: 271): EVQLVESGGGLVQAGGSLTISCAASGITFSDSIVSWYRRARGKQREWVAG ISNGGTTKYAESVLGRFTISRDNAKNNVYLQMNGLNPEDTAVYLCKVRQY WGQGTQVTVSS. In various embodiments, the present chimeric protein has one or more targeting moieties directed against PD-L2. In some embodiments, the chimeric protein has one or more targeting moieties which selectively bind a PD-L2 polypeptide. In some embodiments, the chimeric protein comprises one or more antibodies, antibody derivatives or formats, peptides or polypeptides, or fusion proteins that selectively bind a PD-L2 polypeptide. In an embodiment, the targeting moiety comprises a VHH directed against PD-L2 as disclosed, for example, in US 8,907,065 and WO 2008 / 071447. In illustrative embodiments, the VHHs against PD-1 comprise SEQ ID Nos: 449-455 of US 8,907,065: SEQ ID No: 449 of US 8,907,065 (SEQ ID NO: 272): EVQLVESGGGLVQAGGSLRLSCAASESTVLINAMGWYRQAPGKQRELVAS ISSGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNADVY PQDYGLGYVEGKVYYGHDYWGTGTLVTVSS; SEQ ID No: 450 of US 8,907,065 (SEQ ID NO: 273): EVQLVESGGGLVQAGGSLRLSCAASGSTFSNYVSNYAMGWGRQAPGTQ RELVASISNGDTTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYY CFEHQVAGLTWGQGTQVTVSS; SEQ ID No: 451 of US 8,907,065 (SEQ ID NO: 274): EVQLVESGGGLVQAGGSLRLSCVASGXALKIXVMGWYRQAPGKQRELV AAITSGGRTNYSDSVKGRFTISGDNAXNTVYLQMNSLKSEDTAVYYCRE WNSGYPPVDYWGQGTQVTVSS; SEQ ID No: 452 of US 8,907,065 (SEQ ID NO: 275): EVQLVESGGGLVQAGGSLRLSCAASGRTFSSGTMGWFRRAPGKEREFV ASIPWSGGRTYYADSVKDRFTISRDNAQNTVFLQMNSLKPEDTAVYYCAF KERSTGWDFASWGQGIQVTVSS; SEQ ID No: 453 of US 8,907,065 (SEQ ID NO: 276): EVQLVESGGGLVQTGGSLRLSCAASGFTLDYYGIGWFRQAPGKEREGVS FISGSDGSTYYAESVKGRFTISRDKAKNTVYLQMNSLKPEDTAVYYCAAD PWGPPSIATMTSYEYKHWGQGTQVTVSS; SEQ ID No: 454 of US 8,907,065 (SEQ ID NO: 277): EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYTMIWLRRAPGKGFEWV STIDKDGNTNYVDSVKGRFAVSRDNTKNTLYLQMNSLKPEDTAMYYCTK HGSSARGQGTRVTVSS; SEQ ID No: 455 of US 8,907,065 (SEQ ID NO: 278): EVQLVESGGGLVEPGGSLRLSCVASGFTFSSYDMSWVRQAPGKGLE WVSTINSGGGITYRGSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYY CENGGSSYRRGQGTQVTVSS. In an embodiment, the targeting moiety comprises any one of the anti-PD-L2 antibodies disclosed in US2011 / 0271358 and WO2010 / 036959. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 43-47 of US2011 / 0271358: SEQ ID No: 43 of US2011 / 0271358 (SEQ ID NO: 279): QVQLVQSGAELKKPGASVKMSCKASGYTFTGYTMHWVKQAPGQGLEWIGYINPRSGYTEY NQKFKDRTTLTADKSTSTAYMELSSLRSEDSAVYYCARPWFAYWGQGTLVTVSS; SEQ ID No: 44 of US2011 / 0271358 (SEQ ID NO: 280): QVQLVQSGAEVKKPGASVKMSCKASGYTFTGYTMHWVKQAPGQGLEWIGYINPRSGYTEY NQKFKDRTTLTADKSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS; SEQ ID No: 45 of US2011 / 0271358 (SEQ ID NO: 281): QVQLVQSGAEVKKPGASVKMSCKASGYTFTGYTMHWVRQAPGQGLEWIGYINPRSGYTEY NQKFKDRTTLTADKSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS; SEQ ID No: 46 of US2011 / 0271358 (SEQ ID NO: 282): QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYTMHWVRQAPGQGLEWIGYINPRSGYTEY NQKFKDRTTLTADKSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS; SEQ ID No: 47 of US2011 / 0271358 (SEQ ID NO: 283): QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYTMHWVRQAPGQGLEWIGYINPRSGYTEY NQKFKDRTTITADKSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID Nos: 48-51 of US2011 / 0271358: SEQ ID No: 48 of US2011 / 0271358 (SEQ ID NO: 284): DIVMTQSPASLTVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTR ESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK; SEQ ID No: 49 of US2011 / 0271358 (SEQ ID NO: 285): DIVMTQSPASLSVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTR ESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK; SEQ ID No: 50 of US2011 / 0271358 (SEQ ID NO: 286): DIVMTQSPAFLSVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTR ESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK; SEQ ID No: 51 of US2011 / 0271358 (SEQ ID NO: 287): DIVMTQSPAFLSVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTR ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK. In various embodiments, the targeting moieties of the invention may comprise a sequence that targets PD-1, PD- L1, and / or PD-L2 which is at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to any of the sequences disclosed herein (e.g. about 60%, or about 61%, or about 62%, or about 63%, or about 64%, or about 65%, or about 66%, or about 67%, or about 68%, or about 69%, or about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, about 99% or about 100% sequence identity with any of the sequences disclosed herein). In various embodiments, the targeting moieties of the invention may comprise any combination of heavy chain, light chain, heavy chain variable region, light chain variable region, complementarity determining region (CDR), and framework region sequences that target PD-1, PD-L1, and / or PD-L2 as disclosed herein. Additional antibodies, antibody derivatives or formats, peptides or polypeptides, or fusion proteins that selectively bind or target PD-1, PD-L1 and / or PD-L2 are disclosed in WO 2011 / 066389, US 2008 / 0025980, US 2013 / 0034559, US 8,779,108, US 2014 / 0356353, US 8,609,089, US 2010 / 028330, US 2012 / 0114649, WO 2010 / 027827, WO 2011, / 066342, US 8,907,065, WO 2016 / 062722, WO 2009 / 101611, WO2010 / 027827, WO 2011 / 066342, WO 2007 / 005874, WO 2001 / 014556, US2011 / 0271358, WO 2010 / 036959, WO 2010 / 077634, US 8,217,149, US 2012 / 0039906, WO 2012 / 145493, US 2011 / 0318373, U.S. Patent No. 8,779,108, US 20140044738, WO 2009 / 089149, WO 2007 / 00587, WO 2016061142, WO 2016,02263, WO 2010 / 077634, and WO 2015 / 112900. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a T cell, for example, mediated by targeting to CD8 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against CD8 on T cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a T cell, for example, mediated by targeting to CD4 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against CD4 on T cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a T cell, for example, mediated by targeting to CD3, CXCR3, CCR4, CCR9, CD70, CD103, or one or more immune checkpoint markers and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against CD3 on T cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. In some embodiments, the present chimeric protein has one or more targeting moieties directed against CD3 expressed on T cells. In some embodiments, the chimeric protein has one or more targeting moieties which selectively bind a CD3 polypeptide. In some embodiments, the chimeric protein comprises one or more antibodies, antibody derivatives or formats, peptides or polypeptides, or fusion proteins that selectively bind a CD3 polypeptide. In an embodiment, the targeting moiety comprises the anti-CD3 antibody muromonab-CD3 (aka Orthoclone OKT3), or fragments thereof. Muromonab-CD3 is disclosed in U.S. Patent No. 4,361,549 and Wilde et al. (1996) 51:865-894. In illustrative embodiments, muromonab-CD3 or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising the amino acid sequence of: QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNY NQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSSA KTTAPSVYPLAPVCGGTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDL YTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 288); and / or a light chain comprising the amino acid sequence of: QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAH FRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINRADTAPTVSIFPPS SEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTL TKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC (SEQ ID NO: 289. In an embodiment, the targeting moiety comprises the anti-CD3 antibody otelixizumab, or fragments thereof. Otelixizumab is disclosed in U.S. Patent Publication No. 20160000916 and Chatenoud et al. (2012) 9:372-381. In illustrative embodiments, otelixizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising the amino acid sequence of: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFPMAWVRQAPGKGLEWVSTISTSGGRTYYRDSVKGRF TISRDNSKNTLYLQMNSLRAEDTAVYYCAKFRQYSGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 290); and / or a light chain comprising the amino acid sequence of: DIQLTQPNSVSTSLGSTVKLSCTLSSGNIENNYVHWYQLYEGRSPTTMIYDDDKRPDGVPDRFSGSID RSSNSAFLTIHNVAIEDEAIYFCHSYVSSFNVFGGGTKLTVLRQPKAAPSVTLFPPSSEELQANKATL VCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGS TVEKTVAPTECS (SEQ ID NO: 291). In an embodiment, the targeting moiety comprises the anti-CD3 antibody teplizumab (AKA MGA031 and hOKT3γ1(Ala-Ala)), or fragments thereof. Teplizumab is disclosed in Chatenoud et al. (2012) 9:372-381. In illustrative embodiments, teplizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising the amino acid sequence of: QVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNYNQKVKDRF TISRDNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYCLDYWGQGTPVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 292); and / or a light chain comprising the amino acid sequence of: DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGT DYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLQITRTVAAPSVFIFPPSDEQLKSGTASVVCLLN NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC (SEQ ID NO: 293). In an embodiment, the targeting moiety comprises the anti-CD3 antibody visilizumab (AKA Nuvion®; HuM291), or fragments thereof. Visilizumab is disclosed in U.S. 5,834,597 and WO2004052397, and Cole et al., Transplantation (1999) 68:563-571. In illustrative embodiments, visilizumab or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of: QVQLVQSGAEVKKPGASVKVSCKASGYTFISYTMHWVRQAPGQGLEWMGYINPRSGYTHYNQKLKDKA TLTADKSASTAYMELSSLRSEDTAVYYCARSAYYDYDGFAYWGQGTLVTVSS (SEQ ID NO: 294); and / or a light chain variable region comprising the amino acid sequence of: DIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQKPGKAPKRLIYDTSKLASGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQWSSNPPTFGGGTKVEIK (SEQ ID NO: 295). In an embodiment, the targeting moiety comprises the anti-CD3 antibody foralumab (aka NI-0401), or fragments thereof. In various embodiments, the targeting moiety comprises any one of the anti-CD3 antibodies disclosed in US20140193399, US 7,728,114, US20100183554, and US 8,551,478. In illustrative embodiments, the anti-CD3 antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID Nos: 2 and 6 of US 7,728,114: SEQ ID No: 2 of US 7,728,114 (SEQ ID NO: 296): QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYY VDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLWGRGTLVTVSS; SEQ ID No: 6 of US 7,728,114 (SEQ ID NO: 297): QVQLVQSGGGVVQSGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYDGSKKYY VDSVKGRFTISRDNSKNTLYLQMNSLRGEDTAVYYCARQMGYWHFDLWGRGTLVTVSS; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NOs 4 and 8 of US 7,728,114: SEQ ID No: 4 of US 7,728,114 (SEQ ID NO: 298): EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIK; SEQ ID No: 8 of US 7,728,114 (SEQ ID NO: 299): EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIK; In an embodiment, the targeting moiety comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 of US 7,728,114 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:4 of US 7,728,114. In an embodiment, the targeting moiety comprises any one of the anti-CD3 antibodies disclosed in US2016 / 0168247. In illustrative embodiments, the antibody or an antigen- binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 6-9 of US2016 / 0168247: SEQ ID No: 6 of US2016 / 0168247 (SEQ ID NO: 300): EVKLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYAT YYADSVKDRFTISRDDSKSSLYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTL VTVSS; SEQ ID No: 7 of US2016 / 0168247 (SEQ ID NO: 301): EVKLVESGGGLVKPGRSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYAT YYADSVKDRFTISRDDSKSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTL VTVSS; SEQ ID No: 8 of US2016 / 0168247 (SEQ ID NO: 302): EVKLVESGGGLVKPGRSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYAT YYADSVKDRFTISRDDSKSILYLQMNSLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTL VTVSS; SEQ ID No: 9 of US2016 / 0168247 (SEQ ID NO: 303): EVKLVESGGGLVKPGRSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYAT YYADSVKDRFTISRDDSKSILYLQMNSLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTM VTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID Nos: 10-12 of US2016 / 0168247: SEQ ID No: 10 of US2016 / 0168247 (SEQ ID NO: 304): QAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAFRGLIGGTNKRAPGV PARFSGSLIGDKAALTITGAQADDESIYFCALWYSNLWVFGGGTKLTVL; SEQ ID No: 11 of US2016 / 0168247 (SEQ ID NO: 305): QAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAFRGLIGGTNKRAPGV PARFSGSILGNKAALTITGAQADDESIYFCALWYSNLWVFGGGTKLTVL; SEQ ID No: 12 of US2016 / 0168247 (SEQ ID NO: 306): QAVVTQEPSFSVSPGGTVTLTCRSSTGAVTTSNYANWVQQTPGQAFRGLIGGTNKRAPGV PARFSGSILGNKAALTITGAQADDESDYYCALWYSNLWVFGGGTKLTVL. In an embodiment, the targeting moiety comprises any one of the anti-CD3 antibodies disclosed in US2015 / 0175699. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID No: 9 of US2015 / 0175699: SEQ ID No: 9 of US2015 / 0175699 (SEQ ID NO: 307): QVQLVQSGSELKKPGASVKMSCKASGYTFTRYTMHWVRQAPGKGLEWIGYINPSRGYTNY NQKFKDRATLTTDKSTSTAYMQLSSLRSEDTAVYYCARYYDDHYSLDYWGQGTLVTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID No: 10 of US2015 / 0175699: SEQ ID No: 10 of US2015 / 0175699 (SEQ ID NO: 308): QIVLTQSPATLSLSPGERATMSCSASSSVSYMNWYQQKPGKAPKRWIYDTSKLASGVPSR FRGSGSGTDYTLTISSLQPEDFATYYCQQWSSNPFTFGGGTKVEIK. In an embodiment, the targeting moiety comprises any one of the anti-CD3 antibodies disclosed in US 8,784,821. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 2, 18, 34, 50, 66, 82, 98 and 114 of US 8,784,821: SEQ ID No: 2 of US 8,784,821 (SEQ ID NO: 309): ELQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYY ADSVKGRFTISRDNSKNTLYLQMNSLRSEDTAVYYCARLSPYCTNGVCWDAFDIWGQGTM VTVSS; SEQ ID No: 18 of US 8,784,821 (SEQ ID NO: 310): ELQLVESGGGLVKPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTT EYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCTPQLWLLQDAFDIWGQGTMVTV SS; SEQ ID No: 34 of US 8,784,821 (SEQ ID NO: 311): ELQLVESGPGLVKPSGTLSLTCAVSGGSISSRNWWSWVRQPPGKGLEWIGDIYHSGSTNY NPSLKSRVTISVDKSKNQFSLKLSSVTAADTAVYYCASGYTSCRDAFDIWGQGTMVTVSS; SEQ ID No: 50 of US 8,784,821 (SEQ ID NO: 312): ELQLVEWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYN PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGRGRFLGWLLGGSNWFDPWGQGT LVTVSS; SEQ ID No: 66 of US 8,784,821 (SEQ ID NO: 313): ELQLVEWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYN PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGPDRMGHGFDIWGQGTMVTVSS; SEQ ID No: 82 of US 8,784,821 (SEQ ID NO: 314): ELQLVESGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWY NDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARDRRRIAARQYYGMDVWGQG TTVTVSS; SEQ ID No: 98 of US 8,784,821 (SEQ ID NO: 315): ELQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMGWVRQAPGKGLEWVSAVSGSGGSTYY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAKFLGHYYGMDVWGQGTTVTVS S; SEQ ID No: 114 of US 8,784,821 (SEQ ID NO: 316): ELQLVESGPVLVKPTDTLTLTCTVSGFSLNNPRMGVSWIRQPPGKTLEWLAHIFPSDAKA HSASLKSRLTISKDTSKSQVVPTMTNMDPVDTATYYCARILGEYYPPAWFDPWGQGTLVT VSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID Nos: 10, 26, 42, 58, 74, 90, 106 and 122 of US 8,784,821: SEQ ID No: 10 of US 8,784,821 (SEQ ID NO: 317): ELQMTQSPSSLSASVGDRVSITCRASQTISNYLNWYQLKPGKAPKLLIYAASTLQSEVPT RFSGSGSGTDFTLTISGLHPEDFATYYCQQFNSYPRTFGQGTKVEIK; SEQ ID No: 26 of US 8,784,821 (SEQ ID NO: 318): ELQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPTFGQGTKLEIK; SEQ ID No: 42 of US 8,784,821 (SEQ ID NO: 319): ELVMTQSPSSLSASVGDRVTITCRASQGIGNYLAWYQQKPGQPPKMLIYWASIRESGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSNPQTFGQGTKVEIK; SEQ ID No: 58 of US 8,784,821 (SEQ ID NO: 320): ELVMTQSPSSLSASVGDRVTITCRASQGISNYLNWYQQKPGKAPKLLIYDASNLETGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPYTFGQGTKVDIK; SEQ ID No: 74 of US 8,784,821 (SEQ ID NO: 321): ELQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKSGKAPKLLIYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSSPWTFGQGTKVEIK; SEQ ID No: 90 of US 8,784,821 (SEQ ID NO: 322): ELVLTQSPGTLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYGASSRATGIP DRFSGSGSGTDFTLTISSLQPEDVATYYCQKYNSAPLTFGGGTKVEIK; SEQ ID No: 106 of US 8,784,821 (SEQ ID NO: 323): ELQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPS RFSGSGSGTEFTLTISSLQPEDFATYYCLQHNAYPYTFGQGTKVEIK; SEQ ID No: 122 of US 8,784,821 (SEQ ID NO: 324): ELVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTR ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYLKIPYTFGQGTKVEIK. In an embodiment, the targeting moiety comprises any one of the anti-CD3 binding constructs disclosed in US20150118252. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 6 and 86 of US20150118252: SEQ ID No: 6 of US20150118252 (SEQ ID NO: 325): QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWMGYINPSRGYTNY NQKFKDRVTMTTDTSISTAYMELSRLRSDDTAVYYCARYYDDHYCLDYWGQGTLVTVSS; SEQ ID No: 86 of US20150118252 (SEQ ID NO: 326): QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWMGYINPSRGYTNY NQKFKDRVTMTTDTSISTAYMELSRLRSDDTAVYYCARYYDDHYSLDYWGQGTLVTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID No: 3 of US2015 / 0175699: SEQ ID No: 3 of US20150118252 (SEQ ID NO: 327): EIVLTQSPATLSLSPGERATLSCSASSSVSYMNWYQQKPGQAPRLLIYDTSKLASGVPAH FRGSGSGTDYTLTISSLEPEDFAVYYCQQWSSNPFTFGQGTKVEIK. In an embodiment, the targeting moiety comprises any one of the anti-CD3 binding proteins disclosed in US2016 / 0039934. In illustrative embodiments, the antibody or an antigen-binding fragment thereof for use in the methods provided herein comprises a heavy chain comprising an amino acid sequence selected from SEQ ID Nos: 6-9 of US2016 / 0039934: SEQ ID No: 6 of US2016 / 0039934 (SEQ ID NO: 328): EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYAT YYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARHGNFGNSYVSWFAYWGQGTL VTVSS; SEQ ID No: 7 of US2016 / 0039934 (SEQ ID NO: 329): EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYAT YYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARHGNFGNSYVSWFAYWGQGTL VTVSS; SEQ ID No: 8 of US2016 / 0039934 (SEQ ID NO: 330): EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYAT YYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARHGNFGNSYVSYFAYWGQGTL VTVSS; SEQ ID No: 9 of US2016 / 0039934 (SEQ ID NO: 331): EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYAMNWVRQAPGKGLEWVGRIRSKYNNYAT YYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARHGNFGNSYVSHFAYWGQGTL VTVSS; and / or a light chain comprising an amino acid sequence selected from SEQ ID Nos: 1-4 of US2016 / 0039934: SEQ ID No: 1 of US2016 / 0039934 (SEQ ID NO: 332): DIQMTQSPSSLSASVGDRVTITCRSSTGAVTTSNYANWVQQKPGKAPKGLIGGTNKRAPG VPSRFSGSLIGDKATLTISSLQPEDFATYYCALWYSNLWVFGQGTKVEIK; SEQ ID No: 2 of US2016 / 0039934 (SEQ ID NO: 333): DIQMTQSPSSLSASVGDRVTITCRSSTGAVTTSNYANWVQQKPGKAPKGLIGGTNKRAPG VPARFSGSGSGTDFTLTISSLQPEDFATYYCALWYSNLWVFGQGTKVEIK; SEQ ID No: 3 of US2016 / 0039934 (SEQ ID NO: 334): DIQMTQSPSSLSASVGDRVTITCRSSTGAVTTSNYANWVQQKPGKAPKALIGGTNKRAPG VPSRFSGSLIGDKATLTISSLQPEDFATYYCALWYSNLWVFGQGTKVEIK; SEQ ID No: 4 of US2016 / 0039934 (SEQ ID NO: 335): DIQMTQSPSSLSASVGDRVTITCRSSTGAVTTSNYANWVQQKPGKAPKGLIGGTNKRAPG VPSRFSGSLIGDKATLTISSLQPEDFATYYCALWYSNLWVFGQGTKVEIK; In various embodiments, the targeting moieties of the invention may comprise a sequence that targets CD3 which is at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to any of the sequences disclosed herein (e.g. about 60%, or about 61%, or about 62%, or about 63%, or about 64%, or about 65%, or about 66%, or about 67%, or about 68%, or about 69%, or about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, about 99% or about 100% sequence identity with any of the sequences disclosed herein). In various embodiments, the targeting moieties of the invention may comprise any combination of heavy chain, light chain, heavy chain variable region, light chain variable region, complementarity determining region (CDR), and framework region sequences that target CD3 as disclosed herein. In various embodiments, the targeting moieties of the invention may comprise any heavy chain, light chain, heavy chain variable region, light chain variable region, complementarity determining region (CDR), and framework region sequences of the CD3- specific antibodies including, but not limited to, X35-3, VIT3, BMA030 (BW264 / 56), CLB-T3 / 3, CRIS7, YTH12.5, FI 11-409, CLB-T3.4.2, TR-66, WT32, SPv-T3b, 11D8, XIII-141, XIII-46, XIII-87, 12F6, T3 / RW2-8C8, T3 / RW2- 4B6, OKT3D, M-T301, SMC2, WT31 and F101.01. These CD3-specific antibodies are well known in the art and, inter alia, described in Tunnacliffe (1989), Int. Immunol. 1, 546-550. Additional antibodies, antibody derivatives or formats, peptides or polypeptides, or fusion proteins that selectively bind or target CD3 are disclosed in US Patent Publication No. 2016 / 0000916, US Patent Nos. 4,361,549, 5,834,597, 6,491,916, 6,406,696, 6,143,297, 6,750,325 and International Publication No. WO 2004 / 052397. In some embodiments, the CD3 targeting moiety is a scFv. In some embodiments, the CD3 targeting moiety is: QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYIN PSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYS LDYWGQGTTLTVSSGSTGGGGSGGGGGGGGGSDIVLTQSPAIMSASPGEKVT MTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSL TISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINR (SEQ ID NO: 365). In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a T cell, for example, mediated by targeting to PD-1 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. By way of non-limiting example, in various embodiments, the present chimeric protein has (i) a targeting moiety directed against a B cell, for example, mediated by targeting to CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD38, CD39, CD40, CD70, CD72, CD73, CD74, CDw75, CDw76, CD77, CD78, CD79a / b, CD80, CD81, CD82, CD83, CD84, CD85, CD86, CD89, CD98, CD126, CD127, CDw130, CD138, or CDw150; and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a B cell, for example, mediated by targeting to CD19, CD20 or CD70 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a B cell, for example, mediated by targeting to CD20 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against CD20 on B cells and a second targeting moiety directed against PD-L1 or PD- L2 on tumor cells. In some embodiments, the CD20 targeting moiety is a scFv. In some embodiments, the CD20 targeting moiety is: QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNL ASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK RGSTGGGGGGGGGGGGQVQLQQPGAELVKPGASVKMSCKASGYTFTS YNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQ LSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSS (SEQ ID NO: 366). By way of non-limiting example, in various embodiments, the present chimeric protein has (i) a targeting moiety directed against a NK cell, for example, mediated by targeting to 2B4 / SLAMF4, KIR2DS4, CD155 / PVR, KIR3DL1, CD94, LMIR1 / CD300A, CD69, LMIR2 / CD300c, CRACC / SLAMF7, LMIR3 / CD300LF, DNAM-1, LMIR5 / CD300LB, Fc-epsilon RII, LMIR6 / CD300LE, Fc-y RI / CD64, MICA, Fc-y RIIB / CD32b, MICB, Fc-y RIIC / CD32c, MULT-1, Fc-y RIIA / CD32a, Nectin-2 / CD112, Fc-y RIII / CD16, NKG2A, FcRH1 / IRTA5, NKG2C, FcRH2 / IRTA4, NKG2D, FcRH4 / IRTA1, NKp30, FcRH5 / IRTA2, NKp44, Fc-Receptor-like 3 / CD16-2, NKp46 / NCR1, NKp80 / KLRF1, NTB-A / SLAMF6, Rae-1, Rae-1 α, Rae-1 β, Rae-1 delta, H60, Rae-1 epsilon, ILT2 / CD85j, Rae-1 γ, ILT3 / CD85k, TREM-1, ILT4 / CD85d, TREM-2, ILT5 / CD85a, TREM-3, KIR / CD158, TREML1 / TLT-1, KIR2DL1, ULBP-1, KIR2DL3, ULBP-2, KIR2DL4 / CD158d, or ULBP-3; and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a NK cell, for example, mediated by targeting to Kir1alpha, DNAM-1 or CD64 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a NK cell, for example, mediated by targeting to KIR1 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against KIR1 on NK cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a NK cell, for example, mediated by targeting to TIGIT or KIR1 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against TIGIT on NK cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. By way of non-limiting example, in various embodiments, the present chimeric protein has (i) a targeting moiety directed against a dendritic cell, for example, mediated by targeting to CLEC-9A, XCR1, RANK, CD36 / SRB3, LOX-1 / SR-E1, CD68, MARCO, CD163, SR-A1 / MSR, CD5L, SREC-1, CL-PI / COLEC12, SREC-II, LIMPIIISRB2, RP105, TLR4, TLR1, TLR5, TLR2, TLR6, TLR3, TLR9, 4-IBB Ligand / TNFSF9, IL-12 / IL-23 p40, 4-Amino-1,8- naphthalimide, ILT2 / CD85j, CCL21 / 6Ckine, ILT3 / CD85k, 8-oxo-dG, ILT4 / CD85d, 8D6A, ILT5 / CD85a, A2B5, lutegrin α 4 / CD49d, Aag, Integrin β 2 / CD18, AMICA, Langerin, B7-2 / CD86, Leukotriene B4 RI, B7-H3, LMIR1 / CD300A, BLAME / SLAMF8, LMIR2 / CD300c, Clq R1 / CD93, LMIR3 / CD300LF, CCR6, LMIR5 / CD300LB CCR7, LMIR6 / CD300LE, CD40 / TNFRSF5, MAG / Siglec-4-a, CD43, MCAM, CD45, MD-1, CD68, MD-2, CD83, MDL-1 / CLEC5A, CD84 / SLAMF5, MMR, CD97, NCAMLI, CD2F-10 / SLAMF9, Osteoactivin GPNMB, Chern 23, PD-L2, CLEC-1, RP105, CLEC-2, Siglec-2 / CD22, CRACC / SLAMF7, Siglec-3 / CD33, DC-SIGN, Siglec-5, DC- SIGNR / CD299, Siglec-6, DCAR, Siglec-7, DCIR / CLEC4A, Siglec-9, DEC-205, Siglec-10, Dectin-1 / CLEC7A, Siglec-F, Dectin-2 / CLEC6A, SIGNR1 / CD209, DEP-1 / CD148, SIGNR4, DLEC, SLAM, EMMPRIN / CD147, TCCRWSX-1, Fc-y R1 / CD64, TLR3, Fc-y RIIB / CD32b, TREM-1, Fc-y RIIC / CD32c, TREM-2, Fc-y RIIA / CD32a, TREM-3, Fc-y RIII / CD16, TREML1 / TLT-1, ICAM-2 / CD102, or Vanilloid R1; and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a dendritic cell, for example, mediated by targeting to CLEC-9A, DC-SIGN, CD64, CLEC4A, or DEC205 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against CLEC9A on dendritic cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a dendritic cell, for example, mediated by targeting to CLEC9A and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against CLEC9A on dendritic cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a dendritic cell, for example, mediated by targeting to XCR1 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against XCR1 on dendritic cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a dendritic cell, for example, mediated by targeting to RANK and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against RANK on dendritic cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. By way of non-limiting example, in various embodiments, the present chimeric protein has (i) a targeting moiety directed against a monocyte / macrophage, for example, mediated by targeting to SIRP1a, B7-1 / CD80, ILT4 / CD85d, B7-H1, ILT5 / CD85a, Conmmon β Chain, Integrin α 4 / CD49d, BLAME / SLAMF8, Integrin α X / CDIIc, CCL6 / C10, Integrin β 2 / CD18, CD155 / PVR, Integrin β 3 / CD61, CD31 / PECAM-1, Latexin, CD36 / SR-B3, Leukotriene B4 R1, CD40 / TNFRSF5, LIMPIIISR-B2, CD43, LMIR1 / CD300A, CD45, LMIR2 / CD300c, CD68, LMIR3 / CD300LF, CD84 / SLAMF5, LMIR5 / CD300LB, CD97, LMIR6 / CD300LE, CD163, LRP-1, CD2F- 10 / SLAMF9, MARCO, CRACC / SLAMF7, MD-1, ECF-L, MD-2, EMMPRIN / CD147, MGL2, Endoglin / CD105, Osteoactivin / GPNMB, Fc-y RI / CD64, Osteopontin, Fc-y RIIB / CD32b, PD-L2, Fc-y RIIC / CD32c, Siglec-3 / CD33, Fc-γ RIIA / CD32a, SIGNR1 / CD209, Fc-γ RIII / CD16, SLAM, GM-CSF R α, TCCR / WSX-1, ICAM-2 / CD102, TLR3, IFN-y RI, TLR4, IFN-gannna R2, TREM-I, IL-I RII, TREM-2, ILT2 / CD85j, TREM-3, ILT3 / CD85k, TREML1 / TLT-1, 2B4 / SLAMF 4, IL-10 R α, ALCAM, IL-10 R β, AminopeptidaseN / ANPEP, ILT2 / CD85j, Common β Chain, ILT3 / CD85k, Clq R1 / CD93, ILT4 / CD85d, CCR1, ILT5 / CD85a, CCR2, CD206, Integrin a 4 / CD49d, CCR5, Integrin a M / CDII b, CCR8, Integrin a X / CDIIc, CD155 / PVR, Integrin β 2 / CD18, CD14, Integrin β 3 / CD61, CD36 / SR-B3, LAIR1, CD43, LAIR2, CD45, Leukotriene B4-R1, CD68, LIMPIIISR-B2, CD84 / SLAMF5, LMIR1 / CD300A, CD97, LMIR2 / CD300c, CD163, LMIR3 / CD300LF, Coagulation Factor III / Tissue Factor, LMIR5 / CD300LB, CX3CR1, CX3CL1, LMIR6 / CD300LE, CXCR4, LRP-1, CXCR6, M-CSF R, DEP-1 / CD148, MD- 1, DNAM-1, MD-2, EMMPRIN / CD147, MMR, Endoglin / CD105, NCAM-L1, Fc-y RI / CD64, PSGL-1, Fc-y RIIIICD16, RP105, G-CSF R, L-Selectin, GM-CSF R α, Siglec-3 / CD33, HVEM / TNFRSF14, SLAM, ICAM- 1 / CD54, TCCR / WSX-1, ICAM-2 / CD102, TREM-I, IL-6 R, TREM-2, CXCRI / IL-8 RA, TREM-3, or TREMLI / TLT-1; and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a monocyte / macrophage, for example, mediated by targeting to B7-H1, CD31 / PECAM-1, CD163, CCR2, or Macrophage Mannose Receptor CD206 and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a monocyte / macrophage, for example, mediated by targeting to SIRP1a and (ii) a targeting moiety is directed against a tumor cell, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against SIRP1a on macrophage cells and a second targeting moiety directed against PD-L1 or PD-L2 on tumor cells. In various embodiments, the present chimeric protein has one or more targeting moieties directed against a checkpoint marker, e.g. one or more of PD-1 / PD-L1 or PD-L2, CD28 / CD80 or CD86, CTLA4 / CD80 or CD86, ICOS / ICOSL or B7RP1, BTLA / HVEM, KIR, LAG3, CD137 / CD137L, OX40 / OX40L, CD27, CD40L, TIM3 / Gal9, and A2aR. In one embodiment, the present chimeric protein has (i) a targeting moiety directed against a checkpoint marker on a T cell, for example, PD-1 and (ii) a targeting moiety directed against a tumor cell, for example, PD-L1 or PD-L2, along with any of the modified (e.g. mutant) signaling agents described herein. In an embodiment, the present chimeric protein has a targeting moiety directed against PD-1 on T cells and a second targeting moiety directed against PD-L1 on tumor cells. In another embodiment, the present chimeric protein has a targeting moiety directed against PD-1 on T cells and a second targeting moiety directed against PD-L2 on tumor cells. In some embodiments, the present chimeric protein comprises two or more targeting moieties directed to the same or different immune cells. In some embodiments, the present chimeric protein has (i) one or more targeting moieties directed against an immune cell selected from a T cell, a B cell, a dendritic cell, a macrophage, a NK cell, or subsets thereof and (ii) one or more targeting moieties directed against either the same or another immune cell selected from a T cell, a B cell, a dendritic cell, a macrophage, a NK cell, or subsets thereof, along with any of the modified (e.g. mutant) signaling agents described herein (e.g., modified IFN-β). In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a T cell and one or more targeting moieties directed against the same or another T cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a T cell and one or more targeting moieties directed against a B cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a T cell and one or more targeting moieties directed against a dendritic cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties against a T cell and one or more targeting moieties directed against a macrophage. In one embodiment, the present chimeric protein comprises one or more targeting moieties against a T cell and one or more targeting moieties directed against a NK cell. For example, in an illustrative embodiment, the chimeric protein may include a targeting moiety against CD8 and a targeting moiety against Clec9A. In another illustrative embodiment, the chimeric protein may include a targeting moiety against CD8 and a targeting moiety against CD3. In another illustrative embodiment, the chimeric protein may include a targeting moiety against CD8 and a targeting moiety against PD-1. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a B cell and one or more targeting moieties directed against the same or another B cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a B cell and one or more targeting moieties directed against a T cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a B cell and one or more targeting moieties directed against a dendritic cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties against a B cell and one or more targeting moieties directed against a macrophage. In one embodiment, the present chimeric protein comprises one or more targeting moieties against a B cell and one or more targeting moieties directed against a NK cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a dendritic cell and one or more targeting moieties directed against the same or another dendritic cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a dendritic cell and one or more targeting moieties directed against a T cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a dendritic cell and one or more targeting moieties directed against a B cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties against a dendritic cell and one or more targeting moieties directed against a macrophage. In one embodiment, the present chimeric protein comprises one or more targeting moieties against a dendritic cell and one or more targeting moieties directed against a NK cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a macrophage and one or more targeting moieties directed against the same or another macrophage. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a macrophage and one or more targeting moieties directed against a T cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against a macrophage and one or more targeting moieties directed against a B cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties against a macrophage and one or more targeting moieties directed against a dendritic cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties against a macrophage and one or more targeting moieties directed against a NK cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against an NK cell and one or more targeting moieties directed against the same or another NK cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against an NK cell and one or more targeting moieties directed against a T cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties directed against an NK cell and one or more targeting moieties directed against a B cell. In one embodiment, the present chimeric protein comprises one or more targeting moieties against an NK cell and one or more targeting moieties directed against a macrophage. In one embodiment, the present chimeric protein comprises one or more targeting moieties against an NK cell and one or more targeting moieties directed against a dendritic cell. In one embodiment, the present chimeric protein comprises a targeting moiety directed against a tumor cell and a second targeting moiety directed against the same or a different tumor cell. In such embodiments, the targeting moieties may bind to any of the tumor antigens described herein. In various embodiments, the targeting moiety of the invention may comprise a sequence which has one or more amino acid mutations with respect to any one of the sequences disclosed herein. In various embodiments, the targeting moiety comprises a sequence that has about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 or more amino acid mutations with respect to any one of the amino acid sequences of targeting moieties disclosed herein. In some embodiments, the one or more amino acid mutations may be independently selected from substitutions, insertions, deletions, and truncations. In some embodiments, the amino acid mutations are amino acid substitutions, and may include conservative and / or non-conservative substitutions. "Conservative substitutions" may be made, for instance, on the basis of similarity in polarity, charge, size, solubility, hydrophobicity, hydrophilicity, and / or the amphipathic nature of the amino acid residues involved. The 20 naturally occurring amino acids can be grouped into the following six standard amino acid groups: (1) hydrophobic: Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr; Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe. As used herein, "conservative substitutions" are defined as exchanges of an amino acid by another amino acid listed within the same group of the six standard amino acid groups shown above. For example, the exchange of Asp by Glu retains one negative charge in the so modified polypeptide. In addition, glycine and proline may be substituted for one another based on their ability to disrupt α-helices. As used herein, "non-conservative substitutions" are defined as exchanges of an amino acid by another amino acid listed in a different group of the six standard amino acid groups (1) to (6) shown above. In various embodiments, the substitutions may also include non-classical amino acids (e.g. selenocysteine, pyrrolysine, N-formylmethionine <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-alanine, GABA and <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>-Aminolevulinic acid, 4-aminobenzoic acid (PABA), D- isomers of the common amino acids, 2,4-diaminobutyric acid, α-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, γ-Abu, ε-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosme, citrulline, homocitrulline, cysteic acid, t-butylglycine, t- butylalanine, phenylglycine, cyclohexylalanine, β-alanine, fluoro-amino acids, designer amino acids such as β methyl amino acids, C <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>-methyl amino acids, N <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>-methyl amino acids, and amino acid analogs in general). In various embodiments, the amino acid mutation may be in the CDRs of the targeting moiety (e.g., the CDR1, CDR2 or CDR3 regions). In another embodiment, amino acid alteration may be in the framework regions (FRs) of the targeting moiety (e.g., the FR1, FR2, FR3, or FR4 regions). Modification of the amino acid sequences may be achieved using any known technique in the art e.g., site- directed mutagenesis or PCR based mutagenesis. Such techniques are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Plainview, N.Y., 1989 and Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, N.Y., 1989. Targeting Moiety Formats In various embodiments, the targeting moiety of the present chimeric protein is a protein-based agent capable of specific binding, such as an antibody or derivatives thereof. In an embodiment, the targeting moiety comprises an antibody. In various embodiments, the antibody is a full-length multimeric protein that includes two heavy chains and two light chains. Each heavy chain includes one variable region (e.g., V<com:Sub>H< / com:Sub>) and at least three constant regions (e.g., CH<com:Sub>1< / com:Sub>, CH<com:Sub>2< / com:Sub> and CH<com:Sub>3< / com:Sub>), and each light chain includes one variable region (V<com:Sub>L< / com:Sub>) and one constant region (C<com:Sub>L< / com:Sub>). The variable regions determine the specificity of the antibody. Each variable region comprises three hypervariable regions also known as complementarity determining regions (CDRs) flanked by four relatively conserved framework regions (FRs). The three CDRs, referred to as CDR1, CDR2, and CDR3, contribute to the antibody binding specificity. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the targeting moiety comprises antibody derivatives or formats. In some embodiments, the targeting moiety of the present chimeric protein is a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a shark heavy-chain-only antibody (VNAR), a microprotein (cysteine knot protein, knottin), a DARPin; a Tetranectin; an Affibody™; a Transbody; an Anticalin; an AdNectin™; an Affilin; a Microbody; a peptide aptamer; an alterase; a plastic antibody; a phylomer; a stradobody; a maxibody; an evibody; a fynomer, an armadillo repeat protein, a Kunitz domain, an avimer, an atrimer, a probody, an immunobody, a triomab, a troybody; a pepbody; a vaccibody, a UniBody™; Affimers, a DuoBody, a Fv, a Fab, a Fab', a F(ab')<com:Sub>2< / com:Sub>, a peptide mimetic molecule, or a synthetic molecule, as described in US Patent Nos. or Patent Publication Nos. US 7,417,130, US 2004 / 132094, US 5,831,012, US 2004 / 023334, US 7,250,297, US 6,818,418, US 2004 / 209243, US 7,838,629, US 7,186,524, US 6,004,746, US 5,475,096, US 2004 / 146938, US 2004 / 157209, US 6,994,982, US 6,794,144, US 2010 / 239633, US 7,803,907, US 2010 / 119446, and / or US 7,166,697. See also, Storz MAbs. 2011 May-Jun; 3(3): 310–317. In one embodiment, the targeting moiety comprises a single-domain antibody, such as VHH from, for example, an organism that produces VHH antibody such as a camelid, a shark, or a designed VHH. VHHs are antibody- derived therapeutic proteins that contain the unique structural and functional properties of naturally-occurring heavy-chain antibodies. VHH technology is based on fully functional antibodies from camelids that lack light chains. These heavy-chain antibodies contain a single variable domain (VHH) and two constant domains (CH2) and CH3). VHHs are commercially available under the trademark of NANOBODIES. In some embodiments, the VHH is a humanized VHH or camelized VHH. In various embodiments, the targeting moiety of the present chimeric protein is a protein-based agent capable of specific binding to a cell receptor, such as a natural ligand for the cell receptor. In various embodiments, the cell receptor is found on one or more immune cells, which can include, without limitation, T cells, cytotoxic T lymphocytes, T helper cells, natural killer (NK) cells, natural killer T (NKT) cells, anti-tumor macrophages (e.g. M1 macrophages), B cells, dendritic cells, or subsets thereof. In some embodiments, the cell receptor is found on megakaryocytes, thrombocytes, erythrocytes, mast cells, basophils, neutrophils, eosinophils, or subsets thereof. In some embodiments, the targeting moiety is a natural ligand such as a chemokine. Exemplary chemokines that may be included in the chimeric protein of the invention include, but are not limited to, CCL1, CCL2, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CLL25, CCL26, CCL27, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, XCL1, XCL2, CX3CL1, HCC-4, and LDGF-PBP. In an illustrative embodiment, the targeting moiety may be XCL1 which is a chemokine that recognizes and binds to the dendritic cell receptor XCR1. In another illustrative embodiment, the targeting moiety is CCL1, which is a chemokine that recognizes and binds to CCR8. In another illustrative embodiment, the targeting moiety is CCL2, which is a chemokine that recognizes and binds to CCR2 or CCR9. In another illustrative embodiment, the targeting moiety is CCL3, which is a chemokine that recognizes and binds to CCR1, CCR5, or CCR9. In another illustrative embodiment, the targeting moiety is CCL4, which is a chemokine that recognizes and binds to CCR1 or CCR5 or CCR9. In another illustrative embodiment, the targeting moiety is CCL5, which is a chemokine that recognizes and binds to CCR1 or CCR3 or CCR4 or CCR5. In another illustrative embodiment, the targeting moiety is CCL6, which is a chemokine that recognizes and binds to CCR1. In another illustrative embodiment, the targeting moiety is CCL7, which is a chemokine that recognizes and binds to CCR2 or CCR9. In another illustrative embodiment, the targeting moiety is CCL8, which is a chemokine that recognizes and binds to CCR1 or CCR2 or CCR2B or CCR5 or CCR9. In another illustrative embodiment, the targeting moiety is CCL9, which is a chemokine that recognizes and binds to CCR1. In another illustrative embodiment, the targeting moiety is CCL10, which is a chemokine that recognizes and binds to CCR1. In another illustrative embodiment, the targeting moiety is CCL11, which is a chemokine that recognizes and binds to CCR2 or CCR3 or CCR5 or CCR9. In another illustrative embodiment, the targeting moiety is CCL13, which is a chemokine that recognizes and binds to CCR2 or CCR3 or CCR5 or CCR9. In another illustrative embodiment, the targeting moiety is CCL14, which is a chemokine that recognizes and binds to CCR1 or CCR9. In another illustrative embodiment, the targeting moiety is CCL15, which is a chemokine that recognizes and binds to CCR1 or CCR3. In another illustrative embodiment, the targeting moiety is CCL16, which is a chemokine that recognizes and binds to CCR1, CCR2, CCR5, or CCR8. In another illustrative embodiment, the targeting moiety is CCL17, which is a chemokine that recognizes and binds to CCR4. In another illustrative embodiment, the targeting moiety is CCL19, which is a chemokine that recognizes and binds to CCR7. In another illustrative embodiment, the targeting moiety is CCL20, which is a chemokine that recognizes and binds to CCR6. In another illustrative embodiment, the targeting moiety is CCL21, which is a chemokine that recognizes and binds to CCR7. In another illustrative embodiment, the targeting moiety is CCL22, which is a chemokine that recognizes and binds to CCR4. In another illustrative embodiment, the targeting moiety is CCL23, which is a chemokine that recognizes and binds to CCR1. In another illustrative embodiment, the targeting moiety is CCL24, which is a chemokine that recognizes and binds to CCR3. In another illustrative embodiment, the targeting moiety is CCL25, which is a chemokine that recognizes and binds to CCR9. In another illustrative embodiment, the targeting moiety is CCL26, which is a chemokine that recognizes and binds to CCR3. In another illustrative embodiment, the targeting moiety is CCL27, which is a chemokine that recognizes and binds to CCR10. In another illustrative embodiment, the targeting moiety is CCL28, which is a chemokine that recognizes and binds to CCR3 or CCR10. In another illustrative embodiment, the targeting moiety is CXCL1, which is a chemokine that recognizes and binds to CXCR1 or CXCR2. In another illustrative embodiment, the targeting moiety is CXCL2, which is a chemokine that recognizes and binds to CXCR2. In another illustrative embodiment, the targeting moiety is CXCL3, which is a chemokine that recognizes and binds to CXCR2. In another illustrative embodiment, the targeting moiety is CXCL4, which is a chemokine that recognizes and binds to CXCR3B. In another illustrative embodiment, the targeting moiety is CXCL5, which is a chemokine that recognizes and binds to CXCR2. In another illustrative embodiment, the targeting moiety is CXCL6, which is a chemokine that recognizes and binds to CXCR1 or CXCR2. In another illustrative embodiment, the targeting moiety is CXCL8, which is a chemokine that recognizes and binds to CXCR1 or CXCR2. In another illustrative embodiment, the targeting moiety is CXCL9, which is a chemokine that recognizes and binds to CXCR3. In another illustrative embodiment, the targeting moiety is CXCL10, which is a chemokine that recognizes and binds to CXCR3. In another illustrative embodiment, the targeting moiety is CXCL11, which is a chemokine that recognizes and binds to CXCR3 or CXCR7. In another illustrative embodiment, the targeting moiety is CXCL12, which is a chemokine that recognizes and binds to CXCR4 or CXCR7. In another illustrative embodiment, the targeting moiety is CXCL13, which is a chemokine that recognizes and binds to CXCR5. In another illustrative embodiment, the targeting moiety is CXCL16, which is a chemokine that recognizes and binds to CXCR6. In another illustrative embodiment, the targeting moiety is LDGF-PBP, which is a chemokine that recognizes and binds to CXCR2. In another illustrative embodiment, the targeting moiety is XCL2, which is a chemokine that recognizes and binds to XCR1. In another illustrative embodiment, the targeting moiety is CX3CL1, which is a chemokine that recognizes and binds to CX3CR1. In various embodiments, the present chimeric protein comprises targeting moieties in various combinations. In an illustrative embodiment, the present chimeric protein may comprise two targeting moieties, wherein both targeting moieties are antibodies or derivatives thereof. In another illustrative embodiment, the present chimeric protein may comprise two targeting moieties, wherein both targeting moieties are natural ligands for cell receptors. In a further illustrative embodiment, the present chimeric protein may comprise two targeting moieties, wherein one of the targeting moieties is an antibody or derivative thereof, and the other targeting moiety is a natural ligand for a cell receptor. In various embodiments, the recognition domain of the present chimeric protein functionally modulates (by way of non-limitation, partially or completely neutralizes) the target (e.g. antigen, receptor) of interest, e.g. substantially inhibiting, reducing, or neutralizing a biological effect that the antigen has. For example, various recognition domains may be directed against one or more tumor antigens that are actively suppressing, or have the capacity to suppress, the immune system of, for example, a patient bearing a tumor. For example, in some embodiments, the present chimeric protein functionally modulates immune inhibitory signals (e.g. checkpoint inhibitors), for example, one or more of TIM-3, BTLA, PD-1, CTLA-4, B7-H4, GITR, galectin-9, HVEM, PD-L1, PD-L2, B7-H3, CD244, CD160, TIGIT, SIRPα, ICOS, CD172a, and TMIGD2. For example, in some embodiments, the present chimeric protein is engineered to disrupt, block, reduce, and / or inhibit the transmission of an immune inhibitory signal, by way of non-limiting example, the binding of PD-1 with PD-L1 or PD-L2 and / or the binding of CTLA-4 with one or more of AP2M1, CD80, CD86, SHP-2, and PPP2R5A. In various embodiments, the recognition domain of the present chimeric protein binds but does not functionally modulate the target (e.g. antigen, receptor) of interest, e.g. the recognition domain is, or is akin to, a binding antibody. For instance, in various embodiments, the recognition domain simply targets the antigen or receptor but does not substantially inhibit, reduce or functionally modulate a biological effect that the antigen or receptor has. For example, some of the smaller antibody formats described above (e.g. as compared to, for example, full antibodies) have the ability to target hard to access epitopes and provide a larger spectrum of specific binding locales. In various embodiments, the recognition domain binds an epitope that is physically separate from an antigen or receptor site that is important for its biological activity (e.g. the antigen's active site). Such non-neutralizing binding finds use in various embodiments of the present invention, including methods in which the present chimeric protein is used to directly or indirectly recruit active immune cells to a site of need via an effector antigen, such as any of those described herein. For example, in various embodiments, the present chimeric protein may be used to directly or indirectly recruit cytotoxic T cells via CD8 to a tumor cell in a method of reducing or eliminating a tumor (e.g. the chimeric protein may comprise an anti-CD8 recognition domain and a recognition domain directed against a tumor antigen). In such embodiments, it is desirable to directly or indirectly recruit CD8-expressing cytotoxic T cells but not to functionally modulate the CD8 activity. On the contrary, in these embodiments, CD8 signaling is an important piece of the tumor reducing or eliminating effect. By way of further example, in various methods of reducing or eliminating tumors, the present chimeric protein is used to directly or indirectly recruit dendritic cells (DCs) via CLEC9A (e.g. the chimeric protein may comprise an anti- CLEC9A recognition domain and a recognition domain directed against a tumor antigen). In such embodiments, it is desirable to directly or indirectly recruit CLEC9A-expressing DCs but not to functionally modulate the CLEC9A activity. On the contrary, in these embodiments, CLEC9A signaling is an important piece of the tumor reducing or eliminating effect. In various embodiments, the recognition domain of the present chimeric protein binds to XCR1 e.g. on dendritic cells. For instance, the recognition domain, in some embodiments comprises all or part of XCL1 or a non- neutralizing anti-XCR1 agent. In various embodiments, the recognition domain of the present chimeric protein binds to an immune modulatory antigen (e.g. immune stimulatory or immune inhibitory). In various embodiments, the immune modulatory antigen is one or more of 4-1BB, OX-40, HVEM, GITR, CD27, CD28, CD30, CD40, ICOS ligand; OX-40 ligand, LIGHT (CD258), GITR ligand, CD70, B7-1, B7-2, CD30 ligand, CD40 ligand, ICOS, ICOS ligand, CD137 ligand and TL1A. In various embodiments, such immune stimulatory antigens are expressed on a tumor cell. In various embodiments, the recognition domain of the present chimeric protein binds but does not functionally modulate such immune stimulatory antigens and therefore allows recruitment of cells expressing these antigens without the reduction or loss of their potential tumor reducing or eliminating capacity. In various embodiments, the recognition domain of the present chimeric protein may be in the context of chimeric protein that comprises two recognition domains that have neutralizing activity, or comprises two recognition domains that have non-neutralizing (e.g. binding) activity, or comprises one recognition domain that has neutralizing activity and one recognition domain that has non-neutralizing (e.g. binding) activity. Signaling Agents In one aspect, the present invention provides a chimeric protein that includes a signaling agent (for instance, an immune-modulating agent). In various embodiments, the signaling agent is modified to have reduced affinity or activity for one or more of its receptors, which allows for attenuation of activity (inclusive of agonism or antagonism) and / or prevents non-specific signaling or undesirable sequestration of the chimeric protein. In various embodiments, the signaling agent is antagonistic in its wild type form and bears one or more mutations that attenuate its antagonistic activity. In various embodiments, the signaling agent is antagonistic due to one or more mutations, e.g. an agonistic signaling agent is converted to an antagonistic signaling agent and, such a converted signaling agent, optionally, also bears one or more mutations that attenuate its antagonistic activity (e.g. as described in WO 2015 / 007520). In various embodiments, the signaling agent is selected from modified versions of cytokines, growth factors, and hormones. Illustrative examples of such cytokines, growth factors, and hormones include, but are not limited to, lymphokines, monokines, traditional polypeptide hormones, such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-α and tumor necrosis factor-β; mullerian-inhibiting substance; mouse gonadotropin- associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF-a; platelet-growth factor; transforming growth factors (TGFs) such as TGF-a and TGF-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>; insulin-like growth factor-I and <com:Math><semantics>−II<annotation encoding="application / x-tex">-II< / annotation>< / semantics>< / com:Math>; osteo inductive factors; interferons such as, for example, interferon-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>, interferon-β and interferon-γ (and interferon type I, II, and III), colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (G-CSF); interleukins (ILs) such as, for example, IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, and IL-18; a tumor necrosis factor such as, for example, TNF-α or TNF-β; and other polypeptide factors including, for example, LIF and kit ligand (KL). As used herein, cytokines, growth factors, and hormones include proteins obtained from natural sources or produced from recombinant bacterial, eukaryotic or mammalian cell culture systems and biologically active equivalents of the native sequence cytokines. In some embodiments, the signaling agent is a modified version of a growth factor selected from, but not limited to, transforming growth factors (TGFs) such as TGF-α and TGF-β, epidermal growth factor (EGF), insulin-like growth factor such as insulin-like growth factor-I and -II, fibroblast growth factor (FGF), heregulin, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF). In an embodiment, the growth factor is a modified version of a fibroblast growth factor (FGF). Illustrative FGFs include, but are not limited to, FGF1, FGF2, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF11, FGF12, FGF13, FGF14, murine FGF15, FGF16, FGF17, FGF18, FGF19, FGF20, FGF21, FGF22, and FGF23. In an embodiment, the growth factor is a modified version of a vascular endothelial growth factor (VEGF). Illustrative VEGFs include, but are not limited to, VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PGF and isoforms thereof including the various isoforms of VEGF-A such as VEGF<com:Sub>121< / com:Sub>, VEGF<com:Sub>121< / com:Sub>b, VEGF<com:Sub>145< / com:Sub>, VEGF<com:Sub>165< / com:Sub>b, VEGF<com:Sub>189< / com:Sub>, and VEGF<com:Sub>206< / com:Sub>. In an embodiment, the growth factor is a modified version of a transforming growth factor (TGF). Illustrative TGFs include, but are not limited to, TGF-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> and TGF-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> and subtypes thereof including the various subtypes of TGF-<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> including TGF<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>1, TGF<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>2, and TGF<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>3. In some embodiments, the signaling agent is a modified version of a hormone selected from, but not limited to, human chorionic gonadotropin, gonadotropin releasing hormone, an androgen, an estrogen, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, growth hormone, adrenocorticotropic hormone, antidiuretic hormone, oxytocin, thyrotropin-releasing hormone, growth hormone releasing hormone, corticotropin-releasing hormone, somatostatin, dopamine, melatonin, thyroxine, calcitonin, parathyroid hormone, glucocorticoids, mineralocorticoids, adrenaline, noradrenaline, progesterone, insulin, glucagon, amylin, calcitriol, calciferol, atrial-natriuretic peptide, gastrin, secretin, cholecystokinin, neuropeptide Y, ghrelin, PYY3-36, insulin- like growth factor (IGF), leptin, thrombopoietin, erythropoietin (EPO), and angiotensinogen. In some embodiments, the signaling agent is EPO. In some embodiments, the signaling agent is an immune-modulating agent, e.g. one or more of an interleukin, interferon, and tumor necrosis factor. In some embodiments, the signaling agent is an interleukin or a modified interleukin, including for example IL-1; IL-2; IL-3; IL-4; IL-5; IL-6; IL-7; IL-8; IL-9; IL-10; IL-11; IL-12; IL-13; IL-14; IL-15; IL-16; IL-17; IL-18; IL-19; IL-20; IL-21; IL-22; IL-23; IL-24; IL-25; IL-26; IL-27; IL-28; IL-29; IL-30; IL-31; IL-32; IL-33; IL-35; IL-36 or a fragment, variant, analogue, or family-member thereof. Interleukins are a group of multi- functional cytokines synthesized by lymphocytes, monocytes, and macrophages. Known functions include stimulating proliferation of immune cells (e.g., T helper cells, B cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and / or inhibition of interferons. Interleukin activity can be determined using assays known in the art: Matthews et al., in Lymphokines and Interferens: A Practical Approach, Clemens et al., eds, IRL Press, Washington, D.C. 1987, pp. 221-225; and Orencole & Dinarello (1989) Cytokine 1, 14-20. In some embodiments, the signaling agent is an interferon or a modified version of an interferon such as interferon types I, II, and III. Illustrative interferons, including for example, interferon-α-1, 2, 4, 5, 6, 7, 8, 10, 13, 14, 16, 17, and 21, interferon-β and interferon-γ, interferon κ, interferon ε, interferon <com:Math><semantics>τ<annotation encoding="application / x-tex">\tau< / annotation>< / semantics>< / com:Math>, and interferon <com:Math><semantics>ϖ<annotation encoding="application / x-tex">\varpi< / annotation>< / semantics>< / com:Math>. In some embodiments, the signaling agent is a tumor necrosis factor (TNF) or a modified version of a tumor necrosis factor (TNF) or a protein in the TNF family, including but not limited to, TNF-α, TNF-β, LT-β, CD40L, CD27L, CD30L, FASL, 4-1BBL, OX40L, and TRAIL. In various embodiments, the signaling agent is a modified (e.g. mutant) form of the signaling agent having one or more mutations. In various embodiments, the mutations allow for the modified signaling agent to have one or more of attenuated activity such as one or more of reduced binding affinity, reduced endogenous activity, and reduced specific bioactivity relative to unmodified or unmutated, i.e. the wild type form of the signaling agent (e.g. comparing the same signaling agent in a wild type form versus a modified (e.g. mutant) form). In some embodiments, the mutations which attenuate or reduce binding or affinity include those mutations which substantially reduce or ablate binding or activity. In some embodiments, the mutations which attenuate or reduce binding or affinity are different than those mutations which substantially reduce or ablate binding or activity. Consequentially, in various embodiments, the mutations allow for the signaling agent to have improved safety, e.g. have reduced systemic toxicity, reduced side effects, and reduced off-target effects relative to unmutated, i.e. wild type, signaling agent (e.g. comparing the same signaling agent in a wild type form versus a modified (e.g. mutant) form). In various embodiments, the signaling agent is modified to have one or more mutations that reduce its binding affinity or activity for one or more of its receptors. In some embodiments, the signaling agent is modified to have one or more mutations that substantially reduce or ablate binding affinity or activity for the receptors. In some embodiments, the activity provided by the wild type signaling agent is agonism at the receptor (e.g. activation of a cellular effect at a site of therapy). For example, the wild type signaling agent may activate its receptor. In such embodiments, the mutations result in the modified signaling agent to have reduced or ablated activating activity at the receptor. For example, the mutations may result in the modified signaling agent to deliver a reduced activating signal to a target cell or the activating signal could be ablated. In some embodiments, the activity provided by the wild type signaling agent is antagonism at the receptor (e.g. blocking or dampening of a cellular effect at a site of therapy). For example, the wild type signaling agent may antagonize or inhibit the receptor. In these embodiments, the mutations result in the modified signaling agent to have a reduced or ablated antagonizing activity at the receptor. For example, the mutations may result in the modified signaling agent to deliver a reduced inhibitory signal to a target cell or the inhibitory signal could be ablated. In various embodiments, the signaling agent is antagonistic due to one or more mutations, e.g. an agonistic signaling agent is converted to an antagonistic signaling agent (e.g. as described in WO 2015 / 007520) and, such a converted signaling agent, optionally, also bears one or more mutations that reduce its binding affinity or activity for one or more of its receptors or that substantially reduce or ablate binding affinity or activity for one or more of its receptors. In some embodiments, the reduced affinity or activity at the receptor is restorable by attachment with one or more of the targeting moieties. In other embodiments, the reduced affinity or activity at the receptor is not substantially restorable by the activity of one or more of the targeting moieties. In various embodiments, the chimeric proteins of the present invention reduce off-target effects because their signaling agents have mutations that weaken or ablate binding affinity or activity at a receptor. In various embodiments, this reduction in side effects is observed relative with, for example, the wild type signaling agents. In various embodiments, the signaling agent is active on target cells because the targeting moiety(ies) compensates for the missing / insufficient binding (e.g., without limitation and / or avidity) required for substantial activation. In various embodiments, the modified signaling agent is substantially inactive en route to the site of therapeutic activity and has its effect substantially on specifically targeted cell types which greatly reduces undesired side effects. In some embodiments, the signaling agent may include one or more mutations that attenuate or reduce binding or affinity for one receptor (i.e., a therapeutic receptor) and one or more mutations that substantially reduce or ablate binding or activity at a second receptor. In such embodiments, these mutations may be at the same or at different positions (i.e., the same mutation or multiple mutations). In some embodiments, the mutation(s) that reduce binding and / or activity at one receptor is different than the mutation(s) that substantially reduce or ablate at another receptor. In some embodiments, the mutation(s) that reduce binding and / or activity at one receptor is the same as the mutation(s) that substantially reduce or ablate at another receptor. In some embodiments, the present chimeric proteins have a modified signaling agent that has both mutations that attenuate binding and / or activity at a therapeutic receptor and therefore allow for a more controlled, on-target therapeutic effect (e.g. relative wild type signaling agent) and mutations that substantially reduce or ablate binding and / or activity at another receptor and therefore reduce side effects (e.g. relative to wild type signaling agent). In some embodiments, the substantial reduction or ablation of binding or activity is not substantially restorable with a targeting moiety. In some embodiments, the substantial reduction or ablation of binding or activity is restorable with a targeting moiety. In various embodiments, substantially reducing or ablating binding or activity at a second receptor also may prevent deleterious effects that are mediated by the other receptor. Alternatively, or in addition, substantially reducing or ablating binding or activity at the other receptor causes the therapeutic effect to improve as there is a reduced or eliminated sequestration of the therapeutic chimeric proteins away from the site of therapeutic action. For instance, in some embodiments, this obviates the need of high doses of the present chimeric proteins that compensate for loss at the other receptor. Such ability to reduce dose further provides a lower likelihood of side effects. In various embodiments, the modified signaling agent comprises one or more mutations that cause the signaling agent to have reduced, substantially reduced, or ablated affinity, e.g. binding (e.g. K<com:Sub>D< / com:Sub>) and / or activation (for instance, when the modified signaling agent is an agonist of its receptor, measurable as, for example, <com:Math><semantics>KA<annotation encoding="application / x-tex">K_A< / annotation>< / semantics>< / com:Math> and / or EC<com:Sub>50< / com:Sub>) and / or inhibition (for instance, when the modified signaling agent is an antagonist of its receptor, measurable as, for example, K<com:Sub>1< / com:Sub> and / or IC<com:Sub>50< / com:Sub>), for one or more of its receptors. In various embodiments, the reduced affinity at the immumodulating agent's receptor allows for attenuation of activity (inclusive of agonism or antagonism). In such embodiments, the modified signaling agent has about 1%, or about 3%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 10%-20%, about 20%-40%, about 50%, about 40%-60%, about 60%-80%, about 80%-100% of the affinity for the receptor relative to the wild type signaling agent. In some embodiments, the binding affinity is at least about 2-fold lower, about 3-fold lower, about 4-fold lower, about 5-fold lower, about 6-fold lower, about 7-fold lower, about 8-fold lower, about 9-fold lower, at least about 10-fold lower, at least about 15-fold lower, at least about 20-fold lower, at least about 25-fold lower, at least about 30-fold lower, at least about 35-fold lower, at least about 40-fold lower, at least about 45-fold lower, at least about 50-fold lower, at least about 100-fold lower, at least about 150-fold lower, or about 10-50-fold lower, about 50-100-fold lower, about 100-150-fold lower, about 150-200-fold lower, or more than 200-fold lower relative to the wild type signaling agent. In embodiments wherein the chimeric protein has mutations that reduce binding at one receptor and substantially reduce or ablate binding at a second receptor, the attenuation or reduction in binding affinity of a modified signaling agent for one receptor is less than the substantial reduction or ablation in affinity for the other receptor. In some embodiments, the attenuation or reduction in binding affinity of a modified signaling agent for one receptor is less than the substantial reduction or ablation in affinity for the other receptor by about 1%, or about 3%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In various embodiments, substantial reduction or ablation refers to a greater reduction in binding affinity and / or activity than attenuation or reduction. In various embodiments, the modified signaling agent comprises one or more mutations that reduce the endogenous activity of the signaling agent to about 75%, or about 70%, or about 60%, or about 50%, or about 40%, or about 30%, or about 25%, or about 20%, or about 10%, or about 5%, or about 3%, or about 1%, e.g., relative to the wild type signaling agent In various embodiments, the modified signaling agent comprises one or more mutations that cause the signaling agent to have reduced affinity and / or activity for a receptor of any one of the cytokines, growth factors, and hormones as described herein. In some embodiments, the modified signaling agent comprises one or more mutations that cause the signaling agent to have reduced affinity for its receptor that is lower than the binding affinity of the targeting moiety(ies) for its(their) receptor(s). In some embodiments, this binding affinity differential is between signaling agent / receptor and targeting moiety / receptor on the same cell. In some embodiments, this binding affinity differential allows for the signaling agent, e.g. mutated signaling agent, to have localized, on-target effects and to minimize off-target effects that underlie side effects that are observed with wild type signaling agent. In some embodiments, this binding affinity is at least about 2-fold, or at least about 5-fold, or at least about 10-fold, or at least about 15-fold lower, or at least about 25-fold, or at least about 50-fold lower, or at least about 100-fold, or at least about 150- fold. Receptor binding activity may be measured using methods known in the art. For example, affinity and / or binding activity may be assessed by Scatchard plot analysis and computer-fitting of binding data (e.g. Scatchard, 1949) or by reflectometric interference spectroscopy under flow through conditions, as described by Brecht et al. (1993). The amino acid sequences of the wild type signaling agents described herein are well known in the art. Accordingly, in various embodiments the modified signaling agent comprises an amino acid sequence that has at least about 60%, or at least about 61%, or at least about 62%, or at least about 63%, or at least about 64%, or at least about 65%, or at least about 66%, or at least about 67%, or at least about 68%, or at least about 69%, or at least about 70%, or at least about 71%, or at least about 72%, or at least about 73%, or at least about 74%, or at least about 75%, or at least about 76%, or at least about 77%, or at least about 78%, or at least about 79%, or at least about 80%, or at least about 81%, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% sequence identity with the known wild type amino acid sequences of the signaling agents described herein (e.g. about 60%, or about 61%, or about 62%, or about 63%, or about 64%, or about 65%, or about 66%, or about 67%, or about 68%, or about 69%, or about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% sequence identity). In various embodiments the modified signaling agent comprises an amino acid sequence that has at least about 60%, or at least about 61%, or at least about 62%, or at least about 63%, or at least about 64%, or at least about 65%, or at least about 66%, or at least about 67%, or at least about 68%, or at least about 69%, or at least about 70%, or at least about 71%, or at least about 72%, or at least about 73%, or at least about 74%, or at least about 75%, or at least about 76%, or at least about 77%, or at least about 78%, or at least about 79%, or at least about 80%, or at least about 81%, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% sequence identity with any of amino acid sequences of the signaling agents disclosed herein (e.g. about 60%, or about 61%, or about 62%, or about 63%, or about 64%, or about 65%, or about 66%, or about 67%, or about 68%, or about 69%, or about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% sequence identity). In various embodiments, the modified signaling agent comprises an amino acid sequence having one or more amino acid mutations. In some embodiments, the one or more amino acid mutations may be independently selected from substitutions, insertions, deletions, and truncations. In some embodiments, the amino acid mutations are amino acid substitutions, and may include conservative and / or non-conservative substitutions as described elsewhere herein. As described herein, the modified signaling agents bear mutations that affect affinity and / or activity at one or more receptors. In various embodiments, there is reduced affinity and / or activity at a therapeutic receptor, e.g. a receptor through which a desired therapeutic effect is mediated (e.g. agonism or antagonism). In various embodiments, the modified signaling agents bear mutations that substantially reduce or ablate affinity and / or activity at a receptor, e.g. a receptor through which a desired therapeutic effect is not mediated (e.g. as the result of promiscuity of binding). The receptors of any modified signaling agents, e.g. one of the cytokines, growth factors, and hormones as described herein, are known in the art. Illustrative mutations which provide reduced affinity and / or activity (e.g. agonistic) at a receptor are found in WO 2013 / 107791 (e.g. with regard to interferons), WO 2015 / 007542 (e.g. with regard to interleukins), and WO 2015 / 007903 (e.g. with regard to TNF). Illustrative mutations which provide reduced affinity and / or activity (e.g. antagonistic) at a therapeutic receptor are found in WO 2015 / 007520. In some embodiments, the modified signaling agent comprises one or more mutations that cause the signaling agent to have reduced affinity and / or activity for a type I cytokine receptor, a type II cytokine receptor, a chemokine receptor, a receptor in the Tumor Necrosis Factor Receptor (TNFR) superfamily, TGF-beta Receptors, a receptor in the immunoglobulin (Ig) superfamily, and / or a receptor in the tyrosine kinase superfamily. In various embodiments, the receptor for the signaling agent is a Type I cytokine receptor. Type I cytokine receptors are known in the art and include, but are not limited to receptors for IL2 (beta-subunit), IL3, IL4, IL5, IL6, IL7, IL9, IL11, IL12, GM-CSF, G-CSF, LIF, CNTF, and also the receptors for Thrombopoietin (TPO), Prolactin, and Growth hormone. Illustrative type I cytokine receptors include, but are not limited to, GM-CSF receptor, G-CSF receptor, LIF receptor, CNTF receptor, TPO receptor, and type I IL receptors. In various embodiments, the receptor for the signaling agent is a Type II cytokine receptor. Type II cytokine receptors are multimeric receptors composed of heterologous subunits, and are receptors mainly for interferons. This family of receptors includes, but is not limited to, receptors for interferon-α, interferon-β and interferon-γ, IL10, IL22, and tissue factor. Illustrative type II cytokine receptors include, but are not limited to, IFN-a receptor (e.g. IFNAR1 and IFNAR2), IFN- β receptor, IFN- γ receptor (e.g. IFNGR1 and IFNGR2), and type II IL receptors. In various embodiments, the receptor for the signaling agent is a G protein-coupled receptor. Chemokine receptors are G protein-coupled receptors with seven transmembrane structure and coupled to G-protein for signal transduction. Chemokine receptors include, but are not limited to, CC chemokine receptors, CXC chemokine receptors, CX3C chemokine receptors, and XC chemokine receptor (XCR1). Exemplary chemokine receptors include, but are not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3, CXCR3B, CXCR4, CXCR5, CSCR6, CXCR7, XCR1, and CX3CR1. In various embodiments, the receptor for the signaling agent is a TNFR family member. Tumor necrosis factor receptor (TNFR) family members share a cysteine-rich domain (CRD) formed of three disulfide bonds surrounding a core motif of CXXCXXC creating an elongated molecule. Exemplary tumor necrosis factor receptor family members include: CDI 20a (TNFRSFIA), CD 120b (TNFRSFIB), Lymphotoxin beta receptor (LTBR, TNFRSF3), CD 134 (TNFRSF4), CD40 (CD40, TNFRSF5), FAS (FAS, TNFRSF6), TNFRSF6B (TNFRSF6B), CD27 (CD27, TNFRSF7), CD30 (TNFRSF8), CD137 (TNFRSF9), TNFRSFIOA (TNFRSFIOA), TNFRSFIOB, (TNFRSFIOB), TNFRSFIOC (TNFRSFIOC), TNFRSFIOD (TNFRSFIOD), RANK (TNFRSFI IA), Osteoprotegerin (TNFRSFI IB), TNFRSF12A (TNFRSF12A), TNFRSF13B (TNFRSF13B), TNFRSF13C (TNFRSF13C), TNFRSF14 (TNFRSF14), Nerve growth factor receptor (NGFR, TNFRSF16), TNFRSF17 (TNFRSF17), TNFRSF18 (TNFRSF18), TNFRSF19 (TNFRSF19), TNFRSF21 (TNFRSF21), and TNFRSF25 (TNFRSF25). In various embodiments, the receptor for the signaling agent is a TGF-beta receptor. TGF-beta receptors are single pass serine / threonine kinase receptors. TGF-beta receptors include, but are not limited to, TGFBR1, TGFBR2, and TGFBR3. In various embodiments, the receptor for the signaling agent is an lg superfamily receptor. Receptors in the immunoglobulin (lg) superfamily share structural homology with immunoglobulins. Receptors in the lg superfamily include, but are not limited to, interleukin-1 receptors, CSF-1R, PDGFR (e.g. PDGFRA and PDGFRB), and SCFR. In various embodiments, the receptor for the signaling agent is a tyrosine kinase superfamily receptor. Receptors in the tyrosine kinase superfamily are well known in the art. There are about 58 known receptor tyrosine kinases (RTKs), grouped into 20 subfamilies. Receptors in the tyrosine kinase superfamily include, but are not limited to, FGF receptors and their various isoforms such as FGFR1, FGFR2, FGFR3, FGFR4, and FGFR5. In an embodiment, the modified signaling agent is interferon α. In such embodiments, the modified IFN-α agent has reduced affinity and / or activity for the IFN-<com:Math><semantics>α / β<annotation encoding="application / x-tex">\alpha / \beta< / annotation>< / semantics>< / com:Math> receptor (IFNAR), i.e., IFNAR1 and / or IFNAR2 chains. In some embodiments, the modified IFN-a agent has substantially reduced or ablated affinity and / or activity for the IFN- α / β receptor (IFNAR), i.e., IFNAR1 and / or IFNAR2 chains. Mutant forms of interferon a are known to the person skilled in the art. In an illustrative embodiment, the modified signaling agent is the allelic form IFN-α2a having the amino acid sequence of: IFN-α2a (SEQ ID NO: 336): CDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLH EMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKED SILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE In an illustrative embodiment, the modified signaling agent is the allelic form IFN-α2b having the amino acid sequence of (which differs from IFN-α2a at amino acid position 23): IFN-α2b (SEQ ID NO: 337): CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLH EMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKED SILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE In some embodiments, said IFN-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>2 mutant (IFN-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>2a or IFN-<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>2b) is mutated at one or more amino acids at positions 144-154, such as amino acid positions 148, 149 and / or 153. In some embodiments, the IFN-a2 mutant comprises one or more mutations selected from L153A, R149A, and M148A. Such mutants are described, for example, in WO2013 / 107791 and Piehler et al., (2000) J. Biol. Chem, 275:40425-33. In some embodiments, the IFN-α2 mutants have reduced affinity and / or activity for IFNAR1. In some embodiments, the IFN-α2 mutant comprises one or more mutations selected from F64A, N65A, T69A, L80A, Y85A, and Y89A, as described in WO2010 / 030671. In some embodiments, the IFN-a2 mutant comprises one or more mutations selected from K133A, R144A, R149A, and L153A as described in WO2008 / 124086. In some embodiments, the IFN-a2 mutant comprises one or more mutations selected from R120E and R120E / K121E, as described in WO2015 / 007520 and WO2010 / 030671. In such embodiments, said IFN-α2 mutant antagonizes wild type IFN-α2 activity. In such embodiments, said mutant IFN-α2 has reduced affinity and / or activity for IFNAR1 while affinity and / or activity of IFNR2 is retained. In some embodiments, the human IFN-a2 mutant comprises (1) one or more mutations selected from R120E and R120E / K121E, which, without wishing to be bound by theory, create an antagonistic effect and (2) one or more mutations selected from K133A, R144A, R149A, and L153A, which, without wishing to be bound by theory, allow for an attenuated effect at, for example, IFNAR2. In an embodiment, the human IFN-α2 mutant comprises R120E and L153A. In some embodiments, the human IFN-a2 mutant comprises one or more mutations selected from, L15A, A19W, R22A, R23A, L26A, F27A, L30A, L30V, K31A, D32A, R33K, R33A, R33Q, H34A, D35A, Q40A, D114R, L117A, R120A, R125A, K134A, R144A, A145G, A145M, M148A, R149A, S152A, L153A, and N156A as disclosed in WO 2013 / 059885. In some embodiments, the human IFN-α2 mutant comprises the mutations H57Y, E58N, Q61S, and / or L30A as disclosed in WO 2013 / 059885. In some embodiments, the human IFN-α2 mutant comprises the mutations H57Y, E58N, Q61S, and / or R33A as disclosed in WO 2013 / 059885. In some embodiments, the human IFN-α2 mutant comprises the mutations H57Y, E58N, Q61S, and / or M148A as disclosed in WO 2013 / 059885. In some embodiments, the human IFN-a2 mutant comprises the mutations H57Y, E58N, Q61S, and / or L153A as disclosed in WO 2013 / 059885. In some embodiments, the human IFN-α2 mutant comprises the mutations N65A, L80A, Y85A, and / or Y89A as disclosed in WO 2013 / 059885. In some embodiments, the human IFN-α2 mutant comprises the mutations N65A, L80A, Y85A, Y89A, and / or D114A as disclosed in WO 2013 / 059885. In an embodiment, the modified signaling agent is interferon <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>. In such embodiments, the modified interferon <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> agent has reduced affinity and / or activity for the IFN-<com:Math><semantics>α / β<annotation encoding="application / x-tex">\alpha / \beta< / annotation>< / semantics>< / com:Math> receptor (IFNAR), i.e., IFNAR1 and / or IFNAR2 chains. In some embodiments, the modified interferon β agent has substantially reduced or ablated affinity and / or activity for the IFN-α / β receptor (IFNAR), i.e., IFNAR1 and / or IFNAR2 chains. In an embodiment, the modified signaling agent is interferon γ. In such embodiments, the modified interferon γ agent has reduced affinity and / or activity for the interferon-gamma receptor (IFNGR), i.e., IFNGR1 and IFNGR2 chains. In some embodiments, the modified interferon y agent has substantially reduced or ablated affinity and / or activity for the interferon-gamma receptor (IFNGR), i.e., IFNGR1 and / or IFNGR2 chains. In some embodiments, the modified signaling agent is vascular endothelial growth factor (VEGF). VEGF is a potent growth factor that plays major roles in physiological but also pathological angiogenesis, regulates vascular permeability and can act as a growth factor on cells expressing VEGF receptors. Additional functions include, among others, stimulation of cell migration in macrophage lineage and endothelial cells. Several members of the VEGF family of growth factors exist, as well as at least three receptors (VEGFR-1, VEGFR -2, and VEGFR -3). Members of the VEGF family can bind and activate more than one VEGFR type. For example, VEGF-A binds VEGFR-1 and -2, while VEGF-C can bind VEGFR-2 and -3. VEGFR-1 and -2 activation regulates angiogenesis while VEGFR-3 activation is associated with lymphangiogenesis. The major pro-angiogenic signal is generated from activation of VEGFR-2. VEGFR-1 activation has been reported to be possibly associated with negative role in angiogenesis. It has also been reported that VEGFR-1 signaling is important for progression of tumors in vivo via bone marrow-derived VEGFR-1 positive cells (contributing to formation of premetastatic niche in the bone). Several therapies based on VEGF-A directed / neutralizing therapeutic antibodies have been developed, primarily for use in treatment of various human tumors relying on angiogenesis. These are not without side effects though. This may not be surprising considering that these operate as general, non-cell / tissue specific VEGF / VEGFR interaction inhibitors. Hence, it would be desirable to restrict VEGF (e.g. VEGF-A) / VEGFR-2 inhibition to specific target cells (e.g. tumor vasculature endothelial cells). In some embodiments, the VEGF is VEGF-A, VEGF-B, VEFG-C, VEGF-D, or VEGF-E and isoforms thereof including the various isoforms of VEGF-A such as VEGF<com:Sub>121< / com:Sub>, VEGF<com:Sub>121< / com:Sub>b, VEGF<com:Sub>145< / com:Sub>, VEGF<com:Sub>165< / com:Sub>b, VEGF<com:Sub>165< / com:Sub>b, VEGF<com:Sub>189< / com:Sub>, and VEGF<com:Sub>206< / com:Sub>. In some embodiments, the modified signaling agent has reduced affinity and / or activity for VEGFR-1 (FIt-1) and / or VEGFR-2 (KDR / FIk-1). In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for VEGFR-1 (Flt-1) and / or VEGFR-2 (KDR / Flk-1). In an embodiment, the modified signaling agent has reduced affinity and / or activity for VEGFR-2 (KDR / Flk-1) and / or substantially reduced or ablated affinity and / or activity for VEGFR-1 (Flt-1). Such an embodiment finds use, for example, in wound healing methods or treatment of ischmia-related diseases (without wishing to be bound by theory, mediated by VEGFR-2's effects on endothelial cell function and angiogenesis). In various embodiments, binding to VEGFR-1 (Flt-1), which is linked to cancers and pro-inflammatory activities, is avoided. In various embodiments, VEGFR-1 (Flt-1) acts a decoy receptor and therefore substantially reduces or ablates affinity at this receptor avoids sequestration of the therapeutic agent. In an embodiment, the modified signaling agent has substantially reduced or ablated affinity and / or activity for VEGFR-1 (FIt-1) and / or substantially reduced or ablated affinity and / or activity for VEGFR-2 (KDR / Flk-1). In some embodiments, the VEGF is VEGF-C or VEGF- D. In such embodiments, the modified signaling agent has reduced affinity and / or activity for VEGFR-3. Alternatively, the modified signaling agent has substantially reduced or ablated affinity and / or activity for VEGFR- 3. Proangiogenic therapies are also important in various diseases (e.g. ischemic heart disease, bleeding etc.), and include VEGF-based therapeutics. Activation of VEGFR-2 is proangiogenic (acting on endothelial cells). Activation of VEFGR-1 can cause stimulation of migration of inflammatory cells (including, for example, macrophages) and lead to inflammation associated hypervascular permeability. Activation of VEFGR-1 can also promote bone marrow associated tumor niche formation. Thus, VEGF based therapeutic selective for VEGFR-2 activation would be desirable in this case. In addition, cell specific targeting, e.g. to endothelial cells, would be desirable. In some embodiments, the modified signaling agent has reduced affinity and / or activity (e.g. antagonistic) for VEGFR-2 and / or has substantially reduced or ablated affinity and / or activity for VEGFR-1. When targeted to tumor vasculature endothelial cells via a targeting moiety that binds to a tumor endothelial cell marker (e.g. PSMA and others), such construct inhibits VEGFR-2 activation specifically on such marker-positive cells, while not activating VEGFR-1 en route and on target cells (if activity ablated), thus eliminating induction of inflammatory responses, for example. This would provide a more selective and safe anti-angiogenic therapy for many tumor types as compared to VEGF-A neutralizing therapies. In some embodiments, the modified signaling agent has reduced affinity and / or activity (e.g. agonistic) for VEGFR-2 and / or has substantially reduced or ablated affinity and / or activity for VEGFR-1. Through targeting to vascular endothelial cells, such construct, in some embodiments, promotes angiogenesis without causing VEGFR-1 associated induction of inflammatory responses. Hence, such a construct would have targeted proangiogenic effects with substantially reduced risk of side effects caused by systemic activation of VEGFR-2 as well as VEGR-1. In an illustrative embodiment, the modified signaling agent is VEGF<com:Sub>165< / com:Sub>, which has the amino acid sequence: VEGF 165 (wild type) (SEQ ID NO: 338) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] CECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKAR QLELNERTCRCDKPRR In another illustrative embodiment, the modified signaling agent is VEGF<com:Sub>165b< / com:Sub>, which has the amino acid sequence: VEGF 165b (wild type) (SEQ ID NO: 339) APMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSC VPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK CECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKAR QLELNERTCRSLTRKD In these embodiments, the modified signaling agent has a mutation at amino acid 183 (e.g., a substitution mutation at I83, e.g., I83K, I83R, or I83H). Without wishing to be bound by theory, it is believed that such mutations may result in reduced receptor binding affinity. See, for example, U.S. Patent No. 9,078,860. In an embodiment, the modified signaling agent is TNF-α. TNF is a pleiotropic cytokine with many diverse functions, including regulation of cell growth, differentiation, apoptosis, tumorigenesis, viral replication, autoimmunity, immune cell functions and trafficking, inflammation, and septic shock. It binds to two distinct membrane receptors on target cells: TNFR1 (p55) and TNFR2 (p75). TNFR1 exhibits a very broad expression pattern whereas TNFR2 is expressed preferentially on certain populations of lymphocytes, Tregs, endothelial cells, certain neurons, microglia, cardiac myocytes and mesenchymal stem cells. Very distinct biological pathways are activated in response to receptor activation, although there is also some overlap. As a general rule, without wishing to be bound by theory, TNFR1 signaling is associated with induction of apoptosis (cell death) and TNFR2 signaling is associated with activation of cell survival signals (e.g. activation of NFkB pathway). Administration of TNF is systemically toxic, and this is largely due to TNFR1 engagement. However, it should be noted that activation of TNFR2 is also associated with a broad range of activities and, as with TNFR1, in the context of developing TNF based therapeutics, control over TNF targeting and activity is important. In some embodiments, the modified signaling agent has reduced affinity and / or activity for TNFR1 and / or TNFR2. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for TNFR1 and / or TNFR2. TNFR1 is expressed in most tissues, and is involved in cell death signaling while, by contrast, TNFR2 is involved in cell survival signaling. Accordingly, in embodiments directed to methods of treating cancer, the modified signaling agent has reduced affinity and / or activity for TNFR1 and / or substantially reduced or ablated affinity and / or activity for TNFR2. In these embodiments, the chimeric proteins may be targeted to a cell for which apoptosis is desired, e.g. a tumor cell or a tumor vasculature endothelial cell. In embodiments directed to methods of promoting cell survival, for example, in neurogenesis for the treatment of neurodegenerative disorders, the modified signaling agent has reduced affinity and / or activity for TNFR2 and / or substantially reduced or ablated affinity and / or activity for TNFR1. Stated another way, the present chimeric proteins, in some embodiments, comprise modified TNF-a agent that allows of favoring either death or survival signals. In some embodiments, the chimeric protein has a modified TNF having reduced affinity and / or activity for TNFR1 and / or substantially reduced or ablated affinity and / or activity for TNFR2. Such a chimera, in some embodiments, is a more potent inducer of apoptosis as compared to a wild type TNF and / or a chimera bearing only mutation(s) causing reduced affinity and / or activity for TNFR1. Such a chimera, in some embodiments, finds use in inducing tumor cell death or a tumor vasculature endothelial cell death (e.g. in the treatment of cancers). Also, in some embodiments, these chimeras avoid or reduce activation of T<com:Sub>reg< / com:Sub> cells via TNFR2, for example, thus further supporting TNFR1-mediated antitumor activity in vivo. In some embodiments, the chimeric protein has a modified TNF having reduced affinity and / or activity for TNFR2 and / or substantially reduced or ablated affinity and / or activity for TNFR1. Such a chimera, in some embodiments, is a more potent activator of cell survival in some cell types, which may be a specific therapeutic objective in various disease settings, including without limitation, stimulation of neurogenesis. In addition, such a TNFR2- favoring chimeras also are useful in the treatment of autoimmune diseases (e.g. Crohn's, diabetes, MS, colitis etc. and many others described herein). In some embodiments, the chimera is targeted to auto-reactive T cells. In some embodiments, the chimera promotes T<com:Sub>reg< / com:Sub> cell activation and indirect suppression of cytotoxic T cells. In some embodiments, the chimera causes the death of auto-reactive T cells, e.g. by activation of TNFR2 and / or avoidance of TNFR1 (e.g. a modified TNF having reduced affinity and / or activity for TNFR2 and / or substantially reduced or ablated affinity and / or activity for TNFR1). Without wishing to be bound by theory these auto-reactive T cells, have their apoptosis / survival signals altered e.g. by NFkB pathway activity / signaling alterations. In some embodiments, the chimera causes the death of autoreactive T cells having lesions or modifications in the NFkB pathway, which underlie an imbalance of their cell death (apoptosis) / survival signaling properties and, optionally, altered susceptibility to certain death-inducing signals (e.g., TNFR2 activation). In some embodiments, a TNFR2 based chimera has additional therapeutic applications in diseases, including various autoimmune diseases, heart disease, de-myelinating and neurodegenerative disorders, and infectious disease, among others. In an embodiment, the wild type TNF-a has the amino acid sequence of: TNF-a (SEQ ID NO: 340) VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLV VPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQ RETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYF GIIAL In such embodiments, the modified TNF-α agent has mutations at one or more amino acid positions 29, 31, 32, 84, 85, 86, 87, 88, 89, 145, 146 and 147 which produces a modified TNF-α with reduced receptor binding affinity. See, for example, U.S. Patent No. 7,993,636. In some embodiments, the modified human TNF-α moiety has mutations at one or more amino acid positions R32, N34, Q67, H73, L75, T77, S86, Y87, V91, I97, T105, P106, A109, P113, Y115, E127, N137, D143, and A145, as described, for example, in WO / 2015 / 007903, (numbering according to the human TNF sequence, Genbank accession number BAG70306, version BAG70306.1 GI: 197692685). In some embodiments, the modified human TNF-α moiety has substitution mutations selected from R32G, N34G, Q67G, H73G, L75G, L75A, L75S, T77A, S86G, Y87Q, Y87L, Y87A, Y87F, V91G, V91A, I97A, I97Q, I97S, T105G, P106G, A109Y, P113G, Y115G, Y115A, E127G, N137G, D143N, A145G and A145T. In an embodiment, the human TNF-α moiety has a mutation selected from Y87Q, Y87L, Y87A, and Y87F. In another embodiment, the human TNF-a moiety has a mutation selected from I97A, I97Q, and I97S. In a further embodiment, the human TNF-a moiety has a mutation selected from Y115A and Y115G. In some embodiments, the modified TNF-a agent has one or more mutations selected from N39Y, S147Y, and Y87H, as described in WO2008 / 124086. In some embodiments, the modified human TNF-a moiety has mutations that provide receptor selectivity as described in PCT / IB2016 / 001668. In some embodiments, the mutations to TNF are TNF-R1 selective. In some embodiments, the mutations to TNF which are TNF-R1 selective are at one or more of positions R32, S86, and E146. In some embodiments, the mutations to TNF which are TNF-R1 selective are one or more of R32W, S86T, and E146K. In some embodiments, the mutations to TNF which are TNF-R1 selective are one or more of R32W, R32W / S86T, R32W / E146K and E146K. In some embodiments, the mutations to TNF are TNF-R2 selective. In some embodiments, the mutations to TNF which are TNF-R2 selective are at one or more of positions A145, E146, and S147. In some embodiments, the mutations to TNF which are TNF-R2 selective are one or more of A145T, A145R, E146D, and S147D. In some embodiments, the mutations to TNF which are TNF-R2 selective are one or more of A145R, A145T / S147D, and A145T / E146D / S147D. In an embodiment, the modified signaling agent is TNF-β. TNF-β can form a homotrimer or a heterotrimer with LT-β (LT-α1β2). In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for TNFR1 and / or TNFR2 and / or herpes virus entry mediator (HEVM) and / or LT-βR. In an embodiment, the wild type TNF-β has the amino acid sequence of: TNF-beta (SEQ ID NO: 341) LPGVGLTPSAAQTARQHPKMHLAHSNLKPAAHLIGDPSKQNSLLWRANTD RAFLQDGFSLSNNSLLVPTSGIYFVYSQVVFSGKAYSPKATSSPLYLAHEV QLFSSQYPFHVPLLSSQKMVYPGLQEPWLHSMYHGAAFQLTQGDQLSTH TDGIPHLVLSPSTVFFGAFAL In such embodiments, the modified TNF-β agent may comprise mutations at one or more amino acids at positions 106-113, which produce a modified TNF-β with reduced receptor binding affinity to TNFR2. In an embodiment, the modified signaling agent has one or more substitution mutations at amino acid positions 106- 113. In illustrative embodiments, the substitution mutations are selected from Q107E, Q107D, S106E, S106D, Q107R, Q107N, Q107E / S106E, Q107E / S106D, Q107D / S106E, and Q107D / S106D. In another embodiment, the modified signaling agent has an insertion of about 1 to about 3 amino acids at positions 106-113. In some embodiments, the modified agent is a TNF family member (e.g. TNF-alpha, TNF-beta) which can be a single chain trimeric version as described in WO 2015 / 007903. In some embodiments, the modified agent is a TNF family member (e.g. TNF-alpha, TNF-beta) which has reduced affinity and / or activity, i.e. antagonistic activity (e.g. natural antagonistic activity or antagonistic activity that is the result of one or more mutations, see, e.g., WO 2015 / 007520) at TNFR1. In these embodiments, the modified agent is a TNF family member (e.g. TNF-alpha, TNF-beta) which also, optionally, has substantially reduced or ablated affinity and / or activity for TNFR2. In some embodiments, the modified agent is a TNF family member (e.g. TNF-alpha, TNF-beta) which has reduced affinity and / or activity, i.e. antagonistic activity (e.g. natural antagonistic activity or antagonistic activity that is the result of one or more mutations, see, e.g., WO 2015 / 007520at TNFR2. In these embodiments, the modified agent is a TNF family member (e.g. TNF-alpha, TNF-beta) which also, optionally, has substantially reduced or ablated affinity and / or activity for TNFR1. The constructs of such embodiments find use in, for example, methods of dampening TNF response in a cell specific manner. In some embodiments, the antagonistic TNF family member (e.g. TNF-alpha, TNF-beta) is a single chain trimeric version as described in WO 2015 / 007903. In an embodiment, the modified signaling agent is TRAIL. In some embodiments, the modified TRAIL agent has reduced affinity and / or activity for DR4 (TRAIL-RI) and / or DR5 (TRAIL-RII) and / or DcR1 and / or DcR2. In some embodiments, the modified TRAIL agent has substantially reduced or ablated affinity and / or activity for DR4 (TRAIL-RI) and / or DR5 (TRAIL-RII) and / or DcR1 and / or DcR2. In an embodiment, the wild type TRAIL has the amino acid sequence of: TRAIL (SEQ ID NO: 342) MAMMEVQGGPSLGQTCVLIVIFTVLLQSLCVAVTYVYFTNELKQMQDKYSK SGIACFLKEDDSYWDPNDEESMNSPCWQVKWQLRQLVRKMILRTSEETIS TVQEKQQNISPLVRERGPQRVAAHITGTRGRSNTLSSPNSKNEKALGRKIN SWESSRSGHSFLSNLHLRNGELVIHEKGFYYIYSQTYFRFQEEIKENTKND KQMVQYIYKYTSYPDPILLMKSARNSCWSKDAEYGLYSIYQGGIFELKEND RIFVSVTNEHLIDMDHEASFFGAFLVG In such embodiments, the modified TRAIL agent may comprise a mutation at amino acid positions T127-R132, E144-R149, E155-H161, Y189-Y209, T214-1220,K224-A226, W231, E236-L239, E249-K251, T261-H264 and H270-E271 (Numbering based on the human sequence, Genbank accession number NP _003801, version 10 NP _003801.1, GI: 4507593; see above). In an embodiment, the modified signaling agent is TGFa. In such embodiments, the modified TGFa agent has reduced affinity and / or activity for the epidermal growth factor receptor (EGFR). In some embodiments, the modified TGFa agent has substantially reduced or ablated affinity and / or activity for the epidermal growth factor receptor (EGFR). In an embodiment, the modified signaling agent is TGFβ. In such embodiments, the modified signaling agent has reduced affinity and / or activity for TGFBR1 and / or TGFBR2. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for TGFBR1 and / or TGFBR2. In some embodiments, the modified signaling agent optionally has reduced or substantially reduced or ablated affinity and / or activity for TGFBR3 which, without wishing to be bound by theory, may act as a reservoir of ligand for TGF-beta receptors. In some embodiments, the TGFβ may favor TGFBR1 over TGFBR2 or TGFBR2 over TGFBR1. Similarly, LAP, without wishing to be bound by theory, may act as a reservoir of ligand for TGF-beta receptors. In some embodiments, the modified signaling agent has reduced affinity and / or activity for TGFBR1 and / or TGFBR2 and / or substantially reduced or ablated affinity and / or activity for Latency Associated Peptide (LAP). In some embodiments, such chimeras find use in Camurati-Engelmann disease, or other diseases associated with inappropriate TGFβ signaling. In some embodiments, the modified agent is a TGF family member (e.g. TGFα, TGFβ) which has reduced affinity and / or activity, i.e. antagonistic activity (e.g. natural antagonistic activity or antagonistic activity that is the result of one or more mutations, see, e.g., WO 2015 / 007520) at one or more of TGFBR1, TGFBR2, TGFBR3. In these embodiments, the modified agent is a TGF family member (e.g. TGFα, TGFβ) which also, optionally, has substantially reduced or ablated affinity and / or activity at one or more of TGFBR1, TGFBR2, TGFBR3. In some embodiments, the modified agent is a TGF family member (e.g. TGFα, TGFβ) which has reduced affinity and / or activity, i.e. antagonistic activity (e.g. natural antagonistic activity or antagonistic activity that is the result of one or more mutations, see, e.g., WO 2015 / 007520) at TGFBR1 and / or TGFBR2. In these embodiments, the modified agent is a TGF family member (<com:Math><semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>< / com:Math> TGF<com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>, TGF<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>) which also, optionally, has substantially reduced or ablated affinity and / or activity at TGFBR3. In an embodiment, the modified signaling agent is an interleukin. In an embodiment, the modified signaling agent is IL-1. In an embodiment, the modified signaling agent is IL-1α or IL-1β. In some embodiments, the modified signaling agent has reduced affinity and / or activity for IL-1R1 and / or IL-1RAcP. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-1R1 and / or IL-1RAcP. In some embodiments, the modified signaling agent has reduced affinity and / or activity for IL-1R2. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-1R2. For instance, in some embodiments, the present modified IL-1 agents avoid interaction at IL-1R2 and therefore substantially reduce its function as a decoy and / or sink for therapeutic agents. In an embodiment, the wild type IL-1β has the amino acid sequence of: IL-1 beta (mature form, wild type) (SEQ ID NO: 343) APVRSLNCTLRDSQQKSLVMSGPYELKALHLQGQDMEQQVVFSMSFVQG EESNDKIPVALGLKEKNLYLSCVLKDDKPTLQLESVDPKNYPKKKMEKRFV FNKIEINNKLEFESAQFPNWYISTSQAENMPVFLGGTKGGQDITDFTMQFV SS IL1 is a proinflammatory cytokine and an important immune system regulator. It is a potent activator of CD4 T cell responses, increases proportion of Th17 cells and expansion of IFNy and IL-4 producing cells. IL-1 is also a potent regulator of CD8<com:Sup>+< / com:Sup> T cells, enhancing antigen-specific CD8<com:Sup>+< / com:Sup> T cell expansion, differentiation, migration to periphery and memory. IL-1 receptors comprise IL-1R1 and IL-1R2. Binding to and signaling through the IL-1R1 constitutes the mechanism whereby IL-1 mediates many of its biological (and pathological) activities. IL1-R2 can function as a decoy receptor, thereby reducing IL-1 availability for interaction and signaling through the IL-1R1. In some embodiments, the modified IL-1 has reduced affinity and / or activity (e.g. agonistic activity) for IL-1R1. In some embodiments, the modified IL-1 has substantially reduced or ablated affinity and / or activity for IL-1R2. In such embodiments, there is restorable IL-1 / IL-1R1 signaling and prevention of loss of therapeutic chimeras at IL-R2 and therefore a reduction in dose of IL-1 that is required (e.g. relative to wild type or a chimera bearing only an attenuation mutation for IL-R1). Such constructs find use in, for example, methods of treating cancer, including, for example, stimulating the immune system to mount an anti-cancer response. In some embodiments, the modified IL-1 has reduced affinity and / or activity (e.g. antagonistic activity, e.g. natural antagonistic activity or antagonistic activity that is the result of one or more mutations, see, e.g., WO 2015 / 007520) for IL-1R1. In some embodiments, the modified IL-1 has substantially reduced or ablated affinity and / or activity for IL-1R2. In such embodiments, there is the IL-1 / IL-1R1 signaling is not restorable and prevention of loss of therapeutic chimeras at IL-R2 and therefore a reduction in dose of IL-1 that is required (e.g. relative to wild type or a chimera bearing only an attenuation mutation for IL-R1). Such constructs find use in, for example, methods of treating autoimmune diseases, including, for example, suppressing the immune system. In such embodiments, the modified signaling agent has a deletion of amino acids 52-54 which produces a modified human IL-1β with reduced binding affinity for type I IL-1R and reduced biological activity. See, for example, WO 1994 / 000491. In some embodiments, the modified human IL-1β has one or more substitution mutations selected from A117G / P118G, R120X, L122A, T125G / L126G, R127G, Q130X, Q131G, K132A, S137G / Q138Y, L145G, H146X, L145A / L147A, Q148X, Q148G / Q150G, Q150G / D151A, M152G, F162A, F162A / Q164E, F166A, Q164E / E167K, N169G / D170G, I172A, V174A, K208E, K209X, K209A / K210A, K219X, E221X, E221 S / N224A, N224S / K225S, E244K, N245Q (where X can be any change in amino acid, e.g., a non- conservative change), which exhibit reduced binding to IL-1R, as described, for example, in WO2015 / 007542 and WO / 2015 / 007536, (numbering base on the human IL-1 β sequence, Genbank accession number NP_000567, version NP-000567.1, GI: 10835145). In some embodiments, the modified human IL-1β may have one or more mutations selected from R120A, R120G, Q130A, Q130W, H146A, H146G, H146E, H146N, H146R, Q148E, Q148G, Q148L, K209A, K209D, K219S, K219Q, E221S and E221K. In an embodiment, the modified human IL-1β comprises the mutations Q131G and Q148G. In an embodiment, the modified human IL-1β comprises the mutations Q148G and K208E. In an embodiment, the modified human IL-1β comprises the mutations R120G and Q131G. In an embodiment, the modified human IL-1β comprises the mutations R120G and H146A. In an embodiment, the modified human IL-1β comprises the mutations R120G and H146N. In an embodiment, the modified human IL-1β comprises the mutations R120G and H146R. In an embodiment, the modified human IL-1β comprises the mutations R120G and H146E. In an embodiment, the modified human IL-1β comprises the mutations R120G and H146G. In an embodiment, the modified human IL-1ß comprises the mutations R120G and K208E. In an embodiment, the modified human IL-1β comprises the mutations R120G, F162A, and Q164E. In an embodiment, the modified signaling agent is IL-2. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for IL-2Rα and / or IL-2Rβ and / or IL-2Rγ. In some embodiments, the modified signaling agent has reduced affinity and / or activity for IL-2Rβ and / or IL-2Rγ. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-2Ra. Such embodiments may be relevant for treatment of cancer, for instance when the modified IL-2 is agonistic at IL-2Rβ and / or IL-2Rγ. For instance, the present constructs may favor attenuated activation of CD8<com:Sup>+< / com:Sup> T cells (which can provide an anti-tumor effect), which have IL2 receptors β and γ and disfavor T<com:Sub>regs< / com:Sub> (which can provide an immune suppressive, pro- tumor effect), which have IL2 receptors <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>. Further, in some embodiments, the preferences for IL-2R<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> and / or IL-2Ry over IL-2Ra avoid IL-2 side effects such as pulmonary edema. Also, IL-2-based chimeras are useful for the treatment of autoimmune diseases, for instance when the modified IL-2 is antagonistic (e.g. natural antagonistic activity or antagonistic activity that is the result of one or more mutations, see, e.g., WO 2015 / 007520) at IL-2Rβ and / or IL-2Rγ. For instance, the present constructs may favor attenuated suppression of CD8<com:Sup>+< / com:Sup> T cells (and therefore dampen the immune response), which have IL2 receptors β and γ and disfavor T<com:Sub>regs< / com:Sub> which have IL2 receptors α, β, and γ. Alternatively, in some embodiments, the chimeras bearing IL-2 favor the activation of T<com:Sub>regs< / com:Sub>, and therefore immune suppression, and activation of disfavor of CD8<com:Sup>+< / com:Sup> T cells. For instance, these constructs find use in the treatment of diseases or diseases that would benefit from immune suppression, e.g. autoimmune disorders. In some embodiments, the chimeric protein has targeting moieties as described herein directed to CD8<com:Sup>+< / com:Sup> T cells as well as a modified IL-2 agent having reduced affinity and / or activity for IL-2Rβ and / or IL-2Rγ and / or substantially reduced or ablated affinity and / or activity for IL-2Ra. In some embodiments, these constructs provide targeted CD8+ T cell activity and are generally inactive (or have substantially reduced activity) towards T<com:Sub>reg< / com:Sub> cells. In some embodiments, such constructs have enhanced immune stimulatory effect compared to wild type IL-2 (e.g., without wishing to be bound by theory, by not stimulating Tregs), whilst eliminating or reducing the systemic toxicity associated with IL-2. In an embodiment, the wild type IL-2 has the amino acid sequence of: IL-2 (mature form, wild type) (SEQ ID NO: 344) APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATE LKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMC EYADETATIVEFLNRWITFCQSIISTLT In such embodiments, the modified IL-2 agent has one or more mutations at amino acids L72 (L72G, L72A, L72S, L72T, L72Q, L72E, L72N, L72D, L72R, or L72K), F42 (F42A, F42G, F42S, F42T, F42Q, F42E, F42N, F42D, F42R, or F42K) and Y45 (Y45A, Y45G, Y45S, Y45T, Y45Q, Y45E, Y45N, Y45D, Y45R or Y45K). Without wishing to be bound by theory, it is believed that these modified IL-2 agents have reduced affinity for the high- affinity IL-2 receptor and preserves affinity to the intermediate-affinity IL-2 receptor, as compared to the wild-type IL-2. See, for example, US Patent Publication No. 2012 / 0244112. In an embodiment, the modified signaling agent is IL-3. In some embodiments, the modified signaling agent has reduced affinity and / or activity for the IL-3 receptor, which is a heterodimer with a unique alpha chain paired with the common beta (beta c or CD131) subunit. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for the IL-3 receptor, which is a heterodimer with a unique alpha chain paired with the common beta (beta c or CD131) subunit. In an embodiment, the modified signaling agent is IL-4. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for type 1 and / or type 2 IL-4 receptors. In such an embodiment, the modified signaling agent has substantially reduced or ablated affinity and / or activity for type 1 and / or type 2 IL-4 receptors. Type 1 IL-4 receptors are composed of the IL-4Rα subunit with a common γ chain and specifically bind IL-4. Type 2 IL-4 receptors include an IL-4Ra subunit bound to a different subunit known as IL-13Ra1. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity the type 2 IL-4 receptors. In an embodiment, the wild type IL-4 has the amino acid sequence of: IL-4 (mature form, wild type) (SEQ ID NO: 345) HKCDITLQEIIKTLNSLTEQKTLCTELTVTDIFAASKNTTEKETFCRAATVLRQ FYSHHEKDTRCLGATAQQFHRHKQLIRFLKRLDRNLWGLAGLNSCPVKEA NQSTLENFLERLKTIMREKYSKCSS In such embodiments, the modified IL-4 agent has one or more mutations at amino acids R121 (R121A, R121D, R121E, R121F, R121H, R121I, R121K, R121N, R121P, R121T, R121W), E122 (E122F), Y124 (Y124A, Y124Q, Y124R, Y124S, Y124T) and S125 (S125A). Without wishing to be bound by theory, it is believed that these modified IL-4 agents maintain the activity mediated by the type I receptor, but significantly reduces the biological activity mediated by the other receptors. See, for example, US Patent No. 6,433,157. In an embodiment, the modified signaling agent is IL-6. IL-6 signals through a cell-surface type I cytokine receptor complex including the ligand-binding IL-6R chain (CD126), and the signal-transducing component gp130. IL-6 may also bind to a soluble form of IL-6R (slL-6R), which is the extracellular portion of IL-6R. The slL- 6R / IL-6 complex may be involved in neurites outgrowth and survival of neurons and, hence, may be important in nerve regeneration through remyelination. Accordingly, in some embodiments, the modified signaling agent has reduced affinity and / or activity for IL-6R / gp130 and / or sIL-6R. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-6R / gp130 and / or sIL-6R. In an embodiment, the wild type IL-6 has the amino acid sequence of IL-6 (mature form, wild type) (SEQ ID NO: 346): APVPPGEDSKDVAAPHRQPLTSSERIDKQIRYILDGISALRKETCNKSNMCE SSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLLEFEVYLEYLQN RFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLTTKLQAQN QWLQDMTTHLILRSFKEFLQSSLRALRQM In such embodiments, the modified signaling agent has one or more mutations at amino acids 58, 160, 163, 171 or 177. Without wishing to be bound by theory, it is believed that these modified IL-6 agents exhibit reduced binding affinity to IL-6Ralpha and reduced biological activity. See, for example, WO 97 / 10338. In an embodiment, the modified signaling agent is IL-10. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for IL-10 receptor-1 and IL-10 receptor-2. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-10 receptor-1 and IL-10 receptor-2 In an embodiment, the modified signaling agent is IL-11. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for IL-11Rα and / or IL-11Rβ and / or gp130. In such an embodiment, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-11Rα and / or IL-11Rβ and / or gp130. In an embodiment, the modified signaling agent is IL-12. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for IL-12Rβ1 and / or IL-12Rβ2. In such an embodiment, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-12Rβ1 and / or IL-12Rβ2. In an embodiment, the modified signaling agent is IL-13. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for the IL-4 receptor (IL-4Ra) and IL-13Ra1. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-4 receptor (IL-4Ra) or IL-13Rα1. In an embodiment, the wild type IL-13 has the amino acid sequence of IL-13 (mature form, wild type) (SEQ ID NO: 347): SPGPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALES LINVSGCSAIEKTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLH LKKLFREGRFN In such embodiments, the modified IL-13 agent has one or more mutations at amino acids 13, 16, 17, 66, 69, 99, 102, 104, 105, 106, 107, 108, 109, 112, 113 and 114. Without wishing to be bound by theory, it is believed that these modified IL-13 agents exhibit reduced biological activity. See, for example, WO 2002 / 018422. In an embodiment, the modified signaling agent is IL-18. In some embodiments, the modified signaling agent has reduced affinity and / or activity for IL-18Rα and / or IL-18Rβ. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-18Rα and / or IL-18Rβ. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for IL-18Ra type II, which is an isoform of IL-18Ra that lacks the TIR domain required for signaling. In an embodiment, the wild type IL-18 has the amino acid sequence of IL-18 (wild type) (SEQ ID NO: 348): MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRNLN DQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKC EKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYE GYFLACEKERDLFKLILKKEDELGDRSIMFTVQNEDL In such embodiments, the modified IL-18 agent may comprise one or more mutations in amino acids or amino acid regions selected from Y37-K44, R49-Q54, D59-R63, E67-C74, R80, M87-A97, N 127-K129, Q139-M149, K165-K171, R183 and Q190-N191, as described in WO / 2015 / 007542, (numbering based on the human IL-18 sequence, Genbank accession number AAV38697, version AAV38697.1, GI: 54696650). In an embodiment, the modified signaling agent is IL-33. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for the ST-2 receptor and IL-1RAcP. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for the ST-2 receptor and IL-1RAcP. In an embodiment, the wild type IL-33 has the amino acid sequence of: MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCPMYFMKLRSG LMIKKEACYFRRETTKRPSLKTGRKHKRHLVLAACQQQSTVECFAFGISGV QKYTRALHDSSITGISPITEYLASLSTYNDQSITFALEDESYEIYVEDLKKDEK KDKVLLSYYESQHPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHSVE LHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKDNHLALIKVDSS ENLCTENILFKLSET (SEQ ID NO: 349) In such embodiments, the modified IL-33 agent may comprise one or more mutations in amino acids or amino acid regions selected from I113-Y122, S127-E139, E144-D157, Y163-M183, E200, Q215, L220-C227 and T260- E269, as described in WO / 2015 / 007542, (numbering based on the human sequence, Genbank accession number NP_254274, version NP_254274.1, GI:15559209). In an embodiment, the modified signaling agent is epidermal growth factor (EGF). EGF is a member of a family of potent growth factors. Members include EGF, HB-EGF, and others such as TGFalpha, amphiregulin, neuregulins, epiregulin, betacellulin. EGF family receptors include EGFR (ErbB1), ErbB2, ErbB3 and ErbB4. These may function as homodimeric and / or heterodimeric receptor subtypes. The different EGF family members exhibit differential selectivity for the various receptor subtypes. For example, EGF associates with ErbB1 / ErbB1, ErbB1 / ErbB2, ErbB4 / ErbB2 and some other heterodimeric subtypes. HB-EGF has a similar pattern, although it also associates with ErbB4 / 4. Modulation of EGF (EGF-like) growth factor signaling, positively or negatively, is of considerable therapeutic interest. For example, inhibition of EGFRs signaling is of interest in the treatment of various cancers where EGFR signaling constitutes a major growth promoting signal. Alternatively, stimulation of EGFRs signaling is of therapeutic interest in, for example, promoting wound healing (acute and chronic), oral mucositis (a major side-effect of various cancer therapies, including, without limitation radiation therapy). In some embodiments, the modified signaling agent has reduced affinity and / or activity for ErbB1, ErbB2, ErbB3, and / or ErbB4. Such embodiments find use, for example, in methods of treating wounds. In some embodiments, the modified signaling agent binds to one or more ErbB1, ErbB2, ErbB3, and ErbB4 and antagonizes the activity of the receptor. In such embodiments, the modified signaling agent has reduced affinity and / or activity for ErbB1, ErbB2, ErbB3, and / or ErbB4 which allows for the activity of the receptor to be antagonized in an attenuated fashion. Such embodiments find use in, for example, treatments of cancer. In an embodiment, the modified signaling agent has reduced affinity and / or activity for ErbB1. ErbB1 is the therapeutic target of kinase inhibitors - most have side effects because they are not very selective (e.g., gefitinib, erlotinib, afatinib, brigatinib and icotinib). In some embodiments, attenuated antagonistic ErbB1 signaling is more on-target and has less side effects than other agents targeting receptors for EGF. In some embodiments, the modified signaling agent has reduced affinity and / or activity (e.g. antagonistic e.g. natural antagonistic activity or antagonistic activity that is the result of one or more mutations, see, e.g., WO 2015 / 007520) for ErbB1 and / or substantially reduced or ablated affinity and / or activity for ErbB4 or other subtypes it may interact with. Through specific targeting via the targeting moiety, cell-selective suppression (antagonism e.g. natural antagonistic activity or antagonistic activity that is the result of one or more mutations, see, e.g., WO 2015 / 007520) of ErbB1 / ErbB1 receptor activation would be achieved – while not engaging other receptor subtypes potentially associated with inhibition-associated side effects. Hence, in contrast to EGFR kinase inhibitors, which inhibit EGFR activity in all cell types in the body, such a construct would provide a cell- selective (e.g., tumor cell with activated EGFR signaling due to amplification of receptor, overexpression etc.) anti-EGFR (ErbB1) drug effect with reduced side effects. In some embodiments, the modified signaling agent has reduced affinity and / or activity (e.g. agonistic) for ErbB4 and / or other subtypes it may interact with. Through targeting to specific target cells through the targeting moiety, a selective activation of ErbB1 signaling is achieved (e.g. epithelial cells). Such a construct finds use, in some embodiments, in the treatment of wounds (promoting would healing) with reduced side effects, especially for treatment of chronic conditions and application other than topical application of a therapeutic (e.g. systemic wound healing). In an embodiment, the modified signaling agent is insulin or insulin analogs. In some embodiments, the modified insulin or insulin analog has reduced affinity and / or activity for the insulin receptor and / or IGF1 or IGF2 receptor. In some embodiments, the modified insulin or insulin analog has substantially reduced or ablated affinity and / or activity for the insulin receptor and / or IGF1 or IGF2 receptor. Attenuated response at the insulin receptor allows for the control of diabetes, obesity, metabolic disorders and the like while directing away from IGF1 or IGF2 receptor avoids pro-cancer effects. In an embodiment, the modified signaling agent is insulin-like growth factor-I or insulin-like growth factor-II (IGF-1 or IGF-2). In an embodiment, the modified signaling agent is IGF-1. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for the insulin receptor and / or IGF1 receptor. In an embodiment, the modified signaling agent may bind to the IGF1 receptor and antagonize the activity of the receptor. In such an embodiment, the modified signaling agent has reduced affinity and / or activity for IGF1 receptor which allows for the activity of the receptor to be antagonized in an attenuated fashion. In some embodiments, the modified signaling agent has substantially reduced or ablated affinity and / or activity for the insulin receptor and / or IGF1 receptor. In some embodiments, the modified signaling agent has reduced affinity and / or activity for IGF2 receptor which allows for the activity of the receptor to be antagonized in an attenuated fashion. In an embodiment, the modified signaling agent has substantially reduced or ablated affinity and / or activity for the insulin receptor and accordingly does not interfere with insulin signaling. In various embodiments, this applies to cancer treatment. In various embodiments, the present agents may prevent IR isoform A from causing resistance to cancer treatments. In an embodiment, the modified signaling agent is EPO. In various embodiments, the modified EPO agent has reduced affinity and / or activity for the EPO receptor (EPOR) receptor and / or the ephrin receptor (EphR) relative to wild type EPO or other EPO based agents described herein. In some embodiments, the modified EPO agent has substantially reduced or ablated affinity and / or activity for the EPO receptor (EPOR) receptor and / or the Eph receptor (EphR). Illustrative EPO receptors include, but are not limited to, an EPOR homodimer or an EPOR / CD131 heterodimer. Also included as an EPO receptor is beta-common receptor (βcR). Illustrative Eph receptors include, but are not limited to, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, and EPHB6. In some embodiments, the modified EPO protein comprises one or more mutations that cause the EPO protein to have reduced affinity for receptors that comprise one or more different EPO receptors or Eph receptors (e.g. heterodimer, heterotrimers, etc., including by way of non-limitation: EPOR-EPHB4, EPOR- βcR-EPOR). Also provided are the receptors of EP Patent Publication No. 2492355, including by way of non-limitation, NEPORs. In an embodiment, the human EPO has the amino acid sequence of (the signal peptide is underlined): [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, ...

Claims

1. A chimeric protein comprising: (a) a modified signaling agent, wherein the modified signaling agent is a mutant human interferon alpha 2 (IFNα2) comprising an amino acid sequence having at least 95% identity to the full-length of SEQ ID NO: 336 and having one or more mutations at positions 144- 154; (b) a first targeting moiety comprising a recognition domain that comprises a VHH or scFv that specifically binds to a first antigen or receptor of interest; and (c) a second targeting moiety comprising a recognition domain that comprises a VHH or scFv that specifically binds to a second antigen or receptor of interest; wherein the mutant human IFNα2 has a reduced affinity or activity for its receptor relative to the wild type human IFNα2; wherein the reduced affinity or activity of the mutant human IFN α \alpha 2 for its receptor is restorable by one or more of the targeting moieties; and wherein the first targeting moiety is attached to the second targeting moiety and the second targeting moiety is attached to the modified signaling agent.

2. The chimeric protein of claim 1, wherein the first or second targeting moiety is directed against a tumor cell.

3. The chimeric protein of claim 1, wherein the first or second targeting moiety is directed against an immune cell.

4. The chimeric protein of claim 3, wherein the immune cell is selected from a T cell, a B cell, a dendritic cell, a macrophage, a neutrophil, and a NK cell.

5. The chimeric protein of any one of claims 1-4, wherein (i) the first targeting moiety is directed against an immune cell selected from a T cell, a B cell, a dendritic cell, a neutrophil, a macrophage, and a NK cell, and (ii) the second targeting moiety is directed against a tumor cell.

6. The chimeric protein of claim 1, wherein the recognition domain functionally modulates the antigen or receptor of interest.

7. The chimeric protein of claim 1, wherein the recognition domain binds but does not functionally modulate the antigen or receptor of interest.

8. The chimeric protein of claim 1, wherein the first antigen or receptor of interest is Clec9A and the second antigen or receptor of interest is CD20.

9. The chimeric protein of claim 1, wherein the first antigen or receptor of interest is CD20 and the second antigen or receptor of interest is CD3.

10. The chimeric protein of any one of claims 1-9, wherein the chimeric protein has a molecular mass of about 50 KDa or higher.

11. The chimeric protein of any one of claims 1-10, wherein the chimeric protein substantially evades filtration by the kidney.

12. The chimeric protein of claim 1, wherein the mutant IFNα2 has one or more mutations at positions L153, R149, and M148.

13. The chimeric protein of claim 12, wherein the mutation is R149A.

14. The chimeric protein of claim 12, wherein the mutation is M148A.

15. The chimeric protein of claim 12, wherein the mutation is L153A.

16. A recombinant nucleic acid encoding the chimeric protein of any one of claims 1-15.

17. A host cell comprising the nucleic acid of claim 16.