Long-lived brain delivery of Anti-inflammatory agents

Abstract

Provided herein are systems, compositions, and methods for delivering cytokines and other desired molecules to the brain using a three-component system: 1) a targeting component that binds to a brain-specific molecule (e.g., brain-specific protein); 2) a targeting component that facilitates shuttling of the system across the blood-brain barrier; and 3) an anti-inflammatory and / or immunosuppressive molecule (e.g., cytokine).

Description

[0001]UM-42351.601 LONG-LIVED BRAIN DELIVERY OF ANTI- INFLAMMATORY AGENTS The present application claims priority to United States Provisional Patent Application Serial Number 63 / 580,203, filed September 1, 2023, the disclosure of which is herein incorporated by reference in its entirety. SEQUENCE LISTING The text of the computer readable sequence listing filed herewith, titled “42351- 601_SEQUENCE_LISTING”, created August 29, 2024, having a file size of 33,671 bytes, is hereby incorporated by reference in its entirety. FIELD Provided herein are systems, compositions, and methods for delivering cytokines and other desired molecules to the brain using a three-component system: 1) a targeting component that binds to a brain-specific molecule (e.g., brain-specific protein); 2) a targeting component that facilitates shuttling of the system across the blood-brain barrier; and 3) an anti-inflammatory and / or immunosuppressive molecule (e.g., cytokine). BACKGROUND The blood-brain barrier (BBB) poses a major challenge for developing effective antibody-based therapy for neurological disorders. The blood brain barrier typically allows for small lipophilic molecules, ions, and water to pass through their concentration gradients, whereas nutrients such as amino acids and glucose pass through the blood brain barrier via transporters. However, larger molecules such as antibodies are typically unable to cross the blood brain barrier to accumulate in sufficient amounts within the brain to be effective therapeutics or delivery systems for therapeutics. SUMMARY Provided herein are systems, compositions, and methods for delivering cytokines and other desired molecules to the brain using a three-component system: 1) a targeting component that binds to a brain-specific molecule (e.g., brain-specific protein); 2) a targeting component that facilitates shuttling of the system across the blood-brain barrier; and 3) an anti-inflammatory and / or immunosuppressive molecule (e.g., cytokine). UM-42351.601 In some embodiments, provided herein are systems, compositions, and methods comprising: a) a first component that binds to a brain-specific molecule; b) a second component that binds to a blood-brain barrier protein; and c) an anti-inflammatory and / or immunosuppressive molecule. In some embodiments, the brain-specific molecule is a brain-specific protein. In some embodiments, the brain-specific protein is myelin oligodendrocyte glycoprotein (MOG), neuronal membrane glycoprotein M6a (M6a), Tropomyosin receptor kinase B (TrkB), astrocyte surface antigen M2 (M2), or tau. In some embodiments, the brain specific protein is express on or in a brain cell. In some embodiments, the brain is a neuron or a glial cell (e.g., macroglia or microglia; e.g., an astrocyte, oligodendrocyte, ependymal cell, or scavenger cell). In some embodiments, the first component is an antibody (e.g., IgG). In some embodiments, the first component is an antibody fragment. In some embodiments, the first component is included within a bispecific antibody. In some embodiments, the second component binds to CD98hc. In some embodiments, the second component is an antibody. In some embodiments, the second component is an antibody fragment. In some embodiments, the anti-inflammatory and / or immunosuppressive molecule is a cytokine. In some embodiments, the cytokine is one or more of IL-10, IL-6, TGF-β, IL-27, IL-35, IL-4, or IL-13. In some embodiments, the cytokine is IL-10. In some embodiments, the cytokine is a wild-type cytokine. In some embodiments, the cytokine is a variant (e.g., mutant) cytokine. The anti-inflammatory and / or immunosuppressive molecule may be conjugated to any region of the first or second components. For example, the molecule may be conjugated to a light chain and / or heavy chain of either the first or second component. In some embodiments, a composition comprises one or more or all of CDR sequences SEQ ID NO:1-12, or functional or structural variants thereof. In some embodiments, the composition comprises SEQ ID NOs:1-3 and / or 4-6 and / or 7-9 and / or 10-12. In some embodiments, the composition comprises SEQ ID NO:27 or 28. In some embodiments, the composition comprises one or more of sequences SEQ ID NO:13-26, or functional or structural variants thereof. Such sequences may be provided without or without purification tags (e.g., hex-HIS tags). For example, in some embodiments the composition comprises SEQ ID Nos:13-16 or 17-21 or 22-24 or 25-26. UM-42351.601 Provided herein are uses of the any of the compositions and systems described herein. Uses include research, drug screening, diagnostic, and therapeutic uses. For example, in some embodiments, provided herein is a method comprising delivering a composition comprising a) a first component that binds to a brain-specific molecule; b) a second component that binds to a blood-brain barrier protein; and c) an anti-inflammatory and / or immunosuppressive molecule, to a subject. In some embodiments, the composition is administered intravenously. In some embodiments, the composition accumulates in the central nervous system of the subject following delivery. In some embodiments, the subject has or is at risk of having a neurological disorder. Neurological disorders include, but are not limited to, multiple sclerosis, autoimmune neuromuscular diseases (e.g., Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, inflammatory myopathies), epilepsy, Alzheimer's disease, Parkinson's disease, Huntington' disease, amyotrophic lateral sclerosis, stroke, infections, adverse drug reactions, and traumatic brain injuries. In some embodiments, the systems and compositions described herein are co- administered with other agents, including immunosuppressive agents. For example, in some embodiments, the systems and compositions are co-administered with corticosteroids, intravenous immunoglobulin, cyclophosphamide and / or rituximab. Definitions The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. As used herein, comprising a certain sequence or a certain SEQ ID NO usually implies that at least one copy of said sequence is present in recited peptide or polynucleotide. However, two or more copies are also contemplated. The singular forms “a,” “and,” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. UM-42351.601 “Antibody” and “antibodies” as used herein refers to monoclonal antibodies, monospecific antibodies (e.g., which can either be monoclonal, or may also be produced by other means than producing them from a common germ cell), multi-specific antibodies, human antibodies, humanized antibodies (fully or partially humanized), animal antibodies such as, but not limited to, a bird (for example, a duck or a goose), a shark, a whale, and a mammal, including a non-primate (for example, a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, etc.) or a non- human primate (for example, a monkey, a chimpanzee, etc.), recombinant antibodies, chimeric antibodies, single-chain Fvs (“scFv”), single chain antibodies, single domain antibodies, Fab fragments, F(ab’) fragments, F(ab’)2fragments, disulfide-linked Fvs (“sdFv”), and anti-idiotypic (“anti-Id”) antibodies, dual-domain antibodies, dual variable domain (DVD) or triple variable domain (TVD) antibodies (dual-variable domain immunoglobulins and methods for making them are described in Wu, C., et al., Nature Biotechnology, 25(11):1290-1297 (2007) and PCT International Application WO 2001 / 058956, the contents of each of which are herein incorporated by reference), or domain antibodies (dAbs) (e.g., such as described in Holt et al., Trends in Biotechnology 21:484-490 (2014)), and including single domain antibodies sdAbs that are naturally occurring, e.g., as in cartilaginous fishes and camelid, or which are synthetic, e.g., nanobodies, VHH, or other domain structure), and functionally active epitope-binding fragments of any of the above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, namely, molecules that contain an analyte-binding site. Immunoglobulin molecules can be of any type (for example, IgG, IgE, IgM, IgD, IgA, and IgY), class (for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. For simplicity sake, an antibody against an analyte is frequently referred to herein as being either an “anti-analyte antibody” or merely an “analyte antibody”. “Antibody fragment” as used herein refers to a portion of an intact antibody that retain the ability to specifically bind to an antigen (see, generally, Holliger et al., Nat. Biotech., 23(9): 1126-1129 (2005)) (e.g., comprises the antigen-binding site or variable region). Any antigen-binding fragment of the antibody described herein is within the scope of the present disclosure. The antibody may not include the constant heavy chain domains (e.g., CH2, CH3, or CH4, depending on the antibody isotype) of the Fc region of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab fragments, Fab’ fragments, Fab’- SH fragments, F(ab’)2fragments, Fd fragments, Fv fragments, diabodies, single-chain Fv UM-42351.601 (scFv) molecules, single-chain polypeptides containing only one light chain variable domain, single-chain polypeptides containing the three CDRs of the light-chain variable domain, single-chain polypeptides containing only one heavy chain variable region, and single-chain polypeptides containing the three CDRs of the heavy chain variable region. Typically, an immunoglobulin or antibody is a protein that comprises at least one complementarity determining region (CDR). The CDRs form the “hypervariable region” of an antibody, which is responsible for antigen binding (discussed further below). A whole antibody typically consists of four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains contains one N-terminal variable (VH) region and three C-terminal constant (CH1, CH2, and CH3) regions, and each light chain contains one N-terminal variable (VL) region and one C-terminal constant (CL) region. The light chains of antibodies can be assigned to one of two distinct types, either kappa (κ) or lambda (λ), based upon the amino acid sequences of their constant domains. In a typical antibody, each light chain is linked to a heavy chain by disulfide bonds, and the two heavy chains are linked to each other by disulfide bonds. The light chain variable region is aligned with the variable region of the heavy chain, and the light chain constant region is aligned with the first constant region of the heavy chain. The remaining constant regions of the heavy chains are aligned with each other. The variable regions of each pair of light and heavy chains form the antigen binding site of an antibody. The VHand VLregions have the same general structure, with each region comprising four framework (FW or FR) regions. The term “framework region,” as used herein, refers to the relatively conserved amino acid sequences within the variable region which are located between the CDRs. There are four framework regions in each variable domain, which are designated FR1, FR2, FR3, and FR4. The framework regions form the β sheets that provide the structural framework of the variable region (see, e.g., C. A. Janeway et al. (eds.), Immunobiology, 5th Ed., Garland Publishing, New York, N.Y. (2001)). “CDR” is used herein to refer to the “complementarity determining region” within an antibody variable sequence. There are three CDRs in each of the variable regions of the heavy chain and the light chain. Proceeding from the N-terminus of a heavy or light chain, these regions are denoted “CDR1,” “CDR2,” and “CDR3,” for each of the variable regions. The term “CDR set” as used herein refers to a group of three CDRs that occur in a single variable region that binds the antigen. An antigen-binding site, therefore, may include six UM-42351.601 CDRs, comprising the CDR set from each of a heavy and a light chain variable region. A polypeptide comprising a single CDR, (e.g., a CDR1, CDR2, or CDR3) may be referred to as a “molecular recognition unit.” Crystallographic analyses of antigen-antibody complexes have demonstrated that the amino acid residues of CDRs form extensive contact with bound antigen, wherein the most extensive antigen contact is with the heavy chain CDR3. Thus, the molecular recognition units may be primarily responsible for the specificity of an antigen- binding site. In general, the CDR residues are directly and most substantially involved in influencing antigen binding. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as “Kabat CDRs”. Chothia and coworkers (Chothia and Lesk, J. Mol. Biol., 196: 901-917 (1987); and Chothia et al., Nature, 342: 877-883 (1989)) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub- portions were designated as “L1,” “L2,” and “L3,” or “H1,” “H2,” and “H3,” where the “L” and the “H” designate the light chain and the heavy chain regions, respectively. These regions may be referred to as “Chothia CDRs,” which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan, FASEB J., 9: 133-139 (1995), and MacCallum, J. Mol. Biol., 262(5): 732-745 (1996). Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain aspects use Kabat- or Chothia-defined CDRs. As used herein, when an antibody or other entity (e.g., antigen binding domain) “specifically recognizes” or “specifically binds” an antigen or epitope, it preferentially recognizes the antigen in a complex mixture of proteins and / or macromolecules, and binds the antigen or epitope with affinity which is substantially higher than to other entities not displaying the antigen or epitope. In this regard, “affinity which is substantially higher” UM-42351.601 means affinity that is high enough to enable detection of an antigen or epitope which is distinguished from entities using a desired assay or measurement apparatus. Typically, it means binding affinity having a binding constant (Ka) of at least 107M-1(e.g., >107M-1, >108M-1, >109M-1, >1010M-1, >1011M-1, >1012M-1, >1013M-1, etc.). In certain such embodiments, an antibody is capable of binding different antigens so long as the different antigens comprise that particular epitope. In certain instances, for example, homologous proteins from different species may comprise the same epitope. “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following. The term “monoclonal antibody,” as used herein, refers to an antibody produced by a single clone of B lymphocytes that is directed against a single epitope on an antigen. Monoclonal antibodies typically are produced using hybridoma technology, as first described in Köhler and Milstein, Eur. J. Immunol., 5: 511-519 (1976). Monoclonal antibodies may also be produced using recombinant DNA methods (see, e.g., U.S. Patent 4,816,567), isolated from phage display antibody libraries (see, e.g., Clackson et al. Nature, 352: 624-628 (1991)); and Marks et al., J. Mol. Biol., 222: 581-597 (1991)), or produced from transgenic mice carrying a fully human immunoglobulin system (see, e.g., Lonberg, Nat. Biotechnol., 23(9): 1117-25 (2005), and Lonberg, Handb. Exp. Pharmacol., 181: 69-97 (2008)). In contrast, “polyclonal” antibodies are antibodies that are secreted by different B cell lineages within an animal. Polyclonal antibodies are a collection of immunoglobulin molecules that recognize multiple epitopes on the same antigen. The term “monospecific” antibody as used herein denotes an antibody that has one or more binding sites each of which bind to the same epitope of the same antigen. The term “bispecific” antibody as used herein denotes an antibody that has at least two binding sites each of which bind to different epitopes of the same antigen or a different antigen. UM-42351.601 The term “multispecific” antibody as used herein denotes an antibody that has binding specificities for at least two different sites. The term “valent” as used within the current application denotes the presence of a specified number of binding sites in an antibody molecule. As such, the terms “bivalent,” “tetravalent,” and “hexavalent” denote the presence of two binding sites, four binding sites, and six binding sites, respectively, in an antibody molecule. The bispecific antibodies according to the invention are at least “bivalent” and may be “trivalent” or “multivalent” (e.g., “tetravalent” or “hexavalent”). That is, the antibodies may be bispecific even in cases where there are more than two binding sites (e.g., that the antibody is trivalent or multivalent). The terms “immunogen” and “antigen” are used interchangeably herein and refer to any molecule, compound, or substance that induces an immune response in an animal (e.g., a mammal). An “immune response” can entail, for example, antibody production and / or the activation of immune effector cells. An antigen in the context of the disclosure can comprise any subunit, fragment, or epitope of any proteinaceous or non-proteinaceous (e.g., carbohydrate or lipid) molecule that provokes an immune response in a mammal. By “epitope” is meant a sequence of an antigen that is recognized by an antibody or an antigen receptor. Epitopes also are referred to in the art as “antigenic determinants.” In certain embodiments, an epitope is a region of an antigen that is specifically bound by an antibody. In certain embodiments, an epitope may include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups. In certain embodiments, an epitope may have specific three-dimensional structural characteristics (e.g., a “conformational” epitope) and / or specific charge characteristics. The antigen can be a protein or peptide of viral, bacterial, parasitic, fungal, protozoan, prion, cellular, or extracellular origin, which provokes an immune response in a mammal, preferably leading to protective immunity. A “peptide” or “polypeptide” is a linked sequence of two or more amino acids linked by peptide bonds. Peptides and polypeptides include proteins such as binding proteins, receptors, and antibodies. The terms “polypeptide” and “protein” are used interchangeably herein. As used herein, the terms “providing,” “administering,” and “introducing” are used interchangeably herein and refer to the placement of the nanocomplexes and / or compositions UM-42351.601 of the present disclosure into a subject by a method or route which results in at least partial localization to a desired site. A “subject” or “patient” may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non- human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment, the mammal is a human. As used herein, “treat,” “treating,” and the like means a slowing, stopping, or reversing of progression of a disease or disorder when provided a peptide or composition described herein to an appropriate subject. The term also includes a reversing of the progression of such a disease or disorder to a point of eliminating or greatly reducing the disease. As such, “treating” means an application or administration of the peptides or compositions described herein to a subject, where the subject has a disease or a symptom of a disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or symptoms of the disease. Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. UM-42351.601 Description of Figures FIG.1 shows a schematic of an exemplary system with shuttling across the blood- brain barrier and delivery of IL-10 to the brain and spinal cord. FIG.2 shows exemplary antibody formats in embodiments of the technology. FIG.3 shows SDS PAGE characterization of exemplary antibodies. FIG.4 shows analytical SEC characterization of exemplary antibodies. FIG.5 shows a graph of IL-10 in vitro activity assay data for several exemplary systems and control molecules. FIG.6 shows in vivo brain staining images of animals treated with experimental and control systems. FIG.7 shows pharmacokinetics data (tracer does, 1 h (wild-type mice)) for several organs exposed to different embodiments of the technology (pT2 / Cp1 = control IgG / CD98hc antibody). FIG.8 shows pharmacokinetics data (tracer does, 1 h (wild-type mic) for brains exposed to different embodiments of the technology (pT2 / Cp1 = control IgG / CD98hc antibody). DETAILED DESCRIPTION In some embodiments, provided herein are systems, compositions, and methods comprising: a) a first component that binds to a brain-specific molecule; b) a second component that binds to a blood-brain barrier protein; and c) an anti-inflammatory and / or immunosuppressive molecule. The first and second components may comprise one or more antibodies or antibody fragments. In some embodiments, the antibodies or antibody fragments are conjugated to one another. In some embodiments, they are synthesized into a bispecific antibody. FIG.2 shows a number of different exemplary configurations where an MOG IgG is provided as the first component and Cp1 (anti-CD98hc) is provided as the second components, either tethered to the MOG IgG or combined as a bispecific antibody. In UM-42351.601 these examples, either wild-type or mutant IL-10 is conjugated to one or more regions of the MOG IgG. In some embodiments, provided herein are compositions comprising at least one antigen-binding site directed against CD98 heavy chain (CD98hc). CD98hc (also referred to as SLC3A2) is a multifunctional cell surface, transmembrane protein. CD98hc associates with one of several L-type amino acid transporters (LATs) to form heterodimeric amino acid transporter (HAT) complexes. LATs have multiple membrane-spanning domains and are believed to provide the transport activity of HAT complexes, whereas CD98hc regulates the functional cell surface localization of LATs. CD98hc also associates with integrin β1 and modulates the function of integrin β1 to promote cell adhesion and migration. CD98hc has also emerged as a driver of blood-brain barrier permeability, with antibodies directed against CD98hc shown to be significantly enriched in the brain after administration in vivo (Neuron 2016 Jan 6;89(1):70-82 doi: 10.1016 / j.neuron.2015.11.024. Epub 2015 Dec 10). In some embodiments, provided herein are bispecific antibodies comprising at least one antigen-binding site directed against CD98hc and at least one antigen-binding site directed against a nervous system target. In some embodiments, provided herein are bispecific antibodies comprising a first antigen-binding site directed against a nervous system target, a second antigen-binding site directed against a nervous system target, and a third antigen-binding site directed against CD98hc. In some embodiments, the nervous system target comprises a cell type present in the central nervous system or the peripheral nervous system, including neurons and glial cells (e.g., Schwann cells, microglia, astrocytes, oligodendrocytes). In some embodiments, the nervous system target comprises a protein expressed on the surface of a cell type present in the nervous system, such as a neuron or a glial cell. In some embodiments, the nervous system target comprises a protein expressed on the surface (e.g., a cell surface protein or a transmembrane protein) of a neuron or a glial cell, including Schwann cells, microglia, astrocytes, and oligodendrocytes. In some embodiments, the nervous system target comprises a cell surface protein or a transmembrane protein expressed on oligodendrocytes. In some embodiments, the nervous system target comprises an extracellular protein. In some embodiments, the nervous system target comprises an extracellular protein or a phosphorylated form of the protein, such as tau or phosphorylated tau. In some embodiments, the nervous system target is myelin oligodendrocyte glycoprotein (MOG), UM-42351.601 neuronal membrane glycoprotein M6a (M6a), Tropomyosin receptor kinase B (TrkB), or astrocyte surface antigen M2 (M2). In some embodiments, provided herein are compositions comprising at least one antigen-binding site directed against CD98hc and at least one antigen-binding site directed against myelin oligodendrocyte glycoprotein (MOG). Myelin oligodendrocyte glycoprotein, a member of the immunoglobulin (Ig) superfamily, is a transmembrane myelin protein expressed on the surface of oligodendrocytes and on the outermost surface of myelin sheaths. Various alternatively spliced isoforms of MOG have been identified, the term “MOG” is inclusive of any isoform of the protein. In some embodiments, provided herein are bispecific antibodies comprising at least one antigen-binding site against CD98hc (i.e. at least one anti- CD98hc binding site) and at least one antigen-binding site against MOG1, MOG2, MOG3, or MOG4. In some embodiments, provided herein are compositions comprising at least one antigen-binding site directed against CD98hc and at least one antigen binding site directed against tau or phosphorylated tau. In some embodiments, provided herein are compositions comprising at least one antigen-binding site directed against CD98hc and at least one antigen binding site directed against M6a. In some embodiments, provided herein are compositions comprising at least one antigen-binding site directed against CD98hc and at least one antigen binding site directed against TrkB. In some embodiments, provided herein are compositions comprising at least one antigen-binding site directed against CD98hc and at least one antigen binding site directed against M2. A component of the compositions of the present disclosure may comprise a whole antibody or an antigen-binding fragment of a whole antibody. As defined herein, antigen- binding antibody fragments encompassed by the present disclosure include, but are not limited to, F(ab’)2, Fab’, Fab, Fv, scFv, dsFv, dAb, and single chain binding polypeptides. Antibody fragments and their therapeutic utility are further described in, e.g., Nelson, A.L., MAbs.2010 Jan-Feb; 2(1): 77-83; Joosten et al., Microbial Cell Factories volume 2, Article number: 1 (2003); and Bates A, Power CA., Antibodies (Basel).2019;8(2):28; UM-42351.601 doi:10.3390 / antib8020028). In some embodiments, the at least one antigen binding site directed against CD98hc (e.g. the anti-cd98hc binding site) comprises an antigen-binding fragment. Suitable antigen-binding fragments include single-chain variable fragments (scFv), which are engineered antibodies generated by the fusion of the heavy (VH) and light chains (VL) of immunoglobulins through a short polypeptide linker. Single chain variable domain (Fv) fragments (scFv) are used in the art in a variety of clinical and therapeutic applications, primarily due to their improved pharmacokinetic properties as compared to the parent monoclonal antibodies and the relative ease of producing them in large quantities at low cost (Monnier et al., Antibodies 2013, 2(2), 193-208; doi.org / 10.3390 / antib2020193; Safdari et al., Mol Med.2016; 22: 258-270; and Lu, R., Hwang, Y., Liu, I. et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27, 1 (2020). https: / / doi.org / 10.1186 / s12929-019-0592-z). The compositions of the present disclosure may comprise a diabody. Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al., Nat. Med.9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med.9:129-134 (2003). In some embodiments, a composition of the present disclosure comprises a whole antibody. As defined herein, a whole antibody comprises two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains contains one N-terminal variable (VH) region and three C-terminal constant (CH1, CH2, and CH3) regions, and each light chain contains one N-terminal variable (VL) region and one C-terminal constant (CL). The heavy chain C-terminal constant region contains the fragment crystallizable (Fc) domain, which determines antibody class and is responsible for humoral and cellular effector functions. Antibodies are divided into five major classes (or “isotypes”), IgG, IgM, IgA, IgD and IgE, which differ in their function in the immune system. IgGs are the most abundant immunoglobulins in the blood, representing 60% of total serum antibodies in humans. IgG antibodies may be subclassified as IgG1, IgG2, IgG3, and IgG4, named in order of their abundance in serum (IgG1 being the most abundant) (Vidarsson et al., Frontiers in Immunology.5: 520 (2014)). A whole bispecific antibody described herein may be of any suitable class and / or subclass. In some embodiments, the antibody is of class IgG (e.g., IgG1, IgG2, IgG3, or IgG4). For example, the antibody may be an IgG1 antibody. UM-42351.601 As described above, the compositions of the present disclosure can comprise a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody. In some embodiments, the antibody comprises a fragment selected from the group consisting of Fab, Fab-C, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some embodiments, the compositions of the present disclosure comprise two or more single-domain antibodies that form a bivalent antibody, a trivalent antibody, or a tetravalent antibody that recognizes different epitopes on the same or different antigens. In some embodiments, the bispecific antibodies of the present disclosure comprises an IgG antibody fused to a scFv. In some embodiments, the bispecific antibodies of the present disclosure comprise a dual-variable domain format. In some embodiments, the compositions of the present disclosure comprise chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA.81:6851-6855 (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable domain derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant domain. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof. In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, for example, CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity. Humanized antibodies and methods of making them are reviewed, for example, in Almagro and Fransson, Front. Biosci.13:1619-1633 (2008), and are further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos.5,821,337, 7,527,791, 6,982,321, and UM-42351.601 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol.28:489-498 (1991) (describing “resurfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling). In accordance with the above embodiments, the antibodies of the present disclosure can be made into bivalent, trivalent, or tetravalent formats. In some embodiments, the bispecific antibodies of the present disclosure is bivalent for the nervous system target and comprises an additional binding site for CD98hc. For example, in some embodiments a bispecific antibody of the present disclosure comprises an IgG directed against a nervous system target (e.g., a first binding site directed against the nervous system target and a second binding site directed against the same nervous system target) fused to an antigen binding antibody fragment (e.g., scFv) directed against CD98hc at the C-terminus of one of the two heavy chains of the IgG. As another example, in some embodiments a bispecific antibody of the present disclosure comprises a dual variable domain comprising an outer VH and outer VL region directed against a nervous system target and an inner VH and inner VL region directed against CD98hc. In some embodiments, the inner VH / VL regions are fused to the outer VH / VL regions by a suitable linker. In general, there are more than 100 different bispecific antibody formats that have been produced due to the modular architecture of antibodies. These formats vary in many ways, including based on their molecular weight, the number of antigen-binding sites, the spatial relationship between different binding sites, the valency for each antigen, the ability to support secondary immune functions, and the pharmacokinetic half-life. Recombinant bispecific antibodies can be divided into two classes: bispecific formats with Fc regions, and bispecific formats without Fc regions. Bispecific antibodies with an Fc region retain Fc- mediated effector functions. These formats include, but are not limited to, “knob into hole” IgG, crossMab, ortho-Fab IgG, DVD-Ig, two in one IgG, IgG-scFv and scFv2-Fc. Bispecific antibodies with no Fc lack Fc-mediated effector functions. However, the smaller size of such antibodies offers a better tissue penetration over IgG-like formats. In this format, the variable domains of each parental monoclonal antibody and the linkers are cloned and linked to form a single-chain bispecific antibody. These bispecific antibodies represent many formats, including tandem scFvs, diabody format, single-chain diabodies, tandem UM-42351.601 diabodies (TandAbs), dual-affinity retargeting molecules (DARTs), dock-and-lock (DNL), and nanobodies. A number of strategies have been developed to generate bispecific antibodies. Hybrid hybridoma (also referred to as quadroma) was the earliest technology used to produce bispecific antibodies. It is based on the somatic fusion of two different hybridoma cell lines expressing murine IgGs of desired specificities. However, the real percentage of functional bispecific antibody by a quadroma cell line is unpredictable and a laborious process is required to isolate the bispecific antibody from the side products. By using molecular cloning technology, bispecific IgG antibodies can be assembled from two different heavy and light chains expressed in the same producer cell. The production of bispecific antibodies requires at least two plasmids for heterodimerized heavy chains and one plasmid for a common light chain or two light-chain plasmids if two different light chains are used. Notably, expressing HC and LC on separate plasmids can be advantageous because the manipulation of the plasmid ratio is an easy and efficient approach to optimize protein assembly for desired products. Generally, methods of making bispecific antibodies that can be divided into three groups: chemical recombination, cell fusion, and genetic manipulation (Reichert, J.M, and Dhimolea, E., Drug Discov Today, 2012 Sep;17(17-18):954-63). Recent reviews on the different strategies in constructing bispecific antibodies, with therapeutic application emphasis, include Wu, C., Drug News Perspect.2009 Oct;22(8):453-8; Gu, J., and Ghayur, T., Methods Enzymol.2012; 502:25-41; and Kontermann, R., MAbs, Mar-Apr 2012; 4(2): 182-97. In some embodiments, provided herein is a bispecific antibody comprising a first antigen-binding site directed against a nervous system a nervous system target, a second antigen-binding site directed against a nervous system target, and a third antigen-binding site directed against CD98hc. In some embodiments, the first antigen binding site and the second antigen binding site are portions of an IgG antibody directed against the nervous system target, and the third antigen binding-site comprises an antigen-binding antibody fragment directed against CD98hc. In some embodiments, the antigen-binding antibody fragment is fused to the C-terminus of the first antigen binding site or the second antigen binding site. In some embodiments, the antigen-binding antibody fragment is fused to the C-terminus of the first antigen binding site. In some embodiments, the antigen-binding antibody fragment is fused to the C-terminus of the second antigen binding site. In some embodiments, the antigen-binding antibody fragment comprises a single-chain variable domain fragment (scFv) UM-42351.601 directed against CD98hc. In some embodiments, the nervous system target is myelin oligodendrocyte glycoprotein (MOG), neuronal membrane glycoprotein M6a (M6a), Tropomyosin receptor kinase B (TrkB), or astrocyte surface antigen M2 (M2). In some embodiments, a composition comprises one or more or all of CDR sequences SEQ ID NO:1-12, or functional or structural variants thereof (e.g., sequences having at least 60% sequence identity (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity) to one or more of SEQ ID NO:1-12). In some embodiments, the composition comprises SEQ ID NOs:1-3 and / or 4-6 and / or 7-9 and / or 10-12. In some embodiments, the composition comprises SEQ ID NO:27 or 28. In some embodiments, the composition comprises one or more of sequences SEQ ID NO:13-26, or functional or structural variants thereof. Such sequences may be provided without or without purification tags (e.g., hex-HIS tags). For example, in some embodiments the composition comprises SEQ ID Nos:13-16 or 17-21 or 22-24 or 25-26. One or more components of the composition can be conjugated to one another or expressed together directly or via one or more linkers. The antigen-binding compositions of the present disclosure can be made using any method known in the art. One approach for single cell manufacturing of antibodies is to use antibodies that are based on the same light chain in combination with a minimal set of Fc mutations to drive heavy chain heterodimerization. The resulting bispecific antibodies can readily be purified from the two undesired byproducts. As used herein the term “common light chain” refers to an immunoglobulin light chain comprising a variable domain that can productively associate with multiple heavy chain variable domains to form a paratope with each heavy chain variable region that is capable of specifically binding the epitope bound by the antibody in which the heavy chain variable region was originally encountered. Various antibody heavy or light chains, or portions thereof, are referred to herein as being “related” to the corresponding chain or portion thereof of an enumerated or specifically identified antibody. This denotes that the chain or portion thereof has identical sequence to the corresponding chain or portion thereof of an enumerated or specifically identified antibody, save for specifically indicated modifications, such as amino acid substitutions, of which there may be none. Once administered, the biological activity of the antigen-binding compositions can be measured by any suitable method known in the art. For example, the biological activity can be UM-42351.601 assessed by determining the stability of the composition. The biological activity of the composition also can be assessed by determining its binding affinity to antigen-containing peptides and / or by assessing its binding affinity to peptides with which it may cross-react. The term “affinity” refers to the equilibrium constant for the reversible binding of two agents and is expressed as the dissociation constant (KD). Affinity of a binding agent to a ligand, such as affinity of an antibody for an epitope, can be, for example, from about 1 femtomolar (fM) to about 1 millimolar (mM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM), or from about 1 nM to about 1 micromolar (μM)). Antibody affinity for an antigen or epitope of interest can be measured using any art-recognized assay. Such methods include, for example, fluorescence activated cell sorting (FACS), separable beads (e.g., magnetic beads), antigen panning, and / or ELISA (see, e.g., Janeway et al. (eds.), Immunobiology, 5th ed., Garland Publishing, New York, N.Y., 2001). The compositions may comprise excipients or pharmaceutically acceptable carriers. The choice of excipients or pharmaceutically acceptable carriers will depend on factors including, but not limited to, the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The compositions of the present invention will be readily apparent to those skilled in the art. Techniques and formulations may be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995). The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material, surfactant, cyclodextrins or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; surfactants such as, but not limited to, cremophor EL, cremophor RH 60, Solutol HS 15 and polysorbate 80; cyclodextrins such as, but not limited to, alpha-CD, beta-CD, gamma-CD, HP-beta-CD, SBE-beta-CD; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic UM-42351.601 saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non- toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as releasing agents, coating agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral (e.g., intradermal (IM), subcutaneous (SQ), intramuscular (IM), and intravenous (IV)) injections) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis). Any of the above compositions or formulations disclosed herein may further comprise at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent comprises at least one chemotherapeutic agent. Kits Also disclosed herein are kits comprising a system as disclosed herein. The kits can also comprise other agents and / or products co-packaged, co-formulated, and / or co-delivered with other components. The kits can also comprise instructions for using the components of the kit. The instructions are relevant materials or methodologies pertaining to the kit. The materials may include any combination of the following: background information, list of components, brief or detailed protocols for using the bispecific binding molecule, troubleshooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. It is understood that the disclosed kits can be employed in connection with the disclosed methods. The kit may further contain containers or devices for use with the methods disclosed herein. For example, the kits can comprise delivery devices (e.g., syringes). The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Individual member components of the kits may be physically packaged together or separately. UM-42351.601 Methods Also provided herein are methods comprising providing a system described herein to a subject. In some embodiments, provided herein is a method comprising administering a system described herein to a subject. In some embodiments, the system is administered intravenously to the subject, accumulates in the central nervous system (e.g., brain, spinal cord) of the subject following administration. In some embodiments, the subject has or is at risk of having a neurological disorder. The antibodies provided herein are able to cross the blood brain barrier and enter the nervous system (e.g., the brain), and are thus well-suited for therapeutic use for treating neurological disorders. Examples Antibody Production Expression of antibodies was performed by transfecting 25 mL of mammalian cell culture (2x106cells / mL) with appropriate plasmids. In each conical tube, 15 μg of total DNA (equal parts knob, hole, and light chains) was mixed with 45 μL of 40 kDa polyethylenimine (1 mg / mL) and 3 mL of F17 media (Thermo Fisher, A1383501) in a sterile hood for 15 min. Next, the mixture was added to the cells and then transferred back to the incubator (37 ^C, 5% CO2). After 24 h, 0.75 mL of yeastolate (%20 w / w) (Thermo Fisher, B92804) was added to each tube of transfected cells. The cells were harvested 6 d after transfection and centrifuged at 3500 rcf for 40 min. The supernatant was filtered (Thermo Fisher, 166-0045) and collected. Protein A agarose beads (Thermo Fisher, PI20334) were added to the supernatant and incubated on a shaker at 4 ^C overnight. The Protein A agarose beads are then collected in centrifuge columns (Thermo Fisher PI89898), washed three times with 10 mL PBS, then incubated with glycine buffer (pH 3.0) for 15 minutes. The columns are centrifuged for 2 mins at 1000 rcf and the elution is collected and immediately buffer exchanged into 20 mM Acetate (pH 5.0) using desalting columns (Thermo Fisher, 89891) and stored at -80 ^C. The absorbance (A280) was measured via NanoDrop to determine antibody concentration. Antibodies were run on SDS-PAGE gels as well as analyzed via size exclusion chromatography (SEC) (Superdex 200 Increase 10 / 300 GL, Cytvia #28990944). Antibodies that were <90% monomer after Protein A purification, as determined by SEC, underwent a second-step purification via fraction collection on SEC until desired purity was achieved. UM-42351.601 In vitro IL10 activity assay HEK-Blue™ IL-10 cells from InvivoGen (hkb-il10) were used for in vitro evaluation of IL-10 activity. Cells were cultured and maintained according to the manufacturer’s instructions. Antibody samples are added to a flat-bottom 96-well plate (Thermo Fisher 07- 000-099) at appropriate concentrations, alongside recombinant human IL-10 (R&D Systems 217-IL-005) controls.50,000 cells are then added to each well and incubated at 37 ^C, 5% CO2 for 20-24 hours. The next day, 20 uL of supernatant per well is collected and transferred to a new 96 flat-bottom 96-well plate.180 uL of QUANTI-Blue™ Solution is added per well, and the plates are incubated at 37 ^C for 1-3 hours. A spectrophotometer is then used to measure optical density at 620-655 nm. Immunostaining Antibodies are labeled with Alexa Fluor-647 NHS Ester (Thermo Fisher, A20006) following manufacturer’s protocol to achieve a degree of labeling of ~1.0.10% volume of 1M sodium bicarbonate at pH 8.0 is added to the antibody in PBS. Then the Alexa Fluor-647 NHS Ester dye is added at a dye-to-antibody molar ratio of 5:1, before incubating at room temperature for 1 hour. The solution is then passed through a dye removal column (Thermo Fisher, PIA44297) before the concentration and degree of labeling is determined via NanoDrop. 8-16 week-old C57BL / 6NJ male mice (Jackson Labs) are intravenously (retroorbital plexus) injected with the antibodies at 3.6 mg / kg. After 3 days, the mice are sacrificed and trans-cardiac perfusion is performed with ice cold PBS. The brains are harvested and drop- fixed in 4% paraformaldehyde (Thermo Fisher J61899AP) overnight at 4 ^C. The brains are then transferred to a 30% sucrose solution for 24 hours at 4 ^C. The brains are then bisected sagittally and each hemisphere is embedded in OCT (Thermo Fisher 23-730-571) and frozen in -80 ^C.20um sections are produced with a cryostat (Leica NX50) and transferred to glass slides (Thermo Fisher 1255015). Sections are rehydrated in PBS, followed by antigen retrieval (Thermo Fisher 50-187- 82) and permeabilization with 0.5% Triton-X 100 (Alfa Aesar, A16046). Sections are then blocked with PBS with 5% goat serum and 0.05% Triton-X 100 for 1 hour before incubation with primary antibodies diluted in the same blocking solution overnight at 4 ^C. The sections are then washed with PBS and stained with secondary antibodies at appropriate dilutions for UM-42351.601 1 hour at room temperature before counterstaining with Dapi solution (Thermo Fisher 62248) for 5 minutes and washing again. Sections are mounted with Prolong Gold (P36930) and protected with a coverslip (Thermo Fisher 12543D). Immunofluorescence imaging was performed with a Nikon A1si confocal microscope, and images are analyzed with FIJI. Pharmacokinetic analysis Antibodies were directly radioiodinated with [125I]NaI (Perkin Elmer) using Pierce iodination reagent (Thermo Fisher, 28601) and purified using Zeba desalting columns. Radiochemical purity was assessed via thin layer chromatography (TLC) performed using aluminum TLC silica gel 60 F254 plates (Millipore Sigma, 105554) and a 75%:25% mixture of methanol and 1 M sodium acetate (pH 6.8) as a mobile phase. Radiolabeling efficiency was typically >75% and proteins were only used for radiotracing if free125I was <5% following purification. For all radiotracing experiments, a tracer dose (~1 μg) of125I-labeled IgG or bispecific shuttle was added to the appropriate dose of unlabeled protein to achieve approximately 106cpm on a Wizard22470 gamma counter. Prior to injection, mice were weighed, and doses were sterile-filtered and prepared in sterile PBS to a final volume of 110 μL. Mice were sedated with isoflurane (Henry Schein, 66794-017-25) and injected intravenously via the retroorbital plexus. At the terminal time point, mice were re-sedated and transcardially perfused with ice- cold PBS. Blood and organs of interest were harvested and weighed prior to gamma counting. Sequences (CDR locations represented by double-underline) CDRs GDYIH (SEQ ID NO:1) WINPDRGFTYYTQKFQG (SEQ ID NO:2) ENPRAYFFDL (SEQ ID NO:3) RASEDIYNGLA (SEQ ID NO:4) NIDNLHT (SEQ ID NO:5) QQYYTYAYT (SEQ ID NO:6) UM-42351.601 DYYMA (SEQ ID NO:7) SISYEGSSIYYGDSVKG (SEQ ID NO:8) RGYYGYKPFDY (SEQ ID NO:9) RASQSISGSYVT (SEQ ID NO:10) ATSNRAI (SEQ ID NO:11) QQSVSSPYT (SEQ ID NO:12) IL-10 Wild-type SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFK GYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPC ENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN (SEQ ID NO:27) IL-10 Mutant SPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFK GYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPC ENGGGSGGKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN (SEQ ID NO:28) Hex-Histidine purification tag HHHHHH (SEQ ID NO:29) 2x1_MOG2 / Cp1_LC_wtIL10 HC (Knob) QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP UM-42351.601 KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTIECRASEDIYNGLAWYQ QKPGKSPQLLIYNIDNLHTGVPSRFSGSGSGTQYSLKINSLQSEDVASYFCQQYYTYA YTFGAGTKLELKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLKLSCA ASGFTFSDYYMAWVRQAPKKGLEWVASISYEGSSIYYGDSVKGRVTISRDNAKSTL YLQMNSLRSEDTATYYCARRGYYGYKPFDYWGQGVMVTVSS (SEQ ID NO:13) HC (Hole) QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKGGGSLPETGGHHHHHH (SEQ ID NO:14) LC EIVLTQSPGTLSLSPGERATLSCRASQSISGSYVTWYQQKPGQAPRLLIYATSNR AIGIPDKFSGGGSGRDFTLTINRLEPEDFAVYYCQQSVSSPYTFGQGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSSSSGSSSSGS SSSGSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLL EDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCH RFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN (SEQ ID NO:15) UM-42351.601 2x1_MOG2 / Cp1_LC_IL10M1 HC (Knob) QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTIECRASEDIYNGLAWYQ QKPGKSPQLLIYNIDNLHTGVPSRFSGSGSGTQYSLKINSLQSEDVASYFCQQYYTYA YTFGAGTKLELKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLKLSCA ASGFTFSDYYMAWVRQAPKKGLEWVASISYEGSSIYYGDSVKGRVTISRDNAKSTL YLQMNSLRSEDTATYYCARRGYYGYKPFDYWGQGVMVTVSS (SEQ ID NO:16) HC (Hole) QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKGGGSLPETGGHHHHHH (SEQ ID NO:17 ) LC EIVLTQSPGTLSLSPGERATLSCRASQSISGSYVTWYQQKPGQAPRLLIYATSNR AIGIPDKFSGGGSGRDFTLTINRLEPEDFAVYYCQQSVSSPYTFGQGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSSSSGSSSSGS UM-42351.601 SSSGSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLL EDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCH RFLPCENGGGSGGKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN (SEQ ID NO:18) 2x1_MOG2 / Cp1_Hole_wtIL10 HC (Knob) QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTIECRASEDIYNGLAWYQ QKPGKSPQLLIYNIDNLHTGVPSRFSGSGSGTQYSLKINSLQSEDVASYFCQQYYTYA YTFGAGTKLELKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLKLSCA ASGFTFSDYYMAWVRQAPKKGLEWVASISYEGSSIYYGDSVKGRVTISRDNAKSTL YLQMNSLRSEDTATYYCARRGYYGYKPFDYWGQGVMVTVSS (SEQ ID NO:19) HC (Hole) QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKSSSSGSSSSGSSSSGSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQM KDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLG UM-42351.601 ENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQEKGIYKAMSEFDIFINYIEAY MTMKIRN (SEQ ID NO:20) LC EIVLTQSPGTLSLSPGERATLSCRASQSISGSYVTWYQQKPGQAPRLLIYATSNR AIGIPDKFSGGGSGRDFTLTINRLEPEDFAVYYCQQSVSSPYTFGQGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:21) 2x1_MOG2 / Cp1_Hole_IL10M1 HC (Knob) QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTIECRASEDIYNGLAWYQ QKPGKSPQLLIYNIDNLHTGVPSRFSGSGSGTQYSLKINSLQSEDVASYFCQQYYTYA YTFGAGTKLELKRGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLKLSCA ASGFTFSDYYMAWVRQAPKKGLEWVASISYEGSSIYYGDSVKGRVTISRDNAKSTL YLQMNSLRSEDTATYYCARRGYYGYKPFDYWGQGVMVTVSS (SEQ ID NO:22) HC (Hole) QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF UM-42351.601 NWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALG APIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKSSSSGSSSSGSSSSGSPGQGTQSENSCTHFPGNLPNMLRDLRDAFSRVKTFFQM KDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAENQDPDIKAHVNSLG ENLKTLRLRLRRCHRFLPCENGGGSGGKSKAVEQVKNAFNKLQEKGIYKAMSEFDIF INYIEAYMTMKIRN (SEQ ID NO:23) LC EIVLTQSPGTLSLSPGERATLSCRASQSISGSYVTWYQQKPGQAPRLLIYATSNR AIGIPDKFSGGGSGRDFTLTINRLEPEDFAVYYCQQSVSSPYTFGQGTKVEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:24) DVD_MOG2 / Cp1_wtIL10 HC QVQLVQSGAEVKKPGASVKVSCQASGYTFTGDYIHWVRQAPGQGLEYLGWIN PDRGFTYYTQKFQGRVTMTRDTSSNTAYMELSSLRSDDTAMYYCTRENPRAYF FDLWGQGTLVTVSSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGRSLKLSCAASG FTFSDYYMAWVRQAPKKGLEWVASISYEGSSIYYGDSVKGRVTISRDNAKSTLYLQ MNSLRSEDTATYYCARRGYYGYKPFDYWGQGVMVTVSSASTKGPSVFPLAPSSKST SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGKSSSSGSSSSGSSSSGSPGQGTQSENSCTHF PGNLPNMLRDLRDAFSRVKTFFQMKDQLDNLLLKESLLEDFKGYLGCQALSEMIQF YLEEVMPQAENQDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNA FNKLQEKGIYKAMSEFDIFINYIEAYMTMKIRN (SEQ ID NO:25) UM-42351.601 LC EIVLTQSPGTLSLSPGERATLSCRASQSISGSYVTWYQQKPGQAPRLLIYATSNR AIGIPDKFSGGGSGRDFTLTINRLEPEDFAVYYCQQSVSSPYTFGQGTKVEIKGG GGSGGGGSGGGGSDIQMTQSPASLSASVGETVTIECRASEDIYNGLAWYQQKPGKSP QLLIYNIDNLHTGVPSRFSGSGSGTQYSLKINSLQSEDVASYFCQQYYTYAYTFGAGT KLELKRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:26)

Claims

UM-42351.601 CLAIMS What is claimed is:

1. A composition comprising: a) a first component that binds to a brain-specific molecule; b) a second component that binds to a blood-brain barrier protein; and c) an anti- inflammatory and / or immunosuppressive molecule.

2. The composition of claim 1, wherein said brain-specific molecule is a brain- specific protein.

3. The composition of claim 2, wherein said brain-specific protein is myelin oligodendrocyte glycoprotein (MOG), neuronal membrane glycoprotein M6a (M6a), Tropomyosin receptor kinase B (TrkB), or astrocyte surface antigen M2 (M2).

4. The composition of claim 1, wherein said second component binds to CD98hc.

5. The composition of claim 1, wherein said anti-inflammatory and / or immunosuppressive molecule is a cytokine.

6. The composition of claim 5, wherein said cytokines is IL-10.

7. The composition of claim 6, wherein said IL-10 is wild-type IL-10.

8. The composition of claim 6, wherein said IL-10 is variant IL-10.

9. The composition of claim 1, wherein said composition comprises a bi-specific antibody.

10. The composition of claim 1, wherein said first component is an IgG.

11. The composition of claim 1, wherein said second component is an antibody or antibody fragment.UM-42351.601 12. The composition of claim 1, wherein said first component is an IgG and said second component is an antibody or antibody fragment.

13. The composition of claim 12, wherein said anti-inflammatory and / or immunosuppressive molecule is conjugated to a light chain of said IgG.

14. The composition of claim 12, wherein said anti-inflammatory and / or immunosuppressive molecule is conjugated to heavy chain of said IgG.

15. The composition of any of claims 1 to 14, wherein said composition comprises one or more of CDR sequences SEQ ID NO:1-12.

16. The composition of any of claims 1 to 14, wherein said composition comprises one or more of sequences SEQ ID NO:13-26.

17. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID NO:27 or 28.

18. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID NOs:1-3.

19. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID NOs:4-6.

20. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID NOs:7-9.

21. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID NOs:10-12.

22. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID Nos:13-16 with or without SEQ ID NO:29.UM-42351.601 23. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID Nos:17-21 with or without SEQ ID NO:

29.

24. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID Nos:22-24.

25. The composition of any of claims 1 to 14, wherein said composition comprises SEQ ID Nos:25-26.

26. A method comprising: delivering the composition of any one of the preceding claims to a subject.

27. The method of claim 26, wherein the composition is delivered intravenously.

28. The method of claim 26 or 27, wherein the composition accumulates in the central nervous system of the subject following delivery.

29. The method of any one of claims 26-28, wherein the subject has or is at risk of having a neurological disorder.

30. Use of composition of any of claims 1-25.

31. Use of composition of any of claims 1-25 in the brain.

32. Use of composition of any of claims 1-25 to treat or study a neurological disorder.

Images