Antibodies targeting central nervous system localized antigens

Abstract

Provided herein are antibodies that specifically target central nervous system localized antigens including Brevican, Cadherin-10, NrCAM and PTPRZ1 and compositions comprising such antibodies for therapeutic and diagnostic applications.

Description

Antibodies Targeting Central Nervous System Localized AntigensTechnical Field

[0001] The embodiments disclosed herein relate to antibody therapeutics, and, in particular to antibodies that specifically target Brevican.Introduction

[0002] Development of safe and effective immunotherapies for central nervous system (CNS) disorders such as brain tumours, neuroinflammation and neurodegeneration has proven difficult given the lack of characterized CNS cell-specific surface markers. Targeting CNS-specific antigens to selectively and autonomously deliver therapeutic payloads to the brain could, in principle, reduce systemic off-target toxicity while also increasing local efficacy.

[0003] The brain has a unique extracellular matrix (ECM) composition which includes perineural net structures that stabilize synapses and surround neural cell bodies (Fawcett, J.W., Oohashi, T., Pizzorusso, T. Nat. Rev. Neurosci. 20, 451-465, 2019). The brain ECM is estimated to account for 20% of the adult brain by volume (Nicholson, C. & Sykova, E., Trends Neurosci. 21 , 207-215, 1998). The ECM structures are composed of tenascin R and hyaluronan, which are associated with a family of chondroitin sulfate proteoglycans secreted by glial and neuronal cells.

[0004] Brevican (BCAN) is a brain ECM glycoprotein that is synthesized in high levels by astrocytes, which may be a promising immunotherapeutic target given it is one of the most highly- prevalent molecules in the brain ECM and may represent an ideal disease-agnostic CNS target. BCAN is strongly expressed within glioblastoma tumor samples (Syafruddin, et al., BMC Cancer. 21 , 850, 2021).

[0005] Cadherin-10 (CDH10) is a brain-specific cadherin found on neuron surfaces at synapses. CHD10 expression is maintained in chronically active multiple sclerosis lesions (Elkjaer, et al., Acta Neuropathol. Commun. 7, 205, 2019).

[0006] Neuronal Cell Adhesion Molecule (NrCAM) and Protein Tyrosine Phosphatase Receptor type Z1 (PTPRZ1) are CNS ECM molecules that have pan-brain expression and may be good candidates for targeted CNS antibody therapeutics.

[0007] Accordingly, there is a need for novel antibodies that specifically target CNS antigens for further development of targeted CNS immunotherapies and diagnostics.Summary

[0008] Phage display selection was used to identify antibodies against central nervous system localized antigens including Brevican, Cadherin-10, NrCAM and PTPRZ1 that can be used for diagnostic and therapeutic purposes.

[0009] In some embodiments, provided is an CNS-specific antibody having a KD less than about 10 nM.

[0010] In some embodiments, an anti-Brevican binding domain of the present disclosure has at least one, at least two, or three CDRs of a variable domain sequence of SEQ ID NO:2 or SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain of the present disclosure comprises an HCDR3 of SEQ ID NO:2 and an LCDR3 of SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:2 and LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:3.

[0011] In some embodiments, an anti-Brevican binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:2 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO:2. In some embodiments, an anti-Brevican binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:2 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO:2. In some embodiments, an anti-Brevican binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:2 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO:2.

[0012] In some embodiments, an anti-Brevican binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:3 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 3 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:3 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO:3.

[0013] In some embodiments, an anti-Brevican binding domain of the present disclosure comprises a variable region having at least 70%, 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of a variable region sequence of SEQ ID NO:2 or SEQ ID NO:3. In some embodiments, the variable domain comprises substitutions, insertions, or deletions in the framework of a variable region as shown in SEQ ID NO:2 or SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain of the present disclosure comprises a heavy chain variable region comprising the HCD1 , HCDR2, and HCDR3 sequence of SEQ ID NO:2 and having at least 95% identity to SEQ ID NO:2; and a light chain variable region comprising the LCD1 , LCDR2, LCDR3 sequences of SEQ ID NO:3 and having at least 95% identity to SEQ ID NO:3.

[0014] In some embodiments, an anti-Brevican antibody comprises a single-chain variable fragment of SEQ ID NO:4.

[0015] Other aspects and features will become apparent, to those ordinarily skilled in the art, upon review of the following description of some exemplary embodiments.Brief Description of the Drawings

[0016] The drawings included herewith are for illustrating various examples of articles, methods, and apparatuses of the present specification. In the drawings:

[0017] FIG. 1 is a diagram of phage-fab display selection strategy for developing CNS- specific antibodies;

[0018] FIGS. 2A-2D are representative ELISA plots for phage selected CNS-specific antibody candidates;

[0019] FIG. 3 is a table showing the complementarity-determining regions (CDRs) of the CNS-specific antibody candidates shown in FIGS. 2A-2D;

[0020] FIG. 4 is an ELISA plot showing antigen binding specificity of the CNS-specific antibodies obtained from phage display selection;

[0021] FIG. 5 is a chart showing apparent binding affinities for CNS-specific antibodies as measured by bio-layer interferometry; and

[0022] FIG. 6 is a multi-point ELISA showing binding affinity of an anti-Brevican antibody;Detailed Description

[0023] Various apparatuses or processes will be described below to provide an example of each claimed embodiment. No embodiment described below limits any claimed embodiment and any claimed embodiment may cover processes or apparatuses that differ from those described below. The claimed embodiments are not limited to apparatuses or processes having all of the features of any one apparatus or process described below or to features common to multiple or all of the apparatuses described below.

[0024] The term "about" as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. For example, for KD and IC50 values ± 20%, ± 10%, or ± 5%, are within the intended meaning of the recited value.

[0025] The term Brevican or BCAN, also known as chondroitin sulfate proteoglycan 7, brevican proteoglycan, BEHAB, MGC13038 or CSPG7, as used herein, refers to a polypeptide that is encoded by a BCAN gene (chr1 :156, 646, 055-156, 659, 131 (GRCH38 / hg38), cytogenetically localized to human chromosome 1 q23.1 by HGNC, Entrez Gene, and Ensembl (genomic coordinates (GRCh38 / hg38 assembly December 2013:) and is localized to the surface of neurons in the brain. An illustrative human BCAN protein sequence encoded by a human BCAN gene, is available under Uniprot number Q96GW7 and is provided as SEQ ID NO:1. BCAN isdevelopmentally regulated and may function in the formation of the brain extracellular matrix. BCAN is highly expressed in gliomas and may promote the growth and cell motility of brain tumor cells.

[0026] The terms "anti-Brevican antibody," "Brevican specific antibody," "Brevican antibody," and "anti-Brevican" are used synonymously herein to refer to an antibody that specifically binds to Brevican. An illustrative human Brevican sequence is provided in SEQ ID NO:1.

[0027] An "anti-Brevican binding domain" as used herein refers to an antigen binding domain comprising a H and a L region of an anti-Brevican antibody as described herein, which antigen binding domain binds to Brevican.

[0028] The term Cadherin-10 or CDH10, as used herein, refers to a calcium-dependent adhesion protein that is encoded by a CDH10 gene (chr5:24,487, 100-24,644,978 (GRCH38 / hg38), cytogenetically localized to human chromosome 5p14.2-p14.1 by HGNC, Entrez Gene, and Ensembl (genomic coordinates (GRCh38 / hg38 assembly December 2013:) and is localized on neuron surfaces at synapses. An illustrative human CDH10 protein sequence encoded by a human CDH10 gene, is available under Uniprot number Q9Y6N8 and is provided as SEQ ID NO:5.

[0029] The terms "anti-CHD10 antibody," "Cadherin-10 specific antibody," "Cadherin-10 antibody," and "anti-CDH10" are used synonymously herein to refer to an antibody that specifically binds to Cadherin-10. An illustrative human Cadherin-10 sequence is provided in SEQ ID NO:5.

[0030] An "anti-CDH10 binding domain" as used herein refers to an antigen binding domain comprising a VHand a VLregion of an anti-CDH10 antibody as described herein, which antigen binding domain binds to Cadherin-10.

[0031] The term Neuronal Cell Adhesion Molecule or NrCAM, as used herein, refers to a polypeptide that is encoded by a NRCAM gene (chr7: 108, 147, 623-108, 456, 717 (GRCH38 / hg38), cytogenetically localized to human chromosome 7q31 .1 by HGNC, Entrez Gene, and Ensembl (genomic coordinates (GRCh38 / hg38 assembly December 2013:) and is localized to the extracellular matrix in the central nervous system. An illustrative human NrCAM protein sequence encoded by a human NrCAM gene, is available under Uniprot number Q92823 and is provided as SEQ ID NO: 12. NrCAM mediates cell-cell contacts in the brain.

[0032] The terms "anti-NrCAM antibody," "NrCAM specific antibody," "NrCAM antibody," and "anti-NrCAM" are used synonymously herein to refer to an antibody that specifically binds to NrCAM. An illustrative human NrCAM sequence is provided in SEQ ID NO:12.

[0033] An "anti-NrCAM binding domain" as used herein refers to an antigen binding domain comprising aHand aLregion of an anti-NrCAM antibody as described herein, which antigen binding domain binds to NrCAM.

[0034] The term Protein Tyrosine Phosphatase Receptor type Z1 or PTPRZ1 , also known as phosphocan and HPTPZ, as used herein, refers to a polypeptide that is encoded by a PTPRZ1 gene (chr7:121 , 873, 089-122, 062, 036 (GRCH38 / hg38), cytogenetically localized to human chromosome 7q31.32 by HGNC, Entrez Gene, and Ensembl (genomic coordinates (GRCh38 / hg38 assembly December 2013:) and is localized to the extracellular matrix in the central nervous system. An illustrative human PTPRZ1 protein sequence encoded by a human PTPRZ1 gene, is available under Uniprot number P23471 and is provided as SEQ ID NO: 16.

[0035] The terms "anti-PTPRZ1 antibody," "PTPRZ1 specific antibody," "PTPRZ1 antibody," and "anti-PTPRZ1" are used synonymously herein to refer to an antibody that specifically binds to PTPRZ1. An illustrative human PTPRZ1 sequence is provided in SEQ ID NO:16.

[0036] An "anti-PTPRZ1 binding domain" as used herein refers to an antigen binding domain comprising aHand aLregion of an anti-PTPRZ1 antibody as described herein, which antigen binding domain binds to PTPRZ1.

[0037] The terms “anti-CNS antibody,” “CNS-specific antibody,” CNS antibody,” and “anti- CNS” are used synonymously herein to refer to an antibody that specifically binds to an antigen e.g., Brevican, Cadherin-10, NrCAM and PTPRZ1 that is localized to the CNS.

[0038] As used herein, the term "antibody" refers to a polypeptide comprising a framework region encoded by an immunoglobulin gene, or fragments thereof, that specifically binds and recognizes an antigen, e.g., Brevican. Typically, the "variable region" contains the antigen-binding region of the antibody (or its functional equivalent) and is important in specificity and affinity of binding. The term "antibody" as used herein thus encompasses antigen binding fragments, e.g., an antigen binding domain, or other antigen binding fragment. Antigen binding fragments may be produced by modification of whole antibodies, or produced using recombinant DNA methodologies (e.g., single-chain variable fragment (scFv) formats).

[0039] An illustrative immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kD) and one "heavy" chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain ( L) and variable heavy chain ( H) refer to these light and heavy chains respectively.

[0040] As used herein, "complementarity-determining region (CDR)" refers to the three hypervariable regions that interrupt the four "framework" regions of a variable domain. The CDRsare the primary contributors to binding to an epitope of an antigen. The CDRs are referred to as CDR1 , CDR2, and CDR3, numbered sequentially starting from the N-terminus.

[0041] The amino acid sequences of the CDRs and framework regions can be determined using various well-known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT), and AbM (see, e.g., Johnson et al., supra; Chothia & Lesk, 1987, Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901-917; Chothia C. et al., 1989, Conformations of immunoglobulin hypervariable regions. Nature 342, 877-883; Chothia C. et al., 1992, structural repertoire of the human VH segments J. Mol. Biol. 227, 799-817; Al-Lazikani et al., J. Mol. Biol 1997, 273(4)). Definitions of antigen combining sites are also described in the following: Ruiz et al., IMGT, the international ImMunoGeneTics database. Nucleic Acids Res., 28, 219-221 (2000); and Lefranc,M.-P. IMGT, the international ImMunoGeneTics database. Nucleic Acids Res. Jan 1 ;29(1):207-9 (2001); MacCallum et al, Antibody-antigen interactions: Contact analysis and binding site topography, J. Mol. Biol., 262 (5), 732-745 (1996); and Martin et al, Proc. Natl Acad. Sci. USA, 86, 9268-9272 (1989); Martin, et al, Methods Enzymol., 203, 121-153, (1991); Pedersen et al, Immunomethods, 1 , 126, (1992); and Rees et al, In Sternberg M.J.E. (ed.), Protein Structure Prediction. Oxford University Press, Oxford, 141-172 1996). Reference to CDRs as determined by Kabat numbering are based, for example, on Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institute of Health, Bethesda, MD (1991)). Chothia CDRs are determined as defined by Chothia (see, e.g., Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)).

[0042] As used herein, "V-region" refers to an antibody, e.g., antibody, variable region domain comprising the segments of Framework 1 , CDR1 , Framework 2, CDR2, and Framework 3, including CDR3 and Framework 4, which segments are added to the V-segment as a consequence of rearrangement of V-region genes during B-cell differentiation.

[0043] An "isotype,” as used herein, is a class of antibodies defined by the heavy chain constant region. Antibodies described herein can be of any isotype of isotype class. Immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the isotype classes, IgG, IgM, IgA, IgD and IgE, respectively. In some embodiments, the IgG is an IgG I, lgG2, lgG3 or lgG4.

[0044] Antibodies can exist as intact immunoglobulins or as any of a number of well- characterized fragments that include specific antigen-binding activity. Such fragments can be produced by digestion with various peptidases. Pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology(Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology.

[0045] Antibodies or antigen-binding molecules of the present invention further includes one or more immunoglobulin chains that are chemically conjugated to, or expressed as, fusion proteins with other proteins. It also includes bispecific antibodies. A bispecific or bifunctional antibody is an artificial hybrid antibody having two different heavy / light chain pairs and two different binding sites. Other antigen-binding fragments or antibody portions of the invention include single chain variable fragments (scFv) bivalent scFv (diabody), bispecific scFv antibodies where the antibody molecule recognizes two different epitopes, single binding domains (dAbs), and minibodies. The term "antibody" additionally encompasses bispecific and multispecific antibodies as well as any other monovalent, bivalent, or multivalent antibody format.

[0046] The various antibodies or antigen-binding fragments described herein can be produced by enzymatic or chemical modification of the intact antibodies, or synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv), or identified using yeast or phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554, 1990; Boder, et al (2000) Proc. Natl. Acad. Sci. U S. A. 97:10701). For example, minibodies can be generated using methods described in the art, e.g., Vaughan and Sollazzo, Comb Chem High Throughput Screen. 4:417- 30 2001. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann, Clin. Exp. Immunol. 79:315-321 (1990); Kostelny et al., J. Immunol. 148, 1547-1553 (1992). Single chain antibodies can be identified using phage display libraries, yeast display, or ribosome display libraries, gene shuffled libraries. Such libraries can be constructed from synthetic, semi-synthetic or native and immunocompetent sources.

[0047] A "monoclonal antibody" refers to a clonal preparation of antibodies with a single binding specificity and affinity for a given epitope on an antigen.

[0048] A "chimeric antibody" is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region, CDR, or portion thereof) is linked to a constant region of a different or altered class, effector function and / or species, or an entirely different molecule which confers new properties to the chimeric antibody (e.g., an enzyme, toxin, hormone, growth factor, drug, etc.); or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity (e.g., CDR and framework regions from different species).

[0049] A "humanized" antibody is an antibody that retains the reactivity of a non-human antibody while being less immunogenic in humans. This can be achieved, for instance, byretaining the non-human CDR regions and replacing the remaining parts of the antibody with their human counterparts. In one embodiment, some, most or all of the amino acids outside the CDR domains are replaced with amino acids corresponding to the human immunoglobulin germline, while amino acids within one or more CDR regions are unchanged. In some embodiments, one or more CDR residues may be altered, e.g., to provide a sequence closerto germline orto replace a residue that may impede production.

[0050] The term "specifically bind(s)" or “specially target(s)” refers to a molecule (e.g., antibody or antibody fragment) that binds to a target with at least 2-fold greater affinity than nontarget compounds, e.g., at least 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 25- fold, 50-fold, or 100-fold greater affinity. For example, an antibody that specifically binds Brevican, typically bind to Brevican, with at least a 2-fold greater affinity than a non-Brevican target.

[0051] "Epitope" or "antigenic determinant" refers to a site on an antigen to which an antibody binds. Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x- ray crystallography and 2-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed (1996).

[0052] The term "valency" as used herein refers to the number of different binding sites of an antibody for an antigen. A monovalent antibody comprises one binding site for an antigen. A multivalent antibody comprises multiple binding sites.

[0053] The words "protein", "peptide", and "polypeptide" are used interchangeably to denote an amino acid polymer or a set of two or more interacting or bound amino acid polymers. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers, those containing modified residues, and non-naturally occurring amino acid polymer.

[0054] A "flexible linker" as used herein refers to an amino acid sequence that joins domains to provide a certain degree of movement or interaction. Such linkers are generally composed of small, non-polar (e.g., Gly) or polar (e.g., Ser or Thr) amino acids, but may also comprise polar amino acids such as Lys and Glu, e.g., to improve solubility. The small size of these amino acids provides flexibility, and allows for mobility of the connecting functional domains. The incorporation of Ser or Thr can maintain the stability of the linker in aqueous solutions by forming hydrogen bonds with the water molecules, and therefore reduces the unfavorableinteraction between the linker and the protein moieties. In some embodiments, flexible linkers are primarily composed of stretches of Gly and Ser residues ("GS" linker). An example of the most widely used flexible linker has the sequence of (Gly-Gly-Gly-Gly-Ser)n. By adjusting the copy number "n", the length of this GS linker can be adjusted to achieve appropriate separation of the functional domains and / or to maintain necessary inter-domain interactions. Besides the GS linkers, many other flexible linkers have been designed for recombinant protein expression.

[0055] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, e.g., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs may have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions similarly to a naturally occurring amino acid.

[0056] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0057] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical or associated, e.g., naturally contiguous, sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode most proteins. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to another of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes silent variations of the nucleic acid. One of skill will recognize that in certain contexts each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly,silent variations of a nucleic acid which encodes a polypeptide is implicit in a described sequence with respect to the expression product, but not with respect to actual probe sequences.

[0058] A “substitution” as used herein refers to a substitution of an amino acid such that charge, hydrophobicity, and / or size of the side group chain is maintained. Illustrative sets of amino acids that may be substituted for one another include (i) positively-charged amino acids Lys, Arg and His; (ii) negatively charged amino acids Glu and Asp; (iii) aromatic amino acids Phe, Tyr and Trp; (iv) nitrogen ring amino acids His and Trp; (v) large aliphatic nonpolar amino acids Vai, Leu and lie; (vi) slightly polar amino acids Met and Cys; (vii) small-side chain amino acids Ser, Thr, Asp, Asn, Gly, Ala, Glu, Gin and Pro; (viii) aliphatic amino acids Vai, Leu, lie, Met and Cys; and (ix) small hydroxyl amino acids Ser and Thr. Reference to the charge of an amino acid in this paragraph refers to the charge at physiological pH.

[0059] The terms "nucleic acid" and "polynucleotide" are used interchangeably and as used herein refer to both sense and anti-sense strands of RNA, cDNA, genomic DNA, and synthetic forms and mixed polymers of the above. In particular embodiments, a nucleotide refers to a ribonucleotide, deoxynucleotide or a modified form of either type of nucleotide, and combinations thereof. The terms also include, but is not limited to, single- and double-stranded forms of DNA. In addition, a polynucleotide, e.g., a cDNA or mRNA, may include either or both naturally occurring and modified nucleotides linked together by naturally occurring and / or non- naturally occurring nucleotide linkages. Nucleic acid molecules, e.g. oligonucleotide probes or primers, may be modified chemically or biochemically or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those of skill in the art. Such modifications include, for example, labels, methylation, substitution of one or more of the naturally occurring nucleotides with an analogue, nucleotide modifications such as uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.), charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), pendent moieties (e.g., polypeptides), intercalators (e.g., acridine, psoralen, etc.), chelators, alkylators, and modified linkages (e.g., alpha anomeric nucleic acids, etc.). The above term is also intended to include any topological conformation, including single-stranded, double-stranded, partially duplexed, triplex, hairpinned, circular and padlocked conformations. A reference to a nucleic acid sequence encompasses its complement unless otherwise specified. Thus, a reference to a nucleic acid molecule having a particular sequence should be understood to encompass its complementary strand, with its complementary sequence. The term also includes codon-optimized nucleic acids that encode the same polypeptide sequence.

[0060] The term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a selfreplicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. A "vector" as used here refers to a recombinant construct inwhich a nucleic acid sequence of interest is inserted into the vector. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors".

[0061] The terms "identical" or "percent identity," in the context of two or more nucleic acids, or two or more polypeptides, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides, or amino acids, that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters, or by manual alignment and visual inspection. See e.g., the NCBI web site at ncbi.nlm.nih.gov / BLAST. Such sequences are then said to be "substantially identical." This definition also refers to, or may be applied to, the compliment of a nucleotide test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. As described below, the algorithms can account for gaps and the like. Typically, identity exists over a region comprising an antibody epitope, or a sequence that is at least about 25 amino acids or nucleotides in length, or over a region that is 50-100 amino acids or nucleotides in length, or over the entire length of the reference sequence.

[0062] The terms "corresponding to," "determined with reference to," or "numbered with reference to" when used in the context of the identification of a given amino acid residue in a polypeptide sequence, refers to the position of the residue of a specified reference sequence when the given amino acid sequence is maximally aligned and compared to the reference sequence. Thus, for example, an amino acid residue in a variable domain polypeptide "corresponds to" an amino acid in the variable domain polypeptide of SEQ ID NO:1 when the residue aligns with the amino acid in SEQ ID NO:1 when optimally aligned to SEQ ID NO:1 . The polypeptide that is aligned to the reference sequence need not be the same length as the reference sequence.

[0063] The term "recombinant" when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all.

[0064] The term "heterologous" when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a newfunctional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

[0065] The term "isolated," when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It is preferably in a homogeneous state. It can be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified. In particular, an isolated gene is separated from open reading frames that flank the gene and encode a protein other than the gene of interest. The term "purified" denotes that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. Particularly, it means that the nucleic acid or protein is at least 85% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

[0066] "Subject," "patient," "individual" and like terms are used interchangeably and refer to, except where indicated, mammals such as humans and non-human primates, as well as rabbits, rats, mice, goats, pigs, and other mammalian species. The term does not necessarily indicate that the subject has been diagnosed with a particular disease, but typically refers to an individual under medical supervision. A patient can be an individual that is seeking treatment, monitoring, adjustment or modification of an existing therapeutic regimen, etc.

[0067] "Cancer", "tumor," "transformed" and like terms include precancerous, neoplastic, transformed, and cancerous cells, and can refer to a solid tumor, or a non-solid cancer. Cancer includes both benign and malignant neoplasms (abnormal growth). The term "cancer" can thus refer to glioblastomas, carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, solid and lymphoid cancers, cancer of the central nervous system, etc. In some embodiments, the antibody compositions and methods described herein can be used for treating cancer.

[0068] The antibody sequences described herein are not part of a transmembrane signaling protein. Transmembrane signaling proteins have an extracellular binding domain, (b) a transmembrane domain, and (c) an intracellular signaling domain and are capable of transducing signals from the outside of a cell to the inside of the cell. Types of transmembrane signaling proteins that are explicitly excluded from this disclosure include chimeric antigen receptors (CARs), binding triggered transcriptional switches (e.g., synNotch receptors) and synCAMs. As such, the antibody sequences described herein are not part of a CAR, binding triggered transcriptional switch (e.g., synNotch receptors), synCAM or any other type of transmembrane signaling protein. In other words the antibodies described herein are soluble, not part of a transmembrane protein.Phage display selections of CNS-specific antibodies

[0069] Referring to FIG. 1 , illustrated therein is a diagram of a phage display selection strategy used for developing CNS-specific antibodies. A previously-described Fab-phage display platform (Persson, et al., J. Mol. Biol. 425: 803-811 , 2013), based on a fully human framework sequence, was used to perform selections versus CNS-specific antigens, including Brevican (#13134), Cadherin-10 (#11260 and #11426), NrCAM (#12949) and PTPRZ1 (#13058).

[0070] Briefly, the CNS-specific antigens were immobilized on Maxisorp Immuno plates (ThermoFisher, 12-565-135) and used for positive binding selections with library phage pools that were first exposed to neutravidin coated wells to deplete nonspecific binders. After four rounds of binding selections, clonal phage was prepared and evaluated by phage ELISA and sequencing as previously described (Persson, et al., supra) and summarized below.

[0071] From the initial library diversity of ~1010binders, five Fab hits shown in FIGS. 2A- 2D and FIG. 3 were identified versus CNS-specific antigens. Referring to FIGS. 2A-2D, the phage clones #11260, #11426, #12949, #13058 and #13134 bind to their respective CNS-specific antigens as demonstrated by ELISA. Clonal phage expressing a single antibody fragment antigen binding domain bind to immobilized antigens but not control proteins (BSA - bovine serum albumin; NA - neutravidin; Fc - Fc receptor). Referring to FIG. 2C, phage clone #13058 binds both the PTPZR-CA domain and PTPZR CA-FNI 11 variant.

[0072] Referring to FIG. 4, the Fab hits shown in FIGS. 2A-2D and FIG. 3 were further validated using non-specific ELISA. Antibodies (100 nM) were tested using a previously described ELISA methodology summarized below. Binding in this assay has been correlated with poor in vivo pharmacokinetics and is a valuable parameter to assess in antibody developability studies. The CNS-specific antibodies were found to have lack of binding to irrelevant proteins (Cardiolipin, KLH - Keyhole limpet hemocyanin, LPS - Lipopolysaccharide, ssDNA - single stranded DNA, dsDNA - double stranded DNA and BSA - bovine serum albumin). Anti-Fc control wells are provided as a positive binding control for each protein. Additional assay controls include the gold- standard IgG Trastuzumab (Tras.), which shows low polyreactivity in this assay and a control IgG (Control) that is highly polyreactive.Antibody production

[0073] The Fab hits #11260, #11426, #12949, #13058 and #13134 were cloned into a human IgG 1 backbone for expression in scFC-Fc format in mammalian cell culture. CNS-specific antibodies were produced using the human Expi293 expression system (Thermofisher). Expi293 cells at 2 ml volume were transiently transfected with construct DNA using FectoPro transfection reagent (Polyplus Transfection, 101000014). Following a 5-day expression period, the antibodies were purified using Protein A Chromatography (GE Healthcare), quantified using absorbance at280 nm and stored in phosphate buffer (50 mM NaH2PO4, 75 mM Na2HPO4, 100 mM H3PO4, 154 mM NaCI).Bio-Layer Interferometry (BLI) binding assays

[0074] The binding affinity of CNS-specific antibodies was tested against CNS-specific antigens including Brevican, Cadherin-10, NrCAM, PTPRZ CA and PTPRZ1 CA-FNIII. To determine the binding kinetic parameters of the antibodies, BLI experiments were performed on an Octet HTX instrument (Sartorius) at 1000 rpm and 25 °C. All proteins were diluted in an assay buffer (PBS, 1% BSA, 0.05% Tween 20). Test and control antibodies at a concentration of 2 pg / ml were first captured on AHQ biosensors to achieve the binding signals of 0.8-1.3 nm. Unoccupied Fc-binding sites on the antibody-coated sensors were subsequently quenched by 20 pg / mL of the Fc protein. After equilibration with the assay buffer, the biosensors were then dipped for 600 seconds into wells containing 5-fold serial dilution of anti-CNS antibodies (association phase), followed by a transfer back into an assay buffer for additional 600 seconds (dissociation phase). Assay buffer alone served as a negative control. Binding response data were reference subtracted and were globally fitted with 1 :1 binding model using ForteBio's Octet Systems software 9.0.

[0075] FIG. 5 shows the apparent binding affinity for CNS-specific antibodies measured in BLI assays. The binding affinity for most CNS-specific antibodies is in the low-nM range. In the case of anti-Brevican antibody #13134 and anti-CDH10 antibody #11260, there was no observable dissociation.

[0076] FIG. 6 shows multi-point ELISA data for binding affinity of CNS-specific antibodies.ELISA

[0077] The ELISA protocol to assess interactions of the antibodies with unrelated macromolecules was adapted from Mouquet et al., Nature, 467(7315):591-595, 2010 and Jain et al., Proc Natl Acad Sci USA, 114(5):944-949, 2017. 384-well Maxisorp plates were coated with antigens diluted in PBS to the concentrations listed in Table 1. 30 pl was added to each well and incubated overnight with shaking at 4 degrees Celsius. Plates were blocked with 0.5% bovine serum albumin (BSA) in phosphate buffered saline (PBS) for 1 hour at room temperature and washed 6x with 80 pl PBS + 0.05% Tween20 (PBST) using a Biotek plate washer. 30 pl of 10OnM IgG diluted in PBST was then added to all wells and incubated for 1 hour at room temperature with shaking and washed 3x with PBST using a Biotek plate washer. Antigen binding was detected by adding 30 pl of 1 :5K anti-kappa HRP in PBS + 0.5% BSA to the wells and incubated for 30 minutes with shaking at room temperature. Wells were developed with 25 pl of TMB reagent incubated at room temperature for 10 minutes and quenched with 25 pl of ELISA Neutralization Solution (1 M phosphoric acid). Binding was quantified by absorbance at 450 nm on an Epoch plate reader.Table 1 . Antigens for non-specificity ELISA assayStatistical analysis

[0078] All the statistical analysis were done using GraphPad Prism unless stated otherwise. The data have been represented as ± mean and p Value < 0.05 were considered statistically significant.CNS-specific Antibodies

[0079] In some embodiments, an anti-Brevican binding domain of the present disclosure has at least one, at least two, or three CDRs of a variable domain sequence of SEQ ID NO:2 or SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain of the present disclosure comprises an HCDR3 of SEQ ID NO:2 and an LCDR3 of SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:2 and LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:3.

[0080] In some embodiments, an anti-Brevican binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:2 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO:2. In some embodiments, an anti-Brevican binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:2 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO:2. In some embodiments, an anti-Brevican binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:2 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO:2.

[0081] In some embodiments, an anti-Brevican binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:3 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO:3. In some embodiments, an anti-Brevicanbinding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 3 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:3 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO:3.

[0082] In some embodiments, an anti-Brevican binding domain of the present disclosure comprises a variable region having at least 70%, 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of a variable region sequence of SEQ ID NO:2 or SEQ ID NO:3. In some embodiments, the variable domain comprises substitutions, insertions, or deletions in the framework of a variable region as shown in SEQ ID NO:2 or SEQ ID NO:3. In some embodiments, an anti-Brevican binding domain of the present disclosure comprises a heavy chain variable region comprising the HCD1 , HCDR2, and HCDR3 sequence of SEQ ID NO:2 and having at least 95% identity to SEQ ID NO:2; and a light chain variable region comprising the LCD1 , LCDR2, LCDR3 sequences of SEQ ID NO:3 and having at least 95% identity to SEQ ID NO:3.

[0083] In some embodiments, an anti-Brevican antibody comprises a single-chain variable fragment of SEQ ID NO:4.

[0084] In some embodiments, an anti-CDH10 binding domain of the present disclosure has at least one, at least two, or three CDRs of a variable domain sequence of SEQ ID NO:6 or SEQ ID NO:7. In some embodiments, an anti-CDH10 binding domain of the present disclosure comprises an HCDR3 of SEQ ID NO:6 and an LCDR3 of SEQ ID NO:7. In some embodiments, an anti-CDH10 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:6 and LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:7.

[0085] In some embodiments, an anti-CDH10 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:6 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO:6. In some embodiments, an anti-CDH10 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:6 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO:6. In some embodiments, an anti-CDH10 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:6 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO:6.

[0086] In some embodiments, an anti-CDH10 binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:7 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO:7. In some embodiments, an anti-CDH10 binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 7 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO:7. Insome embodiments, an anti-CDH10 binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:7 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO:7.

[0087] In some embodiments, an anti-CDH10 binding domain of the present disclosure comprises a variable region having at least 70%, 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of a variable region sequence of SEQ ID NO:6 or SEQ ID NO:7. In some embodiments, the variable domain comprises substitutions, insertions, or deletions in the framework of a variable region as shown in SEQ ID NO:6 or SEQ ID NO:7. In some embodiments, an anti-CDH10 binding domain of the present disclosure comprises a heavy chain variable region comprising the HCD1 , HCDR2, and HCDR3 sequence of SEQ ID NO:6 and having at least 95% identity to SEQ ID NO:6; and a light chain variable region comprising the LCD1 , LCDR2, LCDR3 sequences of SEQ ID NO:7 and having at least 95% identity to SEQ ID NO:7.

[0088] In some embodiments, an anti-CDH10 antibody comprises a single-chain variable fragment of SEQ ID NO:8.

[0089] In some embodiments, an anti-CDH10 binding domain of the present disclosure has at least one, at least two, or three CDRs of a variable domain sequence of SEQ ID NO:9 or SEQ ID NQ:10. In some embodiments, an anti-CDH10 binding domain of the present disclosure comprises an HCDR3 of SEQ ID NO:9 and an LCDR3 of SEQ ID NQ:10. In some embodiments, an anti-CDH10 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:9 and LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:10.

[0090] In some embodiments, an anti-CDH10 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:9 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO:9. In some embodiments, an anti-CDH10 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:9 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO:9. In some embodiments, an anti-CDH10 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:9 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO:9.

[0091] In some embodiments, an anti-CDH10 binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 10 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO: 10. In some embodiments, an anti-CDH10 binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 10 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO: 10. In some embodiments, an anti-CDH10 binding domain comprises an LCDR1 , LCDR2, and LCDR3of SEQ ID NO: 10 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO: 10.

[0092] In some embodiments, an anti-CDH10 binding domain of the present disclosure comprises a variable region having at least 70%, 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of a variable region sequence of SEQ ID NO:9 or SEQ ID NO:10. In some embodiments, the variable domain comprises substitutions, insertions, or deletions in the framework of a variable region as shown in SEQ ID NO:9 or SEQ ID NQ:10. In some embodiments, an anti-CDH10 binding domain of the present disclosure comprises a heavy chain variable region comprising the HCD1 , HCDR2, and HCDR3 sequence of SEQ ID NO:9 and having at least 95% identity to SEQ ID NO:9; and a light chain variable region comprising the LCD1 , LCDR2, LCDR3 sequences of SEQ ID NQ:10 and having at least 95% identity to SEQ ID NO: 10.

[0093] In some embodiments, an anti-CDH10 antibody comprises a single-chain variable fragment of SEQ ID NO:11.

[0094] In some embodiments, an anti-NrCAM binding domain of the present disclosure has at least one, at least two, or three CDRs of a variable domain sequence of SEQ ID NO: 13 or SEQ ID NO:14. In some embodiments, an anti-NrCAM binding domain of the present disclosure comprises an HCDR3 of SEQ ID NO:13 and an LCDR3 of SEQ ID NO:14. In some embodiments, an anti-NrCAM binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:13 and LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:14.

[0095] In some embodiments, an anti-NrCAM binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:13 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO: 13. In some embodiments, an anti-NrCAM binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:13 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO: 13. In some embodiments, an anti-NrCAM binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:13 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO: 13.

[0096] In some embodiments, an anti-NrCAM binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:14 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO: 14. In some embodiments, an anti-NrCAM binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 14 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO: 14. In some embodiments, an anti-NrCAM binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 14 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO: 14.

[0097] In some embodiments, an anti-NrCAM binding domain of the present disclosure comprises a variable region having at least 70%, 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of a variable region sequence of SEQ ID NO:13 or SEQ ID NO:14. In some embodiments, the variable domain comprises substitutions, insertions, or deletions in the framework of a variable region as shown in SEQ ID NO:13 or SEQ ID NO:14. In some embodiments, an anti-NrCAM binding domain of the present disclosure comprises a heavy chain variable region comprising the HCD1 , HCDR2, and HCDR3 sequence of SEQ ID NO:13 and having at least 95% identity to SEQ ID NO:13; and a light chain variable region comprising the LCD1 , LCDR2, LCDR3 sequences of SEQ ID NO:14 and having at least 95% identity to SEQ ID NO: 14.

[0098] In some embodiments, an anti-NrCAM antibody comprises a single-chain variable fragment of SEQ ID NO:15.

[0099] In some embodiments, an anti-PTPRZ1 binding domain of the present disclosure has at least one, at least two, or three CDRs of a variable domain sequence of SEQ ID NO: 17 or SEQ ID NO:18. In some embodiments, an anti-PTPRZ1 binding domain of the present disclosure comprises an HCDR3 of SEQ ID NO:17 and an LCDR3 of SEQ ID NO:18. In some embodiments, an anti-PTPRZ1 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:17 and LCDR1 , LCDR2, and LCDR3 of SEQ ID NO:18.

[0100] In some embodiments, an anti-PTPRZ1 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:17 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO: 17. In some embodiments, an anti-PTPRZ1 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:17 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO: 17. In some embodiments, an anti-PTPRZ1 binding domain comprises an HCDR1 , HCDR2, and HCDR3 of SEQ ID NO:17 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO: 17.

[0101] In some embodiments, an anti-PTPRZ1 binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 18 in which one of the CDRs comprises a substitution relative to the corresponding CDR set forth in SEQ ID NO: 18. In some embodiments, an anti-PTPRZ1 binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 18 in which two of the CDRs comprise a substitution relative to the corresponding CDRs set forth in SEQ ID NO: 18. In some embodiments, an anti-PTPRZ1 binding domain comprises an LCDR1 , LCDR2, and LCDR3 of SEQ ID NO: 18 in which all three of the CDRs comprise a substitution relative to the corresponding CDR sequences set forth in SEQ ID NO: 18.

[0102] In some embodiments, an anti-PTPRZ1 binding domain of the present disclosure comprises a variable region having at least 70%, 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of a variable region sequence of SEQ ID NO:17 or SEQ ID NO:18. In some embodiments, the variable domain comprises substitutions, insertions, or deletions in the framework of a variable region as shown in SEQ ID NO:17 or SEQ ID NO:18. In some embodiments, an anti-PTPRZ1 binding domain of the present disclosure comprises a heavy chain variable region comprising the HCD1 , HCDR2, and HCDR3 sequence of SEQ ID NO:17 and having at least 95% identity to SEQ ID NO:17; and a light chain variable region comprising the LCD1 , LCDR2, LCDR3 sequences of SEQ ID NO: 18 and having at least 95% identity to SEQ ID NO: 18.

[0103] In some embodiments, an anti-PTPRZ1 antibody comprises a single-chain variable fragment of SEQ ID NO: 19.Antibody formats

[0104] An CNS-specific antibody of the present disclosure may be incorporated into a bivalent antibody or a multivalent antibody that binds to the same, or a different, antigen. In some embodiments, an anti-CNS antibody of the present disclosure may be incorporated into a bispecific antibody or multispecific antibody that binds to the antigen at different epitopes, or that binds to different antigens. In some embodiments, such an antibody may comprise an Fc region.

[0105] Antibody Conjugates

[0106] In a further aspect, an anti-CNS antibody of the present disclosure may be conjugated or linked, either directly or indirectly, to therapeutic and / or imaging / detectable moieties. For example, in some embodiments, an antibody of the present disclosure, or an antigen binding region comprising an antibody of the present invention, may be conjugated to agents including, but not limited to, a detectable marker, a cytotoxic agent, an imaging agent, a therapeutic agent, or an oligonucleotide. Methods for conjugating or linking an antibody, or antigen binding regions comprising an antibody, to a desired molecule moiety are well known in the art. The moiety may be linked to the antibody covalently or by non-covalent linkages.

[0107] In some embodiments, an anti-CNS antibody of the present disclosure, or an antigen binding domain comprising an anti-CNS antibody of the present disclosure, is conjugated to cytotoxic moiety or other moiety that inhibits cell proliferation.

[0108] In some embodiments, an anti-CNS antibody of the present disclosure is conjugated to a cytotoxic agent including, but not limited to, e.g., ricin A chain, doxorubicin, daunorubicin, a maytansinoid, taxol, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracin dione, methotrexact, actinomycin, a diphtheria toxin, extotoxin A from Pseudomonas, Pseudomonas exotoxin40, abrin, abrin A chain, modeccin A chain, alpha sarcin, gelonin, mitogellin, restrictocin, cobran venom factor, aribonuclease, engineered Shiga toxin, phenomycin, enomycin, curicin, crotin, calicheamicin, Saponaria officinalis inhibitor, glucocorticoid, auristatin, auromycin, yttrium, bismuth, combrestatin, duocarmycins, dolastatin, cc1065, or a cisplatin. In some embodiments, the antibody may be linked to an agent such as an enzyme inhibitor, a proliferation inhibitor, a lytic agent, a DNA or RNA synthesis inhibitors, a membrane permeability modifier, a DNA metabolite, a dichloroethylsulfide derivative, a protein production inhibitor, a ribosome inhibitor, or an inducer of apoptosis.

[0109] In some embodiments, an anti-CNS antibody of the present disclosure, or an antigen binding domain comprising an anti-CNS antibody of the present disclosure, may be linked to a radionuclide, an iron-related compound, a dye, a fluorescent agent, or an imaging agent. In some embodiments, an antibody may be linked to agents, such as, but not limited to, metals; metal chelators; lanthanides; lanthanide chelators; radiometals; radiometal chelators; positronemitting nuclei; microbubbles (for ultrasound); liposomes; molecules microencapsulated in liposomes or nanosphere; monocrystalline iron oxide nanocompounds; magnetic resonance imaging contrast agents; light absorbing, reflecting and / or scattering agents; colloidal particles; fluorophores, such as near-infrared fluorophores.

[0110] While the above description provides examples of one or more antibodies and nucleic acids it will be appreciated that other compositions of matter may be within the scope of the claims as interpreted by one of skill in the art.Polypeptide Sequences:SEQ ID NO: 1 Uniprot Q96GW7 amino acid sequenceMAQLFLPLLAALVLAQAPAALADVLEGDSSEDRAFRVRIAGDAPLQGVLGGALTIPCHVHYLRPPPSRRAVLGSPRVKWTFLSRGREAEVLVARGVRVKVNEAYRFRVALPAYPASLTDVSLALSELRPNDSGIYRCEVQHGIDDSSDAVEVKVKGWFLYREGSARYAFSFSGAQEACARIGAHIATPEQLYAAYLGGYEQCDAGWLSDQTVRYPIQTPREACYGDMDGFPGVRNYGWDPDDLYDVYCYAEDLNGELFLGDPPEKLTLEEARAYCQERGAEIATTGQLYAAWDGGLDHCSPGWLADGSVRYPIVTPSQRCGGGLPGVKTLFLFPNQTGFPNKHSRFNVYCFRDSAQPSAIPEASNPASNPASDGLEAIVTVTETLEELQLPQEATESESRGAIYSIPIMEDGGGGSSTPEDPAEAPRTLLEFETQSMVPPTGFSEEEGKALEEEEKYEDEEEKEEEEEEEEVEDEALWAWPSELSSPGPEASLPTEPAAQEESLSQAPARAVLQPGASPLPDGESEASRPPRVHGPPTETLPTPRERNLASPSPSTLVEAREVGEATGGPELSGVPRGESEETGSSEGAPSLLPATRAPEGTRELEAPSEDNSGRTAPAGTSVQAQPVLPTDSASRGGVAWPASGDCVPSPCHNGGTCLEEEEGVRCLCLPGYGGDLCDVGLRFCNPGWDAFQGACYKHFSTRRSWEEAETQCRMYGAHLASISTPEEQDFINNRYREYQWIGLNDRTI EGDFLWSDGVPLLYENWNPGQPDSYFLSGENCWMVWHDQGQWSDVPCNYHLSYTCKMGLVSCGPPPELPLAQVFGRPRLRYEVDTVLRYRCREGLAQRNLPLIRCQENGRWEAPQISCVPRR PARALHPEEDPEGRQGRLLGRWKALLIPPSSPMPGPSEQ ID NO: 2 Anti-Brevican Antibody-13134 heavy chain variable region; CDRs are underlinedEVQ LVESG GG LVQ PGG SLRLSCAASG FDLSTYWM H WVRQ APG KG LE WVASIYASGGATD YADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYHYPAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGKHCDR1 : LSTYWMHCDR2: SIYASGGATDHCDR3: YYHYPAMSEQ ID NO: 3 Anti-Brevican Antibody-13134 light chain variable region; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFS GSRSGTDFTLTISSLQPEDFATYYCQQYGDPITFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGT ASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC-LCDR1 : SVSSALCDR2: SASDLYSLCDR3: YGDPISEQ ID NO: 4 Anti-Brevican Antibody-13134 single-chain variable fragment; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFS GSRSGTDFTLTISSLQPEDFATYYCQQYGDPITFGQGTKVEIKGTTAASGSSGGSSSGAEVQLV ESG G G LVQ PG GSLRLSCAASG FDLSTYWM H WVRQ APG KG LEWVASIYASGGATDYADSVKG RFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYHYPAMDYWGQGTLVTVSSRSDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLCDR1 : SVSSALCDR2: SASDLYSLCDR3: YGDPIHCDR1 : LSTYWMHCDR2: SIYASGGATDHCDR3: YYHYPAMSEQ ID NO: 5 Uniprot Q9Y6N8 amino acid sequenceMTIHQFLLLFLFWVCLPHFCSPEIMFRRTPVPQQRILSSRVPRSDGKILHRQKRGWMWNQFFLL EEYTGSDYQYVGKLHSDQDKGDGSLKYILSGDGAGTLFIIDEKTGDIHATRRIDREEKAFYTLRA QAINRRTLRPVEPESEFVIKIHDINDNEPTFPEEIYTASVPEMSWGTSWQVTATDADDPSYGN SARVIYSILQGQPYFSVEPETGIIRTALPNMNRENREQYQWIQAKDMGGQMGGLSGTTTVNIT LTDVNDNPPRFPQNTIHLRVLESSPVGTAIGSVKATDADTGKNAEVEYRIIDGDGTDMFDIVTEK DTQEGIITVKKPLDYESRRLYTLKVEAENTHVDPRFYYLGPFKDTTIVKISIEDVDEPPVFSRSSYLFEVHEDIEVGTIIGTVMARDPDSISSPIRFSLDRHTDLDRIFNIHSGNGSLYTSKPLDRELSQWHNLTVIAAEINNPKETTRVAVFVRILDVNDNAPQFAVFYDTFVCENARPGQLIQTISAVDKDDPLGGQKFFFSLAAVNPNFTVQDNEDNTARILTRKNGFNRHEISTYLLPWISDNDYPIQSSTGTLTIRVCACDSQGNMQSCSAEALLLPAGLSTGALIAILLCIIILLVIWLFAALKRQRKKEPLILSKEDIRDNIVSYNDEGGGEEDTQAFDIGTLRNPAAIEEKKLRRDIIPETLFIPRRTPTAPDNTDVRDFINERLKEHDLDPTAPPYDSLATYAYEGNDSIAESLSSLESGTTEGDQNYDYLREWGPRFNKLAEMYGGGESDKDSSEQ ID NO: 6 Anti-Cadherin-10 Antibody-1 1260 heavy chain variable region; CDRs are underlinedEVQ LVESG GG LVQ PGG SLRLSCAASG FDFGAAYM H WVRQ APG KG LEWVAGIYASGGDTDYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWYYGALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHCDR1 : FGAAYMHCDR2: GIYASGGDTDHCDR3: WYYGALSEQ ID NO: 7 Anti-Cadherin-10 Antibody-1 1260 light chain variable region; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQFSSWWGLFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC-LCDR1 : SVSSALCDR2: SASDLYSLCDR3: FSSWWGLFSEQ ID NO: 8 Anti-Cadherin-10 Antibody-11260 single-chain variable fragment; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQFSSWWGLFTFGQGTKVEIKGTTAASGSSGGSSSGAEVQLVESGGG LVQPGGSLRLSCAASG FDFGAAYM H WVRQAPG KG LEWVAGIYASGGDTDYAD SVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARWYYGALDYWGQGTLVTVSSRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLCDR1 : SVSSALCDR2: SASDLYSLCDR3: FSSWWGLFHCDR1 : FGAAYMHCDR2: GIYASGGDTDHCDR3: WYYGALSEQ ID NO: 9 Anti-Cadherin-10 Antibody-11260 single-chain variable fragment; CDRs are underlinedEVQLVESGGGLVQPGGSLRLSCAASGFDFTSSDMHWVRQAPGKGLEWVASISASGGNTDYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYWGALDYWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT LMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHCDR1 : FTSSDMHCDR2: SISASGGNTDHCDR3: YYWGALSEQ ID NO: 10 Anti-Cadherin-10 Antibody- 11426 light chain variable region; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFS GSRSGTDFTLTISSLQPEDFATYYCQQYWSFGYSLITFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEK HKVYACEVTHQGLSSPVTKSFNRGEC-LCDR1 : SVSSALCDR2: SASDLYSLCDR3: YWSFGYSLISEQ ID NO: 11 Anti-Cadherin-10 Antibody- 11426 single-chain variable fragment; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYWSFGYSLITFGQGTKVEIKGTTAASGSSGGSSSGA EVQLVESGGGLVQPGGSLRLSCAASGFDFTSSDMHWVRQAPGKGLEWVASISASGGNTDYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYWGALDYWGQGTLVTVSSRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLCDR1 : SVSSALCDR2: SASDLYSLCDR3: YWSFGYSLIHCDR1 : FTSSDMHCDR2: SISASGGNTDHCDR3: YYWGALSEQ ID NO: 12 Uniprot Q92823 amino acid sequenceMQLKIMPKKKRLSAGRVPLILFLCQMISALEVPLDPKLLEDLVQPPTITQQSPKDYIIDPRENIVIQ CEAKGKPPPSFSWTRNGTHFDIDKDPLVTMKPGTGTLIINIMSEGKAETYEGVYQCTARNERGAAVSNNIWRPSRSPLWTKEKLEPITLQSGQSLVLPCRPPIGLPPPIIFWMDNSFQRLPQSERVSQGLNGDLYFSNVLPEDTREDYICYARFNHTQTIQQKQPISVKVISVDELNDTIAANLSDTEFYGA KSSRERPPTFLTPEGNASNKEELRGNVLSLECIAEGLPTPIIYWAKEDGMLPKNRTVYKNFEKTLQIIHVSEADSGNYQCIAKNALGAIHHTISVRVKAAPYWITAPQNLVLSPGEDGTLICRANGNPKPRISWLTNGVPIEIAPDDPSRKIDGDTIIFSNVQERSSAVYQCNASNEYGYLLANAFVNVLAEPPRILTPANTLYQVIANRPALLDCAFFGSPLPTIEWFKGAKGSALHEDIYVLHENGTLEIPVAQKDSTGTYTCVARNKLGMAKNEVHLEIKDPTWIVKQPEYAWQRGSMVSFECKVKHDHTLSLTVLWLKDNRELPSDERFTVDKDHLWADVSDDDSGTYTCVANTTLDSVSASAVLSWAPTPTPAPVYDVPNPPFDLELTDQLDKSVQLSWTPGDDNNSPITKFIIEYEDAMHKPGLWHHQTEVSGTQTTAQLKLSPYVNYSFRVMAVNSIGKSLPSEASEQYLTKASEPDKNPTAVEGLGSEPDNLVITWKPLNGFES NGPGLQYKVSWRQKDGDDEWTSVWANVSKYIVSGTPTFVPYLIKVQALNDMGFAPEPAWMGHSGEDLPMVAPGNVRVNWNSTLAEVHWDPVPLKSIRGHLQGYRIYYWKTQSSSKRNRRHI EKKILTFQGSKTHGMLPGLEPFSHYTLNVRWNGKGEGPASPDRVFNTPEGVPSAPSSLKIVNPTLDSLTLEWDPPSHPNGILTEYTLKYQPINSTHELGPLVDLKIPANKTRWTLKNLNFSTRYKFYFYAQTSAGSGSQITEEAVTTVDEAGILPPDVGAGKVQAVNPRISNLTAAAAETYANISWEYEGPEHVNFYVEYGVAGSKEEWRKEIVNGSRSFFGLKGLMPGTAYKVRVGAVGDSGFVSSEDVFETGPAMASRQVDIATQGWFIGLMCAVALLILILLIVCFIRRNKGGKYPVKEKEDAHADPEIQPMKEDDGTFGEYSDAEDHKPLKKGSRTPSDRTVKKEDSDDSLVDYGEGVNGQFNEDGSFIGQYSGKKE KEPAEGNESSEAPSPVNAMNSFVSEQ ID NO: 13 Anti-NrCAM Antibody-12949 heavy chain variable region; CDRs are underlinedEVQ LVESG GG LVQ PGG SLRLSCAASG FDFSSSWI H WVRQ APG KG LE WVARIYSSGGYTDYA DSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARFGYRSSPSFALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGKHCDR1 : FSSSWIHCDR2: RIYSSGGYTDHCDR3: FGYRSSPSFALSEQ ID NO: 14 Anti-NrCAM Antibody-12949 light chain variable region; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYRUTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC-LCDR1 : SVSSALCDR2: SASDLYSLCDR3: YYRLISEQ ID NO: 15 Anti-NrCAM Antibody-12949 single-chain variable fragment; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYRLJTFGQGTKVEIKGTTAASGSSGGSSSGAEVQLVESG G G LVQ PG GSLRLSCAASG FDFSSSWI H WVRQ APG KG LEWVARIYSSGGYTDYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYRSSPSFALDYWGQGTLVTVSSRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLCDR1 : SVSSALCDR2: SASDLYSLCDR3: YYRLIHCDR1 : FSSSWIHCDR2: RIYSSGGYTDHCDR3: GYRSSPSFALSEQ ID NO: 16 Uniprot P23471 amino acid sequenceMRILKRFLACIQLLCVCRLDWANGYYRQQRKLVEEIGWSYTGALNQKNWGKKYPTCNSPKQSPINIDEDLTQVNVNLKKLKFQGWDKTSLENTFIHNTGKTVEINLTNDYRVSGGVSEMVFKASKITFHWGKCNMSSDGSEHSLEGQKFPLEMQIYCFDADRFSSFEEAVKGKGKLRALSILFEVGTEENLDFKAIIDGVESVSRFGKQAALDPFILLNLLPNSTDKYYIYNGSLTSPPCTDTVDWIVFKDTVSISESQLAVFCEVLTMQQSGYVMLMDYLQNNFREQQYKFSRQVFSSYTGKEEIHEAVCSSEPENVQADPENYTSLLVTWERPRWYDTMIEKFAVLYQQLDGEDQTKHEFLTDGYQDLGAILNNLLPNMSYVLQIVAICTNGLYGKYSDQLIVDMPTDNPELDLFPELIGTEEIIKEEEEGKDIEEGAIVNPGRDSATNQIRKKEPQISTTTHYNRIGTKYNEAKTNRSPTRGSEFSGKGDVPNTSLNSTSQPVTKLATEKDISLTSQTVTELPPHTVEGTSASLNDGSKTVLRSPHMNLSGTAESLNTVSITEYEEESLLTSFKLDTGAEDSSGSSPATSAIPFISENISQGYIFSSENPETITYDVLIPESARNASEDSTSSGSEESLKDPSMEGNVWFPSSTDITAQPDVGSGRESFLQTNYTEIRVDESEKTTKSFSAGPVMSQGPSVTDLEMPHYSTFAYFPTEVTPHAFTPSSRQQDLVSTVNWYSQTTQPVYNGETPLQPSYSSEVFPLVTPLLLDNQILNTTPAASSSDSALHATPVFPSVDVSFESILSSYDGAPLLPFSSASFSSELFRHLHTVSQILPQVTSATESDKVPLHASLPVAGGDLLLEPSLAQYSDVLSTTHAASETLEFGSESGVLYKTLMFSQVEPPSSDAMMHARSSGPEPSYALSDNEGSQHIFTVSYSSAIPVHDSVGVTYQGSLFSGPSHIPIPKSSLITPTASLLQPTHALSGDGEWSGASSDSEFLLPDTDGLTALNISSPVSVAEFTYTTSVFGDDNKALSKSEIIYGNETELQIPSFNEMVYPSESTVMPNMYDNVNKLNASLQETSVSISSTKGMFPGSLAHTTTKVFDHEISQVPENNFSVQPTHTVSQASGDTSLKPVLSANSEPASSDPASSEMLSPSTQLLFYETSASFSTEVLLQPSFQASDVDTLLKTVLPAVPSDPILVETPKVDKISSTMLHLIVSNSASSENMLHSTSVPVFDVSPTSHMHSASLQGLTISYASEKYEPVLLKSESSHQWPSLYSNDELFQTANLEINQAHPPKGRHVFATPVLSIDEPLNTLINKLIHSDEILTSTKSSVTGKVFAGIPTVASDTFVSTDHSVPIGNGHVAITAVSPHRDGSVTSTKLLFPSKATSELSHSAKSDAGLVGGGEDGDTDDDGDDDDDDRGSDGLSIHKCMSCSSYRESQEKVMNDSDTHENSLMDQNNPISYSLSENSEEDNRVTSVSSDSQTGMDRSPGKSPSANGLSQKHNDGKEENDIQTGSALLPLSPESKAWAVLTSDEESGSGQGTSDSLNENETSTDFSFADTNEKDADGILAAGDSEITPGFPQSPTSSVTSENSEVFHVSEAEASNSSHESRIGLAEGLESEKKAVIPLVIVSALTFICLWLVGILIYWRKCFQTAHFYLEDSTSPRVISTPPTPIFPISDDVGAIPIKHFPKHVADLHASSGFTEEFETLKEFYQEVQSCTVDLGITADSSNHPDNKHKNRYINIVAYDHSRVKLAQLAEKDGKLTDYINANYVDGYNRPKAYIAAQGPLKSTAEDFWRMIWEHNVEVIVMITNLVEKGRRKCDQYWPADGSEEYGNFLVTQKSVQVLAYYTVRNFTLRNTKIKKGSQKGRPSGRWTQYHYTQWPDMGVPEYSLPVLTFVRKAAYAKRHAVGPWVHCSAGVGRTGTYIVLDSMLQQIQHEGTVNIFGFLKHIRSQRNYLVQTEEQYVFIHDTLVEAILSKETEVLDSHIHAYVNALLIPGPAGKTKLEKQFQLLSQSNIQQSDYSAALKQCNREKNRTSSIIPVERSRVGISSLSGEGTDYINASYIMGYYQSNEFIITQHPLLHTIKDFWRMIWDHNAQLWMIPDGQNMAEDEFVYWPNKDEPINCESFKVTLMAEEHKCLSNEEKLIIQDFILEATQDDYVLEVRHFQCPKWPNPDSPISKTFELISVIKEEAANRDGPMIVHDEHGGVTAGTFCALTTLMHQLEKENSVDVYQVAKMINLMRPGVFADIEQYQFLYKVILSLVSTRQEENPSTSLDSNGAALPDGNIAESLESL VSEQ ID NO: 17 Anti-PTPRZ1 Antibody- 13058 heavy chain variable region; CDRs are underlinedEVQ LVESG GG LVQ PGG SLRLSCAASG FDFGGASI H WVRQ APG KG LEWVAGIYASGGATAYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARFGYSYSFSYSALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGKHCDR1 : FGGASIHCDR2: GIYASGGATAHCDR3: GYSYSFSYSALSEQ ID NO: 18 Anti-PTPRZ1 Antibody-13058 light chain variable region; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYYYDSFPITFGQGTKVEIKRTVAAPSVFIFPPSDEQL KSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC-LCDR1 : SVSSALCDR2: SASDLYSLCDR3: YYYYDSFPISEQ ID NO: 19 Anti-PTPRZ1 Antibody-13058 single-chain variable fragment; CDRs are underlinedDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASDLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYYYDSFPITFGQGTKVEIKGTTAASGSSGGSSSGAEVQLVESGGGLVQPGGSLRLSCAASGFDFGGASIHWVRQAPGKGLEWVAGIYASGGATAYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYSYSFSYSALDYWGQGTLVTVSSRSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQG NVFSCSVM H EALHNHYTQKSLSLSPG KLCDR1 : SVSSALCDR2: SASDLYSLCDR3: YYYYDSFPIHCDR1 : FGGASIHCDR2: GIYASGGATAHCDR3: GYSYSFSYSAL

Claims

Claims:1 . An antibody that specifically binds to Brevican, wherein the antibody comprises a Brevican binding domain comprising: a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% identity to SEQ ID NO:2; and a light chain variable region (VL) comprising an amino acid sequence having at least 95% identity to SEQ ID NO:3, wherein the antibody is not part of a transmembrane signaling protein.

2. The antibody of claim 1 , wherein the VHcomprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the VLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

3. The antibody of claim 1 , wherein the H comprises amino acid sequence SEQ ID NO:2; and / or wherein the VLcomprises amino acid sequence SEQ. ID NO:3.

4. The antibody of any one of claims 1-3, wherein the antibody is a single chain variable fragment (scFv).

5. The antibody of claim 4, wherein the VLis N-terminal to the VH.

6. The antibody of claim 4, wherein the H is N-terminal to the V_.

7. The antibody of any one of claims 5-6, wherein the VHand the VLare separated by a flexible linker.

8. The antibody of claim 7, wherein the flexible linker comprises Gly-Ser.

9. The antibody of claim 8, wherein the flexible linker comprises one or more Gly-Ser sequences.

10. The antibody of claim 4, wherein the scFv comprises amino acid SEQ ID NO:4.

11. A bispecific or multispecific antibody comprising the antibody of any one or claims 1 -9.

12. A polynucleotide encoding an antibody of any one of claims 1-11.

13. A vector comprising the polynucleotide of claim 12.

14. A nucleic acid encoding an antibodyHand / or VL, wherein theHcomprises an amino acid sequence having at least 95% identity to SEQ. ID NO:2; and wherein theLcomprises an amino acid sequence having at least 95% identity to SEQ ID NO:3.

15. The nucleic acid of claim 14, wherein theHcomprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein theLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

16. The nucleic acid of claim 14, wherein the H comprises amino acid sequence SEQ ID NO:2; and / or wherein the VLcomprises amino acid sequence SEQ ID NO: 3.

17. A vector comprising the nucleic acid of any one of claims 14-16.

18. A host cell comprising the vector of claim 17.

19. An antibody that specifically binds to Cadherin-10, wherein the antibody comprises a Cadherin-10 binding domain comprising: a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% identity to SEQ ID NO:6; and a light chain variable region (VL) comprising an amino acid sequence having at least 95% identity to SEQ ID NO:7,wherein the antibody is not part of a transmembrane signaling protein.

20. The antibody of claim 19, wherein the VH comprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the VLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.21 . The antibody of claim 19, wherein the H comprises amino acid sequence SEQ ID NO:6; and / or wherein the VLcomprises amino acid sequence SEQ ID NO:7.

22. The antibody of any one of claims 19-21 , wherein the antibody is a single chain variable fragment (scFv).

23. The antibody of claim 22, wherein the VLis N-terminal to the VH.

24. The antibody of claim 22, wherein the H is N-terminal to the _.

25. The antibody of any one of claims 23-24, wherein the VH and the . are separated by a flexible linker.

26. The antibody of claim 25, wherein the flexible linker comprises Gly-Ser.

27. The antibody of claim 26, wherein the flexible linker comprises one or more Gly-Ser sequences.

28. The antibody of claim 22, wherein the scFv comprises amino acid SEQ ID NO:8.

29. A bispecific or multispecific antibody comprising the antibody of any one or claims 19-27.

30. A polynucleotide encoding an antibody of any one of claims 19-29.31 . A vector comprising the polynucleotide of claim 30.

32. A nucleic acid encoding an antibody VH and / or V_, wherein the VH comprises an amino acid sequence having at least 95% identity to SEQ ID NO:6; andwherein the VL comprises an amino acid sequence having at least 95% identity to SEQ ID NO:7.

33. The nucleic acid of claim 32, wherein the VHcomprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the VLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

34. The nucleic acid of claim 32, wherein the VHcomprises amino acid sequence SEQ ID NO:6; and / or wherein the VLcomprises amino acid sequence SEQ ID NO: 7.

35. A vector comprising the nucleic acid of any one of claims 32-34.

36. A host cell comprising the vector of claim 35.

37. An antibody that specifically binds to Cadherin-10, wherein the antibody comprises a Cadherin-10 binding domain comprising: a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% identity to SEQ ID NO:9; and a light chain variable region ( L) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 10, wherein the antibody is not part of a transmembrane signaling protein.

38. The antibody of claim 37, wherein the H comprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the VLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

39. The antibody of claim 37, wherein the VH comprises amino acid sequence SEQ ID NO:9; and / orwherein the L comprises amino acid sequence SEQ ID NO:10.

40. The antibody of any one of claims 37-39, wherein the antibody is a single chain variable fragment (scFv).41 . The antibody of claim 40, wherein the VLis N-terminal to the VH.

42. The antibody of claim 40, wherein the VH is N-terminal to the L.

43. The antibody of any one of claims 41-42, wherein the VHand the VLare separated by a flexible linker.

44. The antibody of claim 43, wherein the flexible linker comprises Gly-Ser.

45. The antibody of claim 44, wherein the flexible linker comprises one or more Gly-Ser sequences.

46. The antibody of claim 40, wherein the scFv comprises amino acid SEQ ID NO:11.

47. A bispecific or multispecific antibody comprising the antibody of any one or claims 37-45.

48. A polynucleotide encoding an antibody of any one of claims 37-47.

49. A vector comprising the polynucleotide of claim 48.

50. A nucleic acid encoding an antibody VHand / or VL, wherein the VHcomprises an amino acid sequence having at least 95% identity to SEQ ID NO:9; and wherein the VLcomprises an amino acid sequence having at least 95% identity to SEQ ID NQ:10.51 . The nucleic acid of claim 50, wherein the VHcomprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the VLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

52. The nucleic acid of claim 50, wherein the VH comprises amino acid sequence SEQ ID NO:9; and / or wherein the VLcomprises amino acid sequence SEQ ID NO: 10.

53. A vector comprising the nucleic acid of any one of claims 50-52.

54. A host cell comprising the vector of claim 53.

55. An antibody that specifically binds to NrCAM, wherein the antibody comprises a NrCAM binding domain comprising: a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 13; and a light chain variable region (VL) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 14, wherein the antibody is not part of a transmembrane signaling protein.

56. The antibody of claim 55, wherein the VHcomprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the VLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

57. The antibody of claim 55, wherein the VHcomprises amino acid sequence SEQ ID NO:13; and / or wherein the VL comprises amino acid sequence SEQ ID NO:14.

58. The antibody of any one of claims 55-57, wherein the antibody is a single chain variable fragment (scFv).

59. The antibody of claim 58, wherein the L is N-terminal to the H.

60. The antibody of claim 58, wherein the VHis N-terminal to the VL.61 . The antibody of any one of claims 59-60, wherein the H and the L are separated by a flexible linker.

62. The antibody of claim 61 , wherein the flexible linker comprises Gly-Ser.

63. The antibody of claim 62, wherein the flexible linker comprises one or more Gly-Ser sequences.

64. The antibody of claim 58, wherein the scFv comprises amino acid SEQ ID NO:15.

65. A bispecific or multispecific antibody comprising the antibody of any one or claims 55-63.

66. A polynucleotide encoding an antibody of any one of claims 55-65.

67. A vector comprising the polynucleotide of claim 66.

68. A nucleic acid encoding an antibody VHand / or VL, wherein the VHcomprises an amino acid sequence having at least 95% identity to SEQ ID NO: 13; and wherein the VLcomprises an amino acid sequence having at least 95% identity to SEQ ID NO:14.

69. The nucleic acid of claim 68, wherein the VHcomprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the VLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

70. The nucleic acid of claim 68, wherein the VHcomprises amino acid sequence SEQ ID NO:13; and / or wherein the VLcomprises amino acid sequence SEQ ID NO: 14.71 . A vector comprising the nucleic acid of any one of claims 68-70.

72. A host cell comprising the vector of claim 71.

73. An antibody that specifically binds to PTPZ1 , wherein the antibody comprises a PTPZ1 binding domain comprising: a heavy chain variable region (VH) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 17; and a light chain variable region (VL) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 18, wherein the antibody is not part of a transmembrane signaling protein.

74. The antibody of claim 73, wherein the VH comprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the VLcomprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

75. The antibody of claim 73, wherein the VHcomprises amino acid sequence SEQ ID NO:17; and / or wherein the VLcomprises amino acid sequence SEQ ID NO:18.

76. The antibody of any one of claims 74-75, wherein the antibody is a single chain variable fragment (scFv).

77. The antibody of claim 76, wherein the VLis N-terminal to the VH.

78. The antibody of claim 76, wherein the H is N-terminal to the L.

79. The antibody of any one of claims 77-78, wherein the H and the VL are separated by a flexible linker.

80. The antibody of claim 79, wherein the flexible linker comprises Gly-Ser.

81. The antibody of claim 80, wherein the flexible linker comprises one or more Gly-Ser sequences.

82. The antibody of claim 76, wherein the scFv comprises amino acid SEQ ID NO:19.

83. A bispecific or multispecific antibody comprising the antibody of any one or claims 73-81.

84. A polynucleotide encoding an antibody of any one of claims 73-83.

85. A vector comprising the polynucleotide of claim 84.

86. A nucleic acid encoding an antibodyHand / or VL, wherein theHcomprises an amino acid sequence having at least 95% identity to SEQ ID NO: 17; and wherein theLcomprises an amino acid sequence having at least 95% identity to SEQ ID NO:18.

87. The nucleic acid of claim 86, wherein theHcomprises an HCDR1 sequence comprising LSTYWM; an HCDR2 sequence comprising SIYASGGATD; and an HCDR3 sequence comprising YYHYPAM; and / or wherein the L comprises an LCDR1 sequence comprising SVSSA; an LCDR2 sequence comprising SASDLYS; and an LCDR3 sequence comprising YGDPI.

88. The nucleic acid of claim 86, wherein the H comprises amino acid sequence SEQ ID NO:17; and / or wherein the VLcomprises amino acid sequence SEQ ID NO: 18.

89. A vector comprising the nucleic acid of any one of claims 86-88.

90. A host cell comprising the vector of claim 89.

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