EP4698566A2 - Agnonistic antibodies targeting jaml - Google Patents

Abstract

Provided herein antibodies or antigen binding fragments thereof that bind to a junction adhesion molecule like (JAML) protein or a fragment thereof.

Description

Atty. Docket No.: 116639-2660 AGNONISTIC ANTIBODIES TARGETING JAML CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial No.63/460,835, filed April 20, 2023, the contents of which are hereby incorporated by reference in their entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on April 5, 2024, is named 116639-2660.SL.xml and is 202,202 bytes in size. FIELD OF THE DISCLOSURE [0003] The present disclosure generally relates to agonistic antibodies that specifically target and bind to Junction Adhesion Molecule Like protein (JAML). BACKGROUND OF THE DISCLOSURE [0004] The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or constitute prior art to the present technology. [0005] Junction adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells with implications for tissue homeostasis and repair. JAML was initially identified as the major co-stimulatory molecule in epithelial γδ T cells, and activation by coxsackie and adenovirus receptor (CXADR), its ligand expressed by epithelial cells, has been shown to be important for tissue homeostasis and wound repair (Verdino et al., Science.2010 Sep 3;329(5996):1210-4; Witherden et al., Science.2010 Sep 3;329(5996):1205-10). While JAML has an overall low sequence identity with the costimulatory molecule CD28 (~11%), their intracellular signaling motifs bear substantial similarities and, upon ligation, recruit phosphatidylinositol-3-OH-kinase (PI3K), leading to cell activation, proliferation and cytokine production (Verdino et al., 2010; Witherden et al., 2010). 1 4861-9829-0104.1 Atty. Docket No.: 116639-2660 SUMMARY OF THE DISCLOSURE [0006] In one aspect, the present disclosure provides for an antibody or an antigen binding fragment thereof that binds to a junction adhesion molecule like (JAML) protein or a fragment thereof. In some aspects, the antibody or antigen binding fragment comprises heavy chain complementarity-determining regions 1-3 (CDRH1-3) and light chain complementarity- determining regions 1-3 (CDRL1-3) selected from a single row of Table 2, or equivalents of each thereof. In yet another aspect, the antibody or antigen binding fragment comprises, consists of, or consists essentially of a heavy chain variable region (HC) and a light chain variable region (LC) selected from a single row of Table 1, or an equivalent thereof of each thereof. [0007] In one aspect, the antibody or antigen binding fragment is a humanized antibody or antigen binding fragment thereof. In some aspects, the antibody or antigen binding fragment thereof comprises, consists of, or consists essentially of a heavy chain complementarity- determining regions 1-3 (CDRH1-3) a CDRH1, a CDRH2, a CDRH3, a light chain complementarity-determining regions 1-3 (CDRH1-3) 1, a CDRH2, and a CDRH3, each selected from Table 5. In some other aspects, the antibody or antigen binding fragment thereof comprises, consists of, or consists essentially of a heavy chain complementarity-determining regions 1-3 (CDRH1-3) and light chain complementarity-determining regions 1-3 (CDRL1-3) selected from a single row of Table 5 or equivalents of each thereof. In yet another aspect, the antibody or antigen binding fragment thereof comprises, consists of, or consists essentially of a HC selected from SEQ ID NOS: 135-138 or an equivalent of each thereof, and a LC selected from SEQ ID NOS:139-142 or an equivalent of each thereof. In some aspects, the equivalent of the HC retains the corresponding CDRH1-3 selected from a single row of Table 5, or wherein the equivalent of the LC retains the corresponding CDRLs selected from a single row of Table 5. In some aspects, the antibody or antigen binding fragment thereof comprises, consists of, or consists essentially of a HC and a LC selected from a single row of Table 3 or an equivalent thereof. In some aspects, the equivalent of the HC retains the corresponding CDRH1-3 selected from a single row of Table 5, and wherein the equivalent of the LC retains the corresponding CDRLs selected from a single row of Table 5. [0008] In some aspects, the antibody is a monoclonal antibody, or a fragment thereof, e.g., an antigen binding fragment thereof. In some aspects, the antibody comprises a constant region 2 4861-9829-0104.1 Atty. Docket No.: 116639-2660 selected from the group of: an IgA constant region, an IgD constant region, an IgE constant region, an IgG constant region or an IgM constant region. In some aspects, the constant region comprises, consist of, or consists essentially of an IgG1 constant region. In some aspects, the antigen binding fragment comprises, consists of, or consists essentially of a Fab, F(ab’)2, Fab’, scFv, or Fv. In some aspects, the antibody or antigen binding fragment thereof comprises, consists of, or consists essentially of an Fc region comprising one or more mutations selected from G237D, P238D, H268D, P271G, and A330R as compared to the wildtype Fc region of the antibody. [0009] In some aspects, the antibody or antigen binding fragment as described herein comprises, a detectable label or a purification label. [0010] In some aspects, the equivalent of the HC or LC of a single row of Table 1 comprises, consists of, or consists essentially of a polypeptide having at least 80%, or at least 85%, or at least 90%, or at least 95% amino acid identity to the polypeptide, or wherein an equivalent to the amino acid sequence comprises a polypeptide that is encoded by a polynucleotide that hybridizes under conditions of high stringency to the complement of the polynucleotide encoding the amino acid sequence, that optionally retains the CDRHs 1-3 or CDRLs 1-3 of the reference or HC or LC, respectively. In one aspect the equivalent encodes a HC and/or LC as relevant that has at least 90% or better binding affinity as the reference or parent HC and/or LC to JAML polypeptide. [0011] In one aspect, the antibody or antigen binding fragment comprises a modification. In some aspects, the modification is selected from the group of a PEGylation, a PEG mimetic, polysialyation, HESylation or glycosylation. [0012] In some aspects, provided herein is an isolated polynucleotide encoding the antibody or antigen binding fragment. In some aspects, the isolated polynucleotide comprises, consists of, or consists essentially of a polynucleotide sequence of any one of SEQ ID NOS: 143-150, or an equivalent of each thereof. In some aspects, the equivalent thereof encodes a HC and a LC selected from a single row of Table 3. [0013] In some aspects, the polynucleotide is operatively linked to a promoter an/or enhancer element. In some aspects, the polynucleotide comprises, consists of, or consists essentially of a detectable label of purification label. In some aspects, a vector comprising, consisting of, or 3 4861-9829-0104.1 Atty. Docket No.: 116639-2660 consisting essentially of the polynucleotide is provided herein. In some aspects, the vector comprises, consists of, or consists essentially of a heterologous promoter sequence. In yet another aspect, isolated host cells comprising, consisting of, or consisting essentially of the polynucleotide or the vector is provided herein. [0014] In one aspect, provided herein is a composition comprising, consisting of, or consisting essentially of a carrier and one or more of: the antibody or antigen binding fragment, the polynucleotide encoding the antibody or antigen binding fragment, the vector, or the host cell. In some aspects, the carrier comprises, consists of, or consists essentially of a pharmaceutically acceptable carrier. [0015] In yet another aspect, provided herein is a kit comprising, consisting of, or consisting essentially of one or more of: the antibody or antigen binding fragment, the polynucleotide encoding the antibody or antigen binding fragment, the vector, or the host cell, each as described herein. In some aspects, the kit further contains instructions for use. [0016] In one aspect, a method of producing an antibody or antigen binding fragment is provided herein. In some aspects, the method comprises, consists of, or consists essentially of culturing a host cell comprising a polynucleotide encoding the antibody or antigen binding fragment thereof that encodes the antibody or antigen binding fragment thereof under conditions for expression of the polynucleotide encoding an antibody or antigen binding fragment thereof. In some aspects, the method further comprises, consists of, or consists essentially of isolating the antibody or antigen binding fragment. Alternatively chemical means such as the use of a polypeptide synthesizer can be used to produce the antibodies or fragments thereof using the sequence of each. [0017] In yet another aspect of this disclosure, provided herein is a method for binding a JAML protein or fragment thereof. In some aspects, the method comprises, consists of, or consists essentially of contacting the JAML protein or fragment thereof with an antibody or antigen binding fragment thereof of this disclosure under conditions that favor binding of the antibody or antigen binding fragment thereof to JAML protein or the fragment, and optionally isolating the antibody or antigen binding fragment thereof bound to the JAML protein. These conditions are known in the art and briefly described herein. 4 4861-9829-0104.1 Atty. Docket No.: 116639-2660 BRIEF DESCRIPTION OF THE FIGURES [0018] FIG.1 illustrates the alignment of humanized heavy chain sequences for the selected three humanized heavy chain sequences compared to the consensus and parental heavy chain amino acid sequences. “HC_hu (IGHV13) BM”, “ HC_hu (IGHV118) BM”, and “ HC_hu (IGHV146) BM”, were selected as the three humanized VH sequences. Figure discloses SEQ ID NOS 205, 20, 206, 172, 207, 174, 208, and 176, respectively, in order of appearance. [0019] FIG.2 illustrates the alignment of humanized light chain sequences for the selected three humanized light chain sequences compared to the consensus and parental light chain amino acid sequences. “LC_hu (IGKV228) BM”, “LC_hu (IGKV230) BM”, and “LC_hu (IGKV2D 30) BM”, were selected as the three humanized VK sequences. Figure discloses SEQ ID NOS 177, 55, 209, 173, 210, 175, 211, and 177, respectively, in order of appearance. [0020] FIG.3 shows interim results for kinetics data of the selected humanized antibodies with heavy and light chain pairs. [0021] FIG.4 shows the qualitative binding assessment data of all IgG antibodies and HC and LC combinations. [0022] FIG.5 shows the sensogram and kinetic data of parental and LC1 in combination of HC1, 2 and 3 for the humanized antibodies for session 2. [0023] FIG.6 shows the sensogram and kinetic data of parental and LC1 in combination of HC1, 2 and 3 for the humanized antibodies for session 3. [0024] FIG.7 shows activation marker data after 24 hour stimulation ((0.5 µg/ml aCD3+co- stim). [0025] FIG.8 shows proliferation data after 72 hour stimulation (0.5 µg/ml aCD3+2.5µg/ml co- stim). [0026] FIG.9 shows activation marker after 24 hour stimulation (0.5 µg/ml aCD3+co-stim). [0027] FIG.10 shows activation marker after 24 hour stimulation (0.5 µg/ml aCD3+co-stim). [0028] FIG.11 shows proliferation data after 72 hour stimulation, as well as pAKT levels after 24 hour stimulation. 5 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0029] FIG.12 shows mouse activation markers after 24 hour stimulation (0.5 µg/ml aCD3+co- stim). [0030] FIG 13 shows mouse activation markers after 72 hour stimulation (0.5µg/ml aCD3+co- stim). [0031] FIG.14 shows activation markers after 24 hour stimulation. Assessed in two separate experiments and representative of 1 early activation marker (CD69). DETAILED DESCRIPTION [0032] Embodiments according to the present disclosure will be described more fully hereinafter. Aspects of the disclosure may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting. [0033] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All nucleotide sequences provided herein are presented in the 5′ to 3′ direction. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, particular, non-limiting exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the disclosure is not entitled to antedate such disclosure by virtue of prior disclosure. [0034] The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art. See, e.g., Sambrook and Russell eds, (2001) Molecular Cloning: A Laboratory Manual, 3rd edition; the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., N.Y.); MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and 6 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Pat. No.4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds, (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); and Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology. [0035] The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. [0036] The practice of the present technology will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art. [0037] Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination. Moreover, the disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. [0038] Unless explicitly indicated otherwise, all specified embodiments, features, and terms intend to include both the recited embodiment, feature, or term and biological equivalents thereof. [0039] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of 1.0 or 0.1, as appropriate, or alternatively by a variation of +/- 15 %, or alternatively 10%, or alternatively 5%, or alternatively 2% and such ranges are included. It is to be understood, 7 4861-9829-0104.1 Atty. Docket No.: 116639-2660 although not always explicitly stated, that all numerical designations are preceded by the term “about”. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art. [0040] Throughout this disclosure, various publications, patents and published patent specifications may be referenced by an identifying citation or by an Arabic numeral. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure in their entirety to more fully describe the state of the art to which this disclosure pertains. Definitions [0041] As used in the description of the disclosure and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. [0042] As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but do not exclude others. As used herein, the transitional phrase consisting essentially of (and grammatical variants) is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basic and novel characteristic(s) of the recited embodiment. Thus, the term “consisting essentially of” as used herein should not be interpreted as equivalent to “comprising”. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions disclosed herein. Aspects defined by each of these transition terms are within the scope of the present disclosure. [0043] The term “about” as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. [0044] As used herein, the terms “increased”, “decreased”, “high”, “low” or any grammatical variation thereof refer to a variation of about 90%, 80%, 50%, 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the reference composition, polypeptide, protein, etc. 8 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0045] The terms or “acceptable,” “effective,” or “sufficient” when used to describe the selection of any components, ranges, dose forms, etc. disclosed herein intend that said component, range, dose form, etc. is suitable for the disclosed purpose. [0046] Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). [0047] An equivalent of a polynucleotide or polypeptide (referred to herein as the reference) shares at least 50% (or at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 97%) identity to the reference (as compared using a comparison program such as BLAST, when run under default parameters), and when referring to a polynucleotide encodes the same polypeptide or similar polypeptide as the one encoded by the reference, or encodes an equivalent of the polypeptide encoded by the reference. [0048] To arrive at a position or a consecutive segment of a test sequence equivalent to (or corresponding to) an/a amino acid/nucleotide residue or a consecutive segment of a reference sequence, a sequence alignment is performed between the test and reference sequences. The positions or segments aligned to each other are determined as equivalents. [0049] The term “analogue” refers to an equivalent having one or more modified amino acids and one or more amino acids replaced with another amino acid. Such modification may include but is not limited to conjugation with a molecule (for example, a small molecule, a cytotoxic molecule, a linker, a pH-sensitive linker, and/or a thiol linker), sialylation, polysialylation, O- glycosylation, N-glycosylation, myristoylation, palmitoylation, isoprenylation or prenylation, glipyatyon, lipoylation, phosphopantetheinylation, ethanolamine phosphoglycerol attachment, diphthamide formation, hypusine formation, acylation, acetylation, formylation, alkylation, methylation, amidation, citrullination, deamidation, eliminylation, ISGylation, SUMOylation, ubiquitination, neddylation, pupylation, biotinylation, carbamylation, oxidation, pegylation, glycation, carbamylation, carbonylation, spontaneous isopeptide bond formation, butyrylation, gamma-carboxylation, malonylation, hydroxylation, iodination, nucleotide addition, phosphate ester (O-linked) or phosphoramidate (N-linked) formation, phosphorylation, adenylylation, uridylylation, propionylation, pyroglutamate formation, S-glutathionylation, S-nitrosylation, S- sulfenylation, S-sulfinylation, S-sulfonylation, succinylation, and/or sulfation. The term 9 4861-9829-0104.1 Atty. Docket No.: 116639-2660 “albumin equivalent,” comprises, or consists essentially of, or yet further consists of, polypeptides which can be expressed at a reasonable quantity and which still retains or improves on certain albumin properties, including the binding of the albumin fragment to an FcRn receptor, as is known in the art or described herein. [0050] The term “affinity tag” refers to a polypeptide that may be included within a fusion protein to allow detection of the fusion protein and/or purification of the fusion protein from the cellular milieu using a ligand that is able to bind to, i.e., has affinity for, the affinity tag. The ligand may be, but is not limited to, an antibody, a resin, or a complementary polypeptide. An affinity tag may comprise a small peptide, commonly a peptide of approximately 4 to 16 amino acids in length, or it may comprise a larger polypeptide. Commonly used affinity tags include polyarginine, FLAG, V5, polyhistidine, c-Myc, Strep II, maltose binding protein (MBP), N- utilization substance protein A (NusA), thioredoxin (Trx), and glutathione S-transferase (GST), among others (for examples, see GST Gene Fusion System Handbook - Sigma-Aldrich). In an embodiment, the affinity tag is a polyhistidine tag, for example a His6 tag (SEQ ID NO: 159). The inclusion of an affinity tag in a fusion protein, or polypeptide allows the fusion protein to be purified from the cellular milieu by affinity purification, using an affinity medium that is able to tightly and specifically bind the affinity tag. The affinity medium may comprise, for example, a metal-charged resin or a ligand covalently linked to a stationary phase (matrix) such as agarose or metal beads. For example, polyhistidine tagged fusion proteins or polypeptides (also referred to as His tagged fusion proteins) can be recovered by immobilized metal ion chromatography using Ni²⁺ or Co²⁺ loaded resins, anti-FLAG affinity gels may be used to capture FLAG tagged fusion proteins, and glutathione cross-linked to a solid support such as agarose may be used to capture GST tagged fusion proteins or polypeptides. [0051] As used herein the terms “purification”, “purifying”, or “separating” refer to the process of isolating one or more polypeptides from a complex mixture, such as a cell lysate or a mixture of polypeptides. The purification, separation, or isolation need not be complete, i.e., some components of the complex mixture may remain with the one or more polypeptides after the purification process. However, the product of purification should be enriched for the one or more polypeptides relative to the complex mixture before purification and a significant portion of the other components initially present within the complex mixture should be removed by the purification process. 10 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0052] The term “cell” as used herein may refer to either a prokaryotic or eukaryotic cell, optionally obtained from a subject or a commercially available source. [0053] “Eukaryotic cells” comprise all of the life kingdoms except monera. They can be easily distinguished through a membrane-bound nucleus. Animals, plants, fungi, and protists are eukaryotes or organisms whose cells are organized into complex structures by internal membranes and a cytoskeleton. The most characteristic membrane-bound structure is the nucleus. Unless specifically recited, the term “host” includes a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Non-limiting examples of eukaryotic cells or hosts include simian, bovine, porcine, murine, rat, avian, reptilian and human, e.g., HEK293 cells, Chinese Hamster Ovary (CHO) cells and 293T cells. [0054] “Prokaryotic cells” that usually lack a nucleus or any other membrane-bound organelles and are divided into two domains, bacteria and archaea. In addition to chromosomal DNA, these cells can also contain genetic information in a circular loop called an episome. Bacterial cells are very small, roughly the size of an animal mitochondrion (about 1-2 μm in diameter and 10 μm long). Prokaryotic cells feature three major shapes: rod shaped, spherical, and spiral. Instead of going through elaborate replication processes like eukaryotes, bacterial cells divide by binary fission. Examples include but are not limited to Bacillus bacteria, E. coli bacterium, and Salmonella bacterium. [0055] The term “encode” as it is applied to nucleic acid sequences refers to a polynucleotide which is said to “encode” a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, can be transcribed and/or translated to produce the mRNA for the polypeptide and/or a fragment thereof. The antisense strand is the complement of such a nucleic acid, and the encoding sequence can be deduced therefrom. [0056] As used herein, “expression” refers to the process by which polynucleotides are transcribed into mRNA and/or the process by which the transcribed mRNA is subsequently being translated into peptides, polypeptides, or proteins. If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell. [0057] The term “isolated” or a grammatical variation thereof as used herein refers to molecules or biologicals or cellular materials being substantially free from other materials. 11 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0058] As used herein, the term “functional” may be used to modify any molecule, biological, or cellular material to intend that it accomplishes a particular, specified effect. [0059] As used herein, the terms “nucleic acid sequence” and “polynucleotide” are used interchangeably to refer to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, this term includes, but is not limited to, single-, double-, or multi- stranded DNA or RNA, genomic DNA, complementary DNA (cDNA), DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. In certain embodiments, the polynucleotide comprises and/or encodes a messenger RNA (mRNA), a short hairpin RNA, and/or small hairpin RNA. In one embodiment, the polynucleotide is or encodes an mRNA. In certain embodiments, the polynucleotide is a double-strand (ds) DNA, such as an engineered ds DNA or a double stranded cDNA synthesized from a single-stranded RNA. [0060] The terms “polynucleotide” and “oligonucleotide” are used interchangeably and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. Polynucleotides can have any three-dimensional structure and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, RNAi, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polynucleotide. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The term also refers to both double- and single-stranded molecules. Unless otherwise specified or required, any embodiment disclosed herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. [0061] A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide 12 4861-9829-0104.1 Atty. Docket No.: 116639-2660 is RNA. Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. [0062] The term “isolated” or “recombinant” as used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs or RNAs, respectively that are present in the natural source of the macromolecule as well as polypeptides. The term “isolated or recombinant nucleic acid” is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state. The term “isolated” is also used herein to refer to polynucleotides, polypeptides and proteins that are isolated from other cellular proteins and is meant to encompass both purified and recombinant polypeptides. In other embodiments, the term “isolated or recombinant” means separated from constituents, cellular and otherwise, in which the cell, tissue, polynucleotide, peptide, polypeptide, protein, antibody or fragment(s) thereof, which are normally associated in nature. For example, an isolated cell is a cell that is separated from tissue or cells of dissimilar phenotype or genotype. An isolated polynucleotide is separated from the 3′ and 5′ contiguous nucleotides with which it is normally associated in its native or natural environment, e.g., on the chromosome. As is apparent to those of skill in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody or fragment(s) thereof, does not require “isolation” to distinguish it from its naturally occurring counterpart. [0063] As used herein, the terms “engineered” “synthetic” “recombinant” and “non-naturally occurring” are interchangeable and indicate intentional human manipulation, for example, a modification from its naturally occurring form, and/or a sequence optimization. [0064] The terms “equivalent” or “biological equivalent” are used interchangeably when referring to a particular molecule, biological, or cellular material and intend those having minimal homology while still maintaining desired structure or functionality (for example, having a similar functional activity). It should be understood, without being explicitly stated that when referring to an equivalent or biological equivalent to a reference polypeptide, protein, or polynucleotide, that an equivalent or biological equivalent has the recited structural relationship to the reference polypeptide, protein, or polynucleotide and equivalent or substantially equivalent 13 4861-9829-0104.1 Atty. Docket No.: 116639-2660 biological activity. For example, non-limiting examples of equivalent polypeptides, proteins, or polynucleotides include a polypeptide, protein or polynucleotide having at least 60%, or alternatively at least 65%, or alternatively at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% or 97% identity thereto or for the reference polypeptide, polynucleotide or protein sequences across the length of the reference polypeptide, polynucleotide or protein sequences, respectively. Alternatively in one embodiment, an equivalent polypeptide is one that is encoded by a polynucleotide or its complement that hybridizes under conditions of high stringency to a polynucleotide encoding such reference polypeptide sequences and that have substantially equivalent or equivalent biological activity. Conditions of high stringency are described herein and incorporated herein by reference. Alternatively, an equivalent thereof is a polypeptide encoded by a polynucleotide or a complement thereto, having at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% identity, or at least 97% sequence identity across the length of the equivalent polynucleotide to the reference polynucleotide, e.g., the wild-type polynucleotide. Such equivalent polypeptides have the same biological or similar activity as the reference polypeptide. [0065] A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) having a certain percentage (for example, 80%, 85%, 90%, or 95%) of “sequence identity” to another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences across the length of the reference polynucleotide or polypeptide . The alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in Current Protocols in Molecular Biology (Ausubel et al., eds.1987) Supplement 30, section 7.7.18, Table 7.7.1. In certain embodiments, default parameters are used for alignment. A non-limiting exemplary alignment program is BLAST, using default parameters. Other exemplary programs include BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov/cgi- 14 4861-9829-0104.1 Atty. Docket No.: 116639-2660 bin/BLAST. Sequence identity and percent identity can be determined by incorporating them into clustalW (available at the web address: https://www.genome.jp/tools/clustalw, last accessed on March 25, 2024). [0066] “Homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence that may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. An “unrelated” or “non- homologous” sequence shares less than 40% identity, or alternatively less than 25% identity, with one of the sequences of the present disclosure. “Homology” or “identity” or “similarity” can also refer to two nucleic acid molecules that hybridize under stringent conditions. [0067] As used herein, the term “at least 90% identical” refers to an identity of two compared sequences (polynucleotides or polypeptides) of about 90% to about 100%. It also include an identity of at least at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, about 91% to about 100%, about 92% to about 100%, about 93% to about 100%, about 94% to about 100%, about 95% to about 100%, about 96% to about 100%, about 97% to about 100%, about 98% to about 100%, or about 99% to about 100%. [0068] As used herein, the terms “retain” “similar” and “same” are used interchangeably while describing a function, an activity or an functional activity of a polynucleotide, a protein and/or a peptide, referring to a functional activity of at least about 20% (including but not limited to: at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or about 100%) of the activity of the reference protein, polynucleotide and/or peptide. [0069] It is to be inferred without explicit recitation and unless otherwise intended, that when the present disclosure relates to a polypeptide, protein, polynucleotide or antibody, an equivalent or a biologically equivalent of such is intended within the scope of this disclosure. As used herein, the term “biological equivalent thereof” is intended to be synonymous with “equivalent thereof” when referring to a reference protein, antibody, fragment, polypeptide or nucleic acid, intends 15 4861-9829-0104.1 Atty. Docket No.: 116639-2660 those having minimal homology while still maintaining desired structure or functionality. Unless specifically recited herein, it is contemplated that any polynucleotide, polypeptide or protein mentioned herein also includes equivalents thereof. In another aspect when referring to an antibody or fragment thereof, the equivalent thereof competes with the binding of the antibody or antigen binding fragment to its antigen under a competitive ELISA assay. [0070] “Hybridization” refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized via hydrogen bonding between the bases of the nucleotide residues. The hydrogen bonding may occur by Watson-Crick base pairing, Hoogstein binding, or in any other sequence-specific manner. The complex may comprise two strands forming a duplex structure, three or more strands forming a multi-stranded complex, a single self-hybridizing strand, or any combination of these. A hybridization reaction may constitute a step in a more extensive process, such as the initiation of a PCR reaction, or the enzymatic cleavage of a polynucleotide by a ribozyme. [0071] Examples of stringent hybridization conditions include: incubation temperatures of about 25° C. to about 37° C.; hybridization buffer concentrations of about 6×SSC to about 10×SSC; formamide concentrations of about 0% to about 25%; and wash solutions from about 4×SSC to about 8×SSC. Examples of moderate hybridization conditions include: incubation temperatures of about 40° C. to about 50° C.; buffer concentrations of about 9×SSC to about 2×SSC; formamide concentrations of about 30% to about 50%; and wash solutions of about 5×SSC to about 2×SSC. Examples of high stringency conditions include: incubation temperatures of about 55° C. to about 68° C.; buffer concentrations of about 1×SSC to about 0.1×SSC; formamide concentrations of about 55% to about 75%; and wash solutions of about 1×SSC, 0.1×SSC, or deionized water. In general, hybridization incubation times are from 5 minutes to 24 hours, with 1, 2, or more washing steps, and wash incubation times are about 1, 2, or 15 minutes. SSC is 0.15 M NaCl and 15 mM citrate buffer. It is understood that equivalents of SSC using other buffer systems can be employed. [0072] The term “protein”, “peptide” and “polypeptide” are used interchangeably and in their broadest sense to refer to a compound of two or more subunits of amino acids, amino acid analogs or peptidomimetics. The subunits may be linked by peptide bonds. In another aspect, the subunit may be linked by other bonds, e.g., ester, ether, etc. A protein or peptide must contain at 16 4861-9829-0104.1 Atty. Docket No.: 116639-2660 least two amino acids and no limitation is placed on the maximum number of amino acids which may comprise a protein’s or peptide’s sequence. As used herein the term “amino acid” refers to either natural and/or unnatural or synthetic amino acids, including glycine and both the D and L optical isomers, amino acid analogs and peptidomimetics. [0073] As used herein, a consecutive amino acid sequence refers to a sequence having at least two amino acids. However, it is noted that a consecutive amino acid sequence of a first part and a second part does not limit the amino acid sequence to have the first part directly conjugated to the second part. It is also possible that the first part is linked to the second part via a third part, such as a link, thus forming one consecutive amino acid sequence. [0074] A polynucleotide disclosed herein can be delivered to a cell or tissue using a gene delivery vehicle. “Gene delivery,” “gene transfer” “mRNA-based delivery”, “transducing,” and the like as used herein, are terms referring to the introduction of an exogenous polynucleotide (sometimes referred to as a “transgene”) into a host cell, irrespective of the method used for the introduction. Such methods include a variety of well-known techniques such as vector-mediated gene transfer (by, e.g., viral infection/transfection, or various other protein-based or lipid-based gene delivery complexes, including for example protamine complexes, lipid nanoparticles, polymeric nanoparticles, lipid-polymer hybrid nanoparticles, and inorganic nanoparticles, or combinations thereof) as well as techniques facilitating the delivery of “naked” polynucleotides (such as electroporation, “gene gun” delivery and various other techniques used for the introduction of polynucleotides). The introduced polynucleotide can be unmodified or can comprise one or more modifications; for example, a modified mRNA may comprise ARCA capping; enzymatic polyadenylation to add a tail of 100-250 adenosine residues (SEQ ID NO: 160); and substitution of one or both of cytidine with 5-methylcytidine and/or uridine with pseudouridine. The introduced polynucleotide may be stably or transiently maintained in the host cell. Stable maintenance typically requires that the introduced polynucleotide either contains an origin of replication compatible with the host cell or integrates into a replicon of the host cell such as an extrachromosomal replicon (e.g., a plasmid) or a nuclear or mitochondrial chromosome. A number of vectors are known to be capable of mediating transfer of genes to mammalian cells, as is known in the art and described herein. 17 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0075] A “plasmid” is an extra-chromosomal DNA molecule separate from the chromosomal DNA which is capable of replicating independently of the chromosomal DNA. In many cases, it is circular and double-stranded. Plasmids provide a mechanism for horizontal gene transfer within a population of microbes and typically provide a selective advantage under a given environmental state. Plasmids may carry genes that provide resistance to naturally occurring antibiotics in a competitive environmental niche, or alternatively the proteins produced may act as toxins under similar circumstances. [0076] “Plasmids” used in genetic engineering are called “plasmid vectors”. Many plasmids are commercially available for such uses. The gene to be replicated is inserted into copies of a plasmid containing genes that make cells resistant to particular antibiotics and a multiple cloning site (MCS, or polylinker), which is a short region containing several commonly used restriction sites allowing the easy insertion of DNA fragments at this location. Another major use of plasmids is to make large amounts of proteins. In this case, researchers grow bacteria containing a plasmid harboring the gene of interest. Just as the bacterium produces proteins to confer its antibiotic resistance, it can also be induced to produce large amounts of proteins from the inserted gene. [0077] A “yeast artificial chromosome” or “YAC” refers to a vector used to clone large DNA fragments (larger than 100 kb and up to 3000 kb).It is an artificially constructed chromosome and contains the telomeric, centromeric, and replication origin sequences needed for replication and preservation in yeast cells. Built using an initial circular plasmid, they are linearized by using restriction enzymes, and then DNA ligase can add a sequence or gene of interest within the linear molecule by the use of cohesive ends. Yeast expression vectors, such as YACs, YIps (yeast integrating plasmid), and YEps (yeast episomal plasmid), are extremely useful as one can get eukaryotic protein products with posttranslational modifications as yeasts are themselves eukaryotic cells, however YACs have been found to be more unstable than BACs, producing chimeric effects. [0078] A “viral vector” is defined as a recombinantly produced virus or viral particle that comprises a polynucleotide to be delivered into a host cell, either in vivo, ex vivo or in vitro. [0079] Examples of viral vectors include retroviral vectors, adenovirus vectors, adeno-associated virus vectors, herpes simplex virus vectors, alphavirus vectors and the like. 18 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0080] As used herein, the term “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term “mammal” includes both human and non-human mammals, e.g., canine, bovine, feline, simian, equine, or murine. [0081] In one aspect, a “subject” or “patient” to whom the therapies such as for example an anti- JMAL therapy or a combination of anti-JMAL therapy and immune checkpoint inhibitor is administered is preferably a mammal such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e.g., monkey or human). The subject or patient can be a human, such as an adult patient or a pediatric patient. [0082] An “effective amount” or “efficacious amount” refers to the amount of an agent, or combined amounts of two or more agents, that, when administered for the treatment of a mammal or other subject, is sufficient to effect such treatment for the disease. The “effective amount” will vary depending on the agent(s), the disease and its severity and the age, weight, etc., of the subject to be treated. [0083] As used herein, a biological sample, or a sample, can be obtained from a subject, cell line or cultured cell or tissue. Exemplary samples include, but are not limited to, cell sample, tissue sample, tumor biopsy, liquid samples such as blood and other liquid samples of biological origin (including, but not limited to, ocular fluids (aqueous and vitreous humor), peripheral blood, sera, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, Cowper’s fluid or pre-ejaculatory fluid, female ejaculate, sweat, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, ascites, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions/flushing, synovial fluid, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, or umbilical cord blood. In some instances, the sample is a tumor/cancer biopsy. [0084] A “solid tumor” is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors can be benign or malignant. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors include sarcomas, carcinomas, and lymphomas. The solid tumor can be localized or metastatic. 19 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0085] In certain embodiments, the terms “disease” “disorder” and “condition” are used interchangeably herein, referring to a cancer, a status of being diagnosed with a cancer, or a status of being suspect of having a cancer. [0086] As used herein, a “cancer” is a disease state characterized by the presence in a subject of cells demonstrating abnormal uncontrolled replication and may be used interchangeably with the term “tumor.” In some embodiments, the cancer is a leukemia or a lymphoma. “Cell associated with the cancer” refers to those subject cells that demonstrate abnormal uncontrolled replication. In certain embodiments, the cancer is acute myeloid leukemia or acute lymphoblastic leukemia. As used herein a “leukemia” is a cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells. The specific condition of acute myeloid leukemia (AML) – also referred to as acute myelogenous leukemia or acute myeloblastic leukemia – is a cancer of the myeloid origin blood cells, characterized by the rapid growth of abnormal myeloid cells that accumulate in the bone marrow and interfere with the production of normal blood cells. The specific condition of acute lymphoblastic leukemia (ALL) – also referred to as acute lymphocytic leukemia or acute lymphoid leukemia – is a cancer of the white blood cells, characterized by the overproduction and accumulation of malignant, immature leukocytes (lymphoblasts) resulting a lack of normal, healthy blood cells. As used herein a “lymphoma” is a cancer of the blood characterized by the development of blood cell tumors and symptoms of enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired. [0087] As used herein, a “cancer” is a disease state characterized by the presence in a subject of cells demonstrating abnormal uncontrolled replication and may be used interchangeably with the term “tumor.” In some embodiments, the cancer is a leukemia or a lymphoma. “Cell associated with the cancer” refers to those subject cells that demonstrate abnormal uncontrolled replication. In certain embodiments, the cancer is acute myeloid leukemia or acute lymphoblastic leukemia. As used herein a “leukemia” is a cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells. The specific condition of acute myeloid leukemia (AML) – also referred to as acute myelogenous leukemia or acute myeloblastic leukemia – is a cancer of the myeloid origin blood cells, characterized by the rapid growth of abnormal myeloid cells that accumulate in the bone marrow and interfere with the production of normal blood cells. The specific condition of acute lymphoblastic leukemia (ALL) – also 20 4861-9829-0104.1 Atty. Docket No.: 116639-2660 referred to as acute lymphocytic leukemia or acute lymphoid leukemia – is a cancer of the white blood cells, characterized by the overproduction and accumulation of malignant, immature leukocytes (lymphoblasts) resulting a lack of normal, healthy blood cells. As used herein a “lymphoma” is a cancer of the blood characterized by the development of blood cell tumors and symptoms of enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired. [0088] “Cancer”, which is also referred to herein as “tumor”, is a known medically as an uncontrolled division of abnormal cells in a part of the body, benign or malignant. In one embodiment, cancer refers to a malignant neoplasm, a broad group of diseases involving unregulated cell division and growth, and invasion to nearby parts of the body. Non-limiting examples of cancers include carcinomas, sarcomas, leukemia and lymphoma, e.g., colon cancer, colorectal cancer, rectal cancer, gastric cancer, esophageal cancer, head and neck cancer, breast cancer, brain cancer, lung cancer, stomach cancer, liver cancer, gall bladder cancer, or pancreatic cancer. In one embodiment, the term “cancer” refers to a solid tumor, which is an abnormal mass of tissue that usually does not contain cysts or liquid areas, including but not limited to, sarcomas, carcinomas, and certain lymphomas (such as Non-Hodgkin's lymphoma). In another embodiment, the term “cancer” refers to a liquid cancer, which is a cancer presenting in body fluids (such as, the blood and bone marrow), for example, leukemias (cancers of the blood) and certain lymphomas. [0089] Additionally or alternatively, a cancer may refer to a local cancer (which is an invasive malignant cancer confined entirely to the organ or tissue where the cancer began), a metastatic cancer (referring to a cancer that spreads from its site of origin to another part of the body), a non-metastatic cancer, a primary cancer (a term used describing an initial cancer a subject experiences), a secondary cancer (referring to a metastasis from primary cancer or second cancer unrelated to the original cancer), an advanced cancer, an unresectable cancer, or a recurrent cancer. As used herein, an advanced cancer refers to a cancer that had progressed after receiving one or more of: the first line therapy, the second line therapy, or the third line therapy. [0090] As used herein, the term “extracellular matrix” (ECM) is a three-dimensional network of extracellular macromolecules, such as collagen, enzymes, and glycoproteins, that provide structural and biochemical support to surrounding cells. It is an essential component of the tumor 21 4861-9829-0104.1 Atty. Docket No.: 116639-2660 microenvironment. Cancer development and progression are associated with increased ECM deposition and crosslink, while the chemical and physical signals elicited from ECM are necessary for cancer cell proliferation and invasion. In one embodiment, the ECM of a cancer comprises a peri-cancerous cell or tissue. [0091] In certain embodiments, the terms “disease” “disorder” and “condition” are used interchangeably herein, referring to a cancer, a status of being diagnosed with a cancer, or a status of being suspect of having a cancer. [0092] As used herein, the term “detectable marker” refers to at least one marker capable of directly or indirectly, producing a detectable signal. A non-exhaustive list of this marker includes enzymes which produce a detectable signal, for example by colorimetry, fluorescence, luminescence, such as horseradish peroxidase, alkaline phosphatase, β-galactosidase, glucose-6 phosphate, dehydrogenase, chromophores such as fluorescent, luminescent dyes, groups with electron density detected by electron microscopy or by their electrical property such as conductivity, amperometry, voltammetry, impedance, detectable groups, for example whose molecules are of sufficient size to induce detectable modifications in their physical and/or chemical properties, such detection may be accomplished by optical methods such as diffraction, surface plasmon resonance, surface variation, the contact angle change or physical methods such as atomic force spectroscopy, tunnel effect, or radioactive molecules such as ³²P, ³⁵S , ⁸⁹Zr or ¹²⁵I. [0093] As used herein, the term “purification marker” refers to at least one marker useful for purification or identification. A non-exhaustive list of this marker includes His, lacZ, GST, maltose-binding protein, NusA, BCCP, c-myc, CaM, FLAG, GFP, YFP, cherry, thioredoxin, poly(NANP), V5, Snap, HA, chitin-binding protein, Softag 1, Softag 3, Strep, or S-protein. Suitable direct or indirect fluorescence marker comprise FLAG, GFP, YFP, RFP, dTomato, cherry, Cy3, Cy 5, Cy 5.5, Cy 7, DNP, AMCA, Biotin, Digoxigenin, Tamra, Texas Red, rhodamine, Alexa fluors, FITC, TRITC or any other fluorescent dye or hapten. [0094] As used herein, “immunophenotyping” refers to the analysis of heterogeneous populations of cells for the purpose of identifying the presence and proportions of the various populations in the sample. Antibodies are used to identify cells by detecting specific antigens (termed markers) expressed by these cells. In an aspect, the cell samples are characterized by 22 4861-9829-0104.1 Atty. Docket No.: 116639-2660 immunophenotyping using techniques such as flow cytometry. In alternative aspects, characterizations of the various cell types, (such as T cells, B cells and their subsets) present in a cell sample may be carried out using any suitable methodology such as reverse transcriptase polymerase chain reaction (RT-PCR) or immunocytochemistry (IHC). [0095] The phrase “first line” or “second line” or “third line” or “fourth line” or “fifth line” refers to the order of treatment received by a patient. First line therapy regimens are treatments given first, whereas second or third line therapy are given after the first line therapy or after the second line therapy, respectively. The National Cancer Institute defines first line therapy as “the first treatment for a disease or condition. In patients with cancer, primary treatment can be surgery, chemotherapy, radiation therapy, or a combination of these therapies. First line therapy is also referred to those skilled in the art as “primary therapy and primary treatment”. Typically, a patient is given a subsequent chemotherapy regimen because the patient did not show a positive clinical or sub-clinical response to the first line therapy or the first line therapy has stopped. [0096] As used herein, the term “T cell,” refers to a type of lymphocyte that matures in the thymus. T cells play an important role in cell-mediated immunity and are distinguished from other lymphocytes, such as B cells, by the presence of a T-cell receptor on the cell surface. T- cells may either be isolated or obtained from a commercially available source. “T cell” includes all types of immune cells expressing CD3 including T-helper cells (CD4+ cells), cytotoxic T- cells (CD8+ cells), natural killer T-cells, T-regulatory cells (Treg), Tissue-resident memory T cells (TRM cells), stem T cells and gamma-delta T cells. A “cytotoxic cell” includes CD8+ T cells, natural-killer (NK) cells, and neutrophils, which cells are capable of mediating cytotoxicity responses. Non-limiting examples of commercially available T-cell lines include lines BCL2 (AAA) Jurkat (ATCC® CRL-2902™), BCL2 (S70A) Jurkat (ATCC® CRL-2900™), BCL2 (S87A) Jurkat (ATCC® CRL-2901™), BCL2 Jurkat (ATCC® CRL-2899™), Neo Jurkat (ATCC® CRL-2898™), TALL-104 cytotoxic human T cell line (ATCC # CRL-11386). Further examples include but are not limited to mature T-cell lines, e.g., such as Deglis, EBT-8, HPB- MLp-W, HUT 78, HUT 102, Karpas 384, Ki 225, My-La, Se-Ax, SKW-3, SMZ-1 and T34; and immature T- cell lines, e.g., ALL-SIL, Be13, CCRF-CEM, CML-T1, DND-41, DU.528, EU-9, HD-Mar, HPB-ALL, H-SB2, HT-1, JK-T1, Jurkat, Karpas 45, KE-37, KOPT-K1, K-T1, L- KAW, Loucy, MAT, MOLT-1, MOLT 3, MOLT-4, MOLT 13, MOLT-16, MT-1, MT-ALL, 23 4861-9829-0104.1 Atty. Docket No.: 116639-2660 P12/Ichikawa, Peer, PER0117, PER-255, PF-382, PFI-285, RPMI-8402, ST-4, SUP-T1 to T14, TALL-1, TALL-101, TALL-103/2, TALL-104, TALL-105, TALL-106, TALL-107, TALL-197, TK-6, TLBR-1, -2, -3, and -4, CCRF-HSB-2 (CCL-120.1), J.RT3-T3.5 (ATCC TIB-153), J45.01 (ATCC CRL-1990), J.CaM1.6 (ATCC CRL-2063), RS4;11 (ATCC CRL-1873), CCRF-CEM (ATCC CRM-CCL-119); and cutaneous T-cell lymphoma lines, e.g., HuT78 (ATCC CRM-TIB- 161), MJ[G11] (ATCC CRL-8294), HuT102 (ATCC TIB-162). Null leukemia cell lines, including but not limited to REH, NALL-1, KM-3, L92-221, are a another commercially available source of immune cells, as are cell lines derived from other leukemias and lymphomas, such as K562 erythroleukemia, THP-1 monocytic leukemia, U937 lymphoma, HEL erythroleukemia, HL60 leukemia, HMC-1 leukemia, KG-1 leukemia, U266 myeloma. Non- limiting exemplary sources for such commercially available cell lines include the American Type Culture Collection, or ATCC, (http://www.atcc.org/) and the German Collection of Microorganisms and Cell Cultures (https://www.dsmz.de/). [0097] “Frequency” of cells expressing any one particular molecule, biomarker, or antigen refers to the likelihood of or ratio of cells expressing the molecule, biomarker, or antigen compared to a population of T cells at large. [0098] As used herein, the terms “antibody,” “antibodies” and “immunoglobulin” includes whole antibodies and any antigen binding fragment or a single chain thereof. Thus the term “antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule. The terms “antibody,” “antibodies” and “immunoglobulin” also include immunoglobulins of any isotype, fragments of antibodies which retain specific binding to antigen, including, but not limited to, Fab, Fab′, F(ab)₂, Fv, scFv, dsFv, Fd fragments, dAb, VH, VL, VhH, and V-NAR domains; minibodies, diabodies, triabodies, tetrabodies and kappa bodies; multispecific antibody fragments formed from antibody fragments and one or more isolated. Examples of such include, but are not limited to a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, at least one portion of a binding protein, chimeric antibodies, humanized antibodies, single-chain antibodies, and fusion proteins comprising an antigen-binding portion of an antibody and a non-antibody protein. The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen. The constant 24 4861-9829-0104.1 Atty. Docket No.: 116639-2660 regions of the antibodies (Abs) may mediate the binding of the immunoglobulin to host tissues. The term “anti-” when used before a protein name, anti-JAML for example, refers to a monoclonal or polyclonal antibody that binds and/or has an affinity to a particular protein. [0099] The antibodies can be polyclonal, monoclonal, multispecific (e.g., bispecific antibodies), humanized and antibody fragments of each thereof, so long as they exhibit the desired biological activity. Antibodies can be isolated from any suitable biological source, e.g., murine, rat, sheep and canine or recombinantly produced. [0100] The term “antibody fragment” refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody. In some embodiments, the term “antibody fragment” refers to at least one portion of an intact antibody, or recombinant variants thereof, and refers to the antigen binding domain, e.g., an antigenic determining variable region of an intact antibody, that is sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, Fv fragments, scFv antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, and multi-specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody. An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3)(see U.S. Pat. No.6,703,199, which describes fibronectin polypeptide minibodies). “Fab” means a monovalent antigen- binding fragment of an immunoglobulin that is composed of the light chain and part of the heavy chain. F(ab′)2 means a bivalent antigen-binding fragment of an immunoglobulin that contains both light chains and part of both heavy chains. [0101] As used herein, the term “Fv fragment” or “variable domain fragment” refers to a VH domain and a VL domain of an antibody specifically binding to an antigen, both domains forming together a Fv fragment. In some embodiment, Fv fragments means an antibody fragment comprising the V_H and V_L domains of an antibody, wherein these domains are present in a single 25 4861-9829-0104.1 Atty. Docket No.: 116639-2660 polypeptide chain. Generally, the Fv fragment polypeptide further comprises a polypeptide linker between the VH and VL domains polypeptide that enables the scFv to form. [0102] The term “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, as used herein an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise V_L-linker-V_H or may comprise V_H-linker-V_L. [0103] As used herein, the term “antibody heavy chain” refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. [0104] As used herein, the term “antibody light chain” refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. Kappa (κ) and lambda (λ) light chains refer to the two major antibody light chain isotypes. [0105] As used herein, the term “synthetic antibody” means an antibody, which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage. The term should also be construed to mean an antibody, which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art. [0106] As used herein, the term “antibody variant” includes synthetic and engineered forms of antibodies which are altered such that they are not naturally occurring, e.g., antibodies that comprise at least two heavy chain portions but not two complete heavy chains (such as, domain deleted antibodies or minibodies); multi-specific forms of antibodies (e.g., bi-specific, tri- specific, etc.) altered to bind to two or more different antigens or to different epitopes on a single antigen); heavy chain molecules joined to scFv molecules and the like. In addition, the term “antibody variant” includes multivalent forms of antibodies (e.g., trivalent, tetravalent, etc., antibodies that bind to three, four or more copies of the same antigen. 26 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0107] As used herein, the term “antigen” or “Ag” is defined as a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full-length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit a desired immune response. Moreover, the skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a biological fluid. [0108] The term “bispecific antibody” refers to an antibody that can simultaneously bind to two different receptors, epitopes or antigens. The bispecific antibodies of the instant disclosure may target and bind antigens on the same cells or different cells. In some aspects, the bispecific antibodies bind to JAML and a second molecule on the T cell. JAML may be expressed on a T cell. In some aspects, the second molecule is expressed on the same T cell. In one aspect, the bispecific antibodies of the claimed disclosure increase target specificity for JAML expressing T cells, while limiting undesirable off-target activity. In some aspects, the bispecific bind and modulate the expression or activity of JAML in or on the T cell or the JAML expressing T cells. [0109] In some other aspects as described herein, the bispecific antibodies bind to JAML and a tumor or cancer antigen expressed by a tumor or cancer cell, including but not limited to tumor associated antigens or tumor specific antigens. The bispecific antibody may simultaneously bind and activate the JAML expressing T cell, while also binding a tumor or cancer antigen. Thus, the activated T cell is able to target the tumor or cancer cells expressing the antigen. In some aspects the antigen is overexpressed or specifically expressed by the tumor or cancer cell. Therefore, the bispecific antibodies of the present disclosure can be configured to bind to overexpressed or specifically expressed tumor or cancer antigens, including tumor associated or tumor specific 27 4861-9829-0104.1 Atty. Docket No.: 116639-2660 antigens, that are identifiable markers of the tumor or cancer cell, rather than undesirably binding to off-target cells and antigens. [0110] As used herein, “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous antibody population. Monoclonal antibodies are highly specific, as each monoclonal antibody is directed against a single determinant on the antigen. The antibodies may be detectably labeled, e.g., with a radioisotope, an enzyme which generates a detectable product, a fluorescent protein, and the like. The antibodies may be further conjugated to other moieties, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), and the like. The antibodies may also be bound to a solid support, including, but not limited to, polystyrene plates or beads, and the like. [0111] Monoclonal antibodies may be generated using hybridoma techniques or recombinant DNA methods known in the art. A hybridoma is a cell that is produced in the laboratory from the fusion of an antibody-producing lymphocyte and a non-antibody producing cancer cell, usually a myeloma or lymphoma. A hybridoma proliferates and produces a continuous sample of a specific monoclonal antibody. Alternative techniques for generating or selecting antibodies include in vitro exposure of lymphocytes to antigens of interest, and screening of antibody display libraries in cells, phage, or similar systems. [0112] The term “human antibody” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies disclosed herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Thus, as used herein, the term “human antibody” refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, C_L, C_H domains (e.g., C_H1, CH2, CH3), hinge, (VL, VH)) is substantially non-immunogenic in humans, with only minor sequence changes or variations. Similarly, antibodies designated primate (monkey, baboon, chimpanzee, etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like) and other mammals designate such species, sub-genus, genus, sub-family, family specific antibodies. 28 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Further, chimeric antibodies include any combination of the above. Such changes or variations optionally retain or reduce the immunogenicity in humans or other species relative to non- modified antibodies. Thus, a human antibody is distinct from a chimeric or humanized antibody. It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes. Further, when a human antibody is a single chain antibody, it can comprise a linker peptide that is not found in native human antibodies. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin. [0113] "Effector functions" deriving from the interaction of an antibody Fc region with certain Fc receptors, include but are not necessarily limited to Clq binding, complement dependent cytotoxicity (CDC), Fc receptor binding, FcyR-mediated effector functions such as ADCC and antibody dependent cell-mediated phagocytosis (ADCP), and down regulation of a cell surface receptor (e.g., the B cell receptor; BCR). Such effector functions generally require the Fc region to be combined with an antigen binding domain (e.g., an antibody variable domain). [0114] An "Fc receptor" or "FcR" is a receptor that binds to the Fc region of an immunoglobulin. FcRs that bind to an IgG antibody comprise receptors of the FcyR family, including allelic variants and alternatively spliced forms of these receptors. The FcyR family consists of three activating (FcyRI, FcyRIII, and FcyRIV in mice; FcyRIA, FcyRIIA, and FcyRIIIA in humans) and one inhibitory (FcyRIIb, or equivalently FcyRIIB) receptor. Various properties of human FcyRs are summarized in Table 1. The majority of innate effector cell types co-express one or more activating FcyR and the inhibitory FcyRIIb, whereas natural killer (NK) cells selectively express one activating Fc receptor (FcyRIII in mice and FcyRIIIA in humans) but not the inhibitory FcyRIIb in mice and humans. Human IgGl binds to most human Fc receptors and is considered equivalent to murine IgG2a with respect to the types of activating Fc receptors that it binds to. [0115] An "Fc region" (fragment crystallizable region) or "Fc domain" or "Fc" refers to the C- terminal region of the heavy chain of an antibody that mediates the binding of the immunoglobulin to host tissues or factors, including binding to Fc receptors located on various 29 4861-9829-0104.1 Atty. Docket No.: 116639-2660 cells of the immune system (e.g., effector cells) or to the first component (Clq) of the classical complement system. Thus, an Fc region comprises the constant region of an antibody excluding the first constant region immunoglobulin domain (e.g., CHI or CL). In IgG, IgA and IgD antibody isotypes, the Fc region comprises CH2 and CH3 constant domains in each of the antibody's two heavy chains; IgM and IgE Fc regions comprise three heavy chain constant domains (CH domains 2-4) in each polypeptide chain. For IgG, the Fc region comprises immunoglobulin domains Cy2 and Cy3 and the hinge between Cyl and Cyl. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position C226 or P230 (or an amino acid between these two amino acids) to the carboxy -terminus of the heavy chain, wherein the numbering is according to the EU index as in Kabat. Kabat et al. (1991) Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, MD; see also figures 3c-3f of U.S. Pat. App. Pub. No.2008/0248028. The CH2 domain of a human IgG Fc region extends from about amino acid 231 to about amino acid 340 of SEQ ID NO: 139, whereas the CH3 domain is positioned on C-terminal side of a CH2 domain in an Fc region, i.e., it extends from about amino acid 341 to about amino acid 447 of an IgG (including a C-terminal lysine). As used herein, the Fc region may be a native sequence Fc, including any allotypic variant, or a variant Fc (e.g., a non-naturally occurring Fc). Fc may also refer to this region in isolation or in the context of an Fc-comprising protein polypeptide such as a "binding protein comprising an Fc region," also referred to as an "Fc fusion protein" (e.g., an antibody or immunoadhesin). [0116] As used herein, a human antibody is “derived from” a particular germline sequence if the antibody is obtained from a system using human immunoglobulin sequences, e.g., by immunizing a transgenic mouse carrying human immunoglobulin genes or by screening a human immunoglobulin gene library. A human antibody that is “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequence of human germline immunoglobulins. A selected human antibody typically is at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences). In 30 4861-9829-0104.1 Atty. Docket No.: 116639-2660 certain cases, a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In certain cases, the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene. [0117] A “human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobulin sequences. The term also intends recombinant human antibodies. Methods to making these antibodies are described herein. [0118] In one embodiment, an antibody as used herein may be a recombinant antibody. The term “recombinant human antibody”, as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. Methods to making these antibodies are described herein. [0119] As used herein, chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from antibody variable and constant region genes belonging to different species. 31 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0120] As used herein, the term “humanized antibody” or “humanized immunoglobulin” refers to a human/non-human chimeric antibody that contains a minimal sequence derived from non- human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a variable region of the recipient are replaced by residues from a variable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity. Humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. The humanized antibody can optionally also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, a non-human antibody containing one or more amino acids in a framework region, a constant region or a CDR, that have been substituted with a correspondingly positioned amino acid from a human antibody. In general, humanized antibodies are expected to produce a reduced immune response in a human host, as compared to a non-humanized version of the same antibody. The humanized antibodies may have conservative amino acid substitutions which have substantially no effect on antigen binding or other antibody functions. Conservative substitutions groupings include: glycine-alanine, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine- valine, serine-threonine and asparagine-glutamine. The antibodies of the present disclosure may bind to an antigen or molecule. In some aspects, the antigens or molecules are expressed in a T cell, tumor cell, or tissue of a subject. [0121] The terms “polyclonal antibody” or “polyclonal antibody composition” as used herein refer to a preparation of antibodies that are derived from different B-cell lines. They are a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope. [0122] As used herein, the term “antibody derivative”, comprises a full-length antibody or a fragment of an antibody, wherein one or more of the amino acids are chemically modified by alkylation, pegylation, acylation, ester formation or amide formation or the like, e.g., for linking the antibody to a second molecule. This includes, but is not limited to, pegylated antibodies, cysteine-pegylated antibodies, and variants thereof. [0123] Complementarity determining regions (CDRs) are part of the variable region of an antibody or a T cell receptor generated by B-cell s and T-cells respectively, wherein these 32 4861-9829-0104.1 Atty. Docket No.: 116639-2660 molecules bind to their specific antigen (also called epitope). In certain embodiments, the terms “variable region” and “variable domain” are used interchangeably, referring to the polypeptide of a light or heavy chain of an antibody that varies greatly in its sequence of amino acid residues from one antibody to another, and that determines the conformation of the combining site which confers the specificity of the antibody for a particular antigen. In a further embodiment, the variable region is about 90 amino acids long to about 200 amino acids long, including but not limited to about 100 amino acids long, or alternatively about 110 amino acids long, or alternatively about 120 amino acids long, or alternatively about 130 amino acids long, or alternatively about 140 amino acids long, or alternatively about 150 amino acids long, or alternatively about 160 amino acids long, or alternatively about 170 amino acids long, or alternatively about 180 amino acids long, or alternatively about 190 amino acids long. In certain embodiments, a variable region of an amino acid sequence, as used herein, refers to that the first about 100 amino acids, or alternatively about 110 amino acids, or alternatively about 120 amino acids, or alternatively about 130 amino acids, or alternatively about 140 amino acids, or alternatively about 150 amino acids of the amino acid sequence (including or excluding a signal peptide if applicable) is the variable region. [0124] A set of CDRs constitutes a paratope also called an antigen-binding site, which is a part of an antibody that recognizes and binds to an antigen. There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, optionally from the amino terminus to the carboxyl terminus, on the amino acid sequence of a variable region of an antigen receptor, such as a heavy chain or a light chain. As used herein, CDRn refers to a CDRn in an immunoglobulin chain or derived from an immunoglobulin chain, wherein the number n is selected from 1-3. In one embodiment, CDRLn refers to a CDRn in a light chain or derived from a light chain, wherein the number n is selected from 1-3; while CDRHn refers to a CDRn in a heavy chain or derived from a heavy chain, wherein the number n is selected from 1-3. In certain embodiments, framework region (FR) refers to the part of a variable region which is not a CDR. In certain embodiments, FRn refers to a FR in a heavy chain or a light chain or derived from a heavy chain or a light chain, and wherein the number n is selected from 1-4. In certain embodiments, a variable region comprises or consists essentially of, or yet further consists of the following (optionally following the order as provided, and further optionally from the amino terminus to the carboxyl terminus): FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. 33 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0125] Variable regions and/or CDRs of an antibody or a fragment thereof can be determined by one of skill in the art, for example, using publicly or commercially available tools. Non-limiting examples of such tools include, IgBlast (accessible at www.ncbi.nlm.nih.gov/igblast/), Scaligner (available from drugdesigntech at www.scaligner.com/), IMGT rules and/or tools (see, for example, www.imgt.org/IMGTScientificChart/Nomenclature/IMGT-FRCDRdefinition.html, also accessible at www.imgt.org/), Chothia Canonical Assignment (accessible at www.bioinf.org.uk/abs/chothia.html), Antigen receptor Numbering And Receptor CalssificatiIon (ANARCI, accessible at opig.stats.ox.ac.uk/webapps/newsabdab/sabpred/anarci/), the Kabat numbering method/scheme (e.g., Kabat, E.A., et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242,) or the Paratome web server (accessible at www.ofranlab.org/paratome/, see Vered Kunik, et al, Nucleic Acids Research, Volume 40, Issue W1, 1 July 2012, Pages W521–W524). [0126] Junction adhesion molecule-like protein (JAML) is a human protein encoding gene (also known as AMICA1 and Gm638) encoding a transmembrane protein of the plasma membrane of leukocytes. JAML may control migration and activation of leukocytes through interactions with the plasma membrane receptor Coxsackie and adenovirus receptor CXADR found on adjacent epithelial and endothelial cells. Interactions between JAML and CXADR may mediate the activation of gamma-delta T cells, which reside in the epithelia. Upon epithelial CXADR- binding, JAML may induce downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases, resulting in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair. JAML may also control the transmigration of leukocytes within epithelial and endothelial tissues through adhesive interactions with epithelial and endothelial CXADR. Further, binding of JAML to its endogenous ligand Coxsackie and adenovirus receptor (CXADR) provides co-stimulation leading to cellular proliferation and cytokine and growth factor production. The protein sequence of JAML is publicly available at https://www.uniprot.org/uniprot/Q86YT9 (accessed on October 28, 2021) and reproduced below: 10 20 30 40 50 MFCPLKLILL PVLLDYSLGL NDLNVSPPEL TVHVGDSALM GCVFQSTEDK 60 70 80 90 100 34 4861-9829-0104.1 Atty. Docket No.: 116639-2660 CIFKIDWTLS PGEHAKDEYV LYYYSNLSVP IGRFQNRVHL MGDILCNDGS 110 120 130 140 150 LLLQDVQEAD QGTYICEIRL KGESQVFKKA VVLHVLPEEP KELMVHVGGL 160 170 180 190 200 IQMGCVFQST EVKHVTKVEW IFSGRRAKEE IVFRYYHKLR MSVEYSQSWG 210 220 230 240 250 HFQNRVNLVG DIFRNDGSIM LQGVRESDGG NYTCSIHLGN LVFKKTIVLH 260 270 280 290 300 VSPEEPRTLV TPAALRPLVL GGNQLVIIVG IVCATILLLP VLILIVKKTC 310 320 330 340 350 GNKSSVNSTV LVKNTKKTNP EIKEKPCHFE RCEGEKHIYS PIIVREVIEE 360 370 380 390 EEPSEKSEAT YMTMHPVWPS LRSDRNNSLE KKSGGGMPKT QQAF (SEQ ID NO: 161) [0127] In general, agonistic antibodies have the ability to bind and activate the target receptor in a way that mimics the activity of the ligand. An agonistic anti-junction adhesion molecule-like protein (JAML) antibody (anti-JAML antibody) intends an antibody, antigen binding fragment, derivative or other modification as described herein that recognizes and binds the JAML protein. The agonizing antibodies described in the application may bind to JAML to increase, enhance, upregulate, and/or otherwise modulate the activity of the JAML receptor and/or the JAML expressing cell. Such activities may include proliferation and cell signaling activities of the cell upon which the JAML receptor is expressed. The agonistic antibodies of this disclosure target and specifically bind to JAML. In some aspects, the agonistic antibody binds the receptor in a manner that mimics the binding of the physiological ligand resulting in antibody-mediated agonism. In some aspects, treatment with an agonistic anti-JAML antibodies significantly impedes tumor growth, which may be mediated via stimulation of tumor infiltrating CD8+ T cells. Immunotherapies utilizing agonistic antibodies, especially those targeting trimeric receptors like 4-1BB or CD40, require antibody crosslinking via Fcg receptors expressed on APCs for efficient T cell activation. Depending on the Immunoglobulin (IgG) antibody subclass, they bind to and can thus get crosslinked by Fcg receptors with different affinities. (Li et al., 2011 Science.2011 Aug 19;333(6045):1030-4; Nimmerjahn et al., 2005 Science 3101510– 1512.; Claus et al., 2019 Sci Transl Med.2019 Jun 12;11(496):eaav5989). Thus, the antibody subclass and the availability, type and degree of expression of Fcg receptors on APCs are critical determinants of immunotherapy treatment efficacy. However, the agonistic activity of antibodies 35 4861-9829-0104.1 Atty. Docket No.: 116639-2660 targeting co-stimulatory receptors depends on a variety of factors and does not always require Fc cross-linking. Such factors include but are not limited to antibody affinity, Fc modifications like glycoengineering or point mutations, the antibody subclass and antigen expression. [0128] “Immune response” broadly refers to the antigen-specific responses of lymphocytes to foreign substances. The terms “immunogen” and “immunogenic” refer to molecules with the capacity to elicit an immune response. All immunogens are antigens, however, not all antigens are immunogenic. An immune response disclosed herein can be humoral (via antibody activity) or cell-mediated (via T cell activation). The response may occur in vivo or in vitro. The skilled artisan will understand that a variety of macromolecules, including proteins, nucleic acids, fatty acids, lipids, lipopolysaccharides and polysaccharides have the potential to be immunogenic. The skilled artisan will further understand that nucleic acids encoding a molecule capable of eliciting an immune response necessarily encode an immunogen. The artisan will further understand that immunogens are not limited to full-length molecules, but may include partial molecules. [0129] As used herein, the term “inducing an immune response in a subject” or “modulating an immune response” are terms well understood in the art and intends that an increase or decrease of at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 100-fold, at least about 500-fold, or at least about 1000-fold or more in an immune response (i.e. T cell or antibody response) to an antigen (or epitope) and can be detected or measured by various methods known in the art. For example, the frequency or activity of antigen-specific T cells can be measured by multiple methods, including, but not limited to, flow cytometry, RNA- sequencing or in vitro assays. [0130] As used herein, the term “modulating activity” refers to increasing or decreasing the activity of specific T cell populations associated with an immune response. Modulating of activity may be accomplished by the administration of agents, including antibodies, that target and bind to specific T cell receptors in order to activate the T cell population expressing that molecule. Modulation may occur when the T cells are engaged by costimulatory ligands, agonistic antibodies or cytokines. In some aspects, modulating activity may include the administration of an agent that targets a molecule on a T cell. In some aspects, the molecule is JAML and the agent is an antibody that targets JAML, thus activating the JAML expressing T cell. 36 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0131] An “immunotherapy agent” means a type of cancer treatment which uses a patient’s own immune system to fight cancer, including but not limited to a physical intervene, a chemical substance, a biological molecule or particle, a cell, a tissue or organ, or any combinations thereof, enhancing or activating or initiating a patient's immune response against cancer. Non- limiting examples of immunotherapy agents include antibodies, immune regulators, checkpoint inhibitors, an antisense oligonucleotide (ASO), a RNA interference (RNAi), a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) system, a viral vector, an anti-cancer cell therapy (e.g., transplanting an anti-cancer immune cell optionally amplified and/or activated in vivo, or administering an immune cell expressing a chimeric antigen receptor (CAR)), a CAR therapy, and cancer vaccines. [0132] As used herein, immune checkpoint refers to a regulator and/or modulator of the immune system (such as an immune response, an anti-tumor immune response, a nascent anti-tumor immune response, an anti-tumor immune cell response, an anti-tumor T cell response, and/or an antigen recognition of T cell receptor in the process of immune response). Their interaction activates either inhibitory or activating immune signaling pathways. Thus a checkpoint may contain one of the two signals: an stimulatory immune checkpoint that stimulates an immune response, and an inhibitory immune checkpoint inhibiting an immune response. In some embodiments, the immune checkpoint is crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets. In some embodiments, the immune checkpoints are present on T cells, antigen-presenting cells (APCs) and/or tumor cells. [0133] As used herein, the term “recombinant host cell,” “recombinant cell,” “engineered host cell,” or “engineered cell,” means a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” or “cell” as used herein. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in total DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation and/or change. A host cell includes a cell transfected or infected in vivo or in vitro with a recombinant vector, an expression 37 4861-9829-0104.1 Atty. Docket No.: 116639-2660 vector, or a nucleic acid encoding an antibody of the present disclosure. A host cell, which comprises a recombinant vector, expression vector, or a nucleic acid encoding an antibody disclosed herein, may also be referred to as a “recombinant host cell,” “engineered host cell,” or “engineered cell”. [0134] As used herein, the term “host cell” refers to a cell, which may be used in a process for purifying an immunogenic protein or recombinant antibody in accordance with the present disclosure. Such host cell expresses the protein of interest (the antibody disclosed herein). A host cell may also be referred to as a protein-expressing cell. “Host cell” refers not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. [0135] A host cell, according to the present disclosure, may be, but is not limited to, prokaryotic cells, eukaryotic cells, archeobacteria, bacterial cells, insect cells, yeast, mammal cells, and/or plant cells. Bacteria envisioned as host cells can be either gram-negative or gram-positive, e.g. Escherichia coli, Erwinia sp., Klebsellia sp., Lactobacillus sp. or Bacillus subtilis. In some embodiments, the host cell is a yeast cell. In that embodiment, the yeast host cell is selected from the group consisting of Saccharomyces cerevisiae, Hansenula polymorpha, and Pichia pastoris. [0136] A “composition” is intended to mean a combination of active agent and another compound or composition, inert (for example, a detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers. Carriers also include pharmaceutical excipients and additives proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri, tetra-oligosaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1- 99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/antibody components, which can also function in a buffering 38 4861-9829-0104.1 Atty. Docket No.: 116639-2660 capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this technology, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol. A “pharmaceutical composition” is intended to include the combination of an active polypeptide, polynucleotide or antibody with a carrier, inert or active such as a solid support, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. [0137] “Pharmaceutically acceptable carriers” refers to any diluents, excipients, or carriers that may be used in the compositions disclosed herein. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. They may be selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. [0138] “Administration” can be completed in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents are known in the art. Route of administration can also be determined and method of 39 4861-9829-0104.1 Atty. Docket No.: 116639-2660 determining the most effective route of administration are known to those of skill in the art and will vary with the composition used for treatment, the purpose of the treatment, the health condition or disease stage of the subject being treated, and target cell or tissue. Non-limiting examples of route of administration include oral administration, nasal administration, injection, and topical application. [0139] An agent of the present disclosure can be administered for therapy by any suitable route of administration. It will also be appreciated that the optimal route will vary with the condition and age of the recipient, and the disease being treated. [0140] The term “effective amount” refers to a quantity sufficient to achieve a desired effect. In the context of therapeutic or prophylactic applications, the effective amount will depend on the type and severity of the condition at issue and the characteristics of the individual subject, such as general health, age, sex, body weight, and tolerance to pharmaceutical compositions. With respect to immunogenic compositions, in some embodiments the effective amount will depend on the intended use, the degree of immunogenicity of a particular antigenic compound, and the health/responsiveness of the subject's immune system, in addition to the factors described above. The skilled artisan will be able to determine appropriate amounts depending on these and other factors. [0141] In the case of an in vitro application, in some embodiments the effective amount will depend on the size and nature of the application in question. It will also depend on the nature and sensitivity of the in vitro target and the methods in use. The skilled artisan will be able to determine the effective amount based on these and other considerations. The effective amount may comprise one or more administrations of a composition depending on the embodiment. [0142] “Simultaneous use” as used herein refers to the administration of the two compounds of the composition according to the disclosure in a single and identical pharmaceutical form or at the same time in two distinct pharmaceutical forms. [0143] “Separate use” as used herein refers to the administration, at the same time, of the two compounds of the composition according to the disclosure in distinct pharmaceutical forms. 40 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0144] “Sequential use” as used herein refers to the successive administration of the two compounds of the composition according to the disclosure, each in a distinct pharmaceutical form. [0145] The term “adjuvant” therapy refers to administration of a therapy or chemotherapeutic regimen to a patient in addition to the primary or initial treatment, such as after removal of a tumor by surgery. Adjuvant therapy is typically given to minimize or prevent a possible cancer reoccurrence. Alternatively, “neoadjuvant” therapy refers to administration of therapy or chemotherapeutic regimen before surgery, typically in an attempt to shrink the tumor prior to a surgical procedure to minimize the extent of tissue removed during the procedure. Additionally or alternatively, such adjuvant therapy potentials (i.e., sensitizes the subject to the original therapy) the subject may help reach one or more of clinical end points of the cancer treatment. [0146] The term “tissue” is used herein to refer to tissue of a living or deceased organism or any tissue derived from or designed to mimic a living or deceased organism. The tissue may be healthy, diseased, and/or have genetic mutations. The biological tissue may include any single tissue (e.g., a collection of cells that may be interconnected) or a group of tissues making up an organ or part or region of the body of an organism. The tissue may comprise a homogeneous cellular material or it may be a composite structure such as that found in regions of the body including the thorax which for instance can include lung tissue, skeletal tissue, and/or muscle tissue. Exemplary tissues include, but are not limited to those derived from liver, lung, thyroid, skin, pancreas, blood vessels, bladder, kidneys, brain, biliary tree, duodenum, abdominal aorta, iliac vein, heart and intestines, including any combination thereof. [0147] As used herein, “treating” or “treatment” of a disease in a subject refers to (1) preventing the symptoms or disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease or the symptoms of the disease. As understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of the present technology, beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease), stabilized (i.e., not worsening) state of a condition (including disease), delay or slowing of condition (including disease), progression, 41 4861-9829-0104.1 Atty. Docket No.: 116639-2660 amelioration or palliation of the condition (including disease), states and remission (whether partial or total), whether detectable or undetectable. In one aspect, the term “treatment” excludes prevention. [0148] The compositions used in accordance with the disclosure can be packaged in dosage unit form for ease of administration and uniformity of dosage. The term "unit dose" or "dosage" refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the composition calculated to produce the desired responses in association with its administration, i.e., the appropriate route and regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the result and/or protection desired. Precise amounts of the composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition. Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described herein. [0149] As used herein, the term “single chain antibodies” refer to antibodies formed by recombinant DNA techniques in which immunoglobulin heavy and light chain fragments are linked to the Fv region via an engineered span of amino acids. Various methods of generating single chain antibodies are known, including those described in U.S. Pat. No.4,694,778; Bird, Science 242:423-442 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879- 5883 (1988); Ward et al., Nature 334:54454 (1989); Skerra et al., Science 242:1038-1041 (1988). [0150] As used herein, the term “specifically binds,” with respect to an antibody, means an antibody or binding fragment thereof (e.g., Fv fragment or scFv) which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. However, such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross 42 4861-9829-0104.1 Atty. Docket No.: 116639-2660 reactivity does not itself alter the classification of an antibody as specific. In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, a chimeric antigen receptor, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, a chimeric antigen receptor recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A,” the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody. Modes for Carrying Out the Disclosure [0151] In some embodiments, the antibody or antibody fragment disclosed herein comprises heavy chain complementarity-determining regions 1-3 (CDRH1-3) and light chain complementarity-determining regions 1-3 (CDRL1-3) selected from Table 2 or Table 5. In some aspects, the combination of CDRH1-3 and CDRL1-3 is selected from a single row of Table 2 or Table 5, or equivalents of each thereof. [0152] In some embodiments, the antibody or antibody fragment disclosed herein comprises, or consists essentially of, or consists of a heavy chain variable sequence having at least 96%, at least 97%, at least 98% or at least 99% identity to a heavy chain variable amino acid sequence in Table 1 or Table 3 and/or a light chain variable sequence having at least 96%, at least 97%, at least 98% or at least 99% identity to a light chain variable amino acid sequence in Table 1 or Table 3. In a further aspect, the equivalent has the stated percent identify but retains 100% identity for each CDR region of the reference antibody or fragment thereof. [0153] In some embodiments, the Fv fragment further comprises a linker domain to generate a single chain variable fragment (scFv). scFv may be obtained by connecting the VH and the VL domains by a linker in a single polypeptide. In one embodiment, the linker domain is operably linked to the heavy chain variable domain and the light chain variable domain. In some embodiments, the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and the scFv retains the specificity of the intact antibody from which it is derived. In some aspects, the 43 4861-9829-0104.1 Atty. Docket No.: 116639-2660 linkers may include a length of 10-25 amino acid residue, or more preferably 15 to 20 amino acid residues, or most preferably 18 to 20 amino acid residues. [0154] In one embodiment, the flexible polypeptide linker includes, but are not limited to, (Gly4 Ser)4 (SEQ ID NO: 162) or (Gly4Ser)3 (SEQ ID NO: 163). In another embodiment, the linker includes multiple repeats of (Gly2Ser), (GlySer) or (Gly3Ser) (SEQ ID NO: 164). This may include a 15-mer (G4S)3 (SEQ ID NO: 163), or an 18-mer GGSSRSSSSGGGGSGGGG (SEQ ID NO: 165), or a the 20-mer (G4S)4 (SEQ ID NO: 162). In some other aspects, the linkers may include the peptide sequences of GSTSGSGKPGSGEGSTKG (SEQ ID NO: 166) (L1), KESGSVSSEQLAQFRSLD (SEQ ID NO: 167) (L2), EGKSSGSGSESKST (SEQ ID NO: 168) (L3), (GGGGS)3 (SEQ ID NO: 163) (L4), and GSAGSAAGSGEF (SEQ ID NO: 169) (L5). See Navabi P et al. Designing and generating a single-chain fragment variable (scFv) antibody against IL2Rα (CD25): An in silico and in vitro study. Iran J Basic Med Sci.2021 Mar;24(3):360-368. [0155] While the above linkers are provided, those of skill in the art will understand that the scFv fragments of the instant disclosure can utilize any conventional linker that can be utilized for connecting a VH and VL domain such that binding activity of the variable domains is maintained. Humanized Antibodies [0156] As demonstrated in the experimental examples section provided below, disclosed herein are JAML-specific humanized antibodies. Specific examples of the humanized antibodies include the following Heavy Chain and Light Chain Sequences: [0157] Humanized IgG1 parental E10 sequence – HC MDPKGSLSWRILLFLSLAFELSYGEVQLQESGAELARPGASVKLSCKASGYTFTSYGISW VKQRTGQGLEWIGEIYPRSGNTYYNEKFKGKATLTADKSSSTAYMELRSLTSEDSAVYF CARERYYGSSYAFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ 44 4861-9829-0104.1 Atty. Docket No.: 116639-2660 PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP G (SEQ ID NO: 135) signal peptide MDPKGSLSWRILLFLSLAFELSYG (SEQ ID NO: 170) Variable region EVQLQESGAELARPGASVKLSCKASGYTFTSYGISWVKQRTGQGLEWIGEIYPRSGNTY YNEKFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCARERYYGSSYAFDYWGQGTTL TVSS (SEQ ID NO: 20) CDR1-3 sequence GYTFTSYG (SEQ IYPRSGNT (SEQ ID ARERYYGSSYAFDY METDTLLLWVLLLWVPGSTGDIVLTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEW YLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVP YTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C (SEQ ID NO: 139) signal peptide METDTLLLWVLLLWVPGSTG (SEQ ID NO: 171) Variable region DIVLTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK (SEQ ID NO: 55) CDR1-3 sequence QSIVHSNGNTY (SEQ FQGSHVPYT (SEQ ID NO: ID NO: 101) KVS 128) MDPKGSLSWRILLFLSLAFELSYGQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGMS WVRQAPGQRLEWMGEIYPRSGNTYYSQKFQGRVTITADTSASTAYMELSSLRSEDTAV 45 4861-9829-0104.1 Atty. Docket No.: 116639-2660 YYCARERYYGSSYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPG (SEQ ID NO: 136) signal peptide MDPKGSLSWRILLFLSLAFELSYG (SEQ ID NO: 170) Variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGMSWVRQAPGQRLEWMGEIYPRSGN TYYSQKFQGRVTITADTSASTAYMELSSLRSEDTAVYYCARERYYGSSYAFDYWGQGT LVTVSS (SEQ ID NO: 172) CDR1-3 sequence GYTFTSYG (SEQ ID IYPRSGNT (SEQ ID ARERYYGSSYAFDY (SEQ METDTLLLWVLLLWVPGSTGDIVMTQSPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEW YLQKPGQSPQLLIYKVSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVP YTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C (SEQ ID NO: 140) signal peptide METDTLLLWVLLLWVPGSTG (SEQ ID NO: 171) Variable region DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRAS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGTKLEIK (SEQ ID NO: 173) CDR1-3 sequence 46 4861-9829-0104.1 Atty. Docket No.: 116639-2660 : u MDPKGSLSWRILLFLSLAFELSYGQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGIS WVRQAPGQGLEWMGEIYPRSGNTYYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTA VYYCARERYYGSSYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG (SEQ ID NO: 137) signal peptide MDPKGSLSWRILLFLSLAFELSYG (SEQ ID NO: 170) Variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGEIYPRSGNT YYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARERYYGSSYAFDYWGQGT LVTVSS (SEQ ID NO: 174) CDR1-3 sequence GYTFTSYG (SEQ ID IYPRSGNT (SEQ ID ARERYYGSSYAFDY (SEQ Q Q Q TYLN WFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSH VPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO: 141) signal peptide METDTLLLWVLLLWVPGSTG (SEQ ID NO: 171) 47 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Variable region DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLNWFQQRPGQSPRRLIYKVSNRD SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKLEIK (SEQ ID NO: 175) CDR1-3 sequence QSIVHSNGNTY (SEQ FQGSHVPYT (SEQ ID NO: [0163] Hu E10 HC3 MDPKGSLSWRILLFLSLAFELSYGQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGMS WVRQAPGQGLEWMGEIYPRSGNTYYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTA VYYCARERYYGSSYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG (SEQ ID NO: 138) signal peptide MDPKGSLSWRILLFLSLAFELSYG (SEQ ID NO: 170) Variable region QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGMSWVRQAPGQGLEWMGEIYPRSGN TYYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARERYYGSSYAFDYWGQG TLVTVSS (SEQ ID NO: 176) CDR1-3 sequence GYTFTSYG (SEQ ID IYPRSGNT (SEQ ID ARERYYGSSYAFDY (SEQ NO: 68) NO: 79) _{ID NO: 90)} 48 4861-9829-0104.1 Atty. Docket No.: 116639-2660 METDTLLLWVLLLWVPGSTGDVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLN WFQQRPGQSPRLLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSH VPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO: 142) signal peptide METDTLLLWVLLLWVPGSTG (SEQ ID NO: 171) Variable region DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLNWFQQRPGQSPRLLIYKVSNRD SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGTKLEIK (SEQ ID NO: 177) CDR1-3 sequence QSIVHSNGNTY (SEQ FQGSHVPYT (SEQ ID NO: Fc Mutations [0165] In some embodiments, the antibody or fragment thereof, or nucleic acid encoding same is conjugated or bound to a label or therapeutic agent. In one aspect, the antibody is an IgG antibody, conjugated to a label, and/or conjugated to a therapeutic agent. In some embodiments, the antibody is an IgG. In some embodiments, the antibody is a recombinant IgG antibody. In some embodiments, the antibody is an antibody fragment comprising an Fc portion mutated to alter (eliminate or enhance) FcR interactions. In one embodiment, the mutated Fc increases the half-life and/or increase the therapeutic efficacy of the antibody disclosed herein. In one embodiment, the mutated Fc portion comprises a LALA, LALA PG, N297, GASD/ALIE, DHS, YTE or LS mutation. In some embodiments, the Fc portion is glycan modified to alter, eliminate, or enhance FcR interactions, such as enzymatic or chemical addition or removal of glycans or expression in a cell line engineered with a defined glycosylating pattern. In some embodiments, the antibody comprises a YTE mutation. [0166] The present disclosure also contemplates isotype modification. By modifying the Fc region to have a different isotype, different functionalities can be achieved. For example, 49 4861-9829-0104.1 Atty. Docket No.: 116639-2660 changing to IgG1 can increase antibody dependent cell cytotoxicity, switching to class A can improve tissue distribution, and switching to class M can improve valency. [0167] Alternatively or additionally, it may be useful to combine amino acid modifications with one or more further amino acid modifications that alter C1q binding and/or the complement dependent cytotoxicity (CDC) function of the Fc region of an IL-23p19 binding molecule. The binding polypeptide of particular interest may be one that binds to C1q and displays complement dependent cytotoxicity. Polypeptides with pre-existing C1q binding activity, optionally further having the ability to mediate CDC may be modified such that one or both of these activities are enhanced. Amino acid modifications that alter C1q and/or modify its complement dependent cytotoxicity function are described in WO 2000/0042072. [0168] One can design an Fc region of an antibody with altered effector function, e.g., by modifying C1q binding and/or FcγR binding and thereby changing CDC activity and/or ADCC activity. “Effector functions” are responsible for activating or diminishing a biological activity (e.g., in a subject). Examples of effector functions include, but are not limited to: C1q binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell- mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor; BCR), etc. Such effector functions may require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.). [0169] For example, one can generate a variant Fc region of an antibody with improved C1q binding and improved FcγRIII binding (e.g., having both improved ADCC activity and improved CDC activity). Alternatively, if it is desired that effector function be reduced or ablated, a variant Fc region can be engineered with reduced CDC activity and/or reduced ADCC activity. In other embodiments, only one of these activities may be increased, and, optionally, also the other activity reduced (e.g., to generate an Fc region variant with improved ADCC activity, but reduced CDC activity and vice versa). [0170] Fc mutations can also be introduced and engineered to alter their interaction with the neonatal Fc receptor (FcRn) and improve their pharmacokinetic properties. A collection of human Fc variants with improved binding to the FcRn have been described (Shields et al., (2001). High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, 50 4861-9829-0104.1 Atty. Docket No.: 116639-2660 and FcRn and design of IgG1 variants with improved binding to the FcγR, (J. Biol. Chem. 276:6591-6604). A number of methods are known that can result in increased half-life (Kuo and Aveson, (2011)), including amino acid modifications may be generated through techniques including alanine scanning mutagenesis, random mutagenesis and screening to assess the binding to the neonatal Fc receptor (FcRn) and/or the in vivo behavior. Computational strategies followed by mutagenesis may also be used to select one of amino acid mutations to mutate. [0171] In some aspects, the antibody or antibody fragment further comprises a label. In some embodiments, the antibody is a chimeric antibody, a bispecific antibody, humanized antibody, a human antibody, or a fully human antibody. [0172] In some aspects, anti-JAML antibodies of the present invention have an Fc that binds to or has enhanced binding to FcyRIIb, which can provide enhanced agonism. See, e.g., WO 2012/087928; Li & Ravetch (2011) Science 333: 1030; Wilson et al. (2011) Cancer Cell 19: 101; White et al. (2011) J. Immunol.187: 1754. Variable regions described herein may be linked to Fc variants that enhance affinity for the inhibitory receptor FcyRIIb, e.g. to enhance apoptosis- inducing or adjuvant activity. Li & Ravetch (2012) Proc. Nat Ί Acad. Sci. (USA) 109: 10966; U.S. Patent Application Publication No.2014/0010812. Such variants may provide an antibody with immunomodulatory activities related to FcyRIIb+ cells, including for example B cells and monocytes. In some aspects, the Fc variants provide selectively enhanced affinity to FcyRIIb relative to one or more activating receptors. Such variants may also exhibit enhanced FcK- mediated cross-linking, resulting in enhanced therapeutic efficacy. Modifications for altering binding to FcyRIlb include one or more modifications at a position selected from the group consisting of 234, 235, 236, 237, 238, 239, 266, 267, 268, 271, 325, 326, 327, 328, 330, and 332. In some aspects, the Fc region comprising one or more mutations selected from G237D, P238D, H268D, P271G, and A330R. [0173] In other aspects, exemplary substitutions for enhancing FcyRIIb affinity include but are not limited to 234D, 234E, 234F, 234W, 235D, 235F, 235R, 235Y, 236D, 236N, 237D, 237N, 239D, 239E, 266M, 267D, 267E, 268D, 268E, 327D, 327E, 328F, 328W, 328Y, and 332E of SEQ ID NO: 152. Exemplary substitutions include 235Y, 236D, 239D, 266M, 267E, 268D, 268E, 328F, 328W, and 328Y. Other Fc variants for enhancing binding to FcyRlIb include 235Y-267E, 236D-267E, 239D-268D, 239D-267E, 267E-268D, 267E-268E, and 267E- 328F. 51 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Specifically, the S267E, G236D, S239D, L328F and I332E variants, including the S267E-L328F double variant, of human IgGl are of particular value in specifically enhancing affinity for the inhibitory FcyRIIb receptor. Chu et al. (2008) Mol. Immunol.45:3926; U.S. Patent Application Publication No.2006/024298; WO 2012/087928. [0174] Among them, alterations that improve the binding selectivity for FcγRIIb rather than for FcγRIIa (type R) are preferred, and alterations that improve the binding selectivity for FcγRIIb rather than for FcγRIIa (type H) are more preferred. Preferred examples of alterations of substituting an amino acid include, the alteration of substituting Gly at position 237 with Trp, the alteration of substituting Gly at position 237 with Phe, the alteration of substituting Pro at position 238 with Phe, the alteration of substituting Asn at position 325 with Met, the alteration of substituting Ser at position 267 with Ile, the alteration of substituting Leu at position 328 with Asp, the alteration of substituting Ser at position 267 with Val, the alteration of substituting Leu at position 328 with Trp, the alteration of substituting Ser at position 267 with Gln, the alteration of substituting Ser at position 267 with Met, the alteration of substituting Gly at position 236 with Asp, the alteration of substituting Ala at position 327 with Asn, the alteration of substituting Asn at position 325 with Ser, the alteration of substituting Leu at position 235 with Tyr, the alteration of substituting Val at position 266 with Met, the alteration of substituting Leu at position 328 with Tyr, the alteration of substituting Leu at position 235 with Trp, the alteration of substituting Leu at position 235 with Phe, the alteration of substituting Ser at position 239 with Gly, the alteration of substituting Ala at position 327 with Glu, the alteration of substituting Ala at position 327 with Gly, the alteration of substituting Pro at position 238 with Leu, the alteration of substituting Ser at position 239 with Leu, 52 4861-9829-0104.1 Atty. Docket No.: 116639-2660 the alteration of substituting Leu at position 328 with Thr, the alteration of substituting Leu at position 328 with Ser, the alteration of substituting Leu at position 328 with Met, the alteration of substituting Pro at position 331 with Trp, the alteration of substituting Pro at position 331 with Tyr, the alteration of substituting Pro at position 331 with Phe, the alteration of substituting Ala at position 327 with Asp, the alteration of substituting Leu at position 328 with Phe, the alteration of substituting Pro at position 271 with Leu, the alteration of substituting Ser at position 267 with Glu, the alteration of substituting Leu at position 328 with Ala, the alteration of substituting Leu at position 328 with Ile, the alteration of substituting Leu at position 328 with Gln, the alteration of substituting Leu at position 328 with Val, the alteration of substituting Lys at position 326 with Trp, the alteration of substituting Lys at position 334 with Arg, the alteration of substituting His at position 268 with Gly, the alteration of substituting His at position 268 with Asn, the alteration of substituting Ser at position 324 with Val, the alteration of substituting Val at position 266 with Leu, the alteration of substituting Pro at position 271 with Gly, the alteration of substituting Ile at position 332 with Phe, the alteration of substituting Ser at position 324 with Ile, the alteration of substituting Glu at position 333 with Pro, the alteration of substituting Tyr at position 300 with Asp, the alteration of substituting Ser at position 337 with Asp, the alteration of substituting Tyr at position 300 with Gln, the alteration of substituting Thr at position 335 with Asp, the alteration of substituting Ser at position 239 with Asn, the alteration of substituting Lys at position 326 with Leu, the alteration of substituting Lys at position 326 with Ile, 53 4861-9829-0104.1 Atty. Docket No.: 116639-2660 the alteration of substituting Ser at position 239 with Glu, the alteration of substituting Lys at position 326 with Phe, the alteration of substituting Lys at position 326 with Val, the alteration of substituting Lys at position 326 with Tyr, the alteration of substituting Ser at position 267 with Asp, the alteration of substituting Lys at position 326 with Pro, the alteration of substituting Lys at position 326 with His, the alteration of substituting Lys at position 334 with Ala, the alteration of substituting Lys at position 334 with Trp, the alteration of substituting His at position 268 with Gln, the alteration of substituting Lys at position 326 with Gln, the alteration of substituting Lys at position 326 with Glu, the alteration of substituting Lys at position 326 with Met, the alteration of substituting Val at position 266 with Ile, the alteration of substituting Lys at position 334 with Glu, the alteration of substituting Tyr at position 300 with Glu, the alteration of substituting Lys at position 334 with Met, the alteration of substituting Lys at position 334 with Val, the alteration of substituting Lys at position 334 with Thr, the alteration of substituting Lys at position 334 with Ser, the alteration of substituting Lys at position 334 with His, the alteration of substituting Lys at position 334 with Phe, the alteration of substituting Lys at position 334 with Gln, the alteration of substituting Lys at position 334 with Pro, the alteration of substituting Lys at position 334 with Tyr, the alteration of substituting Lys at position 334 with Ile, the alteration of substituting Gln at position 295 with Leu, the alteration of substituting Lys at position 334 with Leu, the alteration of substituting Lys at position 334 with Asn, the alteration of substituting His at position 268 with Ala, the alteration of substituting Ser at position 239 with Asp, 54 4861-9829-0104.1 Atty. Docket No.: 116639-2660 the alteration of substituting Ser at position 267 with Ala, the alteration of substituting Leu at position 234 with Trp, the alteration of substituting Leu at position 234 with Tyr, the alteration of substituting Gly at position 237 with Ala, the alteration of substituting Gly at position 237 with Asp, the alteration of substituting Gly at position 237 with Glu, the alteration of substituting Gly at position 237 with Leu, the alteration of substituting Gly at position 237 with Met, the alteration of substituting Gly at position 237 with Tyr, the alteration of substituting Ala at position 330 with Lys, the alteration of substituting Ala at position 330 with Arg, the alteration of substituting Glu at position 233 with Asp, the alteration of substituting His at position 268 with Asp, the alteration of substituting His at position 268 with Glu, the alteration of substituting Lys at position 326 with Asp, the alteration of substituting Lys with Ser at position 326 (EU numbering), the alteration of substituting Lys with Thr at position 326 (EU numbering), the alteration of substituting Val with Ile at position 323 (EU numbering), the alteration of substituting Val with Leu at position 323 (EU numbering), the alteration of substituting Val at position 323 with Met, the alteration of substituting Tyr at position 296 with Asp, the alteration of substituting Lys at position 326 with Ala, the alteration of substituting Lys at position 326 with Asn, and the alteration of substituting Ala at position 330 with Met of SEQ ID NO: 152. [0175] Furthermore, examples of preferred amino acid substitutions among these alterations include the alteration of substituting Gly at position 237 with Trp, the alteration of substituting Gly at position 237 with Phe, the alteration of substituting Ser at position 267 with Val, the alteration of substituting Ser at position 267 with Gln, the alteration of substituting His at position 268 with Asn, the alteration of substituting Pro at position 271 with Gly, 55 4861-9829-0104.1 Atty. Docket No.: 116639-2660 the alteration of substituting Lys at position 326 with Leu, the alteration of substituting Lys at position 326 with Gln, the alteration of substituting Lys at position 326 with Glu, the alteration of substituting Lys at position 326 with Met, the alteration of substituting Ser at position 239 with Asp, the alteration of substituting Ser at position 267 with Ala, the alteration of substituting Leu at position 234 with Trp, the alteration of substituting Leu at position 234 with Tyr, the alteration of substituting Gly at position 237 with Ala, the alteration of substituting Gly at position 237 with Asp, the alteration of substituting Gly at position 237 with Glu, the alteration of substituting Gly at position 237 with Leu, the alteration of substituting Gly at position 237 with Met, the alteration of substituting Gly at position 237 with Tyr, the alteration of substituting Ala at position 330 with Lys, the alteration of substituting Ala at position 330 with Arg, the alteration of substituting Glu at position 233 with Asp, the alteration of substituting His at position 268 with Asp, the alteration of substituting His at position 268 with Glu, the alteration of substituting Lys at position 326 with Asp, the alteration of substituting Lys at position 326 with Ser, the alteration of substituting Lys at position 326 with Thr, the alteration of substituting Val at position 323 with Ile, the alteration of substituting Val at position 323 with Leu, the alteration of substituting Val at position 323 with Met, the alteration of substituting Tyr at position 296 with Asp, the alteration of substituting Lys at position 326 with Ala, the alteration of substituting Lys at position 326 with Asn, and the alteration of substituting Ala at position 330 with Met of SEQ ID NO: 152. [0176] Enhanced specificity for FcyRIIb (as distinguished from FcyRIIaRi3i) may be obtained by adding the P238D substitution and other mutations (Mimoto et al. (2013) Protein. Eng. Des. 56 4861-9829-0104.1 Atty. Docket No.: 116639-2660 & Selection 26:589; WO 2012/1152410), as well as V262E and V264E (Yu et al. (2013) J. Am. Chem. Soc.135:9723, and WO 2014/184545. [0177] In certain aspects, the antibody is modified to increase its biological half-life. Various approaches are possible. For example, this may be done by increasing the binding affinity of the Fc region for FcRn. In one embodiment, the antibody is altered within the CHI or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Patent Nos.5,869,046 and 6,121,022 by Presta et al. Other exemplary Fc variants that increase binding to FcRn and/or improve pharmacokinetic properties include substitutions at positions 259, 308, and 434, including for example 2591, 308F, 428L, 428M, 434S, 434H, 434F, 434Y, and 434M. Other variants that increase Fc binding to FcRn include: 250E, 250Q, 428L, 428F, 250Q/428L (Hinton et al, (2004), J. Biol. Chem.279(8): 6213-6216, Hinton et al. (2006) Journal of Immunology 176:346-356), 256A, 272A, 305A, 307A, 311A, 312A, 378Q, 380A, 382A, 434A (Shields et al, (2001) Journal of Biological Chemistry, 276(9):6591- 6604), 252F, 252Y, 252W, 254T, 256Q, 256E, 256D, 433R, 434F, 434Y, 252Y/254T/256E, 433K/434F/436H (Dall’Acqua et al. (2002) Journal of Immunology, 169:5171-5180, Dall ‘ Acqua et al. , (2006), Journal of Biological Chemistry 281 :23514- 23524). See U.S. Patent No.8,367,805. [0178] Modification of certain conserved residues in IgG Fc (1253, H310, Q311, H433, N434), such as the N434A variant (Yeung et al. (2009) J. Immunol.182:7663), have been proposed as a way to increase FcRn affinity, thus increasing the half-life of the antibody in circulation. WO 98/023289. The combination Fc variant comprising M428L and N434S has been shown to increase FcRn binding and increase serum half-life up to five-fold. Zalevsky et al. (2010) Nat. Biotechnol.28: 157. The combination Fc variant comprising T307A, E380A and N434A modifications also extends half-life of IgGl antibodies. Petkova et al. (2006) Int. Immunol.18: 1759. In addition, combination Fc variants comprising M252Y-M428L, M428L-N434H, M428L-N434F, M428L-N434Y, M428L- N434A, M428L-N434M, and M428L-N434S variants have also been shown to extend half-life. WO 2009/086320. [0179] Further, a combination Fc variant comprising M252Y, S254T and T256E , increases half- life-nearly 4-fold. Dall’Acqua et al. (2006) J Biol. Chem.281 :23514. A related IgGl modification providing increased FcRn affinity but reduced pH dependence (M252Y-S254T- 57 4861-9829-0104.1 Atty. Docket No.: 116639-2660 T256E- H433K- N434F) has been used to create an IgGl construct (“MST-HN Abdeg”) for use as a competitor to prevent binding of other antibodies to FcRn, resulting in increased clearance of that other antibody, either endogenous IgG (e.g., in an autoimmune setting) or another exogenous (therapeutic) mAb. Vaccaro et al. (2005) Nat. Biotechnol.23 : 1283; WO 2006/130834. Other modifications for increasing FcRn binding are described in Yeung et al. (2010) J. Immunol.182:7663-7671; 6,277,375; 6,821,505; WO 97/34631; WO2002/060919. [0180] In certain embodiments, hybrid IgG isotypes may be used to increase FcRn binding, and potentially increase half-life. For example, an IgGl/IgG3 hybrid variant may be constructed by substituting IgGl positions in the CH2 and/or CH3 region with the amino acids from IgG3 at positions where the two isotypes differ. Thus a hybrid variant IgG antibody may be constructed that comprises one or more substitutions, e.g., 274Q, 276K, 300F, 339T, 356E, 358M, 384S, 392N, 397M, 4221, 435R, and 436F. In other embodiments described herein, an IgGl/IgG2 hybrid variant may be constructed by substituting IgG2 positions in the CH2 and/or CH3 region with amino acids from IgGl at positions where the two isotypes differ. Thus a hybrid variant IgG antibody may be constructed that comprises one or more substitutions, e.g., one or more of the following amino acid substitutions: 233E, 234L, 235L, -236G (referring to an insertion of a glycine at position 236), and 327 A. See U.S. Patent No, 8,629, 113. A hybrid of IgGl/IgG2/IgG4 sequences has been generated that purportedly increases serum half-life and improves expression, U.S. Patent No.7,867,491 (sequence number 18 therein). [0181] The serum half-life of the antibodies of the present invention can also be increased by pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with a polyethylene glycol (PEG) reagent, such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment. Preferably, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term “polyethylene glycol” is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (CI -CIO) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are 58 4861-9829-0104.1 Atty. Docket No.: 116639-2660 known in the art and can be applied to the antibodies described herein. See for example, EP 0154316 by Nishimura et al. and EP 0401384 by Ishikawa et al. [0182] Alternatively, under some circumstances it may be desirable to decrease the half- life of an antibody of the present invention, rather than increase it. Modifications such as 1253 A (Hornick et al. (2000) J. Nucl. Med.41 :355) and H435A/R, 1253 A or H310A (Kim et al. (2000) Eur. J. Immunol.29:2819) in Fc of human IgGl can decrease FcRn binding, thus decreasing half-life (increasing clearance) for use in situations where rapid clearance is preferred, such a medical imaging. See also Kenanova et al. (2005) Cancer Res.65:622. Other means to enhance clearance include formatting the antigen binding domains of the present invention as antibody fragments lacking the ability to bind FcRn, such as Fab fragments. Such modification can reduce the circulating half-life of an antibody from a couple of weeks to a matter of hours. Selective PEGylation of antibody fragments can then be used to fine-tune (increase) the half-life of the antibody fragments if necessary. Chapman et al. (1999) Nat. Biotechnol.17:780. Antibody fragments may also be fused to human serum albumin, e.g. in a fusion protein construct, to increase half-life. Yeh et al. (1992) Proc. Nat 7 Acad. Sci. (USA) 89: 1904. Alternatively, a bispecific antibody may be constructed with a first antigen binding domain of the present invention and a second antigen binding domain that binds to human serum albumin (HSA). See Int'l Pat. Appl. Pub. WO 2009/127691 and patent references cited therein. Alternatively, specialized polypeptide sequences can be added to antibody fragments to increase half- life, e.g. "ΧΤΕΝ" polypeptide sequences. Schellenberger et al. (2009) Nat. Biotechnol.27: 1186; Int'l Pat. Appl. Pub. WO 2010/091122. Additional Fc Variants [0183] When using an IgG4 constant domain, it is usually preferable to include the substitution S228P, which mimics the hinge sequence in IgGl and thereby stabilizes IgG4 molecules, e.g. reducing Fab-arm exchange between the therapeutic antibody and endogenous IgG4 in the patient being treated. Labrijn et al. (2009) Nat. Biotechnol.27:767; Reddy et al. (2000) J. Immunol.164: 1925. A potential protease cleavage site in the hinge of IgGl constructs can be eliminated by D221G and K222S modifications, increasing the stability of the antibody. See WO 2014/043344. [0184] The affinities and binding properties of an Fc variant for its ligands (Fc receptors) may be determined by a variety of in vitro assay methods (biochemical or immunological based assays) 59 4861-9829-0104.1 Atty. Docket No.: 116639-2660 known in the art including but not limited to, equilibrium methods {e.g., enzyme-linked immunosorbent assay (ELISA), or radioimmunoassay (RIA)), or kinetics {e.g., BIACORE® SPR analysis), and other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis and chromatography {e.g., gel filtration). These and other methods may utilize a label on one or more of the components being examined and/or employ a variety of detection methods including but not limited to chromogenic, fluorescent, luminescent, or isotopic labels. A detailed description of binding affinities and kinetics can be found in Paul, W. E., ed., Fundamental Immunology, 4th Ed., Lippincott-Raven, Philadelphia (1999), which focuses on antibody -immunogen interactions. [0185] In still other aspects, the glycosylation of an antibody is modified to increase or decrease effector function. For example, an aglycoslated antibody can be made that lacks all effector function by mutating the conserved asparagine residue at position 297 {e.g. N297A), thus abolishing complement and FcyRI binding. Bolt et al. (1993) Eur. J. Immunol.23 :403. See also Tao & Morrison (1989) J. Immunol.143 :2595 (using N297Q in IgGl to eliminate glycosylation at position 297). [0186] Although aglycosylated antibodies generally lack effector function, mutations can be introduced to restore that function. Aglycosylated antibodies, e.g. those resulting from N297A/C/D/or H mutations or produced in systems {e.g. E. coli) that do not glycosylate proteins, can be further mutated to restore FcyR binding, e.g. S298G and/or T299A/G/or H (WO 2009/079242), or E382V and M428I (Jung et al. (2010) Proc. Nat Ί Acad. Sci. (USA) 107:604). [0187] Glycoengineering can also be used to modify the anti-inflammatory properties of an IgG construct by changing the a2,6 sialyl content of the carbohydrate chains attached at Asn297 of the Fc regions, wherein an increased proportion of a2,6 sialylated forms results in enhanced anti- inflammatory effects. See Nimmerjahn et al. (2008) Ann. Rev. Immunol.26:513. Conversely, reduction in the proportion of antibodies having a2,6 sialylated carbohydrates may be useful in cases where anti-inflammatory properties are not wanted. Methods of modifying a2,6 sialylation content of antibodies, for example by selective purification of a2,6 sialylated forms or by enzymatic modification, are provided at U.S. Patent Application Publication No.2008/0206246. In other embodiments, the amino acid sequence of the Fc region may be modified to mimic the 60 4861-9829-0104.1 Atty. Docket No.: 116639-2660 effect of a2,6 sialylation, for example by inclusion of an F241 A modification. WO 2013/095966. Antibody Derivatives [0188] One aspect of the present disclosure provides a “derivative” of an antibody or antigen fragment described herein or disclosed in Table 4. The term “derivative” refers to an antibody or antigen-binding fragment thereof that immunospecifically binds to an antigen but which comprises, one, two, three, four, five or more amino acid substitutions, additions, deletions or modifications relative to a “parental” (or wild-type) molecule. Such amino acid substitutions or additions may introduce naturally occurring (i.e., DNA-encoded) or non-naturally occurring amino acid residues. The term “derivative” encompasses, for example, as variants having altered CH1, hinge, CH2, CH3 or CH4 regions, so as to form, for example, antibodies, etc., having variant Fc regions that exhibit enhanced or impaired effector or binding characteristics. The term “derivative” additionally encompasses non-amino acid modifications, for example, amino acids that may be glycosylated (e.g., have altered mannose, 2-N-acetylglucosamine, galactose, fucose, glucose, sialic acid, 5-N-acetylneuraminic acid, 5-glycolneuraminic acid, etc. content), acetylated, pegylated, phosphorylated, amidated, derivatized by known protecting/blocking groups, proteolytic cleavage, linked to a cellular ligand or other protein, etc. [0189] In some embodiments, the altered carbohydrate modifications modulate one or more of the following: solubilization of the antibody, facilitation of subcellular transport and secretion of the antibody, promotion of antibody assembly, conformational integrity, and antibody-mediated effector function. In a specific embodiment, the altered carbohydrate modifications enhance antibody mediated effector function relative to the antibody lacking the carbohydrate modification. Carbohydrate modifications that lead to altered antibody mediated effector function are well known in the art. See e.g., Shields et al., J. Biol. Chem.277(30): 26733-26740 (2002); Davies J. et al., Biotechnology & Bioengineering 74(4): 288-294 (2001). Methods of altering carbohydrate contents are also known to those skilled in the art. See, e.g., Wallick et al. J. Exp. Med.168(3): 1099-1109 (1988); Tao et al. J. Immunol.143(8): 2595-2601 (1989); Routledge et al., Transplantation 60(8):847-53 (1995); Elliott et al., Nature Biotechnol.21:414- 21 (2003); Shield et al. J. Biol. Chem.277(30): 26733-26740 (2002). 61 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0190] A derivative antibody or antibody fragment can be generated with an engineered sequence or glycosylation state to confer preferred levels of activity in antibody dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antibody- dependent neutrophil phagocytosis (ADNP), or antibody-dependent complement deposition (ADCD) functions as measured by bead-based or cell-based assays or in vivo studies in animal models. [0191] A derivative antibody or antibody fragment may be modified by chemical modifications using techniques known to those of skill in the art, including, but not limited to, specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicamycin, etc. In one embodiment, an antibody derivative will possess a similar or identical function as the parental antibody. In another embodiment, an antibody derivative will exhibit an altered activity relative to the parental antibody. For example, a derivative antibody (or fragment thereof) can bind to its epitope more tightly or be more resistant to proteolysis than the parental antibody. Antibody Conjugates [0192] In some embodiments, the antibody or antibody fragment of the present disclosure may be linked to at least one agent to form an antibody conjugate. In order to increase the efficacy of antibody molecules as diagnostic or therapeutic agents, it is conventional to link or covalently bind or complex at least one desired molecule or moiety. Such a molecule or moiety may be, but is not limited to, at least one effector or reporter molecule. Effector molecules comprise molecules having a desired activity, e.g., cytotoxic activity. Non-limiting examples of effector molecules which have been attached to antibodies include toxins, anti-tumor agents, therapeutic enzymes, radionuclides, antiviral agents, chelating agents, cytokines, growth factors, and oligo- or polynucleotides. By contrast, a reporter molecule is defined as any moiety which may be detected using an assay. Non-limiting examples of reporter molecules, which have been conjugated to antibodies include enzymes, radiolabels, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, photoaffinity molecules, colored particles or ligands, such as biotin. Labeled Antibodies [0193] Antibody conjugates are generally preferred for use as diagnostic agents. Antibody diagnostics generally fall within two classes, those for use in in vitro diagnostics, such as in a 62 4861-9829-0104.1 Atty. Docket No.: 116639-2660 variety of immunoassays, and those for use in vivo diagnostic protocols, generally known as “antibody-directed imaging.” Many appropriate imaging agents are known in the art, as are methods for their attachment to antibodies. See e.g., U.S. Pat. Nos.5,021,236, 4,938,948, and 4,472,509. The imaging moieties used can be paramagnetic ions, radioactive isotopes, fluorochromes, NMR-detectable substances, and X-ray imaging agents. In the case of paramagnetic ions, one might mention by way of example ions such as chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) and/or erbium (III), with gadolinium being particularly preferred. Ions useful in other contexts, such as X-ray imaging, include but are not limited to lanthanum (III), gold (III), lead (II), and especially bismuth (III). [0194] In the case of radioactive isotopes for therapeutic and/or diagnostic application, one might mention astatine211, 14carbon, 51chromium, 36chlorine, 57cobalt, 58cobalt, copper67, 152Eu, gallium67, 3hydrogen, iodine123, iodine125, iodine131, indium111, 59iron, 32phosphorus, rhenium186, rhenium188, 75selenium, 35sulphur, technicium99m and/or yttrium90.125I is often being preferred for use in certain embodiments, and technicium99m and/or indium111 are also often preferred due to their low energy and suitability for long range detection. Radioactively labeled monoclonal antibodies of the present disclosure may be produced according to well-known methods in the art. For instance, monoclonal antibodies can be iodinated by contact with sodium and/or potassium iodide and a chemical oxidizing agent such as sodium hypochlorite, or an enzymatic oxidizing agent, such as lactoperoxidase. Monoclonal antibodies according to the disclosure may be labeled with technetium99m by ligand exchange process, for example, by reducing pertechnate with stannous solution, chelating the reduced technetium onto a Sephadex column and applying the antibody to this column. Alternatively, direct labeling techniques may be used, e.g., by incubating pertechnate, a reducing agent such as SNC12, a buffer solution such as sodium-potassium phthalate solution, and the antibody. Intermediary functional groups which are often used to bind radioisotopes which exist as metallic ions to antibody are diethylenetriaminepentaacetic acid (DTPA) or ethylene diaminetetracetic acid (EDTA). [0195] Among the fluorescent labels contemplated for use as conjugates include Alexa 350, Alexa 430, AMCA, BODIPY 630/650, BODIPY 650/665, BODIPY-FL, BODIPY-R6G, 63 4861-9829-0104.1 Atty. Docket No.: 116639-2660 BODIPY-TMR, BODIPY-TRX, Cascade Blue, Cy3, Cy5,6-FAM, Fluorescein Isothiocyanate, HEX, 6-JOE, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, REG, Rhodamine Green, Rhodamine Red, Renographin, ROX, TAMRA, TET, Tetramethylrhodamine, and/or Texas Red. [0196] Additional types of antibodies contemplated in the present disclosure are those intended primarily for use in vitro, where the antibody is linked to a secondary binding ligand and/or to an enzyme (an enzyme tag) that will generate a colored product upon contact with a chromogenic substrate. Examples of suitable enzymes include urease, alkaline phosphatase, (horseradish) hydrogen peroxidase or glucose oxidase. Preferred secondary binding ligands are biotin and avidin and streptavidin compounds. The use of such labels is well known to those of skill in the art and are described, for example, in U.S. Pat. Nos.3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149 and 4,366,241. [0197] Yet another known method of site-specific attachment of molecules to antibodies comprises the reaction of antibodies with hapten-based affinity labels. Essentially, hapten-based affinity labels react with amino acids in the antigen binding site, thereby destroying this site and blocking specific antigen reaction. However, this may not be advantageous since it results in loss of antigen binding by the antibody conjugate. [0198] Molecules containing azido groups may also be used to form covalent bonds to proteins through reactive nitrene intermediates that are generated by low intensity ultraviolet light (Potter and Haley, Methods Enzymol.1983;91:613-33). In particular, 2- and 8-azido analogues of purine nucleotides have been used as site-directed photoprobes to identify nucleotide binding proteins in crude cell extracts . The 2- and 8-azido nucleotides have also been used to map nucleotide binding domains of purified proteins and may be used as antibody binding agents. [0199] Several methods are known in the art for the attachment or conjugation of an antibody to its conjugate moiety. Some attachment methods involve the use of a metal chelate complex employing, for example, an organic chelating agent such a diethylenetriaminepentaacetic acid anhydride (DTPA); ethylenetriaminetetraacetic acid; N-chloro-p-toluenesulfonamide; and/or tetrachloro-3α-6α-diphenylglycouril-3 attached to the antibody (U.S. Pat. Nos.4,472,509 and 4,938,948). Monoclonal antibodies may also be reacted with an enzyme in the presence of a coupling agent such as glutaraldehyde or periodate. Conjugates with fluorescein markers are 64 4861-9829-0104.1 Atty. Docket No.: 116639-2660 prepared in the presence of these coupling agents or by reaction with an isothiocyanate. In U.S. Pat. No.4,938,948, imaging of breast tumors is achieved using monoclonal antibodies and the detectable imaging moieties are bound to the antibody using linkers such as methyl-p- hydroxybenzimidate or N-succinimidyl-3-(4-hydroxyphenyl)propionate. [0200] In other embodiments, derivatization of immunoglobulins by selectively introducing sulfhydryl groups in the Fc region of an immunoglobulin, using reaction conditions that do not alter the antibody combining site are contemplated. Antibody conjugates produced according to this methodology are disclosed to exhibit improved longevity, specificity and sensitivity (U.S. Pat. No.5,196,066, incorporated herein by reference). Site-specific attachment of effector or reporter molecules, wherein the reporter or effector molecule is conjugated to a carbohydrate residue in the Fc region have also been disclosed in the literature’ (O'Shannessy et al., 1987. Methods.99:153-191). This approach has been reported to produce diagnostically and therapeutically promising antibodies which are currently in clinical evaluation. Constant region of an antibody [0201] In one aspect, the present technology provides an antibody or an antigen binding fragment thereof, comprising a heavy chain immunoglobulin variable domain (V_H) and a light chain immunoglobulin variable domain (V_L) as disclosed herein, and a Fc domain of any isotype, e.g., but are not limited to, IgG (including IgG1, IgG2, IgG3, and IgG4), IgA (including IgA1 and IgA₂), IgD, IgE, or IgM, and IgY. Non-limiting examples of constant region sequences include: [0202] The constant regions of antibodies can also be varied. For example, antibodies are provided with Fc regions of any isotype: IgA (IgA1, IgA2), IgD, IgE, IgG (IgG1, IgG2, IgG3, IgG4) or IgM. Non-limiting examples of constant region sequences include: [0203] Human IgD constant region, Uniprot: P01880 (SEQ ID NO: 151) APTKAPDVFPIISGCRHPKDNSPVVLACLITGYHPTSVTVTWYMGTQSQPQRTFPEIQRR DSYYMTSSQLSTPLQQWRQGEYKCVVQHTASKSKKEIFRWPESPKAQASSVPTAQPQA EGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAV QDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLT LPRSLWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLC EVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYT CVVSHEDSRTLLNASRSLEVSYVTDHGPMK, and equivalents thereof. 65 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0204] Human IgG1 constant region, Uniprot: P01857 (SEQ ID NO: 152) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK, and equivalents thereof. [0205] Human IgG2 constant region, Uniprot: P01859 (SEQ ID NO: 153) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNST FRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK, and equivalents thereof. [0206] Human IgG3 constant region, Uniprot: P01860 (SEQ ID NO: 154) ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVELKTPLGDTTHTCPRCPEPKSC DTPPPCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVK GFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMH EALHNRFTQKSLSLSPGK, and equivalents thereof. [0207] Human IgM constant region, Uniprot: P01871 (SEQ ID NO: 155) GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITLSWKYKNNSDISSTRGFPSVLR GGKYAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPP RDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKV TSTLTIKESDWLGQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKS TKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGE RFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPAD 66 4861-9829-0104.1 Atty. Docket No.: 116639-2660 VFVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVAHEA LPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTCY, and equivalents thereof. [0208] Human IgG4 constant region, Uniprot: P01861 (SEQ ID NO: 156) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK, and equivalents thereof. [0209] Human IgA1 constant region, Uniprot: P01876 (SEQ ID NO: 157) ASPTSPKVFPLSLCSTQPDGNVVIACLVQGFFPQEPLSVTWSESGQGVTARNFPPSQDAS GDLYTTSSQLTLPATQCLAGKSVTCHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPS CCHPRLSLHRPALEDLLLGSEANLTCTLTGLRDASGVTFTWTPSSGKSAVQGPPERDLC GCYSVSSVLPGCAEPWNHGKTFTCTAAYPESKTPLTATLSKSGNTFRPEVHLLPPPSEEL ALNELVTLTCLARGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILR VAAEDWKKGDTFSCMVGHEALPLAFTQKTIDRLAGKPTHVNVSVVMAEVDGTCY, and equivalents thereof. [0210] Human IgA2 constant region, Uniprot: P01877 (SEQ ID NO: 158) ASPTSPKVFPLSLDSTPQDGNVVVACLVQGFFPQEPLSVTWSESGQNVTARNFPPSQDAS GDLYTTSSQLTLPATQCPDGKSVTCHVKHYTNPSQDVTVPCPVPPPPPCCHPRLSLHRPA LEDLLLGSEANLTCTLTGLRDASGATFTWTPSSGKSAVQGPPERDLCGCYSVSSVLPGC AQPWNHGETFTCTAAHPELKTPLTANITKSGNTFRPEVHLLPPPSEELALNELVTLTCLA RGFSPKDVLVRWLQGSQELPREKYLTWASRQEPSQGTTTFAVTSILRVAAEDWKKGDT FSCMVGHEALPLAFTQKTIDRMAGKPTHVNVSVVMAEVDGTCY, and equivalents thereof. [0211] Human Ig kappa constant region, Uniprot: P01834 (SEQ ID NO: 214) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, and equivalents thereof. 67 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Nucleic Acids [0212] In another aspect, the present disclosure provides an isolated nucleic acid molecule comprising, or consisting essentially of, or consisting of a nucleotide sequence encoding the CDR, heavy chain, light chain, scFV, antibody or antibody fragment as disclosed herein that are optionally detectably labeled. [0213] In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a heavy chain variable sequence comprising an amino acid sequence selected from SEQ ID NOs: 1-26 or 135-138. In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a heavy chain variable sequence comprising an amino acid sequence disclosed in Table 1 or Table 3. In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a heavy chain variable sequence comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence disclosed in Table 1 or Table 3. In some embodiments, the nucleic acid comprises a nucleotide sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to a nucleic acid sequence disclosed in Table 4 [0214] In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a light chain variable sequence comprising an amino acid sequence selected from SEQ ID NOs: 27-60 or 139-142. In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a light chain variable sequence comprising an amino acid sequence disclosed in Table 1 Table 3. In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a light chain variable sequence comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence disclosed in Table 1 Table 3. In some embodiments, the nucleic acid comprises a nucleotide sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to a nucleic acid sequence disclosed in Table 4 [0215] In one aspect, the present disclosure provides an isolated polynucleotide comprising a nucleic acid sequence encoding the heavy chain variable region of the antibody or antibody fragment disclosed herein and/or a nucleic acid sequence encoding the light chain variable region of the antibody or antibody fragment disclosed herein. In some embodiments, the isolated polynucleotide comprises a nucleic acid sequence encoding the heavy chain variable region of the antibody or antibody fragment disclosed in Table 1 or Table 3 and/or a nucleic acid sequence 68 4861-9829-0104.1 Atty. Docket No.: 116639-2660 encoding the light chain variable region of the antibody or antibody fragment disclosed in Table 1 or Table 3. In some aspects, the polynucleotide includes a sequence provided in Table 3 In some embodiments, the isolated polynucleotide comprises a nucleic acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to a nucleic acid sequence encoding the amino acid sequence of a heavy chain variable region of the antibody or antibody fragment disclosed in Table 1 and/or a nucleic acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to a nucleic acid sequence encoding the amino acid sequence of a light chain variable region of an antibody or antibody fragment disclosed in Table 1 or Table 3. [0216] In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a heavy chain complementarity determining region (CDRH1, CDRH2, and/or CDRH3). In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a heavy chain complementarity determining region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to a heavy chain complementarity determining region amino acid sequence. The combination of CDRH1-3 may be selected from Table 2 or Table 5. [0217] In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a light chain complementarity determining region (CDRL1, CDRL2, and/or CDRL3). In some embodiments, the nucleic acid comprises a nucleotide sequence encoding a light chain complementarity determining region comprising an amino acid sequence having at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to a light chain complementarity determining region amino acid. The combination of CDRL1-3 may be selected from Table 2 or Table 5. [0218] The polynucleotides can be DNA or RNA, and can be operably linked to expression elements for transcription, translation or replication of the polynucleotides. Such include, for example promoters and enhancer elements, as are known in the art. The polynucleotides can be used for recombinant production of the polynucleotides or antibodies and fragments thereof as disclosed herein. Vectors [0219] In another aspect, the present disclosure provides a vector comprising the isolated nucleic acid molecule comprising, or consisting essentially of, or consisting of a nucleotide sequence 69 4861-9829-0104.1 Atty. Docket No.: 116639-2660 encoding the antibody or antibody fragment disclosed herein. Vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long- term, stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity. [0220] In one embodiment, the vector comprising the nucleic acid encoding the antibody or antibody fragment disclosed herein is a DNA, a RNA, a plasmid, an adenoviral vector, a lentivirus vector, or a retrovirus vector. A retroviral vector may also be, e.g., a gammaretroviral vector. A gammaretroviral vector may include, e.g., a promoter, a packaging signal (w), a primer binding site (PBS), one or more (e.g., two) long terminal repeats (LTR), and a transgene of interest (e.g., a gene encoding the antibody or antibody fragment disclosed herein). A gammaretroviral vector may lack viral structural gens such as gag, pol, and env. Exemplary gammaretroviral vectors include Murine Leukemia Virus (MLV), Spleen-Focus Forming Virus (SFFV), and Myeloproliferative Sarcoma Virus (MPSV), and vectors derived therefrom. Other gammaretroviral vectors are described, e.g., in Tobias Maetzig et al., Viruses 3(6): 677-713 (2011). [0221] In another embodiment, the vector comprising the nucleic acid encoding the antibody or antibody fragment disclosed herein is an adenoviral vector (A5/35). In another embodiment, the expression of nucleic acids encoding the antibody or antibody fragment disclosed herein can be accomplished using of transposons such as sleeping beauty, CRISPR, CAS9, and zinc finger nucleases. See, e.g., June et al. Nature Reviews Immunology 9(10): 704-716 (2009). In brief summary, the expression of natural or synthetic nucleic acids encoding the antibody or antibody fragment disclosed herein is typically achieved by operably linking a nucleic acid encoding the antibody or antibody fragment polypeptide or portions thereof to a promoter and incorporating the construct into an expression vector. The vectors can be suitable for replication and integration eukaryotes. Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence. The expression constructs of the present invention may also be used for nucleic acid immunization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U.S. Pat. Nos.5,399,346, 5,580,859, 5,589,466. 70 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0222] The nucleic acid can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. Further, the expression vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al., 2012, MOLECULAR CLONING: A LABORATORY MANUAL, volumes 1-4, Cold Spring Harbor Press, NY), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers. See e.g., WO 2001/096584; WO 2001/029058; and U.S. Pat. No.6,326,193. [0223] A number of viral based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. A selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo. A number of retroviral systems are known in the art. In some embodiments, adenovirus vectors are used. A number of adenovirus vectors are known in the art. In one embodiment, lentivirus vectors are used. [0224] Additional promoter elements, such as enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription. A vector may also include a signal sequence to facilitate secretion, a polyadenylation signal and transcription terminator (e.g., from Bovine Growth Hormone (BGH) gene), an element allowing episomal replication and replication in prokaryotes (e.g. SV40 origin 71 4861-9829-0104.1 Atty. Docket No.: 116639-2660 and ColE1 or others known in the art) and/or elements to allow selection (e.g., ampicillin resistance gene and/or zeocin marker). [0225] In order to assess the expression of the antibody or antibody fragment, the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers include, for example, antibiotic- resistance genes, such as neo and the like. [0226] Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatory sequences. In general, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. Suitable reporter genes may include genes encoding luciferase, beta-galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tei et al., 2000 FEBS Letters 479: 79-82). Suitable expression systems are well known and may be prepared using known techniques or obtained commercially. In general, the construct with the minimal 5′ flanking region showing the highest level of expression of reporter gene is identified as the promoter. Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to modulate promoter-driven transcription. Methods of Making an Antibody Engineered cells [0227] On aspect of the present disclosure provides an engineered cell comprising an isolated nucleic acid molecule comprising, or consisting essentially of, or consisting of a nucleotide sequence encoding the antibody or antibody fragment disclosed herein or a vector comprising the isolated nucleic acid molecule comprising a nucleotide sequence encoding the antibody or antibody fragment disclosed herein. In some embodiments, the engineered cell produces the antibody or antibody fragment disclosed herein. In some embodiments, the antibody or antibody 72 4861-9829-0104.1 Atty. Docket No.: 116639-2660 fragment disclosed herein binds to a JAML protein. In some embodiments, a host cell or engineered cell comprises the vector disclosed herein. In one aspect the cell is a prokaryotic cell. In another aspect it is a eukaryotic cell, such as for example an HEK 293 cell. Generating an antibody [0228] One aspect of the present disclosure provides a method of making an antibody or antibody fragment comprising, or consisting essentially of, or consisting of culturing the engineered cell disclosed herein; and isolating the antibody or antibody fragment thereof from the cultured cell. The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991), for example. [0229] The methods for generating monoclonal antibodies generally begin along the same lines as those for preparing polyclonal antibodies. The first step for both these methods is immunization of an appropriate host or identification of subjects who are immune due to prior natural infection or vaccination with a licensed or experimental vaccine. As is well known in the art, a given composition for immunization may vary in its immunogenicity. It is often necessary therefore to boost the host immune system, as may be achieved by coupling a peptide or polypeptide immunogen to a carrier. Exemplary and preferred carriers are keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA). Other albumins such as ovalbumin, mouse serum albumin or rabbit serum albumin can also be used as carriers. Means for conjugating a polypeptide to a carrier protein are well known in the art and include glutaraldehyde, m-maleimidobencoyl-N-hydroxysuccinimide ester, carbodiimyde and bis- biazotized benzidine. As also is well known in the art, the immunogenicity of a particular immunogen composition can be enhanced by the use of non-specific stimulators of the immune response, known as adjuvants. Exemplary and preferred adjuvants in animals include complete Freund's adjuvant (a non-specific stimulator of the immune response containing killed Mycobacterium tuberculosis), incomplete Freund's adjuvants and aluminum hydroxide adjuvant and in humans include alum, CpG, MFP59 and combinations of immunostimulatory molecules (“Adjuvant Systems”, such as AS01 or AS03). Additional experimental forms of inoculation to induce JAML-specific B cells is possible, including nanoparticle vaccines, or gene-encoded antigens delivered as DNA or RNA genes in a physical delivery system (such as lipid 73 4861-9829-0104.1 Atty. Docket No.: 116639-2660 nanoparticle or on a gold biolistic bead), and delivered with needle, gene gun, transcutaneous electroporation device. The antigen gene also can be carried as encoded by a replication competent or defective viral vector such as adenovirus, adeno-associated virus, poxvirus, herpesvirus, or alphavirus replicon, or alternatively a virus like particle. [0230] In the case of human antibodies against natural pathogens, a suitable approach is to identify subjects that have been exposed to the pathogens, such as those who have been diagnosed as having contracted the disease, or those who have been vaccinated to generate protective immunity against the pathogen or to test the safety or efficacy of an experimental vaccine. Circulating anti-pathogen antibodies can be detected, and antibody encoding or producing B cells from the antibody-positive subject may then be obtained. [0231] The amount of immunogen composition used in the production of polyclonal antibodies varies upon the nature of the immunogen as well as the animal used for immunization. A variety of routes can be used to administer the immunogen (subcutaneous, intramuscular, intradermal, intravenous and intraperitoneal). The production of polyclonal antibodies may be monitored by sampling blood of the immunized animal at various points following immunization. A second, booster injection, also may be given. The process of boosting and titering is repeated until a suitable titer is achieved. When a desired level of immunogenicity is obtained, the immunized animal can be bled and the serum isolated and stored, and/or the animal can be used to generate monoclonal antibodies. [0232] Monoclonal antibodies produced by either means may be further purified, if desired, using filtration, centrifugation and various chromatographic methods such as FPLC or affinity chromatography. Fragments of the monoclonal antibodies of the disclosure can be obtained from the purified monoclonal antibodies by methods which include digestion with enzymes, such as pepsin or papain, and/or by cleavage of disulfide bonds by chemical reduction. Alternatively, monoclonal antibody fragments encompassed by the present disclosure can be synthesized using an automated peptide synthesizer. [0233] It also is contemplated that a molecular cloning approach may be used to generate monoclonal antibodies. Single B cells identified as responding to infection or vaccination because of plasmablast or activated B cell markers, or memory B cells labelled with the antigen of interest, can be sorted physically using paramagnetic bead selection or flow cytometric 74 4861-9829-0104.1 Atty. Docket No.: 116639-2660 sorting, then RNA can be isolated from the single cells and antibody genes amplified by RT- PCR. Various single-cell RNA-seq methods are available to obtain antibody variable genes from single cells. Alternatively, antigen-specific bulk sorted populations of cells can be segregated into microvesicles and the matched heavy and light chain variable genes recovered from single cells using physical linkage of heavy and light chain amplicons, or common barcoding of heavy and light chain genes from a vesicle. Matched heavy and light chain genes from single cells also can be obtained from populations of antigen specific B cells by treating cells with cell- penetrating nanoparticles bearing RT-PCR primers and barcodes for marking transcripts with one barcode per cell. The antibody variable genes also can be isolated by RNA extraction of a hybridoma line and the antibody genes obtained by RT-PCR and cloned into an immunoglobulin expression vector. Alternatively, combinatorial immunoglobulin phagemid libraries are prepared from RNA isolated from the cell lines and phagemids expressing appropriate antibodies are selected by panning using viral antigens. The advantages of this approach over conventional hybridoma techniques are that approximately 104 times as many antibodies can be produced and screened in a single round, and that new specificities are generated by H and L chain combination which further increases the chance of finding appropriate antibodies. [0234] Other U.S. patents, each incorporated herein by reference, that teach the production of antibodies useful in the present disclosure include U.S. Pat. No.5,565,332, which describes the production of chimeric antibodies using a combinatorial approach; U.S. Pat. No.4,816,567 which describes recombinant immunoglobulin preparations; and U.S. Pat. No.4,867,973 which describes antibody-therapeutic agent conjugates. [0235] In various embodiments, one may choose to engineer sequences of the identified antibodies for a variety of reasons, such as improved expression, improved cross-reactivity or diminished off-target binding. Modified antibodies may be made by any technique known to those of skill in the art, including expression through standard molecular biological techniques, or the chemical synthesis of polypeptides. Methods for recombinant expression are addressed elsewhere in this document. The following is a general discussion of relevant goals techniques for antibody engineering. [0236] Recombinant full-length IgG antibodies can be generated by subcloning heavy and light chain Fv DNAs from the cloning vector into an IgG plasmid vector, transfected into 293 (e.g., 75 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Freestyle) cells or CHO cells, and antibodies can be collected and purified from the 293 or CHO cell supernatant. Other appropriate host cells systems include bacteria, such as E. coli, insect cells (S2, Sf9, Sf29, High Five), plant cells (e.g., tobacco, with or without engineering for human-like glycans), algae, or in a variety of non-human transgenic contexts, such as mice, rats, goats or cows. [0237] Expression of nucleic acids encoding antibodies, both for the purpose of subsequent antibody purification, and for immunization of a host, is also contemplated. Antibody coding sequences can be RNA, such as native RNA or modified RNA. Modified RNA contemplates certain chemical modifications that confer increased stability and low immunogenicity to mRNAs, thereby facilitating expression of therapeutically important proteins. For instance, N1- methyl-pseudouridine (N1mΨ) outperforms several other nucleoside modifications and their combinations in terms of translation capacity. In addition to turning off the immune/eIF2α phosphorylation-dependent inhibition of translation, incorporated N1mΨ nucleotides dramatically alter the dynamics of the translation process by increasing ribosome pausing and density on the mRNA. Increased ribosome loading of modified mRNAs renders them more permissive for initiation by favoring either ribosome recycling on the same mRNA or de novo ribosome recruitment. Such modifications could be used to enhance antibody expression in vivo following inoculation with RNA. The RNA, whether native or modified, may be delivered as naked RNA or in a delivery vehicle, such as a lipid nanoparticle. [0238] DNA encoding the antibody can be employed to produce the antibodies. The DNA is included in an expression cassette comprising a promoter active in the host cell for which it is designed. The expression cassette is advantageously included in a replicable vector, such as a conventional plasmid or minivector. Vectors include viral vectors, such as poxviruses, adenoviruses, herpesviruses, adeno-associated viruses, and lentiviruses are contemplated. Replicons encoding antibody genes such as alphavirus replicons based on VEE virus or Sindbis virus are also contemplated. Delivery of such vectors can be performed by needle through intramuscular, subcutaneous, or intradermal routes, or by transcutaneous electroporation when in vivo expression is desired. [0239] Expression of Recombinant Antibodies. As noted above, the antibodies of the present technology can be produced through the application of recombinant DNA technology. 76 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Recombinant polynucleotide constructs an antibody of the present technology typically include an expression control sequence operably-linked to the coding sequences of the antibody chains, including naturally-associated or heterologous promoter regions. As such, another aspect of the technology includes vectors containing one or more nucleic acid sequences encoding the antibody of the present technology. For recombinant expression of one or more of the polypeptides of the present technology, the nucleic acid containing all or a portion of the nucleotide sequence encoding the antibody is inserted into an appropriate cloning vector, or an expression vector (i.e., a vector that contains the necessary elements for the transcription and translation of the inserted polypeptide coding sequence) by recombinant DNA techniques well known in the art and as detailed below. Methods for producing diverse populations of vectors have been described by Lerner et al., U.S. Pat. Nos.6,291,160 and 6,680,192. [0240] In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. In the present disclosure, “plasmid” and “vector” can be used interchangeably as the plasmid is the most commonly used form of vector. However, the present technology is intended to include such other forms of expression vectors that are not technically plasmids, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. Such viral vectors permit infection of a subject and expression of a construct in that subject. In some embodiments, the expression control sequences are eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells. Once the vector has been incorporated into the appropriate host, the host is maintained under conditions suitable for high level expression of the nucleotide sequences encoding the antibody, and the collection and purification of the antibody, e.g., cross-reacting antibodies. See generally, U.S.2002/0199213. These expression vectors are typically replicable in the host organisms either as episomes or as an integral part of the host chromosomal DNA. Commonly, expression vectors contain selection markers, e.g., ampicillin-resistance or hygromycin-resistance, to permit detection of those cells transformed with the desired DNA sequences. Vectors can also encode signal peptide, e.g., pectate lyase, useful to direct the secretion of extracellular antibody fragments. See U.S. Pat. No.5,576,195. [0241] The recombinant expression vectors of the present technology comprise a nucleic acid encoding a protein with binding properties of the antibodies and fragments thereof as disclosed herein in a form suitable for expression of the nucleic acid in a host cell, which means that the 77 4861-9829-0104.1 Atty. Docket No.: 116639-2660 recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression that is operably-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably-linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, e.g., in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of polypeptide desired, etc. Typical regulatory sequences useful as promoters of recombinant polypeptide expression (i.e., antibody or fragment thereof), include, e.g., but are not limited to, promoters of 3-phosphoglycerate kinase and other glycolytic enzymes. Inducible yeast promoters include, among others, promoters from alcohol dehydrogenase, isocytochrome C, and enzymes responsible for maltose and galactose utilization. In one embodiment, a polynucleotide encoding the antibody of the present technology is operably-linked to an ara B promoter and expressible in a host cell. See U.S. Pat.5,028,530. The expression vectors of the present technology can be introduced into host cells to thereby produce polypeptides or peptides, including fusion polypeptides, encoded by nucleic acids as described herein (e.g., antibody, etc.). [0242] Another aspect of the present technology pertains to an antibody-expressing host cells, which contain a nucleic acid encoding one or more antibodies or fragments thereof. The recombinant expression vectors of the present technology can be designed for expression of an antibody in prokaryotic or eukaryotic cells. For example, an antibody can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors), fungal cells, e.g., yeast, yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can 78 4861-9829-0104.1 Atty. Docket No.: 116639-2660 be transcribed and translated in vitro, e.g., using T7 promoter regulatory sequences and T7 polymerase. Methods useful for the preparation and screening of polypeptides having a predetermined property, e.g., antibody, via expression of stochastically generated polynucleotide sequences has been previously described. See U.S. Pat. Nos.5,763,192; 5,723,323; 5,814,476; 5,817,483; 5,824,514; 5,976,862; 6,492,107; 6,569,641. [0243] Expression of polypeptides in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non- fusion polypeptides. Fusion vectors add a number of amino acids to a polypeptide encoded therein, usually to the amino terminus of the recombinant polypeptide. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant polypeptide; (ii) to increase the solubility of the recombinant polypeptide; and (iii) to aid in the purification of the recombinant polypeptide by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant polypeptide to enable separation of the recombinant polypeptide from the fusion moiety subsequent to purification of the fusion polypeptide. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E binding polypeptide, or polypeptide A, respectively, to the target recombinant polypeptide. [0244] Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al., (1988) Gene 69: 301-315) and pET 11d (Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89). Methods for targeted assembly of distinct active peptide or protein domains to yield multifunctional polypeptides via polypeptide fusion has been described by Pack et al., U.S. Pat. Nos.6,294,353; 6,692,935. One strategy to maximize recombinant polypeptide expression, e.g., an anti-L1-CAM antibody, in E. coli is to express the polypeptide in host bacteria with an impaired capacity to proteolytically cleave the recombinant polypeptide. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino 79 4861-9829-0104.1 Atty. Docket No.: 116639-2660 acid are those preferentially utilized in the expression host, e.g., E. coli (See, e.g., Wada, et al., 1992. Nucl. Acids Res.20: 2111-2118). Such alteration of nucleic acid sequences of the present technology can be carried out by standard DNA synthesis techniques. [0245] In another embodiment, the antibody expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerevisiae include pYepSec1 (Baldari, et al., 1987. EMBO J.6: 229-234), pMFa (Kurjan and Herskowitz, Cell 30: 933-943, 1982), pJRY88 (Schultz et al., Gene 54: 113-123, 1987), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (Invitrogen Corp, San Diego, Calif.). Alternatively, an anti-L1-CAM antibody can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of polypeptides, e.g., anti-L1-CAM antibody, in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al., Mol. Cell. Biol.3: 2156-2165, 1983) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39). [0246] In yet another embodiment, a nucleic acid encoding an antibody or fragment thereof of the present technology is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include, e.g., but are not limited to, pCDM8 (Seed, Nature 329: 840, 1987) and pMT2PC (Kaufman, et al., EMBO J.6: 187-195, 1987). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells that are useful for expression of the anti-L1-CAM antibody of the present technology, see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL.2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. [0247] In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid in a particular cell type (e.g., tissue-specific regulatory elements). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., Genes Dev.1: 268-277, 1987), lymphoid-specific promoters (Calame and Eaton, Adv. Immunol. 43: 235-275, 1988), promoters of T cell receptors (Winoto and Baltimore, EMBO J.8: 729-733, 1989) and immunoglobulins (Banerji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, Cell 80 4861-9829-0104.1 Atty. Docket No.: 116639-2660 33: 741-748, 1983.), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, Proc. Natl. Acad. Sci. USA 86: 5473-5477, 1989), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No.4,873,316 and European Application Publication No.264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, Science 249: 374-379, 1990) and the α-fetoprotein promoter (Campes and Tilghman, Genes Dev.3: 537-546, 1989). [0248] Another aspect of the present methods pertains to host cells into which a recombinant expression vector of the present technology has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. [0249] A host cell can be any prokaryotic or eukaryotic cell. For example, an antibody or fragment thereof can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells. Mammalian cells are a suitable host for expressing nucleotide segments encoding immunoglobulins or fragments thereof. See Winnacker, From Genes To Clones, (VCH Publishers, NY, 1987). A number of suitable host cell lines capable of secreting intact heterologous proteins have been developed in the art, and include Chinese hamster ovary (CHO) cell lines, various COS cell lines, HeLa cells, L cells and myeloma cell lines. In some embodiments, the cells are non-human. Expression vectors for these cells can include expression control sequences, such as an origin of replication, a promoter, an enhancer, and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences. Queen et al., Immunol. Rev.89: 49, 1986. Illustrative expression control sequences are promoters derived from endogenous genes, cytomegalovirus, SV40, adenovirus, bovine papillomavirus, and the like. Co et al., J Immunol. 148: 1149, 1992. Other suitable host cells are known to those skilled in the art. [0250] Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms “transformation” and 81 4861-9829-0104.1 Atty. Docket No.: 116639-2660 “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, electroporation, biolistics or viral-based transfection. Other methods used to transform mammalian cells include the use of polybrene, protoplast fusion, liposomes, electroporation, and microinjection (See generally, Sambrook et al., Molecular Cloning). Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals. The vectors containing the DNA segments of interest can be transferred into the host cell by well-known methods, depending on the type of cellular host. [0251] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding the antibody or fragment thereof or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die). [0252] A host cell that includes an antibody or fragment thereof of the present technology, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) recombinant antibody or fragment thereof. In one embodiment, the method comprises culturing the host cell (into which a recombinant expression vector encoding the antibody or fragment thereof has been introduced) in a suitable medium such that the antibody is produced. In another embodiment, the method further comprises the step of isolating the antibody from the medium or the host cell. Once expressed, collections of the antibody, e.g., the antibodies or the antibody- related polypeptides are purified from culture media and host cells. The antibody can be purified according to standard procedures of the art, including HPLC purification, column chromatography, gel electrophoresis and the like. In one embodiment, the antibody is produced 82 4861-9829-0104.1 Atty. Docket No.: 116639-2660 in a host organism by the method of Boss et al., U.S. Pat. No.4,816,397. Usually, antibody chains are expressed with signal sequences and are thus released to the culture media. However, if the antibody chains are not naturally secreted by host cells, the antibody chains can be released by treatment with mild detergent. Purification of recombinant polypeptides is well known in the art and includes ammonium sulfate precipitation, affinity chromatography purification technique, column chromatography, ion exchange purification technique, gel electrophoresis and the like (See generally Scopes, Protein Purification (Springer-Verlag, N.Y., 1982). [0253] Polynucleotides encoding antibodies, e.g., the antibody coding sequences, can be incorporated in transgenes for introduction into the genome of a transgenic animal and subsequent expression in the milk of the transgenic animal. See, e.g., U.S. Pat. Nos.5,741,957, 5,304,489, and 5,849,992. Suitable transgenes include coding sequences for light and/or heavy chains in operable linkage with a promoter and enhancer from a mammary gland specific gene, such as casein or β-lactoglobulin. For production of transgenic animals, transgenes can be microinjected into fertilized oocytes, or can be incorporated into the genome of embryonic stem cells, and the nuclei of such cells transferred into enucleated oocytes. [0254] Single-Chain Antibodies. In one embodiment, the antibody of the present technology is a single-chain antibody. According to the present technology, techniques can be adapted for the production of single-chain antibodies specific to a JAML protein. Examples of techniques which can be used to produce single-chain Fvs and antibodies of the present technology include those described in U.S. Pat. Nos.4,946,778 and 5,258,498; Huston et al., Methods in Enzymology, 203: 46-88, 1991; Shu, L. et al., Proc. Natl. Acad. Sci. USA, 90: 7995-7999, 1993; and Skerra et al., Science 240: 1038-1040, 1988. [0255] Chimeric Antibodies. In one embodiment, the antibody of the present technology is a chimeric antibody. In one embodiment of the present technology, the donor and acceptor antibodies are monoclonal antibodies from different species. For example, the acceptor antibody is a murine antibody (to minimize its antigenicity in a murine animal model). [0256] Recombinant antibodies, such as chimeric monoclonal antibodies, comprising both human and non-human portions, can be made using standard recombinant DNA techniques, and are within the scope of the present technology. For some uses, including in vivo use of the antibody of the present technology in humans or non-human animals as well as use of these 83 4861-9829-0104.1 Atty. Docket No.: 116639-2660 agents in in vitro detection assays, it is possible to use chimeric antibodies. Such chimeric monoclonal antibodies can be produced by recombinant DNA techniques known in the art. Such useful methods include, e.g., but are not limited to, methods described in International Application No. PCT/US86/02269; U.S. Pat. No.5,225,539; European Patent No.184187; European Patent No.171496; European Patent No.173494; PCT International Publication No. WO 86/01533; U.S. Pat. Nos.4,816,567; 5,225,539; European Patent No.125023; Better, et al., 1988. Science 240: 1041-1043; Liu, et al., 1987. Proc. Natl. Acad. Sci. USA 84: 3439-3443; Liu, et al., 1987. J. Immunol.139: 3521-3526; Sun, et al., 1987. Proc. Natl. Acad. Sci. USA 84: 214- 218; Nishimura, et al., 1987. Cancer Res.47: 999-1005; Wood, et al., 1985. Nature 314: 446- 449; Shaw, et al., 1988. J. Natl. Cancer Inst.80: 1553-1559; Morrison (1985) Science 229: 1202- 1207; Oi, et al. (1986) BioTechniques 4: 214; Jones, et al., 1986. Nature 321: 552-525; Verhoeyan, et al., 1988. Science 239: 1534; Morrison, Science 229: 1202, 1985; Oi et al., BioTechniques 4: 214, 1986; Gillies et al., J. Immunol. Methods, 125: 191-202, 1989; U.S. Pat. No.5,807,715; and Beidler, et al., 1988. J. Immunol.141: 4053-4060. For example, antibodies can be made chimerice using a variety of techniques including CDR-grafting (EP 0239400; WO 91/09967; U.S. Pat. No.5,530,101; 5,585,089; 5,859,205; 6,248,516; EP460167), veneering or resurfacing (EP 0592106; EP 0519596; Padlan E. A., Molecular Immunology, 28: 489-498, 1991; Studnicka et al., Protein Engineering 7: 805-814, 1994; Roguska et al., PNAS 91: 969-973, 1994), and chain shuffling (U.S. Pat. No.5,565,332). In one embodiment, a cDNA encoding an monoclonal antibody is digested with a restriction enzyme selected specifically to remove the sequence encoding the Fc constant region, and the equivalent portion of a cDNA encoding a different Fc constant region is substituted (See Robinson et al., PCT/US86/02269; Akira et al., European Patent Application 184,187; Taniguchi, European Patent Application 171,496; Morrison et al., European Patent Application 173,494; Neuberger et al., WO 86/01533; Cabilly et al. U.S. Patent No.4,816,567; Cabilly et al., European Patent Application 125,023; Better et al. (1988) Science 240: 1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84: 3439-3443; Liu et al. (1987) J Immunol 139: 3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. USA 84: 214-218; Nishimura et al. (1987) Cancer Res 47: 999-1005; Wood et al. (1985) Nature 314: 446- 449; and Shaw et al. (1988) J. Natl. Cancer Inst.80: 1553-1559; U.S. Pat. No.6,180,370; U.S. Pat. Nos.6,300,064; 6,696,248; 6,706,484; 6,828,422. 84 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0257] CDR Antibodies. Generally the donor and acceptor antibodies used to generate the antibody are monoclonal antibodies from different species; typically the acceptor antibody is a non-human antibody (to minimize its antigenicity in a non-human animal). The graft may be of a single CDR (or even a portion of a single CDR) within a single VH or VL of the acceptor antibody, or can be of multiple CDRs (or portions thereof) within one or both of the VH and VL. Frequently, all three CDRs in all variable domains of the acceptor antibody will be replaced with the corresponding donor CDRs, though one need replace only as many as necessary to permit adequate binding of the resulting CDR-grafted antibody. Methods for generating CDR-grafted antibodies are taught by Queen et al. U.S. Pat. No.5,585,089; U.S. Pat. No.5,693,761; U.S. Pat. No.5,693,762; and Winter U.S.5,225,539; and EP 0682040. Methods useful to prepare V_H and VL polypeptides are taught by Winter et al., U.S. Pat. Nos.4,816,397; 6,291,158; 6,291,159; 6,291,161; 6,545,142; EP 0368684; EP0451216; and EP0120694. [0258] After selecting suitable framework region candidates from the same family and/or the same family member, either or both the heavy and light chain variable regions are produced by grafting the CDRs from the originating species into the hybrid framework regions. Assembly of hybrid antibodies or hybrid antibody fragments having hybrid variable chain regions with regard to either of the above aspects can be accomplished using conventional methods known to those skilled in the art. For example, DNA sequences encoding the hybrid variable domains described herein (i.e., frameworks based on the target species and CDRs from the originating species) can be produced by oligonucleotide synthesis and/or PCR. The nucleic acid encoding CDR regions can also be isolated from the originating species antibodies using suitable restriction enzymes and ligated into the target species framework by ligating with suitable ligation enzymes. Alternatively, the framework regions of the variable chains of the originating species antibody can be changed by site-directed mutagenesis. [0259] Since the hybrids are constructed from choices among multiple candidates corresponding to each framework region, there exist many combinations of sequences which are amenable to construction in accordance with the principles described herein. Accordingly, libraries of hybrids can be assembled having members with different combinations of individual framework regions. Such libraries can be electronic database collections of sequences or physical collections of hybrids. 85 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0260] This process typically does not alter the acceptor antibody’s FRs flanking the grafted CDRs. However, one skilled in the art can sometimes improve antigen binding affinity of the resulting CDR-grafted antibody by replacing certain residues of a given FR to make the FR more similar to the corresponding FR of the donor antibody. Suitable locations of the substitutions include amino acid residues adjacent to the CDR, or which are capable of interacting with a CDR (See, e.g., US 5,585,089, especially columns 12-16). Techniques for making these modifications are known in the art. Particularly if the resulting FR fits a human consensus FR for that position, or is at least 90% or more identical to such a consensus FR, doing so may not increase the antigenicity of the resulting modified anti- CDR-grafted antibody significantly compared to the same antibody with a fully human FR. [0261] The rapid availability of antibody produced in the same host cell and cell culture process as the final cGMP manufacturing process has the potential to reduce the duration of process development programs. Lonza has developed a generic method using pooled transfectants grown in CDACF medium, for the rapid production of small quantities (up to 50 g) of antibodies in CHO cells. Although slightly slower than a true transient system, the advantages include a higher product concentration and use of the same host and process as the production cell line. Example of growth and productivity of GS-CHO pools, expressing a model antibody, in a disposable bioreactor: in a disposable bag bioreactor culture (5 L working volume) operated in fed-batch mode, a harvest antibody concentration of 2 g/L was achieved within 9 weeks of transfection. [0262] Antibody molecules will comprise fragments (such as F(ab′), F(ab′)2) that are produced, for example, by the proteolytic cleavage of the monoclonal antibodies, or single-chain immunoglobulins producible, for example, via recombinant means. F(ab′) antibody derivatives are monovalent, while F(ab′)2 antibody derivatives are bivalent. In one embodiment, such fragments can be combined with one another, or with other antibody fragments or receptor ligands to form “chimeric” binding molecules. Significantly, such chimeric molecules may contain substituents capable of binding to different epitopes of the same molecule. [0263] In related embodiments, the antibody is a derivative of the disclosed antibodies, e.g., an antibody comprising the CDR sequences identical to those in the disclosed antibodies (e.g., a chimeric, or CDR-grafted antibody). Alternatively, one may wish to make modifications, such as introducing conservative changes into an antibody molecule. In making such changes, the 86 4861-9829-0104.1 Atty. Docket No.: 116639-2660 hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte and Doolittle, 1982). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like. [0264] It also is understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Pat. No.4,554,101, incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein. As detailed in U.S. Pat. No.4,554,101, the following hydrophilicity values have been assigned to amino acid residues: basic amino acids: arginine (+3.0), lysine (+3.0), and histidine (−0.5); acidic amino acids: aspartate (+3.0±1), glutamate (+3.0±1), asparagine (+0.2), and glutamine (+0.2); hydrophilic, nonionic amino acids: serine (+0.3), asparagine (+0.2), glutamine (+0.2), and threonine (−0.4), sulfur containing amino acids: cysteine (−1.0) and methionine (−1.3); hydrophobic, nonaromatic amino acids: valine (−1.5), leucine (−1.8), isoleucine (−1.8), proline (−0.5±1), alanine (−0.5), and glycine (0); hydrophobic, aromatic amino acids: tryptophan (−3.4), phenylalanine (−2.5), and tyrosine (−2.3). [0265] It is understood that an amino acid can be substituted for another having a similar hydrophilicity and produce a biologically or immunologically modified protein. In such changes, the substitution of amino acids whose hydrophilicity values are within ±2 is preferred, those that are within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred. [0266] Amino acid substitutions generally are based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take into consideration the various foregoing characteristics are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine. [0267] Antibodies according to the present disclosure may be defined, in the first instance, by their binding specificity. Those of skill in the art, by assessing the binding specificity/affinity of 87 4861-9829-0104.1 Atty. Docket No.: 116639-2660 a given antibody using techniques well known to those of skill in the art, can determine whether such antibodies fall within the scope of the instant claims. For example, the epitope to which a given antibody bind may consist of a single contiguous sequence of 3 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) amino acids located within the antigen molecule (e.g., a linear epitope in a domain). Alternatively, the epitope may consist of a plurality of non- contiguous amino acids (or amino acid sequences) located within the antigen molecule (e.g., a conformational epitope). [0268] Various techniques known to persons of ordinary skill in the art can be used to determine whether an antibody “interacts with one or more amino acids” within a polypeptide or protein. Exemplary techniques include, for example, routine cross-blocking assays, such as that described in Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harbor, N.Y.). Cross- blocking can be measured in various binding assays such as ELISA, biolayer interferometry, or surface plasmon resonance. Other methods include alanine scanning mutational analysis, peptide blot analysis (Reineke, Methods Mol. Biol.248: 443-63, 2004), peptide cleavage analysis, high- resolution electron microscopy techniques using single particle reconstruction, cryoEM, or tomography, crystallographic studies and NMR analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer Prot. Sci.9: 487-496, 2000). Another method that can be used to identify the amino acids within a polypeptide with which an antibody interacts is hydrogen/deuterium exchange detected by mass spectrometry. In general terms, the hydrogen/deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antibody to the deuterium- labeled protein. Next, the protein/antibody complex is transferred to water and exchangeable protons within amino acids that are protected by the antibody complex undergo deuterium-to- hydrogen back-exchange at a slower rate than exchangeable protons within amino acids that are not part of the interface. As a result, amino acids that form part of the protein/antibody interface may retain deuterium and therefore exhibit relatively higher mass compared to amino acids not included in the interface. After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues which correspond to the specific amino acids with which the antibody interacts. See, e.g., Ehring, Analytical Biochemistry 267: 252-259 (1999), Engen and Smith, Anal. Chem.73: 256A-265A (2001). 88 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0269] The term “epitope” refers to a site on an antigen to which B and/or T cells respond. B-cell 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. [0270] Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody Profiling (ASAP) is a method that categorizes large numbers of monoclonal antibodies (mAbs) directed against the same antigen according to the similarities of the binding profile of each antibody to chemically or enzymatically modified antigen surfaces (see U.S. Patent Publication 2004/0101920, herein specifically incorporated by reference in its entirety). Each category may reflect a unique epitope either distinctly different from or partially overlapping with epitope represented by another category. This technology allows rapid filtering of genetically identical antibodies, such that characterization can be focused on genetically distinct antibodies. When applied to hybridoma screening, MAP may facilitate identification of rare hybridoma. clones that produce mAbs haying the desired characteristics. MAP may be used to sort the antibodies of the disclosure into groups of antibodies binding different epitopes. [0271] The present disclosure includes antibodies that may bind to the same epitope, or a portion of the epitope. Likewise, the present disclosure also includes antibodies that compete for binding to a target or a fragment thereof with any of the specific exemplary antibodies described herein. One can easily determine whether an antibody binds to the same epitope as, or competes for binding with, a reference antibody by using routine methods known in the art. For example, to determine if a test antibody binds to the same epitope as a reference, the reference antibody is allowed to bind to target under saturating conditions. Next, the ability of a test antibody to bind to the target molecule is assessed. If the test antibody is able to bind to the target molecule following saturation binding with the reference antibody, it can be concluded that the test antibody binds to a different epitope than the reference antibody. On the other hand, if the test antibody is not able to bind to the target molecule following saturation binding with the reference antibody, then the test antibody may bind to the same epitope as the epitope bound by the reference antibody. 89 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0272] To determine if an antibody competes for binding with a reference anti-JAML antibody, the above-described binding methodology is performed in two orientations: to a first orientation, the reference antibody is allowed to bind to the JAML antigen under saturating conditions followed by assessment of binding of the test antibody to the JAML molecule. In a second orientation, the test antibody is allowed to bind to the JAML antigen molecule under saturating conditions followed by assessment of binding of the reference antibody to the JAML molecule. If, in both orientations, only the first (saturating) antibody is capable of binding to JAML, then it is concluded that the test antibody and the reference antibody compete for binding to JAML. As will be appreciated by a person of ordinary skill in the art, an antibody that competes for binding with a reference antibody may not necessarily bind to the identical epitope as the reference antibody but may sterically block binding of the reference antibody by binding an overlapping or adjacent epitope. [0273] Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et at., Cancer Res.199050:1495- 1502). Alternatively, two antibodies have the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. [0274] Additional routine experimentation (e.g., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art. Structural studies with EM or crystallography also can demonstrate whether or not two antibodies that compete for binding recognize the same epitope. [0275] In another aspect, there are provided monoclonal antibodies having clone-paired CDRs from the heavy and light chains as illustrated in Table 1 or Table 3. The combination of heavy 90 4861-9829-0104.1 Atty. Docket No.: 116639-2660 and light chain CDRs may be selected from Table 2 or Table 5. Such antibodies may be produced by the clones disclosed in the Examples section using methods described herein. [0276] In another aspect, the antibodies may be defined by their variable sequence, which include additional “framework” regions. Furthermore, the antibodies sequences may vary from these sequences, optionally using methods discussed in greater detail below. For example, nucleic acid sequences may vary from those set out above in that (a) the variable regions may be segregated away from the constant domains of the light and heavy chains, (b) the nucleic acids may vary from those set out above while not affecting the residues encoded thereby, (c) the nucleic acids may vary from those set out above by a given percentage, e.g., 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homology, (d) the nucleic acids may vary from those set out above by virtue of the ability to hybridize under high stringency conditions, as exemplified by low salt and/or high temperature conditions, such as provided by about 0.02 M to about 0.15 M NaCl at temperatures of about 50° C. to about 70° C., (e) the amino acids may vary from those set out above by a given percentage, e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homology, or (f) the amino acids may vary from those set out above by permitting conservative substitutions (discussed below). Each of the foregoing applies to the nucleic acid sequences and the amino acid sequences. Additionally, various publications describe methods for obtaining physiologically active molecules whose half-lives are modified, see for example Kontermann (2009) either by introducing an FcRn-binding polypeptide into the molecules or by fusing the molecules with antibodies whose FcRn-binding affinities are preserved but affinities for other Fc receptors have been greatly reduced or fusing with FcRn binding domains of antibodies. Derivatized antibodies [0277] Derivatized antibodies may be used to alter the half-lives (e.g., serum half-lives) of parental antibodies in a mammal, particularly a human. Such alterations may result in a half-life of greater than 15 days, preferably greater than 20 days, greater than 25 days, greater than 30 days, greater than 35 days, greater than 40 days, greater than 45 days, greater than 2 months, greater than 3 months, greater than 4 months, or greater than 5 months. The increased half-lives of the antibodies of the present disclosure or fragments thereof in a mammal, preferably a human, results in a higher serum titer of said antibodies or antibody fragments in the mammal, 91 4861-9829-0104.1 Atty. Docket No.: 116639-2660 and thus reduces the frequency of the administration of said antibodies or antibody fragments and/or reduces the concentration of said antibodies or antibody fragments to be administered. Antibodies or fragments thereof having increased in vivo half-lives can be generated by techniques known to those of skill in the art. For example, antibodies or fragments thereof with increased in vivo half-lives can be generated by modifying (e.g., substituting, deleting or adding) amino acid residues identified as involved in the interaction between the Fc domain and the FcRn receptor. [0278] Beltramello et al. (2010) previously reported the modification of neutralizing mAbs, due to their tendency to enhance dengue virus infection, by generating in which leucine residues at positions 1.3 and 1.2 of CH2 domain (according to the IMGT unique numbering for C-domain) were substituted with alanine residues. This modification, also known as “LALA” mutation, abolishes antibody binding to FcγRI, FcγRII and FcγRIIIa, as described by Hessell et al. (2007). The variant and unmodified recombinant mAbs were compared for their capacity to neutralize and enhance infection by the four dengue virus serotypes. LALA variants retained the same neutralizing activity as unmodified mAb but were completely devoid of enhancing activity. LALA mutations of this nature are therefore contemplated in the context of the presently disclosed antibodies. Altered Glycosylation [0279] A particular embodiment of the present disclosure is an isolated monoclonal antibody, or antigen binding fragment thereof, containing a substantially homogeneous glycan without sialic acid, galactose, or fucose. The monoclonal antibody comprises a heavy chain variable region and a light chain variable region, both of which may be attached to heavy chain or light chain constant regions respectively. The aforementioned substantially homogeneous glycan may be covalently attached to the heavy chain constant region. [0280] Another embodiment of the present disclosure comprises a monoclonal antibody with a novel Fc glycosylation pattern. The isolated monoclonal antibody, or antigen binding fragment thereof, is present in a substantially homogenous composition represented by the GNGN or G1/G2 glycoform. Fc glycosylation plays a significant role in anti-viral and anti-cancer properties of therapeutic monoclonal antibodies. The disclosure is in line with a recent study that shows increased anti-lentivirus cell-mediated viral inhibition of a fucose free anti-HIV 92 4861-9829-0104.1 Atty. Docket No.: 116639-2660 monoclonal antibody in vitro. This embodiment of the present disclosure with homogenous glycans lacking a core fucose, showed increased protection against specific viruses by a factor greater than two-fold. Elimination of core fucose dramatically improves the ADCC activity of monoclonal antibodies mediated by natural killer (NK) cells but appears to have the opposite effect on the ADCC activity of polymorphonuclear cells (PMNs). [0281] The isolated monoclonal antibody, or antigen binding fragment thereof, comprising a substantially homogenous composition represented by the GNGN or G1/G2 glycoform exhibits increased binding affinity for Fc gamma RI and Fc gamma RIII compared to the same antibody without the substantially homogeneous GNGN glycoform and with G0, G1F, G2F, GNF, GNGNF or GNGNFX containing glycoforms. In one embodiment of the present disclosure, the antibody dissociates from Fc gamma RI with a KD of 1×10⁻⁸ M or less and from Fc gamma RIII with a KD of 1×10⁻⁷ M or less. [0282] Glycosylation of an Fc region is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. The recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain peptide sequences are asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline. Thus, the presence of either of these peptide sequences in a polypeptide creates a potential glycosylation site. [0283] The glycosylation pattern may be altered, for example, by deleting one or more glycosylation sites found in the polypeptide, and/or adding one or more glycosylation sites that are not present in the polypeptide. Addition of glycosylation sites to the Fc region of an antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution of residue Asn 297 of the heavy chain. The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original polypeptide (for O-linked glycosylation sites). Additionally, a change of Asn 297 to Ala can remove one of the glycosylation sites. 93 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0284] In certain embodiments, the antibody is expressed in cells that express beta (1,4)-N- acetylglucosaminyltransferase III (GnT III), such that GnT III adds GlcNAc to the IL-23p19 antibody. Methods for producing antibodies in such a fashion are provided in WO/9954342, WO 2003/011878, U.S. Pat. Pub.2003/0003097A1, and Umana et al., Nature Biotechnology, 17:176- 180 (1999). Cell lines can be altered to enhance or reduce or eliminate certain post-translational modifications, such as glycosylation, using genome editing technology such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). For example, CRISPR technology can be used to eliminate genes encoding glycosylating enzymes in HEK 293 or CHO cells used to express recombinant monoclonal antibodies. [0285] It is possible to eliminate protein sequence liabilities of monoclonal antibodies. For instance, it is possible to engineer the antibody variable gene sequences obtained from human B cells to enhance their manufacturability and safety. Potential protein sequence liabilities can be identified by searching for sequence motifs associated with sites containing: 1) Unpaired Cys residues, 2) N-linked glycosylation, 3) Asn deamidation, 4) Asp isomerization, 5) SYE truncation, 6) Met oxidation, 7) Trp oxidation, 8) N-terminal glutamate, 9) Integrin binding, 10) CD11c/CD18 binding, or 11) Fragmentation. Such motifs can be eliminated by altering the synthetic gene for the cDNA encoding recombinant antibodies. [0286] Protein engineering efforts in the field of development of therapeutic antibodies clearly reveal that certain sequences or residues are associated with solubility differences (Fernandez- Escamilla et al., Nature Biotech., 22 (10), 1302-1306 (2004); Chennamsetty et al., PNAS 106: (29), 11937-11942 (2009); Voynov et al., Biocon. Chem., 21:(2), 385-392, (2010). Evidence from solubility-altering mutations in the literature indicate that some hydrophilic residues such as aspartic acid, glutamic acid, and serine contribute significantly more favorably to protein solubility than other hydrophilic residues, such as asparagine, glutamine, threonine, lysine, and arginine. Stability [0287] Antibodies can be engineered for enhanced biophysical properties. One can use elevated temperature to unfold antibodies to determine relative stability, using average apparent melting temperatures. Differential Scanning Calorimetry (DSC) measures the heat capacity, Cp, of a molecule (the heat required to warm it, per degree) as a function of temperature. One can use 94 4861-9829-0104.1 Atty. Docket No.: 116639-2660 DSC to study the thermal stability of antibodies. DSC data for mAbs is particularly interesting because it sometimes resolves the unfolding of individual domains within the mAb structure, producing up to three peaks in the thermogram (from unfolding of the Fab, CH2, and CH3 domains). Typically unfolding of the Fab domain produces the strongest peak. The DSC profiles and relative stability of the Fc portion show characteristic differences for the human IgG1, IgG2, IgG3, and IgG4 subclasses (Garber and Demarest, Biochem. Biophys. Res. Commun.355, 751- 757, 2007). One also can determine average apparent melting temperature using circular dichroism (CD), performed with a CD spectrometer. Far-UV CD spectra will be measured for antibodies in the range of 200 to 260 nm at increments of 0.5 nm. The final spectra can be determined as averages of 20 accumulations. Residue ellipticity values can be calculated after background subtraction. Thermal unfolding of antibodies (0.1 mg/mL) can be monitored at 235 nm from 25-95° C. and a heating rate of 1° C./min. One can use dynamic light scattering (DLS) to assess for propensity for aggregation. DLS is used to characterize size of various particles including proteins. If the system is not disperse in size, the mean effective diameter of the particles can be determined. This measurement depends on the size of the particle core, the size of surface structures, and particle concentration. Since DLS essentially measures fluctuations in scattered light intensity due to particles, the diffusion coefficient of the particles can be determined. DLS software in commercial DLA instruments displays the particle population at different diameters. Stability studies can be done conveniently using DLS. DLS measurements of a sample can show whether the particles aggregate over time or with temperature variation by determining whether the hydrodynamic radius of the particle increases. If particles aggregate, one can see a larger population of particles with a larger radius. Stability depending on temperature can be analyzed by controlling the temperature in situ. Capillary electrophoresis (CE) techniques include proven methodologies for determining features of antibody stability. One can use an iCE approach to resolve antibody protein charge variants due to deamidation, C- terminal lysines, sialylation, oxidation, glycosylation, and any other change to the protein that can result in a change in pI of the protein. Each of the expressed antibody proteins can be evaluated by high throughput, free solution isoelectric focusing (IEF) in a capillary column (cIEF), using a Protein Simple Maurice instrument. Whole-column UV absorption detection can be performed every 30 seconds for real time monitoring of molecules focusing at the isoelectric points (pIs). This approach combines the high resolution of traditional gel IEF with the 95 4861-9829-0104.1 Atty. Docket No.: 116639-2660 advantages of quantitation and automation found in column-based separations while eliminating the need for a mobilization step. The technique yields reproducible, quantitative analysis of identity, purity, and heterogeneity profiles for the expressed antibodies. The results identify charge heterogeneity and molecular sizing on the antibodies, with both absorbance and native fluorescence detection modes and with sensitivity of detection down to 0.7 μg/mL. Solubility [0288] One can determine the intrinsic solubility score of antibody sequences. The intrinsic solubility scores can be calculated using CamSol Intrinsic (Sormanni et al., J Mol Biol 427, 478- 490, 2015). The amino acid in HCDR3 (heavy chain CDR3; CDRH3) of each antibody fragment, such as a scFv or a Fv fragment, can be evaluated via the online program to calculate the solubility scores. One also can determine solubility using laboratory techniques. Various techniques exist, including addition of lyophilized protein to a solution until the solution becomes saturated and the solubility limit is reached, or concentration by ultrafiltration in a microconcentrator with a suitable molecular weight cut-off. The most straightforward method is induction of amorphous precipitation, which measures protein solubility using a method involving protein precipitation using ammonium sulfate (Trevino et al., J Mol Biol, 366: 449- 460, 2007). Ammonium sulfate precipitation gives quick and accurate information on relative solubility values. Ammonium sulfate precipitation produces precipitated solutions with well- defined aqueous and solid phases and requires relatively small amounts of protein. Solubility measurements performed using induction of amorphous precipitation by ammonium sulfate also can be done easily at different pH values. Protein solubility is highly pH dependent, and pH is considered the most important extrinsic factor that affects solubility. Auto-reactivity [0289] Generally, it is thought that autoreactive clones should be eliminated during ontogeny by negative selection, however it has become clear that many naturally occurring human antibodies with autoreactive properties persist in adult mature repertoires, and the autoreactivity may enhance the antiviral function of many antibodies to pathogens. It has been noted that CDRH3 (heavy chain CDR3; CDRH3) loops in antibodies during early B cell development are often rich in positive charge and exhibit autoreactive patterns (Wardemann et al., Science 301, 1374-1377, 2003). One can test a given antibody for autoreactivity by assessing the level of binding to 96 4861-9829-0104.1 Atty. Docket No.: 116639-2660 human origin cells in microscopy (using adherent Hela or HEp-2 epithelial cells) and flow cytometric cell surface staining (using suspension Jurkat T cells and 293 S human embryonic kidney cells). Autoreactivity also can be surveyed using assessment of binding to tissues in tissue arrays. [0290] Preferred residues (“Human Likeness”). B cell repertoire deep sequencing of human B cells from blood donors is being performed on a wide scale in many recent studies. Sequence information about a significant portion of the human antibody repertoire facilitates statistical assessment of antibody sequence features common in healthy humans. With knowledge about the antibody sequence features in a human recombined antibody variable gene reference database, the position specific degree of “Human Likeness” (HL) of an antibody sequence can be estimated. HL has been shown to be useful for the development of antibodies in clinical use, like therapeutic antibodies or antibodies as vaccines. The goal is to increase the human likeness of antibodies to reduce potential adverse effects and anti-antibody immune responses that will lead to significantly decreased efficacy of the antibody drug or can induce serious health implications. One can assess antibody characteristics of the combined antibody repertoire of three healthy human blood donors of about 400 million sequences in total and created a novel “relative Human Likeness” (rHL) score that focuses on the hypervariable region of the antibody. The rHL score allows one to easily distinguish between human (positive score) and non-human sequences (negative score). Antibodies can be engineered to eliminate residues that are not common in human repertoires. Compositions [0291] Another aspect of the present disclosure provides a composition comprising, or consisting essentially of, or consisting of one or more antibodies or antibody fragments disclosed herein; the isolated nucleic acid, or the vector described herein. In some embodiments, the composition is a pharmaceutically acceptable composition, and optionally can comprise other therapeutic agents for combination therapy. [0292] The present disclosure provides pharmaceutical compositions comprising, or consisting essentially of, or consisting of anti-JAML antibodies and antigens for generating the same. Such compositions comprise a prophylactically or therapeutically effective amount of an antibody or a fragment thereof, or a peptide immunogen, and a pharmaceutically acceptable carrier. In a 97 4861-9829-0104.1 Atty. Docket No.: 116639-2660 specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a particular carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Other suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. [0293] The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical agents are described in “Remington's Pharmaceutical Sciences.” Such compositions will contain a prophylactically or therapeutically effective amount of the antibody or fragment thereof, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration, which can be oral, intravenous, buccal, systemic, nasal, intraarterial, intrabuccal, intranasal, ocular, nebulized, injection, infusion, bronchial inhalation, inhalation, insufflation, intra-rectal, transdermal, rectal, vaginal, topical or delivered by mechanical ventilation. [0294] Generally, the ingredients of compositions of the disclosure are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where 98 4861-9829-0104.1 Atty. Docket No.: 116639-2660 the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. [0295] The compositions can further comprise an additional agent for the augmentation of the antibody response or treatment. [0296] This disclosure includes antibodies or antigen binding fragments thereof that bind to a junction adhesion molecule like (JAML) protein or a fragment thereof. In some aspects, the antibody or antigen binding fragment comprises, consists of, or consists essentially of heavy chain complementarity-determining regions 1-3 (CDRH1-3) and light chain complementarity- determining regions 1-3 (CDRL1-3) selected from a single row of Table 2 or Table 5, or equivalents thereof. In one aspect, the antibody or antigen binding fragment comprises, consists of, or consists essentially of a heavy chain variable region (HC) and a light chain variable region (LC) selected from a single row of Tables 1 or 3 or an equivalent thereof. [0297] In some aspects, the antibody comprises, consists of, or consists essentially of a monoclonal antibody, or a fragment thereof. In some aspects, the antibody comprises, consists of, or consists essentially of a constant region selected from the group of: an IgA constant region, an IgD constant region, an IgE constant region, an IgG constant region or an IgM constant region. In some aspects, the constant region comprises, consist of, or consists essentially of an IgG1 constant region. [0298] In some aspects, the antigen binding fragment comprises, consists of, or consists essentially of a Fab, F(ab’)2, Fab’, scFv, or Fv. In some aspects, the antibody or antigen binding fragment comprises, consists of, or consists essentially of a detectable label or a purification label. [0299] In some aspects, the equivalent comprises, consists of, or consists essentially of a polypeptide having at least 80% amino acid identity to the polypeptide, or wherein an equivalent to the amino acid sequence comprises a polypeptide that is encoded by a polynucleotide that hybridizes under conditions of high stringency to the complement of the polynucleotide encoding the amino acid sequence. 99 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0300] In one aspect, the antibody or antigen binding fragment comprises a modification. In some aspects, the modification comprises, consists of, or consists essentially of a PEGylation, a PEG mimetic, polysialyation, HESylation or glycosylation. [0301] In some aspects, provided herein is an isolated polynucleotide encoding the antibody or antigen binding fragment. In some aspects, the polynucleotide is operatively linked to a promoter an/or enhancer element. In some aspects, the polynucleotide comprises, consists of, or consists essentially of a detectable label of purification label. In some aspects, a vector comprising, consisting of, or consisting essentially of the polynucleotide is provided herein. In some aspects, the vector comprises, consists of, or consists essentially of a heterologous promoter sequence. In yet another aspect, an isolated host cells comprising, consisting of, or consisting essentially of the polynucleotide or the vector is provided herein. [0302] In one aspect, provided herein is a composition comprising, consisting of, or consisting essentially of a carrier and the antibody or antigen binding fragment, the polynucleotide encoding the antibody or antigen binding fragment, the vector, or the host cell. In some aspects, the carrier comprises, consists of, or consists essentially of a pharmaceutically acceptable carrier. [0303] In yet another aspect, provided herein is a kit comprising, consisting of, or consisting essentially of the antibody or antigen binding fragment, the polynucleotide encoding the antibody or antigen binding fragment, the vector, or the host cell. In some aspects, the kit comprises, consists of, or consists essentially of instructions for use. Methods [0304] Provided herein are methods for producing an antibody or antigen binding fragment is provided herein. In some aspects, the method comprises, consists of, or consists essentially of culturing a host cell comprising a polynucleotide encoding the antibody or antigen binding fragment thereof that encodes the antibody or antigen binding fragment thereof under conditions for expression of the antibody or antigen binding fragment thereof. In some aspects, the method further comprises, consists of, or consists essentially of isolating the antibody or antigen binding fragment. [0305] In yet another aspect of this disclosure, provided herein is a method for binding a JAML protein or fragment thereof. In some aspects, the method comprises, consists of, or consists 100 4861-9829-0104.1 Atty. Docket No.: 116639-2660 essentially of contacting the JAML protein with an antibody or antigen binding fragment thereof under conditions that favor binding of the antibody or antigen binding fragment thereof, and optionally isolating the antibody or antigen binding fragment thereof bound to the JAML protein. The disclosed methods are useful for the in vitro or in vivo detection of the JAML proteins, when optionally the antibodies or antigen binding fragment thereof, are detectably labeled. The cells can be animal or mammalian, such as human. They can be from a patient biopsy or from a cultured cell line such as a commercially available cell line (e.g., available from the American Type Culture Collection.) [0306] When practiced in vitro or in vivo in an animal model, the compositions are useful to assay for agonist or antagonist agents that mediate the JAML pathway (e.g., leading to cell activation, proliferation and/or cytokine production) when the JAML protein is bound to the antibody, agonist or antagonist. As understood by those of skill in the art, one or more controls should be assayed concurrently or sequentially and can be used for comparison purposes. [0307] This disclosure also provides methods to activate or agonize the JAML pathway comprising or consisting essentially of, or yet further consisting of administering to a subject a composition of this disclosure thereby activating or agonizing the JAML pathway in the subject. [0308] Further provided are methods for treating a tumor or cancer in a subject in need thereof, comprising or consisting essentially of, or yet further consisting of administering to a subject a composition of this disclosure thereby treating cancer in the subject. The subject can be an animal, mammal or human patient. [0309] In some aspects, compositions comprising the antibodies disclosed herein are administered for the treatment of cancer in a subject. In some aspects of this disclosure, the cancer or tumor is a cancer of at least one of the following organs: circulatory system; respiratory tract; gastrointestinal system genitourinary tract; live; bone; nervous system; reproductive system; hematologic system; oral cavity; skin and other tissues comprising connective and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma, and adnexa, breast, head or/and neck, anal region, thyroid, parathyroid, adrenal gland colon cancer, pancreatic cancer, and other endocrine glands and related structures, and lymph nodes. The cancer may be a solid tumor or alternatively wherein the cancer is a liquid cancer, The cancer may be a primary cancer or a metastasis and/or a cancer selected from a carcinoma, a sarcoma, a myeloma, a leukemia, or lymphoma, testis cancer, brain cancer, a metastasis or recurring cancer a non-small cell lung 101 4861-9829-0104.1 Atty. Docket No.: 116639-2660 cancer (NSCLC) and/ or head and neck squamous cell cancer (HNSCC). In addition, cancer of a tissue selected from an epithelial, a head, neck, lung, prostate, colon, breast, testis, bone, lymphatic system, blood, endometrium, uterus, ovary, pancreas, esophagus, liver, skin, kidney, adrenal gland, brain. The cancer can be from the group of; a lymphoma, leukemia, breast cancer, an early-stage triple negative breast cancer, endometrial cancer , uterine , ovarian cancer , testicular cancer, lung cancer, prostate cancer, colon cancer, rectal cancer pancreatic cancer , esophageal cancer , liver cancer, melanoma, or other skin cancers, ovarian cancer, kidney cancer, adrenal gland cancer, a non-small cell lung cancer (NSCLC) and/ or head and neck squamous cell cancer (HNSCC)and/or brain cancer or tumor. It can be of any stage (primary or metastatic) or a recurring tumor or cancer or neoplasia. Experimental Materials and Methods [0310] Immunization.5 C57BL/6J mice (Jackson Laboratories) were immunized intraperitoneally with 100µg recombinant protein (human JAML – Sinobiological) in 100µl ddH20 mixed with 100µl of alum (Prime immunization) and again 4 weeks later (booster immunization).7 days later, 3 mice were euthanized by CO₂ and cervical dislocation, and spleens and femurs were harvested. Plasma cells from these organs were purified (Stemcell Technologies), pooled and resuspended in 15ml of Plasma B cell media (Berkeley Lights) and loaded onto the chip (Beacon instrument) according to manufacturer’s instructions. Plasma cells secreting antibodies against target antigen (human JAML) were identified on the Beacon (specific workflow described in MAN-08133). [0311] Opto Plasma B discovery 4.0 workflow. Purified plasma cells were loaded onto a 23k Optoselect chip and isolated as single cells into Nanopens via optoelectronic positioning (OEP). Cells were then assayed for secretion of antigen-specific (extracellular domain of human JAML) IgG antibodies by loading biotinylated human JAML bound to Streptavidin coated beads and fluorescently labeled anti-mouse IgG antibodies onto the chip (slide 6 in the pptx document). Subsequently, beads and antibodies are flushed out and mRNA capture beads are loaded onto the chip and into each nanopen containing the (antigen-specific) plasma cells. Next, cells were lysed and cDNA was synthesized via reverse transcription. cDNA bound to barcoded BCR beads was exported (‘unpenned’) into a 96-well plate with up to 12 barcoded cDNAs/well for downstream 102 4861-9829-0104.1 Atty. Docket No.: 116639-2660 processing (NGS sequencing and antibody re-expression). Metadata summarized in excel sheet ‘OptoSeq BCR summary file’. [0312] Amplification and NGS sequencing of barcoded cDNA. Exported cDNA was amplified and purified according to the manufacturer’s instructions (MAN-08137). Subsequently, cDNA was quantified via PicoGreen assay (highly sensitive method to quantify DNA using a fluorescent nucleic acid stain) and their fragment size was determined using a Bioanalyzer. A part of this cDNA was used for the Re-expression of antibodies described in MAN-08148. After determining the fragment sizes with a Bioanalyzer, Applicant performed BCR amplification by utilizing the provided Barcoded BCR forward primers, quantified the BCR amplification products via PicoGreen and then pooled the amplicons into single tube. The amplicons were then bead purified and quantified. Applicant then performed library tagmentation by using the Nextera XT DNA Library Preparation kit and then performed PCR Library Indexing. Lastly, the libraries were purified, quantified, analyzed with a fragment analyzer and then sequenced on a NovaSeq. The generated fastq files were subsequently analyzed with PrineSeq BCR software (Berkeley Lights). Hc and Lc sequences derived from the NGS sequencing workflow are summarized in excel sheet ‘Pipeline_output_summary’. [0313] Re-expression of antibodies from Opto Plasma B discovery 4.0 workflow. Applicant first performed the Hc and Lc domain amplification from the cDNA (described in step 3), quantified the cDNA concentration via PicoGreen and the Hc and Lc amplicon size via gel electrophoresis. Applicant then generated the heavy chain and light chain constructs and again quantified the amplicon concentration as well as their respective sizes via gel electrophoresis. Applicant then combined the respective Hc and Lc constructs and transfected HEK293T cells and grew the cells at 37C for 4-5 days. Afterwards, Applicant harvested the supernatants and tested the antigen-specificity of the generated antibodies via enzyme-linked immunosorbent assay (ELISA). [0314] Sequencing of Hc and Lc chains and production of monoclonal antibodies. Given that Applicant only got a small fraction of Hc sequences from the 287 exported unique cDNAs (51/287) from the NGS sequencing step, Applicant additionally conducted a deconvolution assay for antigen-specific antibodies (ELISA assay) from wells A3-A10 from the Beacon export plate (summarized in excel sheet, tab ‘Antibody re-expression’) by performing nested PCRs of the 103 4861-9829-0104.1 Atty. Docket No.: 116639-2660 cDNA that was cloned into expression vectors (MAN-08148). The final PCR product was used for Gibson cloning of the Hc (MsHC Koz IgG pHCMV R1/Xho vector and Lc MsKLC Koz IgG pHCMV R1/Xho vector) – mouse IgG1 backbone. The Hc and Lc (kappa light chain) plasmids were then used for bacterial transformation (DH5a competent cells). Bacteria were grown at 37C for 24h in SOC media containing Kanamycin to enable only bacteria to grow that successfully incorporated the plasmid with the Kanamycin resistance gene. Using a multichannel, 6µl of the cells were streaked onto a Kanamycin plate to generate single colonies, grown for 20h at 37C and then stored at 4C. Plasmid DNA of the bulk transformation was then purified (QIAprep 96 Turbo kit) and sent for Sanger sequencing. Plasmid DNA from the bulk transformation was then used to transfect CHO cells to produce antibodies. To test the antigen-specificity (recognizing human JAML), ELISAs were performed with the CHO cell culture supernatant. As the Sanger sequencing revealed impure sequences for some of the Hc and Lc plasmids, new S blocks were seeded (bacterial growth) of 8 single colonies for each of the Hc and Lc plasmids from the previous step and grew the bacteria from the individual colonies for 20h at 37C, purified the plasmid DNA (QIAprep 96 Turbo kit) and sent the purified plasmids for Sanger Sequencing. The rest of the DNA was stored at 4C. For some of the Hc and Lc plasmids, Applicant obtained diverse sequences from the 8 individual colonies, implying that some of the antibodies derived from MAN-08148 were polyclonal. To generate true monoclonal antibodies, Applicant utilized the Hc plasmids from individual colonies and paired them with the respective Lc plasmids from the same antibody clone for subsequent CHO transfection. As before, Applicant used the CHO supernatants to identify hJAML-specific antibodies (monoclonal). Humanization of JAML-specific Antibodies [0315] Affinity Measurement with Octet [0316] Kinetic analysis of the recombinantly produced humanized variants and parental chimera was performed using Bio layer Interferometry. Very slow dissociation kinetics 1 E 05 s 1 were observed using standard assay conditions and biosensor regeneration, which were beyond the detection limits of the instrument. Additionally, an unstable (e.g. dissociative) baseline was observed in at least one reference well, which may give rise to poor line fits or miscalculated kinetic rates. The processed sensorgrams with Reference subtraction from one Octet session were included. Based on the current results, humanized variants appeared to bind huJAML in the 104 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Octet assay as compared to the parental chimera. Two additional sessions were run to evaluate if alternate conditions would give rise to improved results. The first session was performed to assess qualitative “yes/ binding of all IgG and 1000 nM JAML Analyte, where Reference subtraction was employed. The second session run included kinetic analysis of up to 4 antibodies that showed qualitative binding in session one, where they were tested for huJAML HIS binding using non regenerative conditions. Though sensor regeneration is common, typically employed in standard conditions, and did not appear to impair re loading of IgG’s, regeneration was excluded to minimize potential variables. [0317] Humanness Assessment for HC [0318] The humanness scores for the parental and humanized antibodies are shown in the table below. Based on this method, a score of 90 or above is indicative of a human-like heavy chain framework. For full-length variable region, cutoff score of 80 for the VH is recommended. T₂₀ T₂₀ A l A l [0320] The humanness scores for the parental and humanized antibodies are shown in the table below. Based on this method, a score of 90 or above is indicative of humanness for a kappa light chain framework. For full-length variable region, cutoff score of 86 for the Vκis recommended. 105 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0321] Antibody Production Yields [0322] Humanized variants and (1) Parental Chimera were transiently produced using 0.01 L TunaCHOTM extended 14-day process and purified by Protein A chromatography. Yield are summarized in the following table: 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0323] Octet Methods [0324] Ligands were diluted in assay buffer to prepare a 5 µg/mL solution for assay use. huJAML-HIS protein was re-constituted in water to prepare a 0.25 mg/mL analyte solution per manufacturer COA. Buffer exchange (1X) of the resulting JAML protein solution was performed by diafiltrationusing an AmiconUltra Centricon, where 100% recovery is assumed. A serial dilution series of huJAML was prepared, starting from 1000 nM and diluting 1:3 to generate 7 concentrations (i.e., 1000, 333, 111, 37, 12.4, 4.1, and 1.4 nM). Binding experiments were performed on Octet HTX at 25°C. [0325] The 8.4 Ab Parental Chimera and (9) humanized 8.4 Ab variants hIgG were captured onto AHC sensors. The loaded sensors were dipped into serial dilutions of huJAML-HIS protein. A reference sample well (buffer) was included and used as a Reference for subtraction during data processing. Kinetic constants were calculated using a monovalent (1:1) binding model. [0326] Binding curves of analyte concentration at 12.4 nM and 1.4 nM were excluded from analysis due to low binding signals. SR # SR-24951 [0327] Scouting experiments indicated that the parental chimera and the three humanized variants paired with LC1 associated with JAML. Subsequent assaying of these four IgG against dilution series of JAML analyte show once again that HC2+LC1 and HC3+LC1 did not show repeatable and titratable binding to JAML. Importantly, the parental chimera and humanized Hu8.4 Ab HC1+LC1 show binding to JAML with mid-range nMaffinity. 107 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0328] The baseline instability was improved while buffer effects persisted, most notably in the Reference-subtracted 1000 nMbinding curves. Even with additional buffer exchange performed on the JAML protein, from run-to-run, the sensitive Octet assay continued to yield some aberrant behavior for the JAML. Affinity determination of HC1+LC1 and parental chimera may require additional studies to resolve the variance amongst experiments, including using SPR, a more sensitive assay method, and testing other assay buffer formulations. (FIG.3) E^{st kdiss ^ ^2} 4₅ 1 ^{77 . 95 . . . . .} [0330] Humanized variants and (1) Parental Chimera were loaded on AHC sensors at 5 μg/mL and binding kinetics were assessed with JAML at 1000 nM in assay buffer. Sensorgrams and results are summarized in the table below. (3) humanized variants (Hu8.4 Ab HC1+LC1, HC2+LC1 and HC3+LC1) and Parental Chimera (8.4 Ab Parental) showed JAML binding response > 0.05 nm. Subsequent kinetics analysis with Octet (BLI) was performed on these (4) test articles in Session Two. (FIG.4) 108 4861-9829-0104.1 Atty. Docket No.: 116639-2660 to te. ng. [0331] K_d Results Summary (Session 2) [0332] Test Articles were assayed for binding to human JAML His protein by Octet (BLI), and their affinity (KD) values are reported in the summary table below and in subsequent slides alongside sensorgrams. A 1:1 binding model was used for all 4 test articles. The KD was calculated using the ratio k dis /k a. [0333] Ab Parental and Hu8.4 Ab HC1+LC1 exhibited nanomolar affinities (K_D). [0334] Dissociation beyond detection limit (K_DIS 1<10-5) was observed for Hu8.4 Ab HC1+LC1. [0335] Hu8.4 Ab HC2+LC1 and Hu8.4 Ab HC3+LC1 response signal were non-detectable (n.d., response < 0.05). (FIG.5) L^{igand Analyte K} _D ^(M) 8.4 Ab Parental huJAML-His 3.02E-07 109 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0337] Prior to the kinetic analysis, a buffer exchange of the analyte into assay buffer using a MilliPoreAmicon column, 30Kda MWCO, was performed. Binding experiments were performed on Octet HTX at 25°C.8.4 Ab Parental Chimera (1) and humanized 8.4 Ab variants (3) (5 µg/mL) were loaded onto AHC sensors. Loaded sensors were dipped into a serial dilutions of protein samples (1000 nM start, 1:3 dilution, 7 points) for 300 s and followed by dissociation in assay buffer for 600 s. Reference sample well (buffer) was used for data analysis. Kinetic constants were calculated using a monovalent (1:1) binding model first for all four test articles. [0338] Binding curves of analyte concentration at 12.35 nM, 1.37 nM and 0.15 nM were excluded from sensorgrams and analysis due to low binding signals. SR # SR-24951 Ligand Analyte Response ^KD ^{(M) k} _a ^{(1/Ms) k} _dis X^2 R^2 (nm) (1/s) 9 5 [0339] Humanization Process Part 2 (3^rd Session) [0340] The previous binding assessments were performed on Greiner One Bio plates (Cat. #781900) Through a series of multiple BLI experiments at Curia, Curia observed a more stable baseline well to well in Sartorius Octet plates (Cat. #185080) and proceeded with testing binding of 4 antibodies (8.4 Ab Parental, Hu8.4 Ab HC1+ LC1, Hu8.4 Ab HC2+ LC1, and Hu8.4 Ab 110 4861-9829-0104.1 Atty. Docket No.: 116639-2660 HC3+ LC1) against human JAML His protein under standard Octet conditions using Sartorius plates. [0341] Affinity (K_D) values are reported in the summary table below and in subsequent slides alongside sensorgrams.1:1 curve fitting model used for kinetics calculation. The KD was calculated using the ratio KDIS / KA. [0342] Ab Parental and the humanized 3 variants showed equivalent nanomolar affinities (K_D). L^{i d A l} Octet Methods [0343] Binding experiments were performed on Octet HTX at 25°C.8.4 Ab Parental Chimera (1) and humanized 8.4 Ab variants (3) (5ug/mL) were loaded onto AHC sensors. Loaded sensors were dipped into a serial dilutions of protein samples (1000 nMstart, 1:3 dilution, 7 points) for 300 s and followed by dissociation in assay buffer for 600 s. Reference sample well (buffer) was used for data analysis. Kinetic constants were calculated using a monovalent (1:1) binding model first for all four testing articles. [0344] Binding curves of analyte concentration at 12.35 nM, 1.37 nM and 0.15 nM were excluded from sensorgrams and analysis due to low binding signals. SR # SR-24951 Equipment Octet HTX 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0345] Sensogram and Kinetics Table [0346] Sensograms and Kinetics Tables are shown in the table below and FIG.6. Ligand Analyte Response ^K _D ^{(M) k} _a ^{(1/Ms) k} _dis ^{(1/s) X^2 R^2} 7 * * * [0347] Agonistic Immunotherapy [0348] Agonistic immunotherapies frequently target co-stimulatory molecules like 4-1BB, ICOS or OX-40. Engagement of the inhibitory Fc^RIIB is crucial for the in vivo efficacy of such murine and human agonistic immunotherapy antibodies, as it mimics engagement by multimeric endogenous ligands (i.e., most TNF receptors like CD40, OX-40 or 4-1BB are trimeric and thus require multimeric ligands for proper activation). Accordingly, antibodies with enhanced affinity for Fc^RIIB like IgG1 or with Fc-directed mutations that increase their affinity to Fc^RIIB exhibit increased anti-tumor effects. [0349] To test the agonistic activity of such Fc-optimized human antibodies faithfully and convincingly in mouse models requires the expression of human Fc^ receptors. Therefore, syngeneic tumor models – such as the MC38 model of colon cancer (see Schrörs et. al. Front Immunol.2023 Mar 8;14:1102282. doi: 10.3389/fimmu.2023.1102282. PMID: 36969213; PMCID: PMC10030996), the B16F10 (available at: https://www.atcc.org/products/crl-6475) model of melanoma, lung cancer, as well as head and neck cancer models – in humanized Fc^R mice are utilized to conduct in-depth analyses of the Fc-optimized humanized antibody variants. When compared to parental (intermediate Fc^RIIB binding) or Fc silenced IgG1 antibody lacking detectable Fc^R binding, the Fc-optimized antibody will (increased affinity for Fc^RIIB) have substantially enhanced anti-tumor effects. 112 4861-9829-0104.1 Atty. Docket No.: 116639-2660 Equivalents [0350] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains. [0351] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All nucleotide sequences provided herein are presented in the 5′ to 3′ direction. [0352] The embodiments illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure. [0353] Thus, it should be understood that although the present disclosure has been specifically disclosed by specific embodiments and optional features, modification, improvement and variation of the embodiments therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of particular embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure. [0354] The scoped of the disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. 113 4861-9829-0104.1 Atty. Docket No.: 116639-2660 [0355] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that embodiments of the disclosure may also thereby be described in terms of any individual member or subgroup of members of the Markush group. [0356] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. In some aspect, the publication is referenced by an Arabic numeral. The full citation for these publications are provided below. 114 4861-9829-0104.1 LS L ^TS ^Y S ^GY ^NR^A F N S ^GY ^NR F L_S A^D _S QG_{E T} ^D _S Y _L ^T K^RD ^D _S Y _L ^{T A} K^R A ^{V S Y} _S ^E _LA _L ^D I Q ^KNA ^L _LV ^L S ^KG _{S S L} ^N AD _{I S} ^P Q A D_I Y Q _L ^{D L} _LV ^L S ^KG _{S S L} ^N AD _{I S} ^P Q A D_{I S S S} ^D _{S L} K^L _L ^{V K} _S ^S GA ^{QG S K} _P ^L _{S L} ^S GA ^QG _{P I} ^AT R_{L E} Q E ^S _S ^V _L ^D _{E S} ^Y K_I LQ^N _{S C} Q AQ LY ^S _S ^V _L ^D _{E S} ^Y K_I LQ^N _S AQ L Q Q Q^KD Q^KD _{P L} ^S _{T P L} ^S _{T P L} ^S _{T P L} ^S _{T P L} ^S _{T P L} V_E ^RG GK W^V _E ^RW G_S ^S G QKG_S ^S G QKG_S ^S G QKG_S ^S G QKG_S ^S G QKG L ^P _{S S} ^{I Y} _L ^P _{S S} ^{I Y G} _LQ G_TG^G _LQ G_TG^G _LQ_TG^V _LQ_TG^V _LQ_TG^V _LQ G _{T R}G _{T R} ^E D ^E D ^EGD ^EGD ^EGD ^EG G^QF G^QF _P ^{P V}W_P ^{P V}W ^P W ^P W ^P W ^P G_R ^F V_RLG_R ^F V_RLG_RTYG_RTY_P G_R ^V _TY_P G_R ^V _TY_P G_R ^V _TY_P G_R S_E GG^S GG^S Q K^{L Q}WK _T ^A _L ^S Q K^L _T ^A _L ^S Q K^L _T ^A _L ^S Q K^L _TD^S Q K^L _TD^S Q K LNV^T _E S _C ^QWK V^T _E Q _E QVA _E QVA _E Q G VA _E G VAD D D _E V^QVAV^QV Y_LN^S _C Y_LWK^D _LWK^D _LWK^D _LWK^P _LWK QM_E M_{E R R R R} ^P R _LW V _EWA^Y Y Y_I Q G^V _EWA^Y Y Y_I Q G^VN E _I G D^K _F ^AQ C ^VN E _I G D^K _F ^AQ C ^VN E _I G D^K _F ^AQ^N C ^V _{E I} G D^K _F ^QQ^N C ^V _{E I} G D^K _F ^QQ^N C ^V _{E I} D 1_: ¹ _: ² _: ² _: ² _: ³ _: ^{3 3} O O O O O O _: O _: ¹ _. N ^{N N N N N N} O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _I ^D _I ^D _{0 I} ^D _I -₉ ² Q E Q Q Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E _S ^E _S ^E - _S ¹ ₆ ⁸ ₄ N ^YRR ^NR^{A T}L ^YRR ^NR ^TL Y^F NR D _S ^{I A}Q _L ^T L_{S S} ^A _L ^{T A} L_S ^N _RG ^{S A} Y Q _{S P} S V^{H L} S ^G _{C S S L} ^LAD ^I _P Q AD _S A QGA _S V^{H L} A ^S _S ^G _{C S S L} AD ^L _S AD A _S A QGA ^S _I ^A _PQ _S ^I _P V V^Q _S ^{S G} T ^T W W W S_{S T} ^G _P ^E _T ^L _T ^G _P ^E _T ^L _T ^G _P ^E _T ^L _T ^G _{P L} G^S _EG Q^G _{P L} G^S _EG Q^G _{P L} G^S _EG Q^G _E ^V _{E P} ^L _S ^S _T ^G _P ^{L S} GK_L ^S G_S GK_L ^S G_S GK_L ^S G_S GQ^KD TQ G^V _LQ^S _TQ G^V _LQ^S _TQ G^V _LQ^S _TQ^V _E G_L ^{P R}GQ^KDGQ^KDGK_{S S} V F _S ^I W^V _E Y _L ^{P R} F _S ^I W^V _E Y _L ^{P R} _S ^I W^VKK^TK_S K LGD_T ^V _LG D VW^EG P ^PD VW^EG P ^PD G VW^E _P ^PD VWG G^Q _T G _T G_{F T} ^{Y HVG H} R^F _R ^F G^Q R^F _R ^F G^Q R^F _R ^{F E} _{P S T T} ^E G_{P S T}Y L G_RTYG_RTYG_RTY _{R R R} Q^L Q TD Q ^A Q ^A Q ^AGVG_LGVG_LGV _LG _T G G^S _EK^L _{T L} ^S _EK^L _{T L} ^S _EK^L _{T L} ^S _E KG^S _E KG^S _E G KG^S _EK AW^S _EK A K ^QVAD VAD VAD W ^T W ^T W ^T V_RV V V^{P Q Q Q}NV_C ^QNV_C ^QNV_C ^QW ^{D Q}W G K_{R L} QWK^D R _L K QW ^D R _L K QW ^D R _LM^S _EY_LM^S _EY_LM^S _EY_LNG_S T _LN F ^Q C ^VN E _I G D^K _F ^A C ^VN E _I G D^K _F ^A C ^VN E _I G D^K _F ^AQ C ^V _EWA^Y Y Y_I Q G^V _EWA^Y Y Y_I Q G^V _EWA^Y Y Y_I QM^K G^V _E Y_F Q_CQM Y^V _E Y 4_: ⁴ _: ⁴ _: ⁵ _: ⁵ _: ⁵ _: ^{6 6} O O O O O O _: O _: ¹ _. N ^{N N N N N N} O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _I ^D _I ^D _{0 I} ^D _I -₉ ² Q E Q Q Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E _S ^E _S ^E - _S ¹ ₆ ⁸ ₄ RG NRG ^I L LR^{A F Y} NRG NRG ^{I A}Q ^{S A}Q L_S ^T _L H _I ^{S A}Q ^{S A}Q L_{S P} ^Q _{S P} ^LA^{D L} _{S S} V_R ^G _{S P S P} ^LA V ^I V^Q _S G_E A^{D I N} _L ^I V^{Q I Q} _S G G_{C S} ^G _C Q^YA^KQG_{E S S} ^D _S ^G _{C S} V G_C Q^Y E ^{V L} _{S S} ^S _TA S V^GW^A _TA _TA _TA _TA _T W W T _P ^E _TV^GW^{A S T} _{I P} ^E _TV^GW^{A S T} _{I P} ^E _TV^GW^{A S T} _{I P} ^E _TV^GW^AV^{G S T} _P ^E _TV T ^G _P ^E I _P ^E _T ^{S T} _I K_L ^S _{S I} GK_L KK G _TK_L G_S ^{S G}K_L G_S ^{S G}K_L G_S ^GK_L G_S ^GK_L G_S ^{G V}G G Q^S _T ^VQ HD S ^{VG V} Q_{T T L}Q_{T T} ^V _LQ_{T T} ^V _LQ^S _{T T} ^V _LQ^S _{T T} ^V _LQ^S _{T T L}G_T DG_LG G^DG^PDG^DG^PDG^DGDG^DGDG^DGDG^E _P ^{P E} R^VW_P ^P R K^L _{T P} WG_R ^V _TW_{P R} ^V _TW_P ^P R^V _TW_P ^P R^V _TW_P ^P R^V _TWGQ_TVGQ V^{A S} Q^LVG^S Q^LVG^S Q^LVG^S Q^LVG^S Q^LV^S _EK^L _TD L ^S _EK W_RV D _E QK_TD A^L _E QK_TD L _EK_TD L _EK_TD L _EK_TD L ^QVA_S ^QV NG_S TAVK_S AVA K_S Q A AVK_S Q A AVK_S Q A AVK_{S L}WK^D R _LW M^K Y_F Q_CAWD^D Y G^N _I K_RAWD^D A G^N _I K_RAWD^D A G^N _I K_RAWD^D A G^N _I K_RAWD^D A G^N _I K_RQ A^VN E _I D D^K _F ^AQ^N C ^V _{E I} D 7_: ⁷ _: ⁷ _: ⁷ _: ^{7 8 8} O O O O _: O _{: :} ¹ _. N ^{N N N N} O N O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _{0 I} ^D _I ^D _I -₉ ² Q E Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E Q S ^E - _S ¹ ₆ ⁸ ₄ L D LR^{A F Y} NRG NRG ^I L LR^{A F Y} NR E ^L _S ^T _{S L} H_RI ^{S A}Q ^{S A}Q L_S ^T _L H_RI ^{S A} A^KQA^D V^I G_{E S} ^NG S _{L S} ^I _P D _S V^Q _S ^I _P ^LA^{D L G} _{C S} V^Q _S G_{E S S} V A^{D I NG G} _C Q^YA ^KQ _{L S} ^I _P V G_{E S S} ^D _S ^G TV S ^{T G}W V P ^E _T ^{S T G}W V P ^E _T ^{S T G}W V P ^E _T ^{S T G}W W W W W P ^E _T ^{S MG} _P ^E _T ^{S MG} _P ^E _T ^MG _P ^E _T ^MG _P ^E S _I GK_{L S I} GK_{L S I} GK_{L S I} GK_{L S I} GK_{L S I} GK_L ^S _{S I} GK_L ^S _{S I} GK_L S _T G^S _T G^S _T G^S _T G^S _T G^S G^S G^S G T ^VQ_T ^VQ ^VQ ^VQ ^VQ _T ^VQ _T ^VQ _T ^VQ DG_L EGDG_{L T} EGDG_{L T} EGDG_{L T} EGDG_LG_T DG_LG_T DG_LG_T DG_LG V_TW_P ^{P L}VG_R ^VW_P ^P R^VW_P ^P R^VW_P ^P R^VW^E _P ^P R^VW^E _P ^P R^VW^E _P ^P R^VW^E _P ^P TD L ^S Q_{T E}K^LVG TD Q_T L ^S _EK^LVG TD Q_T L ^S _EK^LVG TD^S Q_{T E}K^LVG TD^S Q_{T E}K^LVG TD^S Q_{T E}K^LVG TD^S Q_{T E}K^LVG_{R T}D^S Q EK A_S D ^Q _LVA_S D ^Q _LVA_S D ^QVA^L _S ^QVA^L _S ^QVA^L _S ^QVA^L _S ^QVA^L _S ^QV K D K_RQWK RQWK R _L K QW ^D R _L K QW ^D R _L K QW ^D R _L K QW ^D R _L K QW ^D R _LW F ^A C ^VN E _I D D^K _F ^A C ^VN E _I D D^K _F ^A C ^VN E _I D D^K _F ^A C ^VN E _I N D^K _F ^A C ^VN E _I N D^K _F ^A C ^VN E _I N D^K _F ^A C ^VN E _I N D^K _F ^AQ C ^VN E _I D 8_: ⁸ _: ⁸ _: ⁹ _: ⁹ _: ^{9 9 9} O O O O O _: O _{: :} ¹ _. N ^{N N N N N} O N O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _I ^D _{0 I} ^D _I ^D _I -₉ ² Q E Q Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E _S ^E Q S ^E - _S ¹ ₆ ⁸ ₄ R^{R N} _S D I ^P D_I Y L^T _S L KF N N G^{Q L} _S A _I ^RD R^R _S D ^T Y L_S L KF N N I ^RD R^R _S D ^T Y L_{S L} QG^{D Y} _E D_S ^P A ^Q _I Y ^N Q _I ^P D_I G^{Q L} _S A L QG^{D Y} _E D_S ^PY ^N _I ^P _I A ^Q _I Q D^{GQ L} _S A L QG Y G_P ^E _L ^A _TV^G _P ^E _L ^A _TV^G _P ^E _L ^A _TV^GW P ^E _T ^GW W ^{E V E S T} _{T P} ^E _T ^{S T} _T ^G _P ^E _T ^{S T} _T ^G _{P L T}Y^{G A} _{P L} KG^N _S ^T _TKG^N _S ^T _TKG^N _S ^T _TK_L G_S ^GK_L G_S ^GK_L G_S ^GKG^N _{S F} KG V L ^Q E _E ^{S G}V T _T ^{L Q} _E ^{S G}V^Q _E ^{S G}VQ^S _{T T}VQ^S _{T T}VQ^S _{T T}V^Q _E ^S WV^Q _E D_{T E} ^T _T D_T ^L _E ^T _T D_T ^L _EGDG^L _EGDG^L _EGDG^L _E ^T _T D^{G L} _E ^T A_R G Q^AWA_R G Q^AWA_R G Q^AWX^P R^VWX^P R^VWX^P R^VWA_R ^A _R LA_R G _T G _T G _T G _TVG _TVG _TVGQ_T GQ S_EK QV^I _TV K D^S _EV^I _TV K D^S _EV^I _TV Q D^S _EK^L _TD Q L ^S _EK^L _TD Q L ^S _EK^L _TD L ^S _EK V^I _{L T}G^S _EK V LWA^L _S ^Q _LWA^L _S ^Q _LWA^L _S ^Q _LVA_S D ^Q _LVA_S D ^QVA_S ^QWAG^QW QHK G^DQHK G^DQHK G^DQWK G_RQWK _L G_RQWK^D R _L QHK^G R _L QH V _EM Y^Q _{F R E}M A^V Y^Q _{F R} A^V _EM Y^Q _{F R} A^VN E _I D^K _F ^A C ^VN E _I D^K _F ^A C ^VN E _I G D^K _F ^A C ^V _EMG Y^Q _F ^A C ^V _EM Y 0¹ ₀ ¹ ₀ ¹ ₁ ¹ ₁ ¹ ₁ ¹ ₂ ¹ _{2 :} O _: N O _: N O _: N O _: N O _: N O _: ^{1 N} O _: N O ¹ _. N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _I ^D _I ^D _I ^D _{0 I} -₉ ² Q E Q Q Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E _S ^E _S ^E - _S ¹ ₆ ⁸ ₄ L KF D ^N _I ^RN D R^R _S D L^T _S L KF N N S ^G I ^RD Y S ^GY S ^GY S ^G H_S Y H_S H_S H_{S E} D_S ^P _I Y ^N _I ^P _I Y Q ^L _S A G^D _E D_S ^P Y V^F RV V^{I F} RY V V^F RY V V^{I F} R A ^Q Q D^G _L Q^YA ^Q _I Q ^I _S ^NG _S ^{NG I} _S ^NG _S ^{N V} _TY^{G N} _P ^E _L ^V _TY^GW W W P ^E _T ^GW ^{S G}W ^S W W S ^A _F KG^N _S ^A _F K_L ^{S T} _T ^G _P ^E _T ^{S T G} _P ^E _T ^{S T} _P ^E _T T _{T P} ^E _T T _T ^G _P ^E _T ^{S T G} _P ^E G_S ^GK_L G_{S T} GK_L G_{S T} GK_{L S} GK_{L S} GK_{L S T} GK_L S V T ^{Q S} _T ^S _T ^S _T ^VG^S Q^VG^S Q G^S _T G W _E ^S W^VQ_T ^VQ_T ^VQ_T Q_T Q_T ^VQ_T ^VQ D^{G L} _E ^T _T D^G _L EGDG_L EGDG_L EGDG_L DGNG_L DGNG_L EGDG_L EG A_{R T} ^LA_R ^A _R L _P ^{P I} _LGQ_{T R} ^VW_P ^P R^VW_P ^P R^VW_P ^P R^VW Y_P ^P R^VW ^P Y_{P R} ^VW_P ^P R _TG^S _EK V^I _LG T Q_T G^S _EK^LVG TD Q_T L ^S _EK^LVG TD Q_T L ^S _EK^LV^G TD L _S Q_T DK^L _TD^{G V} _S Q_T DK^L _TDGQ_T V ^S _EK^LVG TD Q L ^S _EK AG G ^Q _LWAG G ^Q _LVA_S D ^Q _LVA_S D ^Q _LVA_S D ^Q _LVA_S ^QVA_S ^QVA_S ^QV K K G_RQHG_RQWK G_RQWK G_RQWK G_RQWK^D R _L QWK^D R _L QWK^D R _L QW Q _F ^A C ^V _EM Y^Q _F ^A C ^VN E _I D^K _F ^A C ^VN E _I D^K _F ^A C ^VN E _I D^K _F ^A C ^VN E _I G D^K _F ^A C ^VN E _I G D^K _F ^A C ^VN E _I G D^K _F ^A C ^VN E _I D 2¹ ₃ ¹ ₃ ¹ _{3 4 4 5 5 : : :} ¹ _: ¹ _: ^{1 1 1} O O O O O _: O _{: :} ¹ _. N ^{N N N N N} O N O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _I ^D _{0 I} ^D _I ^D _I -₉ ² Q E Q Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E _S ^E Q S ^E - _S ¹ ₆ ⁸ ₄ Y S ^GY S ^GY S ^GY S ^GY ^S GP ^{T T A} L^T Y H_S Y H_S H_S H_{S T} ^{S W} L L _S A L_{S L} ^L _S V V^{F I} _R NV V^{I F} S _RY NV V^{F I} _RY NV V^{I F} S _RY G NV ^I _{F S S} ^R _S ^N _S A^{D L} QG_{E S} A QG^D _{E S} A QG ^{0 G} _S ^{G G} _S ^{G G} _S ^A A ₆ ⁶ ₂-₉ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A T ^{T G}W E ^A _TY^GW E ^A _TY^GE _L ^A _TY^GE _L ^A _TY^GE _TY^GE _TY^GE _TY^{GE S} _{T P} ^A _P ^A _P ^A _P ^A _{P L} ^A _{P L} ^A _{P L} ^A _{P L S L} ^N _L ^{N S G} KG^N KG^N KG^N KG^N KG^N KG T _TK VG_S ^S _F KG_{S F} W^{V S} WV^Q _S ^S _F V^Q _S ^S _F V^Q _S ^S _F V^Q _S ^S _F V^Q _S ^S _F V^Q DG_LQ Q EG^P _T D^G _{L R} ^EG^P _T D^{G L} _E W R _E ^T _{T R}D^{G L} _{E E} W T _T D^{G L} _{E E} T _TW D^{G L} _{E E} T _TW D^{G L} _{E E} T _TW D^{G L} _{E E} T ^VW_{P P} A _RA_{R R}A_R ^A _RA_R ^A _RA_{R R}A_{R T} LVG_R ^A _T ^L _LG_R ^A _T ^L _LGQ^A _T ^L _LGQ^A _T ^L _LGQ_T ^L _LGQ_T ^L _LGQ^A _T ^LGQ TD^S Q EK^I _TG^S Q K^I _TG^S K^I _TG^S K^I _TG^S K^I _TG^S K^I _TG^S K^I _{T L} G^S K A^L _S ^QVAG_E QVAG_E QV WAG_E QV WAG_E QV WAG_E QV WAG_E QVAG_E QV K^D _L ^G _L ^G _L ^G _L ^G _L K^G _L K^G _LWK^G _LW G_RQWK N _R WK R HK R HK R HG_R HG_R HG H F _{C E I} G Q^N D^Q _{F C E I} G QMG QMG QMQ Q Q _RQ K^{A V A V} D^Q _F ^A C ^V _E Y^Q _F ^A C ^V _E Y^Q _F ^A C ^V _E Y Y^A C ^V _EMQ Y Y^A C ^V _EMQ Y Y^A C ^V _EM Y 6¹ _{6 7 7 8 8 8 8 :} ¹ _: ¹ _: ^{1 1 1 1 1} O O O _: O _{: : : :} ¹ _. N ^{N N N} O N O N O N O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _{0 I} ^D _I ^D _I ^D _I -₉ ² Q E Q Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E _S ^E Q S ^E - _S ¹ ₆ ⁸ ₄ ^A _L ^{S D} _TGP G^{S W} L^{T T A L} _S A L_{S L} L^{T A Y L} _{S L S} ^S _PH S S^FY S HS^FY ^Y _S ^S _{P E} ^I _{F S S} ^RN _S A^{D L}A G_{E S} G^D _{E S} A G^D _E ^Y _I V^Q H V C V_R ^G V V I _R ^{G Y} _I V A _{S S} Q ^A Q A Q A N^GY ^I _S ^N _{L S} ^N _L N^G TYGWAWGWAW W W W W W W W W W W^{GE N} _S ^A _F ^P R^E _L ^TY^{P E T}YG^{P E}A TYG^{P E}A TYG^{P E}A TYG^{P E}A TYG^{P E}A TY_{P L} G_{S T} ^{S D} _RL G_S ^{S D} _RL G_S ^D _RL G_S ^D _RL G_S ^D _RL G_S ^D _RL G_S ^DKG S WAQ_{S F} AAQ_{S F} AAQ^S _{S F} AAQ^S _{S F} AAQ^S _{S F} AAQ^S _{S F} AQ^S _{S F} V^Q _E D^{G L A} _{R E}GKY^L _EGKY^L _EGKY^L _EGKY^L _EGKY^L _EGKA Y^L _EGKA Y^L _E ^{T L}A^T RD^S _S A^T RD^S _S A^TD^S _S A^TD^S _S A^TD^S _S A^TD^S _S A^TD^S _S A_{R T} ^I _LGQ^A _TGGQ^A _TGG_R Q^A _TGG_R Q^A _TGG_R ^A _TGG_R ^A _TGG_R ^A _TGGQ TG^S _EK^LY^S _EK^LY^S _EK^LY^S _EK^LY^S _EQ K^LY^S _EQ K^LY^S _EQ K^LY^S _EK AG^Q _T ^{Y Q} _T ^{Y Q} _T ^{Y Q} _T ^{Y Q} _T ^{Y Q} _{T T} V K^G VA VA VA VA VA VA^{Y Q}VA^{Y Q}W G_{R L} QWK_R E _L QWK_R E _L QWK_R E _L QWK_R E _LWK_R E _LWK_R E _LWK_R E _LH Q^{A VS} _I G_R ^VS _I G_R ^VS _I G_R ^VS _I G_RQ V^S _I G_RQ V^S _I G_RQ V^S _I G_RQM Y _{C E} G K A _E G K A _E G K A _E G K A _E G K A _E G K A _E G K A^V _E Y 9¹ ₉ ¹ _{9 9 0 0 0 1 : :} ¹ _: ¹ _: ^{2 2 2 2} O O O O _: O _{: : :} ¹ _. N ^{N N N N} O N O N O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _I ^D _{0 I} ^D _I ^D _I -₉ ² Q E Q Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E _S ^E Q S ^E - _S ¹ ₆ ⁸ ₄ H S Q HS^FY S HS^FY S HS^FY YS Y ^NRV S D^{E Y} _L ^{T A} HS^FY YS Y ^NR D^{E Y} _L ^T C V^I _RV G V^I _RV G V^I _RV G ^V _{L S} ^N _T ^L _{S L} A _S A^D V V I _R ^{G V} _{L S} ^N _T ^L _S A _S A ⁰ Y _S ^N _{L S} ^N _{L S} ^N _{L S} Q _{E S} ^N _{L S} Q ₆ ⁶ ₂-₉ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A ^A _TY^G _P ^E _L ^A _TY^GE _L ^A _TYG^EA T ^TG^EA T ^TG^EA T ^TG^EA T ^TG^EA T ^TG^{E ND} _F KG^ND _{F P} KG^ND _F ^{P S} _RL G_{S T} ^P R_L G_{S T} ^P R_{L S T} ^P R_{L S T} ^P R_{L S T} ^P R_{L S} A TY ^Q _S A ^Q _S A ^S G ^S G G^S G G^S G G^S G G V V V^H _S QV^H _S QV^H _S QV^H _S V^H _S V^{H S L} _{E E} ^{S T} _TY^{S L} _{E E} ^{S T} _TY^{S L} _EKG^L _EKG^L _EKG^L _E Q KG^L _E Q KG^L _E D A_S A_RD_S A_RD_{S E} A^P _TDW_E A^P _TDW_E A^P _TDW_E A^P _TDW_E A^P _TDW_E A^P _{T T}G I Q^AG Q^AG YG _TYG _TYGQ^A _TDGQ^A _TDGQ^A _TDGQ^A _TDGQ^A _TDGQ T ^S _EK^I _T ^S _EK^I _T ^S _EK^L _I K^S _EK^L _I K^S _EK^L _I K^S _EK^L _I K^S _EK^L _I K^S _EK A^Y R ^QV WA^Y R ^QV WA^Y R ^QV WA^G _F ^QV WA^G _F ^QVA^G _F ^QVA^G _F ^QVA^G _F ^QV K^E _L K^E _L K^E _L K _L K _LWK _LWK _LW _LW G_RQH _RQH _RQH ^GQH ^GQH ^G H ^G HK^G H F ^A C _EMG Y _F ^A C _EMG Y _F ^A G_{R C E E F} ^T G_R G_RQ G_RQ G_RQ Q ^{V Q V Q VMK} _C ^V _E ^M _E ^K _F ^T C ^V _E ^M _E ^K _F ^T C ^V _E ^M _E ^K _F ^T C ^V _E ^M _E ^K _F ^T C ^V _E ^M _{E 1} ² _{1 2 2 2 3 3 3 :} ² _: ² _: ^{2 2 2 2 2} O O O _: O _{: : : :} ¹ _. N ^{N N N} O N O N O N O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _{0 I} ^D _I ^D _I ^D _I -₉ ² Q E Q Q Q Q Q Q ₈ ⁹ S ^E _S ^E _S ^E _S ^E _S ^E _S ^E Q S ^E - _S ¹ ₆ ⁸ ₄ V A S S Y YS Y ^N L H^FV D^E _L ^Y _LRV NP L ^{T A H}V^{Q N} _LRV T ^A NP ^NRV HV^Q _L ^{T A D} V E ^I _{S R} N^G _L ^V _S ^N _{T S} A _{S S L I} G_C ^L _{S L I} G_C ^L _{S L} QA^D _E NDY Y _S A^D _E NDY Y _S A^D _{E E S E S E S E S} KVQ KVQ VQ MV^VGMV^VGMV^VGMVV V V^M V^MVQV Y^T _S G A A^I Y^T _S G A^I Y^T _S G^I Y^{T S} _I ^G _I M^DV F ^S _I ^G _I M^D _{F S} ^G _I M^D _{F S} ^G _I M^D _F T _{L R}A_{L R}A_LA_RA_L WY WY AWY AWY S ^{T S} _TG^{P E T}G^{E T}G^{E T}G^EAYG AY^G AY^G AY R_L ^T _{S T} ^P R_L ^T _{S T} ^P _L ^T _{S T} ^P R_L ^T _S W^P R^E _L ^T _S W_P ^E _L ^T _S W_P ^E _L ^T _S W S G G QV^HS _S G G QV^HS _S G_RG QV^HS _S G Q^VG^S D G DK G^{V S V}G^S DK VG^S D KG^L D _{E E} ^PKG^L _{E E}KG^L _{E E}KG_LQ_S VGK^G _LQ_S G Q_S G Q_S G VGK^G _LGK^G _LGK^{G A}WA_TD AWA^P _TD AWA^P _TD AWA^P RD_E DA^P RD_E ^E D_P ^P RD_E ^E D_P ^PD_{E T}DGQ L _TDGQ DGQ DG ^A G ^A G ^A G_R ^AD I K^S K^S _TK^S _TK^S Q G _EK _TY^S Q_TY^S Q_TY Q_TY V^L _I ^G _EK V^L _I ^G _EK V^L _I ^G _EK V^L _TD_EK V^L _TD_EK^{L S} TD_EK^L _TD A K_F ^Q _LWA K_F G^Q _LWA K_F G^Q _LWA K_F G^Q _L A^H _L ^Q _L A^H _L ^Q _LVA^H _L ^Q _LVA^H _L G^G RQHG^R _TQHG^R _TQHG^{R W} E _TQ_EK E G^{A W} RQ_EK E G^A W RQ^N E _I K G^A W RQ^NK^{A K} _F ^T C ^V _E ^M _E ^K _F Y^V _E ^M _E ^K _F Y^VM _E ^K _F Y^VL _L K A^VL _L K A^V D K A^V _{E I} G D K_R A 4² ₄ ² ₄ ² ₅ ² _{5 6 6 : : :} ^{2 2 2} O O O _: O _: O _{: :} ¹ _. N ^{N N N N} O N O N ⁴ ₀ ^{1 D} _I ^D _I ^D _I ^D _I ^D _I ^D _I ^D _{0 I} -₉ ² Q E Q Q ₈ ⁹ S ^E _S ^E Q S ^E Q S ^E Q Q - _S ^E _S ^E _S ¹ ₆ ⁸ ₄ ⁰ ₆ ⁶ Q ₂ ^D _: O₁ ^{- E} _I ² Q^D _: O₂ ² Q _: E ^DO₃ ² Q _: E ^DO₁ ² Q _: E ^DO₁ ² Q^D _: O₃ ² Q^D _: O₁ ² _{9 S} N ₁ ^E _{S I} N _{1 S I} N _{1 S I} N _{1 S I} N ₁ ^E _{S I} N ₁ ^E _{S I} N₁ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A Q _: 3 Q _: E _S ^D _I O N ₇ ^E _S ^D _I O² N ₇ T _{T S} A Y G N D R ^D P _S Y _I ^K L R : _I Q _{: E} ^{S D} _I O² N ₆ ^Q E ^DO^{3 S} _I N ₆ D W ¹ Y _. ^{4 S} Y _{0 T} N ¹ ₀- ^{F S} T _{F 9} ^{2 T} ₈ Y ⁹- G _F ¹ G ₆ ⁸ ₄ ⁰ ₆ ⁶ Q ₂ ^D _: O₁ ^{- E} _I ² Q _: E ^DO₄ ² Q _: E ^DO₄ ² Q _: E ^DO₄ ² Q^D _: O₄ ² Q^D _: O₅ ² Q^D _: O₈ ¹ _{9 S} N_{1 S I} N_{1 S I} N_{1 S I} N₁ ^E _{S I} N₁ ^E _{S I} N₁ ^E _{S I} N₁ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A Q _: Q _: E _S ^D _I O⁴ N ₇ ^E _S ^D _I O⁵ N _{7 T T} G G V G N N D P ^{R K} _{P I} ^Y _I Q _: ^Q _{: E} ^{S D} _I O⁴ N _{6 E} ^{D S} _I O⁵ N ₆ Y D ¹ Y D Y _. ⁴ _{0 T} ^{R 1} ₀- ^F _{T T} ^F _{9 I} ² ₈ Y Y ⁹-¹ G G ₆ ⁸ ₄ ⁰ ₆ ⁶ Q^D _: O₆ ^{- 2} Q^D _: O₄ Q^D _: O₄ Q^D _: O₅ Q^D _: O₈ Q^D _: O₆ Q^D _: O_{4 2} ^E _{I 9 S} N₁ ^E _{S I} N² ₁ ^E _{S I} N² ₁ ^E _{S I} N² ₁ ^E _{S I} N¹ ₁ ^E _{S I} N² ₁ ^E _{S I} N² ₁ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A Q _: E ⁵ S ^D _I O N _{7 T} G G D R_P Y _I Q _{: E} O^{5 S D} _I N ₆ D ¹ _. Y ^{4 R} ₀ ¹ T ₀- ^F _{9 I} ² ₈ Y ⁹- G ¹ ₆ ⁸ ₄ ⁰ ₆ ⁶ Q _{: 2} ^{- E D} _I O₄ ² Q^D _: O₅ ² Q^D _: O₈ ¹ Q^D _: O₆ ² Q^D _: O₄ ² Q _: E ^DO₇ ² Q _: E ^DO₈ ¹ _{9 S} N₁ ^E _{S I} N₁ ^E _{S I} N₁ ^E _{S I} N₁ ^E _{S I} N_{1 S I} N_{1 S I} N₁ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A Q _: Q _: E _S ^D _I O⁵ N ₇ ^E _S ^D _I O⁶ N _{7 T} G ^T G _E G D D R_P ^E _P Y _I ^D _I Q _: ^Q _{: E} ^{D S} _I O⁵ N _{6 E} ^{S D} _I O⁶ N ₆ D Y ¹ Y R Y _. ⁴ D ₀ ¹ T ₀- ^F _I ^K _{I 9} ² ₈ Y ^{N 9}-¹ G _L G ₆ ⁸ ₄ ⁰ ₆ ⁶ Q ₂ ^{- E D} _{: I} O₇ ² Q _: E ^D ₈ Q _{: 7} Q _{: I} O^{1 E D} _I O^{2 E D} _I O₈ ² Q _: E ^D _I O₈ ² Q _: E ^DO₈ ² Q _: E ^DO₈ ² _{9 S} N_{1 S} N_{1 S} N_{1 S} N_{1 S} N_{1 S I} N_{1 S I} N₁ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A Q _: E ⁵ Q _: O⁷ Q _: 8 S ^D _I O N ₇ ^E _S ^D _I N ₇ ^E _S ^D _I O N _{7 T T} G _T G G G G G D D D R_P ^{K R Y} _{P I} ^Y _{P I} ^Y T Q E ^D _: O^{2 Q} _: O^{2 QD} _: ^{2 S} _I N _{6 E} ^{S D} _I N _{6 E} ^S _I O N ₆ D D D ¹ Y^S Y Y _. ⁴ _{0 T} ^{S S} T ¹ ₀- ^F _{T T} ^F _T ^F ₉ ² ₈ Y Y _T Y ⁹-¹ G G G ₆ ⁸ ₄ ⁰ ₆ ⁶ Q _{: 2} ^{- E D} _I O₈ ² Q _: E ^D _I O₈ ² Q _: E ^D _I O₈ ² Q _: E ^D _I O₈ ² Q _: E ^D _I O₉ ² Q _: E ^D _I O₀ ³ Q _: E ^D _I O₁ ³ ₉ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A A A A Q _: Q _{: :} E ^DO⁵ ₇ ^{E D}O⁶ Q E ^DO⁶ S _I N _{S I} N _{7 S I} N _{7 T} G ^T E ^T G G _E G D R D P ^E D E ^Y _{P I} ^D _{P I} ^D _I Q _{: : : E} ^DO^{2 QD}O^{7 Q} _E ^DO^{7 S} _I N _{6 E} ^S _I N ₆ ^S _I N ₆ D Y Y ¹ Y _. ^{4 S} Y T D Y ₀ ^{1 F K} D ₀-_{9 T I} ^K _I ² ₈ Y ^{N N} G _{F F} ⁹-¹ G G ₆ ⁸ ₄ ⁰ ₆ ⁶ Q _{: 2} ^{- E D} _I O₆ ² Q _: E ^DO₃ ³ Q _: E ^DO₁ ³ Q _: E ^D _I O₆ ² Q _: E ^D _I O₃ ³ Q _: E ^DO₁ ³ Q _: E ^DO₄ ³ _{9 1 I 1 I 1 1 1 I 1 I 1} ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A R : _: A Q E _S ^D _I O¹ Q N ₈ ^E _S ^D _I O⁰ Q N ₈ ^E _S ^D _{: I} O² N _{8 T} G _T G G ^T _{S T} ^{G G E} _{T S P} ^{E D} _P ^G F ^D _{P I} ^N _I Q E _S ^D _{: : I} O⁹ Q N ₆ ^E _S ^D _I O⁹ Q N ₆ ^E _S ^D _{: I} O⁰ N _{7 E} Y _{E L} ¹ Y Y _. ^{4 D} T ^D _T N ₀ ^{1 T} ₀- ^F T ^F _{T F 9} A ² ₈ Y Y Y ⁹-¹ G G G ₆ ⁸ ₄ ⁰ ₆ ⁶ Q _{: 2} ^{- E D} _I O₁ ³ Q _: E ^D _I O₄ ³ Q _: E ^DO₁ ³ Q^N _S S ^{V K}S A K ^P R^H _S VD^F _{S 9} N_{1 S} N_{1 S I} N₁ G_{S S E} ^{N V 3} ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A Y ^L V _T N Y N ⁿ W i ^L _S ^F G_P W L ^Q _{S R}G _{T E l} ^{L I} _S F _T ^{R L} G^Y _F ^{S S} ₍ ^a _{t L S R}G_{P T} K K ^a _h ^{L S D} _P ^F N_S L ^{C n} _e ^{L Q} _S ^DQ G^Y _F ^S _S A _d ⁱ _c Y_I ^E _{C P E}Q ^L _a ^t _{E T} ^{G L} _E Q _: A ^S _R ^G LWA^G L _L ^{P S} _F ^R _P GY_{S n} Y KNK^e _r ^{S L} _S V L _RD^{T S} _{L S} ^EV E ^DO^{2 n} _i ^{E E C} _S ^L _F ^K N^{Qa E}Q^E _S ^L _P G S _I N _{8 o F L F} A^S AGY^A _P V^S _TA^E _{T P F} ^G _S ^K _S AD K^K _P Y^_ A_P ^R _S ^{Y P} V m ^LQV_T ^V _P A_S ^I QH_C ^LA_L S ^S _{P L C}Y T_S ^A _S G^AG_TG G ⁿ _i ^L _F ^T _S ^G N_TGN ^H _S ^Q _{S S} VGH^KN^H ₎ ^{7 L} _R ^{L A}G^P L ^S _P W C ^N S ^a _h ^L _RD LQ^{E T}V S ^{S L} _{E L} ^{V I S} _{L 1 F} V_{E P E} ^P _S A^mL _{T F L} M_F ^{Q H}K G_P ^{C I} K_S t _RV^T L ^K _{S S} ^{L E} _{E S P} VA^W _{E 1} ^{I W} _S YV_{L T}V G^P _EHG_R A^S VK^{E N} _{I h} ^g _i ^{n L} _i ^{W a} _S W S ^S R ^S _P ^YA L ^P D_LV A^AM⁽ ₁ ^WM^T _P ^{A G} _S G_S G_P D_P C ^D h ^L _{I S} G^L E ^A _CV LG K_I V S ^P _P Y^ND S ^S _g ^LYAK^F C ^I _{h S} ^{S S T} _{T S E} K^{H Q} _E ^{S D} _: ^d I O¹ _n ^C N ₇ ^{a y} GY K ^S M^P _{F S} ^CW_S V_P ^{S y} _{v P T}YV^Q _F ^l _a ^t G_T K ^F _{T S} H DAV^P _{S E}V v ^a _e D^F A^S _{L T} H^N _F ^{K Y} _F V_n ^e _{r P T} DY^{A S} T _S ^G _S VD D ^a _{T P} V_TK_CGN KV F _e H M Y^T _S G A K V K K G^a _p M^G _S ^I T ^V T ^T L K V ¹ _. ^{4 S} H _{0 T} ^F _– ¹ _{0 T 3 s} -_{9 e} ^e _i ^c ₉ ⁸ ₀ ² ₈ Y ^l G _b ^a _e ^{9 9 p} _{3 3 -} ¹ T _S ⁶ ₁ ⁶ _{1 6} ⁸ ₄ ⁰ ₆ ⁶ P ^N _S S ^{V K}S P ^NS ^{V K}S ₂- Q ₉ GVG_S Q^A _S ^K T Q_S G GV _S Q^A _S ^K T ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A Q P ^{T L} _S H _P Q^D _{F E}N^LN^RY_T ^_ _P Y_S D^Q T ^LK_P ^W E _CG ^d _CG^C _{C E T}K^G KAA^P _F ^C _TY_P NY_C K^Y TGK^G _F AA ^{S g} _{I e} GG_CG RK P Y^Q _{I T (} K u ^VY YY^S Y_I DQQNH ^HK YV_LVN^P V_F ^{h z} _i ^TAG^G D^{Y KE}G^EN₎ ^{7 V}N^{Y L S S} H_L ^A _I V^{3 n} _C ^GG_C QNY _h ^_ _{E T S} K_{T P E}K_P ^H _{1 E} ^G _{S R C S P} ^VADN_{C a} ^C _CAG GNH_C A GNGV^Q T ^K _P ^R _P AQ_L A^mA 1 ^{G R E G} L ^S _P G_E GVK^S _P GH^{- m} _{u T}G A^{G G}A A^P V^S C _g ^I Y ^{G S} WV_S V^{L S} _LV_LDV Y _L ^{C T} _{e C} GA^S N^{2 S} G^E _S S G_TVG_{S L :} ^d _i AG_{C C L} ^A _I ^S _{h L} ^E L ^AT _S ^E K_P G_{C L}Q_{S P} ^{S HE N}V^KO ^{t G}A^GG AD_F ^EG_{T S} ^L _P D^{N Y}QH^{E GR} L ^A _{S T P L}Q_S ^NM _o ^e _T ^G _CA K^S V _F D^K _S AV_{S F} Q-_{b F P} ^S _L ^QK^DWNY^{D B} _l ^{c C} _CGG N_P N AQ G ^D _S S ^{Y P} CYVG ^AAA_S ^P _LD_ED^KL _{I ) u C} ^TG^T S ^YG ^L _{P S P L} ^P W^KKW ^{L QL} _F V^{C H} _S Q_{T F} F ^{Q 6} ₄ ⁿ G_TA_C V_F Q¹ _S A^{R A}G_P ^N _C ^{V R 4} _{. S R E}V^A _S ^HM_{S E} - _y ^{l AC C}G KGQ_C ^L _{L L} ^{S C} _F K_{L S} ⁸ _u ^LVM^S _P KV_L ^{E S} _{( 1 o C C T}A CK H- _F L ^{Q S} R ^P _{S T}K^{Y C}K _F L ^WY_P ^{F P} D G V_E V ^P GGGA K^VW Y_L ^R _{b L R F} ^Q E ^C _S ^{A I} V^L EV_L ^H TV E _{E T}D ^{H L}V₎ ⁷ _L ^I _S ^VG_{T E}V TKHVV^T L ^{R D} S _S G P H ⁿ S ^G _i G a G^GA^G TG_T K_TK⁴ _{. R}W ^S VK_P K_S ^T _{3 R}M 8 ^WS _I M_P ^AD^DGV_L ¹ _: ^WG^{S T}V T _S ^GKV K^{C V P D} S _{P L} ^L _{I( h S} ^{u C} A A^C CA^G C G^LD N_S V_u H _S YG_P LG^AK^F T ^C _E ^NQ^K _S Y S ^H _LN_S O^{L S S} A T ^S _{S S} ^TD_T VV^{L V} _TV^P _P ^L _{h S} ^{_ t} C _h ⁿ _i ^{C A}G CG_CA LV^T Q_{L )} ⁶ _S Y_T ^T G^{S S} _S HK WN^K ₃ ^K _T ^P _S W VD^KY ^N _{S T} F _TAV_ED _T ^{L D}G^F D _LV Q _F ^F _I ^K _T ^{E R V} Y_{T T}A^{K G} _{T P R}Y TYV^T TK ^{g Q} H _i L ^a _h ^CAG TQK_T ^{d C} _C ^{G T G} A_{T C C} D^K _S ¹ _{: P T} ^S T ^S _S ^GVV^{H M} _S ^Q _P ^MV_S N_{R S} ^P YY _n ^{y C}G^G Q_TYO DY _S KV_{L E}G_E D^G _{S T} ^L TN^S _P ^S _I N_E ^a _v G_C ^A _T H M^L _F N M G^D T ^V T ^T L K V V^E R D^S ₍ M A V G W K M Y^RNH P N N ^y _v ^{a GT} _CG ^{1 a} _{e T T} ^{T G} _{. e} H A G _{T C} ⁴ ₀ H ¹ _{0 1} ⁹ _{2 4 s} ^{e -} i ₉ c ₉ ² _{8 3} ⁹ _e 6 ₃ ^l _e ^{8 9}- ₁ ⁶ _{1 b} ^{a p} ₃ ^{6 1} _{6 T S 1} ⁸ ₄ ⁰ ₆ ⁶ ₂-₉ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A C T ^{G A} _T ^T GGAA^G _{C C} ^G _C A^T _{T T C}G C _C ^A A^G _{T C} ^{C C}G^G _{C C} ^D GA GGG^C CG_TAG_C A AGA CG ^TGA^{C A} _C ^A C ^C _{C C}G_C ^{T C} C _TA^{G C} _TA_C C _C ^A C _T ^A I GG_C ^l _a AG A^A T _CAGG G A^{T AA G}G_C ^AG_{C C}G A^{T C} CAG A^A _C G CA^AG_CGA G G_CAA^{C A} CA^Q E ^t _n ^{G T} T _C GG^{C A}G G^C _{C C} AG_{C T}G^C _C ^{A A} _C ^G _C G^{C T} _CG_{C C} ^GGG_TG^GAGAAG GAA^A T ^CG_C ^{T S} A^T _C ( ^e _r ^{a C}G G T ^G A_{T C} A _C AA_C G ^TA^A _{C C} ^T TA^C CA_C AG^C _{T C} GA _CG^{A T A} CA^CA _CG _{T T} ^{C C}G^TG^GAG _P ^_ _CA G^{G T C} _CGG C _CA ^T _{C C} ^{T G}A_{C C}G^C G A G^T _T ^{C T A C T G A}G C _CA^CG_{T C} G ^GA G^C _{C T} T ^G _C ^{T G} _{C T} ^C C ^A T _C ^A _C T G^{A T} T _{C T} ^GG^A _C ^G _{C C T} ^A _CG_C T _C G^{C C} C ^G _CAG AG^A _{T T} GA_CA G^G _{C C} GA_TG^G CAA ^H ) _C G_T GG_C ^CG^C _C ^T _CG _C ^C _{C C} ^T _CG GAG _T ^AGAA^AG^{7 C} A CGG_CA_T ^T _C ^CGG _CG A^C _C ^{C G} _C ^{C C}A G_C ^{C A} _CG₁ G_C A^GAG^T _T ^T C _CG^C C ^A C ^{T G} T ^C CG A_C ^C _CG_TG A^GA_C ^A A_{C T}GAG GG G_{C C} ^A C ^A C ^C G C ^m ₁ AG C ^C _C ^{C G} _C ^C CG^{C T} A^G _C ^CG G_C ^C _C ^{A A} AAA^CGG ^{G A} _{C C T} ^A _{C C T} ^A _C ^{A C T} _C ^G GG_{T C}G A _T ^A G^CG⁽ A_{T C} G GAG^A _T ^GA ^{C G G} _C G_{C T}G_T A G^A _T C _{C T} ^A _CGG CA ^{T G}A_CG^{C C}G CA^GG A^C G C _CG^T C _C G₁ ^C C ^{C T} TG G_C C C ^CG CGA^A _TA^G T ^G TG^GA^{G A} _TG^TG C ^C _C ^{AC C} _CG_T ^A C _{C C} ^C C ^G TG^C _CG^GA_{C T}G^{T C}A_T GG^{C A} _T ^A C ^{C G} _{C C}A_g ^{I C}G C ^{C C} AG G _CG^CA^{G C C} _CA CG G _{C C} G ^GG ^{G G}G_C ^GG G _C A^GGG^G T _{h C} AA AAA_{C C}G^CG_{C C}G A_{C T} CG_C G_CG G ^A _C A _C G_{T C} A G_CA _{T T} A ^{C T}G ^G G_C C G G ^{G C} _C ^AA G_C ^{C C} _CA ^{G A} _CGA^G T _C C _T GA^{G C} _{T T} ^CG _CAG^{C C} _T ^AG^C GG G G_T ^{A C C C C} _C ^C _CA_C ^T A_{C C C C C} AA_CG^GG ^G T _C ¹ _{. T} A _C G _C G _{C T T} A G _C G A G G _{T T T} G _{C C} G G G G G^G T G G^T T G _C A A^C T ⁴ ₀ ¹ ₀- 0 ₉ 9 ² _{8 3} ^{9 6} - ₁ ¹ ₆ ⁸ ₄ ⁰ ₆ ⁶ ₂-₉ ³ ₆ ⁶ ₁ ¹ _: ^{G .} _{C o} ^{C N} _{C t} ^e G _k A ^c _o ^{G D} _{T .} G ^y _t ^G _{t C} A ^C C C C A G T G C C C G T C C G A G T C A C C C G A G G T G G C C C G A A G A A G T _C G_T ^GA A_CG^GT _T GG_CAG^AAA^G CG AAG_C A^C G C ^T _CG^{C G} T ^C _C A^CGG^{G GI} ₍ ^T CG GGG AAG_C ^GA_{C C} GA_C ^GA^C _C ^G C ^C C ^C C ^G _{C C}G^A CG^{C G}G _CA _C ^C _C A_C ^A _T ^AAA^AAG_CG^T _T ^GA_{T C} ^T _T ^{G C u} _h GA G A^AG A TG^{C C} T _C ^T C _CG AAG^CA T G^AA G^A _C ^{C A C} _C CGA_C ^CG ^A GG^A _C ^T G_{C C C}G^C _CG_{C C} ^_ A TAGG^AG _C ^{G T} G_{C C} ^G _C ^CG^AA^{C GT T} G _{T C C}A^C _C ^T GG^CA ^{A AC} A ^H _{T C} CG _TG_CA_TG_{C C C C} ^CG^T _C ^G _CAAA_C ^GA _{C C C C} G ₎ ^CG C ^TGA GG ^CG_{C C} TG^AA_C ^C _C ^{G C} _TA^{C G} _{T C}AG ^G _T ⁷ _CA G_CAG^{A A}GGG_CAA A_CAG_C ^C _{C C}G^A _{C T} ^{C A}GA ^C _{T 1} G^G AG^G _{C C} GA_T ^G G TAAAAAG^{C T} _CG^{C G} C _C ^{G A} _{C T}A^C _C ^CAG G_C ^T _{C C} ^AG_T A_C A G^{G G} _TA^{C m} _C G _CG ^A _CG_CG^G _{C 1} ^{A T G} C ^{G A} T _CG^T CG^GG GA^{A A} _TA^CG A_{C C}G^AGG_C ^G T ^G C ^CGGA_C ^GGG_C ^GG_T ^C A T ^{T G} _C ^A GG_TG ^C _TA AA^GG^TA A_C A^G T ^{C C}AAA C _T ^G T ^G C ^A _TG C ^GA G⁽ _C G_T G ₁ G^C GG G_{T C} AGG C ^{T C}AG_{C T C} ^G _T ^A _{C C}GGA^{C C}GA_C GG_C AG^G G _CG^CG CGGG GG^CAA AG_{C C} ^AG^{C C} CG_C ^G _C ^G T ^GAGA_C C _C ^A GA G^AA ^g _I AG A ^T _C ^{A A} _CG ^G _CA_{C C}G _T G G ^{h G} AA C ^{C T} _C G^A _{C C}A_CA CG T ^AA^G T ^A C _TA G^GG TA^T C ^T T ^CA C ^CGAG CGAA G^C _{C C} ^G _CG TA^AAA_TG^{A 1} A_{T C} ^{C C G} _{T C T} ^GGGA^CG A^A _TA_{C C C} ^AGA _T G AG_C A^CG^C AG^G AG^G _C ^G _TA^{C A} _C ^G TG_C ^GG_CAA A GAG_CGA AAA ^A CG^C C ^C _T ^C C ^C _CGG TGG^{C T} C _{C C} C ₎ ⁴ H_{C C 4} -_b ^C _{C C}G CAG_C ^T _C ^{T T A} _TG^G _T ^A _C ^G _C ^C T G^ACGA^{T G T} G ¹ _: AA GG^C G^{C T} _CG_{C C C} ^CG_T ^G _{C T} ^G TGG^T _{T T}A _{C C C}A^{A A A} G G _CA _C G^TA _C ^{T C} _C ^AA^CGA ^GG_C G^AG^G T ^GG_{C C}O⁴ _. G^T TA AA^{C G}A C _{C C} ^GA_CG^G CG AG T _{C C}G_T CG_C AA C ^G T ^G C _T GG^G TA_C GA CGAG^A _T ^{T G} _C ^T TA T ^N8 _u ^G _{T C} ¹ _. G _{C T} G G _T G^A T ^C T G _{C C} ^C T ^C T A _C ^G T _{C C} A A _C ^C T G G _C G G G _{C C} G G _C ^D _I H A^C T ⁴ ₀ ¹ ₀- 1 ₉ 9 ² _{8 3} ^{9 6} - ₁ ¹ ₆ ⁸ ₄ ⁰ ₆ ⁶ ₂-₉ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A AAGGA A _C C ^{G T} _C AA^GT C _C TA^C C _T G ^G _C C ^C C ^C C ^C C _{C C} AG^GG_C CGG A^G TA_C ^AG^A C ^G C _h ^_ A A G^AGG_{C T C C}A^C _CA_CG _T ^TG G A ^C G^C _CGG^C _C ^{G C} _C ^T C ^G G T ^{C C}A^A TG_CG^{T G A G} _CG_{C C T}AG^T _T G A G A^GG_T GG_C T _CAG CG ^{C GG}G_C ^A A_TG^T _C ^H _T TGA_{C C}GGG^C CA C _C A_C G _C ^G GG^{C A}A^C _T ^C T ^G _T ^C T _CG A_C G _{C C T} ^G T ^{C G A} _CC C ^CG₎ ^{7 C} C G_CA CG^G C ^A CGGG AG_C ^T _CA _T ^{G C}G GG^{C A}G^G _{C C} ^G _{C T} G_C ^GA^G _{C C}A^A _CA^C _CGA^CG_CA₁ m G AG_T ^GAAAA^CG G_C A_T ^G _C ^G _{C C} ^C _C ^GA ^AG^G ₁ ^A GA _T ^{T G}G G_C G^{G A} A ^{G G} A_TG_T ^AG^GG_C ^C _T G_{C C}G_{T C T C}G_CG C _{T C} CAGAG G A^A _T G_T ^C T ^{A C A}AA_T GGA_T G^GG_CG GA^T GA^{C G} _TGA^CG C ⁽ ₁ G C GA^A _C G AA^G _C G^A _{C C C}G^GGA _C ^T _{C T} ^{AC G G} G GG G_{T C} G^CG_T ^C A^{AC T C G}A_CG^CA _{C T T C}GG G AG^G C ^GCAGGG A_C ^G _{C C} ^C GG_CAGAG_T ^AG_{C C C T} G^T C _{C T} GA^C CG_C G C ^{G C}A T ^TG^AA^g _I ^h A GA A A_{T C}AA ^{A AG G} _T ^{G A}A^C AA_CG A _{T C C}G_C ^G A A ^{C A} G ^T _{C C T}G^T _{C C} ^{C C T} _{T C}G_C ^G G ^TGA_C ^C _CG^C _T ^{2 G} _{T C C C}A GG^C C _C G AGG^{C T} _C CG_CG^C T ^GGGA _C ^{G A} _T G^A CAG C _CG^{C C} C _{C C}G CA^A _C ^G T ^C C _C ^C H _C G^A _TA A G^{GT T A} _{C C}G_{C C} ^AAG _{C C C}G A A^GT TA C _CGA AGGG A_T ^A C _C G^C TAG-_b ^C C G_CA CG_CA C ^T _{C C} T _CGA_CG^{T C T} A G C _{T T}G^AAGGG_T GG_C ^AG T ^T C _CG^T C ^{G A} CA^GG^G TA ^A A GG TA_CAG C ^G _C G^{T G G A}A C _C ^AG^G C _CA GA_C A_C TG_C CG_T ^{C G} _CA_C C ^CA AG T _{C C} ^AGG A_CA^{G A} _C ^C AA C ^T C ^AG TA GA_CA^{A A C} _T A _C AA GGG_CA A ^GG C G A⁴ _. G_{C C} ^{A A}G^CA^G _CGA⁸ _u ^G _T ¹ _. G _{C T} G G _T G _{T T} A _C G _{C C C} A _C A G _{C C T} A _C G G G _C A _C G _C A A G H A ⁴ ₀ ¹ ₀- 2 ₉ 9 ² _{8 3} ^{9 6} - ₁ ¹ ₆ ⁸ ₄ ⁰ ₆ ⁶ ₂-₉ ³ ₆ ⁶ ₁ ¹ _: ^. _o ^N _t ^e _k ^c _o ^D _. ^y _tt A ^T C ^{C T G} _T ^AG ^TGG_C ^{C A C}G^G _{C C}G^AGA _{T C T} ^{G G A} _CH G_{C C T} AG_TA^A C ^C C _C AA^A _T ^{C T} CG^G _{C C C C} ^T C _C A C ^{C G C}A_T ^T C ^AA CGGA^C A_{C T C T} CG_C ^GG-_b AGG AA_CA G^C C ^C CG A^{G T} C ^T CG^T C _T ^A C ^CG C ^T _C G_CG_C ^T _{C C} AGG G ^AG T ^GAG AG^C _C ^AA G_CA G ^{A G} CG^GG G^{G A}AG_C GA^GA CGG C ^{AT G C}A C ^C G_{C C} ^{C C} _CG_{T C T}A A_CG_C G GGGG^CA^AAA^{G A}A⁴ _. ⁸ M T_T ^G _{T C}G_{C T} C _C A^G T ^T C ^{T G} _C G G^CG_{C C} G_C A _T CGAG_C ^CG CA^G CA^C CAA_T C ^C _T C ^CG_T G_CA G_u ^{B C}GGA CAA^T _C G^AA _{C C} CGA^{T A} _C C ^TA G _{T T C}A^A T ^C C ^T T ^{A G}GGA^AG C ^C _{C C C}G A_TG^{T C}G T ^{A H} _{) )} ⁶ ₄ GGA_C GG_C G_CA^T _{T C C} G AG_C ^C CG_C G^C _TG^GG^A C ^GA_T C ^A _C ^{C C G} _{C C} A^GG CA_{C C T}G^C _CAG G^{T A} _TG A C _T ^{A G T} G_{T C} ^G _{C C} A_{C C} ⁶ G_C ^G G^C ₄ - ¹ ₁ G^{A C} TA ^{G G GA} AG _CG_C GG^{C C} A G_C A A_TG^A _{C :} V T C _C ^{G C}A C _C G_{T T T} ^G C ^G T _{C C} ^G _C ^G G T ^{T C C G} G^C GGG^A _CAG^A _CG^A _CA^T _{C C C} GGG G^G TA^CG G GGG^AG^T C _C T ^A COH N ^G G_{C T}AG_C T _{C C} GGG^G C _CAG_C ^TG G ^C _TAA^G T ^{C G}G_C A _C ^CG G^{T C} AG_{C T}A^{D I} ₍ ^u AG _CGG ^AG^{T A T} _C A GA ^{GC G G} _{T C C C}GA ^CA^GT I A ^G CGG A _T ^C _{T C}G_C ^{C C}A C ^{G C}G A ^{A G} _{T C T}G^T _{T T T} G _C ^C CGA A ^GC CA A A^GG_T ^A _{T C h C} ^GA^{Q _ GT A} _T A_C ^{G A}A_CA_{C C C C} G_C ^GA_C ^A A_{C C T} ^C _{C E C T} C _{T C} G ^C C ^C C ^CG_TG G C ^{G C} _C ^{G T A} _T ^AA _C CG^C _CG_T ^T TA^CAG^C C ^G CA^C _C G^G _TG TAGA^G TG^CG A^G CGA G_CG A^C C ^S ₍ H G^GG_CGA^GAA_C AAGGAG^G _C CG^G TG^C C ^A C ^AAG T _CG G _{C C} G G_{C C} ^AA A ^A _CGG_T ^{G C T}G G^{G T G} _C ^G _{C C C T} T _C T ^A _T ^{A G} _CA_T C _CG^G T ^T C ^C C ^G TA_T G^C C ^C C ^G TA^A TG^A C ^A T ¹ _. G^G T _C ^A T G^A T _{C C} A G _{C C} G _{C C C C} G A _C ^C C ^T C G A A G A^C C G G G G^C C G G A A ⁴ ₀ ¹ ₀-₉ ² ₈ ⁹-¹ ₆ ⁸ ₄ ⁰ ₆ ⁶ ₂ ^D - _{I : 9} QO ³ ₆ ^E N⁰ ₃ ⁰ ₃ ⁰ ₄ ^{0 0} ₃ ⁰ ₃ ⁰ ₄ ^{0 0} ₃ ⁰ ₃ ⁰ ₄ ^{0 0} ₃ ⁰ ₃ ⁰ ₄ ⁰ ₈ ² ₈ ² _{8 9 8 8 8 9 8 8 8 9} ⁶ _{S 9 2 2 2 9 2 2 2 9 2 2 2 9 2 2 2 1 1} ² ₁ ⁸ ₁ ² ₁ ² ₁ ² ₁ ⁸ ₁ ² ₁ ² ₁ ² ₁ ⁸ _{1 1} ¹ _: ^. Y D ^D Y D ^D Y D Y _o ^N _F A Y Y _F A _F A Y Y _F A _F ^D A Y Y _F ^D A _F Y Y ^D _{F t} ^{D D D D D D} A ^{D D} A ^e _k ^c _o ^D _. ^y _tt A m^e _T ^t _{a a a a a a h} G _a ^{i b} _{h a} ^{t c} o _a ^t _T ^t _a ⁱ _h ^{t c} _a ^t _T ^t _a ⁱ _h ^{t c} _{a T} ^t _{a a} ⁱ _h ^c _{a T} ^t _a ⁱ _h ^c _{a T} ^t _a ⁱ _h ^c _{a T} ^t _a ⁱ _h ^c _a h _n ^o G ^b _{a o} ^h _n ^o G ^b _{a o} ^{t h} _n ^o G ^b _a ^t _o ^{t h} _n ^o G ^b _a ^t _o ^{t h} _n G ^b _a ^t _o ^t _n G ^b _a ^t _o ^t _{n s} ^{c e} _S ^M _I K _{C C} ^M _I K _{C C} ^M _I K _{C C} ^M _I K _{C C} ^M _I K _C ^o C ^M _I K ^h C ^o C ^M _I K ^h C ^o C _i d_o ^{n b} _i ^y _v ^{y y y} _{t t t i} ^{a a} _v ^a _v ^a _v ^{a h h h t} _{h n} C _e H _e H _e H _{e g} H ⁱ _{g L} ⁱ _{g L} ⁱ _L A ^{d -} e - _b z_{i b} ^{4 n A} _. ^{) 4} ₎ ^{8 4} ₎ ⁶ A ^{4 4} a ^{4 8} _{u 3}- _. ⁸ _{u 1}- _. ⁸ _{u 4}- ₄ ^. _{. . 8} ⁸ _u ^{- 8 - m} _. ⁸ u _y ^{: l H} ₁ : V ^H ₁ : V ^H ₁ : V ^{m: l H} _{2 u} V ^H ₂ V f ^d _{e a} ^t _{n e} H G _e H G _e H G _{e a} ^{t : :} n _e K G _e K H ^o _{o 9} ^{m e} _{r 0} ^{m I} _{( 1} ^{m I} _{( 2} ^{m I} _{( 9} ^{m e} ₀ ^{m I} ₁ ^{m GI} s ^b _i ^{t 8} _{a 3} ^{a 9} _a ^{u 9} _a ^{u 9} _a ^{u 8} _{a r} ^{a 9} _{a (} 6 N _{P 3} ⁶ N _{h 3} ⁶ N _{h 3} ⁶ N _{h 3} N _{P 3} N ^u _h ⁹ _{a ( 3} N ^u _h R _{n e} A ₁ ^{l _} _e ^{l _} _e ^{l _} _e ^{l _ 6} _e ^{l _ 6} _e ^{l _ 6} _e ^{l _ 1 H} _p ^l _{C 1} H_{p C 1 p C 1 p C 1 p . l C 1 p C 1 p C} ⁴ D C _{: 5} ^Dm I _{a a} ^{t S} _n ^H _{: :} D^m _a ^H _: ^H _: ^m _a ^H _: ^H _: ^m _a ^H _: ^L _: ^m _a ^a _t ^{L L n} _{: :} ^m _a ^L _: M ^L _: ^m _a ^L _{0 :} M ¹ ₀- e^{l a} _i ^{t e} _r ^e _{t n} ^a _p ^o I ^S n ^a _i ^{t 1} n _C ^e _t ^D I ^{S 2} H^o _n ^a _i ^t _{n C} ^e _t ^D I ^{S 3} H^o _n ^a _i ^t _{n C} ^e _t ^D I ^S _e ^{r e} _t ^D I ^S ₁ ^e _t ^{B) D} I ^S ₂ ^e _t ^B) ₉ H^o _n ^a _i ^t _{n a} ² b ^{r p o} _n ^a _i ^t _n ^C _L ^o _{n 1} ^{0 a} _i ^t _n ^C _L ^o _{n 1} ⁰ ₈ a _u ^e _i C_l C_C ^y H_e ^r K _u ^ei C_l - C_b ^y A_e ^r K^M _u ^ei_l -_b ^y _e ^Mr _u ^ei_l -_b ^y _e ^Mr _u ^ei_l ^Cy _e ^r _u ^ei_l -_b ^y _{e *} ^{8 r} _u ^ei_l -_b ^y _{e *} ^{9 0} -¹ _{6 T B} C C A K _B C C A K _B C C _L K C C A K ₂ C C A K ₃ ⁸ ₄ ⁰ ₆ ⁶ ₂- ^N _t W e_k ^c _{T T T} ^N _{L o} ^{Y Y D} _P ^Y . V _P ^Y _{P T} y_t ^H V N H V G t _S G _S ^H _S ^N A ^Q G F ^Q G F ^Q _{S F} H V 1⁰ _{1 2 2} ⁰ ₂ ⁰ ₂ D_{R S} ^{N D} _{S S R} ^D _R V S ^{N N} K Y V _S V _S V _I K K K ^L R _{1 3} 0 _{7 1} ⁸ _{7 1} ⁸ ₉ ⁴ 1 ⁸ _{1 1} N_L ^{N Y} _{L T} ^Y N _T Y N T G N ^N G G _S ^N _S ^{Y N} H H _{P S} V V V H ^I _S ^I V^{I Q} _S Q ^H _{S S S} ^S _S ^S G Q _{R R} ^Q _{F a} ⁱ _{t T} ^{t b} _h ^c G _a ^t _a ^{t M} _{I a o} K ^h _{n C} ^o C _t ^h _g ⁱ _L 4_. ⁸ - u ^{D H} ₂ :_e V K 2 ^{m 9} _a ^GI _{( 3} N ^{u 6} _{1 e} ^l _h ^{_ 1 L} _{p C .} ⁴ : ₀ D^m I _a ^{L S a} _{3 :} ^e M ¹ t ^B ₀-_{9 i} ^{t Co ) r} _{n u} ^ei _L- _{n 1} ^{2 0} ₈ ⁹ C_l C_b ^y A_{e * -} K⁰ ₃ ¹ ₆ ⁸ ₄

Claims

Atty. Docket No.: 116639-2660 WHAT IS CLAIMED IS: 1. An antibody or antigen binding fragment thereof that binds to a junction adhesion molecule like (JAML) protein or a fragment thereof. 2. The antibody or antigen binding fragment thereof of claim 1, comprising heavy chain complementarity-determining regions 1-3 (CDRH 1-3) and light chain complementarity- determining regions 1-3 (CDRL 1-3) selected from a single row of Table 2, or equivalents thereof. 3. The antibody or antigen binding fragment thereof of claim 1, comprising a heavy chain variable region (HC) and a light chain variable region (LC) selected from a single row of Table 1 or an equivalent thereof, optionally wherein the equivalent of the HC retains the corresponding CDRH1-3 selected from a single row of Table 2, or wherein the equivalent of the LC retains the corresponding CDRL1-3 selected from a single row of Table 2. 4. The antibody or antigen binding fragment of claim 1, wherein the antibody or antigen binding fragment is a humanized antibody or antigen binding fragment thereof. 5. The antibody or antigen binding fragment thereof of claim 4, comprising a heavy chain complementarity-determining region (CDRH)1, a CDRH2, a CDRH3, a light chain complementarity-determining region (CDRL)1, a CDRL2, and a CDRL3 each selected from Table 5. 6. The antibody or antigen binding fragment thereof of claim 4, comprising heavy chain complementarity-determining regions 1-3 (CDRH1-3) and light chain complementarity- determining regions 1-3 (CDRL1-3) selected from a single row of Table 5 or equivalents thereof. 7. The antibody or antigen binding fragment thereof of claim 4, comprising a HC selected from SEQ ID NOS: 135-138 or an equivalent thereof, and a LC selected from SEQ ID NOS:139- 142 or an equivalent thereof, optionally wherein the equivalent of the HC retains the corresponding CDRH1-3 selected from a single row of Table 5, or wherein the equivalent of the LC retains the corresponding CDRLs selected from a single row of Table 5. 144 4861-9829-0104.1 Atty. Docket No.: 116639-2660 8. The antibody or antigen binding fragment thereof of claim 4, comprising a HC and a LC selected from a single row of Table 3 or an equivalent thereof, optionally wherein the equivalent of the HC retains the corresponding CDRH1-3 selected from a single row of Table 5, and wherein the equivalent of the LC retains the corresponding CDRLs selected from a single row of Table 5. 9. The antibody or antigen binding fragment thereof of any one of claims 1-3 or 5-8, wherein the antibody is a monoclonal antibody, or a fragment thereof. 10. The antibody or antigen binding fragment thereof of any one of claims 1-9, wherein the antibody further comprises a constant region selected from the group of: an IgA constant region, an IgD constant region, an IgE constant region, an IgG constant region or an IgM constant region. 11. The antibody or antigen binding fragment thereof of claim 10, wherein the constant region is an IgG1 constant region. 12. The antigen binding fragment of any one of claims 1-11, wherein the antigen binding fragment is selected from the group of Fab, F(ab’)2, Fab’, scFv, or Fv. 13. The antibody or antigen binding fragment thereof of any one of claims 2-12, wherein an equivalent comprises a polypeptide having at least 80% amino acid identity to the polypeptide, or wherein an equivalent to the amino acid sequence comprises a polypeptide that is encoded by a polynucleotide that hybridizes under conditions of high stringency to the complement of the polynucleotide encoding the amino acid sequence. 14. The antibody or antigen binding fragment thereof of any one of claims 1-13, wherein the antibody or fragment thereof is modified, and optionally wherein the modification is selected from the group of PEGylation, a PEG mimetic, polysialyation, HESylation or glycosylation. 15. The antibody or antigen binding fragment thereof of any one of claims 1-14, further comprising an Fc region comprising one or more mutations selected from G237D, P238D, H268D, P271G, and A330R. 145 4861-9829-0104.1 Atty. Docket No.: 116639-2660 16. An isolated polynucleotide encoding the antibody or antigen binding fragment thereof of any one of claims 1-15, and optionally operatively linked to a promoter and/or enhancer element. 17. An isolated polynucleotide encoding the antibody or antigen binding fragment thereof of claim 4, comprising a polynucleotide sequence of any one of SEQ ID NOS: 143-150, or an equivalent thereof, optionally wherein the equivalent thereof encodes a HC and a LC selected from a single row of Table 3. 18. A vector comprising the polynucleotide of claim 16 or claim 17 and, optionally, a heterologous promoter sequence. 19. An isolated host cell comprising the isolated polynucleotide of claim 16 or claim 17 and/or the vector of claim 18. 20. A method of producing an antibody or an antigen binding fragment thereof of any one of claims 1-15, comprising culturing a host cell comprising a polynucleotide encoding the antibody or antigen binding fragment thereof that encodes the antibody or antigen binding fragment thereof under conditions for expression of the antibody or antigen binding fragment thereof, and optionally isolating the antibody or antigen binding fragment thereof. 21. The antibody or antigen binding fragment thereof of any one of claims 1-15, further comprising a detectable label, affinity tag or a purification label. 22. The polynucleotide of claim 16 or claim 17, further comprising a detectable label or a purification label. 23. A method for binding a JAML protein or a fragment thereof, comprising contacting the JAML protein with an antibody or antigen binding fragment thereof of any one of claims 1-15 or 21 under conditions that favor binding of the antibody or antigen binding fragment thereof, and optionally isolating the antibody or antigen binding fragment thereof bound to the JAML protein. 24. A composition comprising a carrier, and one or more of the antibody or antigen binding fragment thereof of any one of claims 1-15 or 21, the polynucleotide of any one of claims 16, 17, or 22, the vector of claim 18, the host cell of claim 19, optionally wherein the carrier is a pharmaceutically acceptable carrier. 146 4861-9829-0104.1 Atty. Docket No.: 116639-2660 25. A kit comprising one or more of one or more of the antibody or antigen binding fragment thereof of any one of claims 1-15 or 21, the polynucleotide of any one of claims 16, 17, or 22, the vector of claim 18, the host cell of claim 19, optionally instructions for use. 147 4861-9829-0104.1