WO2024044722A1 - Drip-antibodies and use thereof - Google Patents

Abstract

Provided herein are, inter alia, antibodies (e.g., humanized antibodies, chimeric antibodies, monoclonal antibodies, antibody fragments (e.g., Fab')) and antibody complex which bind DRiP proteins with high efficiency and specificity. The highly selective antibodies provided may be used, inter alia, as diabetes diagnostics targeting immunogenic DRiP proteins on pancreatic beta cells.

Description

DRIP-ANTIBODIES AND USE THEREOF

RELATED APPLICATION DATA

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of the U.S. Patent Application No. 63/400,729, filed on August 24, 2022, which is hereby incorporated by reference in its entirety and for all purposes.

SEQUENCE LISTING

[0002] The material in the accompanying Sequence Listing is hereby incorporated by reference in its entirety. The accompanying file, named “048440- 773001WO_Sequence_Listing.xmr’ was created on August 21, 2023 and is 8,963,672,316 bytes in size.

BACKGROUND

[0003] T cells can recognize defective ribosomal insulin gene product (DRiP) proteins expressed on the cell surface of pancreatic beta cells and cause selective destruction of these cells in type 1 diabetes (T1D). There is a need in the art for highly selective monoclonal antibodies that can target immunogenic DRiP proteins on pancreatic beta cells. The compositions and methods provided herein, inter alia, address these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

[0004] In an aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 1, a CDR H2 as set forth in SEQ ID NO:2, and a CDR H3 as set forth in SEQ ID NO:3; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:4, a CDR L2 as set forth in SEQ ID NO:5 and a CDR L3 as set forth in SEQ ID NO: 6.

[0005] In an aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 166, a CDR H2 as set forth in SEQ ID NO: 167, and a CDR H3 as set forth in SEQ ID NO: 168; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO: 169, a CDR L2 as set forth in SEQ ID NO: 170 and a CDR L3 as set forth in SEQ ID NO: 171.

[0006] In another aspect is provided an anti-DRiP antibody including a heavy chain vanable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 17, a CDR H2 as set forth in SEQ ID NO: 18, and a CDR H3 as set forth in SEQ ID NO: 19; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:20, a CDR L2 as set forth in SEQ ID NO:21 and a CDR L3 as set forth in SEQ ID NO: 22.

[0007] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:180, a CDR H2 as set forth in SEQ ID NO: 181, and a CDR H3 as set forth in SEQ ID NO: 182; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO: 183, a CDR L2 as set forth in SEQ ID NO: 184 and a CDR L3 as set forth in SEQ ID NO: 185.

[0008] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:33, a CDR H2 as set forth in SEQ ID NO:34, and a CDR H3 as set forth in SEQ ID NO:35; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:36, a CDR L2 as set forth in SEQ ID NO:37 and a CDR L3 as set forth in SEQ ID NO:38.

[0009] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 196, a CDR H2 as set forth in SEQ ID NO: 197, and a CDR H3 as set forth in SEQ ID NO: 198; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO: 199, a CDR L2 as set forth in SEQ ID NO:200 and a CDR L3 as set forth in SEQ ID NO: 201.

[0010] In another aspect is provided a complex including an anti-DRiP antibody as provided herein including embodiments thereof, wherein the antibody is non-covalently bound to the N- terminus of a DRiP protein. [0011] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:49, a CDR H2 as set forth in SEQ ID NO:50, and a CDR H3 as set forth in SEQ ID NO:51; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:52, a CDR L2 as set forth in SEQ ID NO:53 and a CDR L3 as set forth in SEQ ID NO:54.

[0012] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:210, a CDR H2 as set forth in SEQ ID NO:211, and a CDR H3 as set forth in SEQ ID NO:212; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:213, a CDR L2 as set forth in SEQ ID NO:214 and a CDR L3 as set forth in SEQ ID NO:215.

[0013] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:65, a CDR H2 as set forth in SEQ ID NO:66, and a CDR H3 as set forth in SEQ ID NO:67; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:68, a CDR L2 as set forth in SEQ ID NO:69 and a CDR L3 as set forth in SEQ ID NO:70.

[0014] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:224, a CDR H2 as set forth in SEQ ID NO:225, and a CDR H3 as set forth in SEQ ID NO:226; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:227, a CDR L2 as set forth in SEQ ID NO:228 and a CDR L3 as set forth in SEQ ID NO: 229.

[0015] In another aspect is provided a complex including an anti-DRiP antibody as provided herein including embodiments thereof, wherein the antibody is non-covalently bound to the C- terminus of a DRiP protein.

[0016] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:81, a CDR H2 as set forth in SEQ ID NO:82, and a CDR H3 as set forth in SEQ ID NO:83; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:84, a CDR L2 as set forth in SEQ ID NO:85 and a CDR L3 as set forth in SEQ ID NO: 86.

[0017] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR HI as set forth in SEQ ID NO:238, a CDR H2 as set forth in SEQ ID NO:239, and a CDR H3 as set forth in SEQ ID NO:240; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:241, a CDR L2 as set forth in SEQ ID NO:242 and a CDR L3 as set forth in SEQ ID NO: 243.

[0018] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:99, a CDR H2 as set forth in SEQ ID NO: 100, and a CDR H3 as set forth in SEQ ID NO: 101; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:102, a CDR L2 as set forth in SEQ ID NO:103 and a CDR L3 as set forth in SEQ ID NO: 104.

[0019] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:252, a CDR H2 as set forth in SEQ ID NO:253, and a CDR H3 as set forth in SEQ ID NO:254; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:255, a CDR L2 as set forth in SEQ ID NO:256 and a CDR L3 as set forth in SEQ ID NO:257.

[0020] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 117, a CDR H2 as set forth in SEQ ID NO: 118, and a CDR H3 as set forth in SEQ ID NO: 119; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO: 120, a CDR L2 as set forth in SEQ ID NO: 121 and a CDR L3 as set forth in SEQ ID NO: 122. [0021] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:266, a CDR H2 as set forth in SEQ ID NO:267, and a CDR H3 as set forth in SEQ ID NO:268; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:269, a CDR L2 as set forth in SEQ ID NO:270 and a CDR L3 as set forth in SEQ ID NO:271.

[0022] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 135, a CDR H2 as set forth in SEQ ID NO: 136, and a CDR H3 as set forth in SEQ ID NO: 137; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO: 138, a CDR L2 as set forth in SEQ ID NO: 139 and a CDR L3 as set forth in SEQ ID NO: 140.

[0023] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:280, a CDR H2 as set forth in SEQ ID NO:281, and a CDR H3 as set forth in SEQ ID NO:282; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:283, a CDR L2 as set forth in SEQ ID NO:284 and a CDR L3 as set forth in SEQ ID NO:285.

[0024] In an aspect is provided a complex including an anti-DRiP antibody as provided herein including embodiments thereof, wherein the antibody is non-covalently bound to the N- terminus of a DRiP protein.

[0025] In another aspect is provided an isolated nucleic acid encoding an anti-DRiP antibody as provided herein including embodiments thereof.

[0026] In another aspect is provided a cell including an anti-DRiP antibody as provided herein including embodiments thereof, or a nucleic acid as provided herein including embodiments thereof.

[0027] In another aspect is provided a method of forming an antibody capable of binding to a DRiP protein, the method including immunizing a mammal with a peptide including the sequence of SEQ ID NO:153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO:162, SEQ ID NO: 164, or SEQ ID NO: 165.

[0028] In another aspect is provided a method of detecting a DRiP-expressmg cell, the method including (i) contacting a DRiP-expressing cell with an antibody as provided herein including embodiments thereof; (ii) and detecting binding of the antibody to a DRiP protein expressed by the cell.

[0029] In another aspect is provided a complex including a first anti-DRiP antibody non- covalently bound to the C-terminus of a DRiP protein and a second anti-DRiP antibody non- covalently bound to the N-terminus of the DRiP protein, wherein the first anti-DRiP antibody is an antibody as provided herein including embodiments thereof and wherein the second anti- DRiP antibody is an antibody as provided herein including embodiments thereof.

[0030] In another aspect is provided a method of detecting a DRiP-expressing cell in a human subject having or being at risk of developing diabetes, the method including: (i) obtaining a biological sample from a human subject having or being at risk of developing diabetes; (ii) contacting the biological sample with an anti-DRiP antibody as provided herein including embodiments thereof; and (ii) detecting binding of the antibody to a DRiP protein in the sample, thereby detecting a DRiP-expressing cell in the subject.

[0031] In another aspect is provided a method of diagnosing and treating diabetes in a human subject in need thereof, the method including: (i) obtaining a biological sample from a human subject; (ii) detecting whether a DRiP protein is present in the sample by contacting the sample with an antibody as provided herein including embodiments thereof; (iii) diagnosing the human subject with diabetes when a detectable complex is formed by the DRiP protein and the antibody; and (iv) administering to the diagnosed human subject an effective amount of a diabetes treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1 illustrates serum ELISA data from 10 mice immunized with SEQ ID NO: 155 to quantify production of monoclonal antibodies.

[0033] FIG. 2 illustrates high-performance liquid chromatography (HPLC) data of a DRiP peptide (SEQ ID NO: 165). [0034] FIG. 3 illustrates a schema of the process used to identify anti-DRiP monoclonal antibodies provide herein.

[0035] FIGS. 4A-4B show purification and charactenzation of anti-DRiP antibodies provided herein. FIG. 4A presents graphs showing size exclusion chromatograph of anti- DRiP antibodies provided herein. Each Fab was expressed using ExpiCHO cells, purified using protein G beads and size exclusion chromatography (SEC). The peaks are symmetric indicating homogeneous product. FIG. 4B shows pictures of SDS-PAGE blots with anti-DRiP antibodies (NR-non-reduced and R-reduced) provided herein. SDS-PAGE was used to confirm the purity of the Fabs. The left side of the gel was samples that are not reduced (e.g., disulfides intact). The right side are the same samples, but reduced. The middle lane are molecular markers. The masses are consistent with theoretical weight derived from the sequences.

[0036] FIG. 5 presents graphs demonstrating binding of anti-DRiP antibodies provided herein to a DRiP peptide (SEQ ID NO: 165) on surface plasmon resonance (SPR). SPR was used to characterized the affinity of each Fab to the DRiP peptide (SEQ ID NO: 165). The on and off rates were determined and the KD calculated from the ratio of k_Off/k_On.

[0037] FIGS. 6A-6B show purification and characterization of anti-DRiP antibodies provided herein. FIG. 6A presents graphs showing size exclusion chromatograph of anti- DRiP antibodies provided herein. The Fab’ fragments for DRiP4 and DRiP7 were produced in an IgG format. Size SEC shows both produce a symmetric peak indicating homogeneity.

FIG. 6B shows pictures of SDS-PAGE blots with anti-DRiP antibodies (NR-non-reduced and R-reduced) provided herein. The SDS-PAGE indicates each is highly purified and are at the appropriate mass.

[0038] FIG. 7 presents graphs demonstrating binding of anti-DRiP antibodies provided herein to a DRiP peptide (SEQ ID NO: 165) on SPR. SPR shows each binds as an IgG. As noted, the IgG are bivalent and expected to bind with higher affinity due to avidity. As controls, a sample of a polyclonal anti-DRiP antibody was applied to the same chip and showed positive binding. Likewise, trastuzumab IgG was applied to the chip and did not bind as expected. [0039] FIG. 8 shows the crystal structure of a DRiP peptide bound to an anti-DRiP antibody as provided herein.

[0040] FIG. 9 presents graphs demonstrating binding of anti-DRiP antibodies provided herein to a DRiP peptide (SEQ ID NO: 162) on SPR.

[0041] FIG. 10 presents graphs demonstrating binding of anti-DRiP antibodies provided herein to a DRiP peptide (SEQ ID NO: 165) on SPR.

[0042] FIG. 11A-11B present graphs demonstrating binding of anti-DRiP antibodies provided herein to a DRiP peptide (SEQ ID NO: 163) on SPR in the absence (FIG. 11A) or presence (FIG. 11B) of the N-terminal DRiP peptide.

[0043] FIGS. 12A-12E show results from a sandwich ELISA experiment using anti-DRiP antibodies provided herein. FIG. 12A illustrates a schema of the sandwich ELISA experiment. FIGS. 12B-12C present data from a sandwich ELISA experiment to quantify binding of anti- DRiP antibodies provided herein to a DRiP protein (SEQ ID NO: 160). FIGS. 12D-12E present data from a sandwich ELISA experiment to quantify binding of anti-DRiP antibodies provided herein to a DRiP protein (SEQ ID NO: 161).

[0044] FIG. 13 presents Western Blot data using anti-DRiP antibodies provided herein.

[0045] FIG. 14 presents data from immunohistochemistry experiments showing that an immunization peptide can block binding of an anti-DRiP antibody (DRiPV2-7) provided herein. Antibody: Mouse monoclonal anti DRiP v2#7 antibody [20ug/ml, 1 :50], Pancreatic tissue was stained with: Mouse monoclonal anti DRiP v2#7 (white); Somatostatin (top and middle panel) or Glucagon (bottom panel) (blue); Insulin (red); and Hoechst (green). DRiP staining is detected in the islet, not in exocrine tissue (top panel). Blocking the mouse monoclonal anti DRiP v2#7 with the immunization peptide results is no or non-specific staining (middle and bottom panel), indicating good antibody specificity. Top panel is not blocked with immunization peptide. Islet is indicated by hormone staining.

[0046] FIG. 15 presents data from immunohistochemistry experiments were pancreatic tissue was stained with: Mouse monoclonal anti DRiP v2#7 (white); Somatostatin (blue); Insulin (red); and Hoechst (green). Overlap of DRiP and insulin staining shows that DRiP is detected in beta cells; and DRiP staining outside insulin area shows that some DRiP is detected in non-beta cells (top panel). Staining of DRiP and somatostatin do not overlap showing that DRiP is not expressed in delta cells. Image is zoomed in to show detailed single beta and delta cells

[0047] FIG. 16 presents data from immunohistochemistry experiments showing staining of pancreatic tissue with: Mouse monoclonal anti DRiP v2#7 (white); Somatostatin (blue); Insulin (red); and Hoechst (green). DRiP staining is similar between different pancreas donors: Hui 036 (top panel) and Hui 151 (bottom panel). No DRiP staining is detected in delta cells. DRiP staining similar in different pancreas donors (n=2) with SST.

[0048] FIG. 17 presents data from immunohistochemistry experiments where pancreatic tissue was stained with: Mouse monoclonal anti DRiP v2#7 (white); Glucagon (blue); Insulin (red); and Hoechst (green). DRiP staining is similar between different pancreas donors: Hui 036 (top panel) and Hui 151 (bottom panel). DRiP staining is detected in beta cells. Overlap of DRiP staining with Glucagon staining suggests there is some DRiP detected in a subset of alpha cells. DRiP staining similar in different pancreas donors (n=2) with GCG

[0049] FIG. 18 presents data from immunohistochemistry experiments where pancreatic tissue was stained with: Mouse monoclonal anti DRiP v2#7 (white); Glucagon (blue); Insulin (red); and Hoechst (green). DRiP staining was performed with a titration of antibody concentrations: 20ug/ml or 1:50 (top panel); lOug/ml or 1: 100 (middle panel); and 5ug/ml (1 :200). Concentrations of 10-20ug/ml show good signal to noise ratio and seem to work best for the DRiP antibody. DRiP monoclonal titration (1 :50 or 1 : 100)

[0050] FIGS. 19A-19B show the structure of exemplary Fabs described herein bound to the DRiP peptide. FIG. 19A shows the top and side views of an exemplary Fab generated by immunizing animals with a DRiP peptide with a biotin tag on the N-terminus. This immunization protocol produced Fabs in which the N-terminus of the DRiP peptide is not buried. FIG. 19B shows the top and side views of an exemplar}' Fab in which the N-terminus of the DRiP peptide is buried between the light and heavy chains of the Fab. The modification of the N-terminal end of the DRiP peptide interferes with binding with the Fab which binds the N-terminus of the DRiP peptide. In the second immunization (FIG. 19 A), we prevented the N- terminus from binding between the light and heavy chains by hanging off a biotin at the N- terminus and immunizing mice. When we screened using the Berkeley lights, we conjugated the DRiP peptide to beads through the C-termmus. This ensured that we would not find peptides that buried the C-terminal end. The crystal structure confirms that the DRiP peptide binds “across” the Fab. Moreover, N-terminal modifications (oxidation) is not expected to interfere with binding. This was confirmed by SPR and subsequently by staining. While the N- terminus -targeting Fab that buries the N-terminus binds to the DRiP with high affinity by SPR, it failed to stain tissue.

DETAILED DESCRIPTION

DEFINITIONS

[0051] As used herein, the term "about" means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about means the specified value.

[0052] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Spnngs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0053] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.

[0054] Nucleic acids, including e g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.

[0055] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non- naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.: and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the intemucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0056] Nucleic acids can include nonspecific sequences. As used herein, the term "nonspecific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory' nucleic acid when contacted with a cell or organism. In embodiments, the nonspecific nucleic acid sequence does not encode a biological function. In embodiments, the nonspecific nucleic acid sequence is a scrambled nucleic acid sequence. A “scrambled nucleic acid sequence” as provided herein is a recombinant nucleic acid sequence that includes nucleotides randomly linked to each other in vitro. Scrambled nucleic acid sequences are commonly used in the art as control or reference sequences relative to the activity (biological function) of test nucleic acid sequences.

[0057] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. 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. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and/or modified nucleotides.

[0058] Methods for determining whether a ligand (e.g., antibody) binds to a protein (antigen) and/or the affinity for a ligand to a protein are known in the art. For example, the binding of a ligand to a protein can be detected and/or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance method (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), isothermal titration calorimetry (ITC), enzyme-lmked immunosorbent assays (ELISA), sandwich ELISA, fluorescence-activated cell sorting (FACS), immunohistochemistry, or immunoprecipitation.

[0059] Immunoassays which can be used to analyze immunospecific binding and crossreactivity of the ligand include, but are not limited to, competitive and non- competitive assay systems using techniques such as Western blots, RIA, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, and fluorescent immunoassays. Such assays are routine and well known in the art.

[0060] A "label" or a "detectable moiety" is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include ³²P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any appropriate method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.

[0061] A "labeled protein or polypeptide" is one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic, van der Waals, electrostatic, or hydrogen bonds to a label such that the presence of the labeled protein or polypeptide may be detected by detecting the presence of the label bound to the labeled protein or polypeptide. Alternatively, methods using high affinity interactions may achieve the same results where one of a pair of binding partners binds to the other, e.g., biotin, streptavidin.

[0062] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y- carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e. , an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g. , homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0063] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter sy mbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0064] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may be conjugated to a moiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0065] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that may be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N- terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0066] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue. For example, a selected residue in a selected antibody (or Fab domain) corresponds to light chain threonine at Kabat position 40, when the selected residue occupies the same essential spatial or other structural relationship as a light chain threonine at Kabat position 40. In some embodiments, where a selected protein is aligned for maximum homology with the light chain of an antibody (or Fab domain), the position in the aligned selected protein aligning with threonine 40 is said to correspond to threonine 40. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the light chain threonine at Kabat position 40, and the overall structures compared. In this case, an amino acid that occupies the same essential position as threonine 40 in the structural model is said to correspond to the threonine 40 residue.

[0067] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0068] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.

[0069] The following eight groups each contain amino acids that are conservative substitutions for one another:

1) Alanine (A), Glycine (G);

2) Aspartic acid (D), Glutamic acid (E);

3) Asparagine (N), Glutamine (Q);

4) Arginine (R), Lysine (K);

5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);

6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);

7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M)

(see, e.g, Creighton, Proteins (1984)).

[0070] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 60% identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identity over a specified region, e.g., of the entire polypeptide sequences of the invention or individual domains of the polypeptides of the invention), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Such sequences are then said to be "substantially identical." This definition also refers to the complement of a test sequence. Optionally, the identity exists over a region that is at least about 50 nucleotides in length, or more preferably over a region that is 100 to 500 or 1000 or more nucleotides in length.

[0071] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

[0072] For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary', and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. [0073] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are w ell-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology' algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat ’l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[0074] An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query' sequence, which either match or satisfy some positivevalued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al. , supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0075] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873- 5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0076] An indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the antibodies raised against the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules or their complements hybridize to each other under stringent conditions, as described below. Yet another indication that two nucleic acid sequences are substantially identical is that the same primers can be used to amplify the sequence.

[0077] The term "isolated", when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0078] Antibodies are large, complex molecules (molecular weight of -150,000 or about 1320 amino acids) with intricate internal structure. A natural antibody molecule contains two identical pairs of polypeptide chains, each pair having one light chain and one heavy chain. Each light chain and heavy chain in turn consists of two regions: a variable (“V”) region, involved in binding the target antigen, and a constant (“C”) region that interacts with other components of the immune system. The light and heavy chain variable regions (also referred to herein as light chain variable (VL) domain and heavy chain variable (VH) domain, respectively) come together in 3 -dimensional space to fomi a variable region that binds the antigen (for example, a receptor on the surface of a cell). Within each light or heavy chain vanable region, there are three short segments (averaging 10 amino acids in length) called the complementarity determining regions (“CDRs”). The six CDRs in an antibody variable domain (three from the light chain and three from the heavy chain) fold up together in 3- dimensional space to form the actual antibody binding site which docks onto the target antigen. The position and length of the CDRs have been precisely defined by Kabat, E. et al.. Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1983, 1987. The part of a variable region not contained in the CDRs is called the framework ("FR"), which fonns the environment for the CDRs.

[0079] The term "antibody" is used according to its commonly known meaning in the art. Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CHI by a disulfide bond. The F(ab)'z may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e g , McCafferty etal., Nature 348:552-554 (1990)).

[0080] An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL), variable light chain (VL) domain or light chain variable region and variable heavy chain (VH), variable heavy chain (VH) domain or heavy chain variable region refer to these light and heavy chain regions, respectively. The terms variable light chain (VL), variable light chain (VL) domain and light chain variable region as referred to herein may be used interchangeably. The terms variable heavy chain (VH), variable heavy chain (VH) domain and heavy chain variable region as referred to herein may be used interchangeably. The Fc (i.e. fragment crystallizable region; also referred to herein as “Fc domain”) is the "base" or "tail" of an immunoglobulin and is typically composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody. By binding to specific proteins, the Fc region ensures that each antibody generates an appropriate immune response for a given antigen. The Fc region also binds to various cell receptors, such as Fc receptors, and other immune molecules, such as complement proteins. In embodiments, the Fc region includes a constant heavy chain domain 3 (CH3 domain) and a constant heavy chain domain 2 (CH2 domain).

[0081] In embodiments of the disclosure, the assignment of amino acids to each domain (e g., CDR LI, CDR L2, CDR L3, CDR Hl, CDR H2, or CDR H3) is in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

[0082] The epitope of an antibody is the region of its antigen to which the antibody binds. Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) binding of the other to the antigen. That is, a lx, 5x, lOx, 20x or lOOx excess of one antibody inhibits binding of the other by at least 30% but preferably 50%, 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 50: 1495, 1990). 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.

[0083] The term "antigen" as provided herein refers to molecules capable of binding to the antigen binding domain provided herein. An "antigen binding domain" as provided herein is a region of an antibody that binds to an antigen (epitope). As described above, the antigen binding domain is generally composed of one constant and one variable domain of each of the heavy and the light chain (VL, VH, CL and CHI, respectively). The paratope or antigenbinding site is formed on the N-terminus of the antigen binding domain. The two variable domains of an antigen binding domain typically bind the epitope on an antigen.

[0084] For preparation of monoclonal or polyclonal antibodies, any technique known in the art can be used see, e.g, Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4:72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy (1985)). "Monoclonal" antibodies (mAb) refer to antibodies derived from a single clone. Techniques for the production of single chain antibodies (U.S. Pat. No. 4,946,778) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized antibodies. Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens {see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al. , Biotechnology 10:779-783 (1992)).

[0085] For preparation of suitable antibodies of the invention and for use according to the invention, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2d ed. 1986)). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Patent 4,946,778, U.S. Patent No. 4,816,567) can be adapted to produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al, Bio/Technology 10:779-783 (1992); Lonberg et al, Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93/08829, Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al, Methods in Enzymology 121 :210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Patent No. 4,676,980 , WO 91/00360; WO 92/200373; and EP 03089).

[0086] Methods for humanizing or primatizing non-human antibodies are well known in the art (e.g., U.S. Patent Nos. 4,816,567; 5,530,101; 5,859,205; 5,585,089; 5,693,761; 5,693,762; 5,777,085; 6,180,370; 6,210,671; and 6,329,511; WO 87/02671; EP Patent Application 0173494; Jones et al. (1986) Nature 321:522; and Verhoyen et al. (1988) Science 239: 1534). Humanized antibodies are further described in, e.g., Winter and Milstein (1991) Nature 349:293. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Morrison et al., PNAS USA, 81 :6851-6855 (1984), Jones et al., Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988), Verhoeyen et al., Science 239:1534-1536 (1988) and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992), Padlan, Molec. Immun., 28:489-498 (1991); Padlan, Molec. Immun., 31(3): 169-217 (1994)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U.S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. For example, polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and a second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated in accordance with well known procedures from a variety of human cells.

[0087] A "chimeric antibody" is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity. The preferred antibodies of, and for use according to the invention include humanized and/or chimeric monoclonal antibodies.

[0088] An “antibody variant” as provided herein refers to a polypeptide capable of binding to an antigen and including one or more structural domains of an antibody or fragment thereof. Non-limiting examples of antibody variants include single-domain antibodies or nanobodies, affibodies (polypeptides smaller than monoclonal antibodies (e.g., about 6kDA) and capable of binding antigens with high affinity and imitating monoclonal antibodies, monospecific Fab2, bispecific Fab2, trispecific Fabs, monovalent IgGs, scFv, bispecific diabodies, trispecific triabodies, scFv-Fc, minibodies, IgNAR, V-NAR, hdgG, VhH, or peptibodies. A “nanobody” or “single domain antibody” as described herein is commonly well known in the art and refers to an antibody fragment consisting of a single monomeric variable antibody domain (e g., a VH or a VL domain). Like a whole antibody, it is able to bind selectively to a specific antigen. A “peptibody” as provided herein refers to a peptide moiety attached (through a covalent or non-covalent linker) to the Fc domain of an antibody. Further non-limiting examples of antibody variants known in the art include antibodies produced by cartilaginous fish or camelids. A general description of antibodies from camelids and the variable regions thereof and methods for their production, isolation, and use may be found in references WO97/49805 and WO 97/49805 which are incorporated by reference herein in their entirety and for all purposes. Likewise, antibodies from cartilaginous fish and the variable regions thereof and methods for their production, isolation, and use may be found in W02005/118629, which is incorporated by reference herein in its entirety and for all purposes.

[0089] An “affibody” as described herein is commonly well known in the art and refers to small, robust proteins engineered to bind to a large number of target proteins or peptides with high affinity, by imitating monoclonal antibodies. Affibodies are therefore a member of the family of antibody mimetics In embodiments, an affibody is a molecule including of three alpha helices with about 58 amino acids and a molar mass of about 6 kDa.

[0090] A “single domain antibody” as provided herein refers to an antibody fragment including a single monomeric variable antibody domain (e.g., a VH or a VL domain). Like a whole antibody, a single domain antibody is able to bind selectively to a specific antigen. The molecular weight of a single domain antibody is 12-15 kDa, single domain antibody In embodiments, a single domain antibody is a variable heavy chain domain. In embodiments, a single domain antibody includes a variable heavy chain domain. In embodiments, a single domain antibody is a variable light chain domain. In embodiments, a single domain antibody includes a variable light chain domain. Non-limiting examples of single domain antibodies include camelid-derived VHH fragments and VNAR (variable immunoglobulin new antigen receptor) fragments. In embodiments, the single-domain antibody is a peptide domain of about 110 amino acids. [0091] A single-chain variable fragment (scFv) is typically a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of 10 to about 25 amino acids. The linker may usually be rich in glycine for flexibility, as well as serine or threonine for solubility. The linker can either connect the N- terminus of the VH with the C-terminus of the VL, or vice versa.

[0092] The phrase "specifically (or selectively) binds" to an antibody or "specifically (or selectively) immunoreactive with," when referring to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologies. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

[0093] A "ligand" refers to an agent, e.g., a polypeptide or other molecule, capable of binding to a ligand binding domain (e.g., receptor or antibody, antibody variant, antibody region or fragment thereof).

[0094] "Contacting" is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells, an antibody provided herein and its epitope) to become sufficiently proximal to react, interact or physically touch. It should be appreciated, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intennediate from one or more of the added reagents which can be produced in the reaction mixture. [0095] The term "contacting" may include allowing two species to react, interact, or physically touch (e.g., bind), wherein the two species may be, for example, an antibody construct as described herein and a cancer protein In embodiments, contacting includes, for example, allowing an antibody construct to bind to a cancer protein expressed on a cancer cell.

[0096] A "cell" as used herein, refers to a cell carrying out metabolic or other functions sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.

[0097] The term "plasmid," "expression vector," or “viral vector” refers to a nucleic acid molecule that encodes for genes and/or regulatory elements necessary for the expression of genes. Expression of a gene from a plasmid can occur in cis or in trans. If a gene is expressed in cis, gene and regulatory elements are encoded by the same plasmid. Expression in trans refers to the instance where the gene and the regulatory elements are encoded by separate plasmids. Suitable viral vectors contemplated herein include, for example, lentiviral vectors and onco-retro viral vectors.

[0098] "Biological sample" or "sample" refer to materials obtained from or derived from a subject or patient. A biological sample includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histological purposes. Such samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, synovial fluid, joint tissue, synovial tissue, synoviocytes, fibroblast-like synoviocytes, macrophage-like synoviocytes, immune cells, hematopoietic cells, fibroblasts, macrophages, T cells, etc. A biological sample is ty pically obtained from a eukaryotic organism, such as a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish. In some embodiments, the sample is obtained from a human.

[0099] A “control” or “standard control” refers to a sample, measurement, or value that serves as a reference, usually a known reference, for comparison to a test sample, measurement, or value. For example, a test sample can be taken from a patient suspected of having a given disease (e.g. diabetes) and compared to a known normal (non-diseased) individual (e.g. a standard control subject). A standard control can also represent an average measurement or value gathered from a population of similar individuals (e.g. standard control subjects) that do not have a given disease (i.e. standard control population), e.g., healthy individuals with a similar medical background, same age, weight, etc. A standard control value can also be obtained from the same individual, e.g. from an earlier-obtained sample from the patient prior to disease onset. For example, a control can be devised to compare therapeutic benefit based on pharmacological data (e.g., half-life) or therapeutic measures (e.g., comparison of side effects). Controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in controls, variation in test samples will not be considered as significant. One of skill will recognize that standard controls can be designed for assessment of any number of parameters (e g. RNA levels, protein levels, specific cell types, specific bodily fluids, specific tissues, etc).

[0100] One of skill in the art will understand which standard controls are most appropriate in a given situation and be able to analyze data based on comparisons to standard control values. Standard controls are also valuable for determining the significance (e.g. statistical significance) of data. For example, if values for a given parameter are widely variant in standard controls, variation in test samples will not be considered as significant.

[0101] “Patient” or “subject in need thereof’ refers to a living organism suffering from or prone to a disease (e.g. diabetes) or condition that can be treated by administration of a composition or pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkey s, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.

[0102] The terms “disease” or “condition” refer to a state of being or health status of a patient or subj ect capable of being treated with the compounds or methods provided herein. The disease may be diabetes. The disease may be type I diabetes (T1D). The disease may be type II diabetes (T2D). Type I diabetes mellitus (T1D) precipitates from the autoimmune attack of pancreatic beta cells, resulting in a loss of functional beta cell mass. Thus, subjects with T1D do not make insulin or make very little insulin as compared to the standard amount produced by a subject without T1D. Functional beta cell mass is impacted positively by processes that increase the number and size of beta cells and negatively by those that deplete the numbers of cells (i. e. , apoptosis, necrosis, and other modes of cell death). Type 2 diabetes (T2D) occurs when a subject is ineffective at using insulin that the body has produced (e g. insulin resistance) and/or when a subj ect is unable to produce enough insulin. Thus, patients with T2D may have hyperglycemia (high blood glucose levels), due to lack of the standard effect of insulin (e.g. driving glucose in the blood inside the cells).

[0103] As used herein, the term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (such as diabetes (T1D or T2D)) means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. For example, diabetes may be treated with a composition (e g. gastrin-treated islet cells) effective for increasing beta cell production.

[0104] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treatment includes preventing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition prior to the induction of the disease; suppressing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition after the inductive event but prior to the clinical appearance or reappearance of the disease; inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a protective composition after their initial appearance; preventing re-occurring of the disease and/or relieving the disease, that is, causing the regression of clinical symptoms by administration of a protective composition after their initial appearance. For example, certain methods herein diabetes (e.g., type 1 diabetes). For example, certain methods herein treat diabetes by decreasing or reducing or preventing the occurrence, growth, or progression of diabetes; or treat diabetes by decreasing a symptom of diabetes.

[0105] As used herein the terms “treatment,” “treat,” or “treating” refers to a method of reducing the effects of one or more symptoms of a disease or condition characterized by expression of a DRiP protein or fragment thereof or symptom of the disease or condition characterized by expression of the DRiP protein or fragment thereof. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination.

[0106] An "effective amount" is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An "activity decreasing amount," as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme or protein relative to the absence of the antagonist. A "function disrupting amount," as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. Guidance can be found in the literature for appropriate dosages for given classes of phannaceutical products. For example, for the given parameter, an effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g. , Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0107] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, mtralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g, buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example cancer therapies such as chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. The compounds of the invention can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0108] Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the antibodies provided herein suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions. Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, com starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fdlers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible earners.

Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.

[0109] Pharmaceutical compositions can also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized sepharose(TM), agarose, cellulose, and the like), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes). Additionally, these carriers can function as immunostimulating agents (z.e., adjuvants). [0110] The term “adjuvant” or “adjuvant moiety” is used herein according to its plain ordinary meaning and refers to a compound or a chemical added to an immunizing peptide to promote an immune response. Tn embodiments, the adjuvant increases the quanity of the antibody produced. In embodiments, the adjuvant is an emulsion including an oil. In embodiments, the oil is mineral oil or a metabolizable oil. In embodiments, the metabolizable oil is squalene. In embodiments, the emulsion further includes an antigen. The antigen may be an inactivated bacterial protein. In embodiments, the inactivated bacterial protein is an inactivated mycobacterial protein. The antigen may be a Gram negative bacterial product. In embodiments, the Gram negative bacterial product is monophosphoryl lipid A. In embodiments, the adjuvant does not include an antigen. In embodiments, the adjuvant includes saline. In embodiments, the adjuvant further includes a detergent. In embodiments, the detergent is Tween 80. In embodiments, the adjuvant includes a non-ionic copolymer. The non-ionic copolymer may be surfactant acting, linear, a block, or a chain. In embodiments, the non-ionic copolymer includes polyoxypropylene (POP) or polyoxyethylene (POE). In embodiments, the adjuvant includes an emulsifier. In embodiments, the emulsifier is sorbitan monooleate 80. In embodiments, the adjuvant increases the quality of the antibody produced. In embodiments, the adjuvant is a Freund’s adjuvant, a Ribi adjuvant, a Titermax adjuvant, a specol adjuvant, an aluminum salt, a saponin, or a polysaccharide chain. In embodiments, the adjuvant is a Freund’s adjuvant. In further embodiments, the Freund's adjuvant is Freund’s complete adjuvant (FCA) or Freund’s incomplete adjuvant (FIA). In embodiments, the adjuvant is a Ribi adjuvant. In embodiments, the adjuvant is a Titermax adjuvant. In embodiments, the adjuvant is a specol adjuvant. In embodiments, the adjuvant is an aluminum salt. In embodiments, the alumninm salt is aluminium hydroxide, aluminum phosphate, or aluminum potassium sulfate. In embodiments, the adjuvant is a saponin. In embodiments, the adjuvant is a polysaccharide chain

[OHl] Suitable formulations for rectal administration include, for example, suppositories, which consist of the packaged nucleic acid with a suppository base. Suitable suppository bases include natural or synthetic triglycerides or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the compound of choice with a base, including, for example, liquid triglycerides, polyethylene glycols, and paraffin hydrocarbons. [0112] Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically or intrathecally. Parenteral administration, oral administration, and intravenous administration are the preferred methods of administration. The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials.

[0113] Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. Cells transduced by nucleic acids for ex vivo therapy can also be administered intravenously or parenterally as described above.

[0114] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The composition can, if desired, also contain other compatible therapeutic agents.

[0115] The combined administration contemplates co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.

[0116] Effective doses of the compositions provided herein vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. However, a person of ordinary skill in the art would immediately recognize appropriate and/or equivalent doses looking at dosages of approved compositions for treating and preventing cancer for guidance.

[0117] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable earner” refer to a substance that aids the administration of an active agent to and absorption by a subj ect and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances, and the like, that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0118] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0119] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0120] The pharmaceutical preparation is optionally in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The unit dosage form can be of a frozen dispersion.

ANTI-DRIP ANTIBODIES

[0121] T cells can recognize defective ribosomal insulin gene product (DRiP) proteins expressed on the cell surface of pancreatic beta cells and cause selective destruction of these cells in type I diabetes (TID). Provided herein are, inter aha, highly selective monoclonal antibodies that can target immunogenic DRiP proteins on pancreatic beta cells and methods of using these antibodies for diagnosing and monitoring TID. The anti- DRiP antibodies provided herein bind to N-terminal or C -terminal regions of a DRiP protein with selective affinity and may be used in detection assays (e.g., sandwich ELISA (enzyme linked immunosorbent assay) including one or more anti- DRiP antibodies binding different epitopes of a DRiP protein.

[0122] The terms "DRiP", "DRiP protein" or "DRiP peptide" can be used interchangeably throughout and refer to any of the recombinant or naturally-occurring forms of a defective ribosomal insulin gene product (DRiP) protein or variants or homologs thereof that maintain DRiP activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to DRiP). A DRiP provided herein refers to a neoantigen formed by alternative splicing of mRNA and/or misreads originating from ribosomal infidelity. The DRiP neoantigens exhibit high immunogenicity and contribute to loss of immune tolerance and epitope spreading. Therefore, the term DRiP activity refers to the ability of a DRiP protein to induce a immune response, the loss of immune tolerance and induce epitope spreading In embodiments, the DRiP protein is a defective ribosomal insulin gene product. In embodiments, the DRiP protein is an insulin DRiP protein. In embodiments, the DRiP protein is formed by a pancreatic cell. In embodiments, the DRiP protein is formed by an islet cell. In embodiments, the DRiP protein is an insulin DRiP protein.

[0123] The term "insulin gene" as provided herein refers to any of the recombinant or naturally-occurring forms of a human insulin gene or variants or homologs thereof that have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% nucleotide sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous nucleotide portion) compared to a naturally occurring insulin gene. In embodiments, the insulin gene is substantially identical to the nuecleotide sequence identified by the Entrez reference number 3630 or a variant or homolog having substantial identity thereto. Tn embodiments, the insulin gene refers to an mRNA transcript substantially identical to the nucleotide sequence identified by RefSeq NM_000207, NM_001185097, NM_001185098 or NM_001291897, or a variant or homolog having substantial identity thereto. In embodiments, the insulin gene encodes a protein substantially identical to the protein sequence identified by RefSeq NP_000198, NP_001172026, NP_001172027, NP_001278826, NP_000198. 1, or a variant or homolog having substantial identity thereto.

[0124] In some aspects, the variants or homologs of a DRiP protein provided herein including embodiments thereof have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring DRiP protein (insulin DRiP protein). In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 158 or a variant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 159 or a variant or homolog having substantial identity' thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 153 or a variant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 154 or a variant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 155 or a variant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 156 or a variant or homolog having substantial identity' thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 157 or a variant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 160 or a variant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 161 or a variant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 162 or a variant or homolog having substantial identity' thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 163 or a vanant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 1 4 or a variant or homolog having substantial identity thereto. In embodiments, the DRiP protein is substantially identical to the protein identified by SEQ ID NO: 165 or a variant or homolog having substantial identity thereto.

[0125] For the compositions and methods provided herein including embodiments thereof any one of the DRiP proteins described in Kracht et al. Nat Med, 2017; 23(4):501-507 and Roep, Front Immunol, 203; 14: 1112858, both of which are incorporated herein by reference in their entirety and for all purposes, may be used.

[0126] The anti-DRiP antibodies provided herein, including embodiments thereof may bind to the N-terminus of a DRiP protein provided herein including embodiments thereof.

[0127] In an aspect is provided an anti-DRiP antibody including a heavy chain vanable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 1, a CDR H2 as set forth in SEQ ID NO:2, and a CDR H3 as set forth in SEQ ID NO:3; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:4, a CDR L2 as set forth in SEQ ID NO:5 and a CDR L3 as set forth in SEQ ID NO: 6.

[0128] In embodiments, the heavy chain variable domain includes a FR Hl as set forth in SEQ ID NO: 7, a FR H2 as set forth in SEQ ID NO: 8, a FR H3 as set forth in SEQ ID NO: 9 and a FR H4 as set forth in SEQ ID NOTO. In embodiments, light chain variable domain includes a FR LI as set forth in SEQ ID NO: 11, a FR L2 as set forth in SEQ ID NO: 12, a FR L3 as set forth in SEQ ID NO: 13 and a FR L4 as set forth in SEQ ID NO: 14.

[0129] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO: 15. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 15. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO: 16. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 16. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO: 15 and the light chain variable domain includes the sequence of SEQ ID NO: 16. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 15 and the light chain variable domain is the sequence of SEQ ID NO: 16. In embodiments, the anti-DRiP antibody is referred to herein as DRiPV2-5.

[0130] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 17, a CDR H2 as set forth in SEQ ID NO: 18, and a CDR H3 as set forth in SEQ ID NO: 19; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:20, a CDR L2 as set forth in SEQ ID NO:21 and a CDR L3 as set forth in SEQ ID NO: 22.

[0131] In embodiments, the heavy chain variable domain includes a FR Hl as set forth in SEQ ID NO:23, a FR H2 as set forth in SEQ ID NO:24, a FR H3 as set forth in SEQ ID NO:25 and a FR H4 as set forth in SEQ ID NO:26. In embodiments, the light chain variable domain includes a FR LI as set forth in SEQ ID NO:27, a FR L2 as set forth in SEQ ID NO:28, a FR L3 as set forth in SEQ ID NO:29 and a FR L4 as set forth in SEQ ID NO:30.

[0132] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:31. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:31. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO:32. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 32. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:31 and the light chain variable domain includes the sequence of SEQ ID NO:32. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:31 and the light chain variable domain is the sequence of SEQ ID NO:32. In embodiments, the anti-DRiP antibody is referred to herein as DRiPV2-7.

[0133] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:33, a CDR H2 as set forth in SEQ ID NO:34, and a CDR H3 as set forth in SEQ ID NO:35; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:36, a CDR L2 as set forth in SEQ ID NO:37 and a CDR L3 as set forth in SEQ ID NO:38. [0134] In embodiments, the heavy chain variable domain includes a FR Hl as set forth in SEQ ID NO:39, a FR H2 as set forth in SEQ ID NO:40, a FR H3 as set forth in SEQ ID NO:41 and a FR H4 as set forth in SEQ ID NO:42. In embodiments, the light chain variable domain includes a FR LI as set forth in SEQ ID NO:43, a FR L2 as set forth in SEQ ID NO:44, a FR L3 as set forth in SEQ ID NO:45 and a FR L4 as set forth in SEQ ID NO:46.

[0135] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:47. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:47. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO:48. In embodiments, the light chain variable domain is the sequence of SEQ ID NO:48. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:47 and the light chain variable domain includes the sequence of SEQ ID NO:48. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:47 and the light chain variable domain is the sequence of SEQ ID NO:48. In embodiments, the anti-DRiP antibody is referred to herein as DRiPV2-ll.

[0136] In embodiments, the anti-DRiP antibody is a chimeric antibody. In embodiments the anti-DRiP antibody is a Fab’ fragment. In embodiments, the anti-DRiP antibody is an IgG. In embodiments, the heavy chain vanable domain and the light chain variable domain form part of a scFv.

[0137] In embodiments, the antibody binds a DRiP protein. In embodiments, the antibody binds the N-terminus of a DRiP protein. In embodiments, the DRiP protein includes the sequence of SEQ ID NO: 158 or SEQ ID NO: 159. In embodiments, the DRiP protein includes the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes the sequence of SEQ ID NO:159. In embodiments, the DRiP protein is the sequence of SEQ ID NO:158 or SEQ ID NO: 159. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 159. In embodiments, the anti- DRiP antibody binds to amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158 or SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds to amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds to amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds a peptide including the sequence of SEQ ID NO: 162. In embodiments, the anti-DRiP antibody binds a peptide having the sequence of SEQ ID NO: 162. In embodiments, the anti-DRiP antibody binds a peptide including the sequence of SEQ ID NO: 153. In embodiments, the anti-DRiP antibody binds a peptide having the sequence of SEQ ID NO: 153.

[0138] In embodiments, the DRIP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence SEQ ID NO:158. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to the sequence SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to the sequence SEQ ID NO: 158.

[0139] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes a sequence having 100% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 158.

[0140] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence SEQ ID NO:159. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to the sequence SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to the sequence SEQ ID NO: 159. [0141] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein includes a sequence having 100% sequence identity to 5, 10, 15, 20, 25, 30, 35, or 40 contiguous amino acids of the sequence of SEQ ID NO: 159.

[0142] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence SEQ ID NO:162. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to the sequence SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to the sequence SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to the sequence SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to the sequence SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to the sequence SEQ ID NO:162. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to the sequence SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to the sequence SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to the sequence SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to the sequence SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to the sequence SEQ ID NO: 162.

[0143] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to5, 10, 15, or 20 contiguous ammo acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein includes a sequence having 100% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 162.

[0144] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence SEQ ID NO:163. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to the sequence SEQ ID NO: 163.

[0145] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 5, 10, 15, or 20 contiguous ammo acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 100% sequence identity to 5, 10, 15, or 20 contiguous amino acids of the sequence of SEQ ID NO: 163.

[0146] In embodiments, the anti-DRiP antibody binds at least 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO:158. In embodiments, the anti-DRiP antibody binds at least 5 contiguous amino acid residues included in amino acid residues corresponding to positions 1- 20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 10 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 11 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 12 contiguous amino acid residues included in ammo acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 13 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 14 contiguous amino acid residues included in ammo acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 15 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 16 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 17 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 18 contiguous amino acid residues included in ammo acid residues corresponding to positions 1-20 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 19 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158.

[0147] In embodiments, the anti-DRiP antibody binds at least 5, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO:159. In embodiments, the anti-DRiP antibody binds at least 5 contiguous amino acid residues included in amino acid residues corresponding to positions 1- 20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 10 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 11 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 12 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 13 contiguous amino acid residues included in ammo acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 14 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 15 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 16 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 17 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 18 contiguous ammo acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 19 contiguous amino acid residues included in amino acid residues corresponding to positions 1-20 of SEQ ID NO: 159.

[0148] The anti-DRiP antibodies provided herein, including embodiments thereof may bind to the C-terminus of a DRiP protein provided herein including embodiments thereof. [0149] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:49, a CDR H2 as set forth in SEQ ID NO:50, and a CDR H3 as set forth in SEQ ID NO:51; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:52, a CDR L2 as set forth in SEQ ID NO:53 and a CDR L3 as set forth in SEQ ID NO:54.

[0150] In embodiments, the heavy chain variable domain includes a FR H l as set forth in SEQ ID NO:55, a FR H2 as set forth in SEQ ID NO:56, a FR H3 as set forth in SEQ ID NO:57 and a FR H4 as set forth in SEQ ID NO:58. In embodiments, the light chain variable domain includes a FR LI as set forth in SEQ ID NO:59, a FR L2 as set forth in SEQ ID NO:60, a FR L3 as set forth in SEQ ID NO:61 and a FR L4 as set forth in SEQ ID NO:62.

[0151] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:63. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:63. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO:64. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 64. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:63 and the light chain variable domain includes the sequence of SEQ ID NO:64. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:63 and the light chain variable domain is the sequence of SEQ ID NO:64. In embodiments, the anti-DRiP antibody is referred to herein as SPD-2.

[0152] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:65, a CDR H2 as set forth in SEQ ID NO:66, and a CDR H3 as set forth in SEQ ID NO:67; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:68, a CDR L2 as set forth in SEQ ID NO:69 and a CDR L3 as set forth in SEQ ID NO:70.

[0153] In embodiments, the heavy chain variable domain includes a FR Hl as set forth in SEQ ID NO:71, a FR H2 as set forth in SEQ ID NO:72, a FR H3 as set forth in SEQ ID NO:73 and a FR H4 as set forth in SEQ ID NO:74. In embodiments, the light chain variable domain includes a FR LI as set forth in SEQ ID NO:75, a FR L2 as set forth in SEQ ID NO:76, a FR L3 as set forth in SEQ ID NO:77 and a FR L4 as set forth in SEQ ID NO:78.

[0154] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:79. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:79. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO: 80. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 80. In embodiments, the heavy chain vanable domain includes the sequence of SEQ ID NO:79 and the light chain variable domain includes the sequence of SEQ ID NO: 80. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:79 and the light chain variable domain is the sequence of SEQ ID NO: 80. In embodiments, the anti-DRiP antibody is referred to herein as SPD-4.

[0155] In embodiments, the anti-DRiP antibody is a chimeric antibody. In embodiments the anti-DRiP antibody is a Fab’ fragment. In embodiments, the anti-DRiP antibody is an IgG. In embodiments, the heavy chain variable domain and the light chain variable domain form part of a scFv.

[0156] In embodiments, the antibody binds a DRiP protein. In embodiments, the antibody binds the C-terminus of a DRiP protein. In embodiments the DRiP protein includes the sequence of SEQ ID NO: 158 or SEQ ID NO: 159. In embodiments, the DRiP protein includes the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 158 or SEQ ID NO: 159. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 159. In embodiments, the anti- DRiP antibody binds to amino acid residues corresponding to positions 29-43 of SEQ ID NO: 158 or SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds to amino acid residues corresponding to positions 28-43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds to amino acid residues corresponding to positions 29-43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds a peptide including the sequence of SEQ ID NO: 163. In embodiments, the anti-DRiP antibody binds a peptide having the sequence of SEQ ID NO: 163. In embodiments, the anti-DRiP antibody binds a peptide including the sequence of SEQ ID NO: 154 In embodiments, the anti-DRiP antibody binds a peptide having the sequence of SEQ ID NO: 154.

[0157] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence SEQ ID NO:163. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to the sequence SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to the sequence SEQ ID NO: 163.

[0158] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 1 3. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163. In embodiments, the DRiP protein includes a sequence having 100% sequence identity to 5, 10, 11, 12, 13, 14, or 15 contiguous amino acids of the sequence of SEQ ID NO: 163.

[0159] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence SEQ ID NO:154. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to the sequence SEQ ID NO: 154 In embodiments, the DRiP protein includes a sequence having 75% sequence identity to the sequence SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to the sequence SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to the sequence SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to the sequence SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to the sequence SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to the sequence SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to the sequence SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to the sequence SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to the sequence SEQ ID NO: 154. [0160] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154. In embodiments, the DRiP protein includes a sequence having 100% sequence identity to 5, 10, 15, 16, 17, 18, or 19 contiguous amino acids of the sequence of SEQ ID NO: 154.

[0161] In embodiments, the anti-DRiP antibody binds at least 5, 10, 11, 12, 13, 14, 15, or 16 contiguous amino acid residues included in amino acid residues corresponding to positions 28- 43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 5 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 10 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 11 contiguous amino acid residues included in ammo acid residues corresponding to positions 28-43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 12 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 13 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 14 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 15 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 16 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 158.

[0162] In embodiments, the anti-DRiP antibody binds at least 5, 10, 11, 12, 13, 14, 15, or 16 contiguous amino acid residues included in amino acid residues corresponding to positions 28- 43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 5 contiguous ammo acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 10 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 11 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 12 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 13 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 14 contiguous ammo acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 15 contiguous amino acid residues included in amino acid residues corresponding to positions 28-43 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 16 contiguous amino acid residues included in ammo acid residues corresponding to positions 28-43 of SEQ ID NO: 159. [0163] The anti-DRiP antibodies provided herein, including embodiments thereof may bind to the N-terminus of a DRiP protein.

[0164] In another aspect is provided an anti-DRiP antibody including a heavy chain vanable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:81, a CDR H2 as set forth in SEQ ID NO:82, and a CDR H3 as set forth in SEQ ID NO:83; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:84, a CDR L2 as set forth in SEQ ID NO:85 and a CDR L3 as set forth in SEQ ID NO: 86.

[0165] In embodiments, the heavy chain variable domain includes a FR Hl as set forth in SEQ ID NO:87, a FR H2 as set forth in SEQ ID NO:88, a FR H3 as set forth in SEQ ID NO:89 and a FR H4 as set forth in SEQ ID NO:90. In embodiments, the light chain variable domain includes a FR LI as set forth in SEQ ID NO:91, a FR L2 as set forth in SEQ ID NO:92, a FR L3 as set forth in SEQ ID NO:93 and a FR L4 as set forth in SEQ ID NO:94.

[0166] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:95. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:95. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO:96. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 96. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:95 and the light chain variable domain includes the sequence of SEQ ID NO:96. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO:95 and the light chain variable domain is the sequence of SEQ ID NO:96. In embodiments, the anti-DRiP antibody is referred to herein as DRiP2.

[0167] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO:99, a CDR H2 as set forth in SEQ ID NO: 100, and a CDR H3 as set forth in SEQ ID NO: 101; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO:102, a CDR L2 as set forth in SEQ ID NO:103 and a CDR L3 as set forth in SEQ ID NO: 104. [0168] In embodiments, the heavy chain variable domain includes a FR Hl as set forth in SEQ ID NO: 105, a FR H2 as set forth in SEQ ID NO: 106, a FR H3 as set forth in SEQ ID NO: 107 and a FR H4 as set forth in SEQ ID NO: 108. In embodiments, the light chain variable domain includes a FR LI as set forth in SEQ ID NO: 109, a FR L2 as set forth in SEQ ID NO: 110, a FR L3 as set forth in SEQ ID NO: 111 and a FR L4 as set forth in SEQ ID NO: 112.

[0169] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO: 113. In embodiments, the heavv chain variable domain is the sequence of SEQ ID NO: 113. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO: 114. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 114. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO:113 and the light chain variable domain includes the sequence of SEQ ID NO: 114. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 113 and the light chain variable domain is the sequence of SEQ ID NO: 114. In embodiments, the anti- DRiP antibody is referred to herein as DRiP4.

[0170] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR Hl as set forth in SEQ ID NO: 117, a CDR H2 as set forth in SEQ ID NO: 118, and a CDR H3 as set forth in SEQ ID NO: 119; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO: 120, a CDR L2 as set forth in SEQ ID NO: 121 and a CDR L3 as set forth in SEQ ID NO: 122.

[0171] In embodiments, the heavy chain variable domain includes a FR Hl as set forth in SEQ ID NO: 123, a FR H2 as set forth in SEQ ID NO: 124, a FR H3 as set forth in SEQ ID NO: 125 and a FR H4 as set forth in SEQ ID NO: 126. In embodiments, the light chain variable domain includes a FR LI as set forth in SEQ ID NO:27, a FR L2 as set forth in SEQ ID NO: 128, a FR L3 as set forth in SEQ ID NO: 129 and a FR L4 as set forth in SEQ ID NO: 130.

[0172] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO: 131. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 131. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO: 132. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 132. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO: 131 and the light chain variable domain includes the sequence of SEQ ID NO: 132. In embodiments, the heavy chain vanable domain is the sequence of SEQ ID NO: 131 and the light chain variable domain is the sequence of SEQ ID NO: 132. In embodiments, the anti- DRiP antibody is referred to herein as DRiP5.

[0173] In another aspect is provided an anti-DRiP antibody including a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes a CDR HI as set forth in SEQ ID NO: 135, a CDR H2 as set forth in SEQ ID NO: 136, and a CDR H3 as set forth in SEQ ID NO: 137; and wherein the light chain variable domain includes a CDR LI as set forth in SEQ ID NO: 138, a CDR L2 as set forth in SEQ ID NO: 139 and a CDR L3 as set forth in SEQ ID NO: 140.

[0174] In embodiments, the heavy chain variable domain includes a FR Hl as set forth in SEQ ID NO: 141, a FR H2 as set forth in SEQ ID NO: 142, a FR H3 as set forth in SEQ ID NO: 143 and a FR H4 as set forth in SEQ ID NO: 144. In embodiments, light chain variable domain includes a FR LI as set forth in SEQ ID NO: 146, a FR L2 as set forth in SEQ ID NO: 146, a FR L3 as set forth in SEQ ID NO: 147 and a FR L4 as set forth in SEQ ID NO: 148.

[0175] In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO: 149. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 149. In embodiments, the light chain variable domain includes the sequence of SEQ ID NO: 150. In embodiments, the light chain variable domain is the sequence of SEQ ID NO: 150. In embodiments, the heavy chain variable domain includes the sequence of SEQ ID NO: 149 and the light chain variable domain includes the sequence of SEQ ID NO: 150. In embodiments, the heavy chain variable domain is the sequence of SEQ ID NO: 149 and the light chain variable domain is the sequence of SEQ ID NO: 150. In embodiments, the anti- DRiP antibody is referred to herein as DRiP7.

[0176] In embodiments, the anti-DRiP antibody is a chimeric antibody. In embodiments the anti-DRiP antibody is a Fab’ fragment. In embodiments, the anti-DRiP antibody is an IgG. In embodiments, the heavy chain variable domain and the light chain variable domain form part of a scFv. [0177] In embodiments, the antibody binds a DRiP protein. In embodiments, the antibody binds the N-terminus of a DRiP protein. In embodiments the DRiP protein includes the sequence of SEQ ID NO: 158 or SEQ ID NO: 159. In embodiments, the DRiP protein includes the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein includes the sequence of SEQ ID NO: 159. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 158 or SEQ ID NO: 159. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 158. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 159. In embodiments, the anti- DRiP antibody binds to amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158 or SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds to amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds to amino acid residues corresponding to positions 1-13 of SEQ ID NO: 159. In embodiments, the antibody binds a peptide including the sequence of SEQ ID NO: 155 or SEQ ID NO: 165. In embodiments, the anti-DRiP antibody binds a peptide including the sequence of SEQ ID NO: 155. In embodiments, the anti-DRiP antibody binds a peptide including the sequence of SEQ ID NO: 165. In embodiments, the anti-DRiP antibody binds a peptide having the sequence of SEQ ID NO: 155 or SEQ ID NO: 165. In embodiments, the anti-DRiP antibody binds a peptide having the sequence of SEQ ID NO: 155 In embodiments, the anti-DRiP antibody binds a peptide having the sequence of SEQ ID NO: 165.

[0178] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence SEQ ID NO:155. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to the sequence SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to the sequence SEQ ID NO: 155

[0179] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155. In embodiments, the DRiP protein includes a sequence having 100% sequence identity to 5, 10, 15, 16, 17, 18, 19, 20, or 21 contiguous amino acids of the sequence of SEQ ID NO: 155.

[0180] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence SEQ ID NO:163. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to the sequence SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to the sequence SEQ ID NO:165. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to the sequence SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to the sequence SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to the sequence SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to the sequence SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to the sequence SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to the sequence SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to the sequence SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to the sequence SEQ ID NO: 165.

[0181] In embodiments, the DRiP protein includes a sequence having 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 70% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 75% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 80% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 85% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 90% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 95% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 96% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 97% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 98% sequence identity to 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 99% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165. In embodiments, the DRiP protein includes a sequence having 100% sequence identity to 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acids of the sequence of SEQ ID NO: 165.

[0182] In embodiments, the anti-DRiP antibody binds at least 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acid residues included in amino acid residues corresponding to positions 1- 13 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 5 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 6 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 7 contiguous amino acid residues included in ammo acid residues corresponding to positions 1-13 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 8 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 1 8. In embodiments, the anti-DRiP antibody binds at least 9 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 10 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO:158. In embodiments, the anti-DRiP antibody binds at least 11 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158. In embodiments, the anti-DRiP antibody binds at least 12 contiguous amino acid residues included in ammo acid residues corresponding to positions 1-13 of SEQ ID NO:158. In embodiments, the anti-DRiP antibody binds at least 13 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158.

[0183] In embodiments, the anti-DRiP antibody binds at least 5, 6, 7, 8, 9, 10, 11, 12, or 13 contiguous amino acid residues included in amino acid residues corresponding to positions 1- 13 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 5 contiguous ammo acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 6 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 7 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 8 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 9 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 10 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO:159 In embodiments, the anti-DRiP antibody binds at least 11 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 159. In embodiments, the anti-DRiP antibody binds at least 12 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO:159. In embodiments, the anti-DRiP antibody binds at least 13 contiguous amino acid residues included in amino acid residues corresponding to positions 1-13 of SEQ ID NO: 159.

[0184] The ability of an antibody to bind a specific epitope (e.g., DRiP protein) can be described by the equilibrium dissociation constant (KD). The equilibrium dissociation constant (KD) as defined herein is the ratio of the dissociation rate (K-off) and the association rate (IC- on) of an antibody to a DRiP protein. It is described by the following formula: KD = K-off/K- on. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) as shown in Figure 5. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 5.99 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 4.60 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 141 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 6.01 nM. [0185] In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 2-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 3-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 4-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 5- 150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 6-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 7-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 8-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 9-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 10-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 20-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 30-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 40-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 50-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 75-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 100-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 125-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 130-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 135-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 140-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 141-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 142-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 143-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 144-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 145-150 nM. In embodiments, the antibody is capable of binding DRiP w ith an equilibrium dissociation constant (KD) of about 146-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 147-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 148-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 149-150 nM.

[0186] In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-149 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-148 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-147 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-146 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1- 145 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-144 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-143 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-142 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-141 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1- 140 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-135 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-130 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-125 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-100 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1- 75 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-50 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-40 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-30 nM. hi embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-20 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1- 10 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-9 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-8 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1 -7 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-6 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-5 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-4 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-3 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1-2 nM.

[0187] In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 5.99 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 4.60 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 141 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 6.01 nM.

[0188] In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 2-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 3-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 4-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 5-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 6-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 7-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 8-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 9-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 10-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 20-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 30-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 40-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 50-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 75-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 100-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 125-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 130-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 135-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 140-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 141-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 142-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 143-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 144-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 145-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 146-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 147-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 148-150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 149-150 nM.

[0189] In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-149 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-148 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-147 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-146 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-145 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-144 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-143 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-142 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-141 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-140 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-135 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-130 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-125 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-100 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-75 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-50 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-40 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-30 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-20 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-10 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-9 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1 -8 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-7 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-6 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-5 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1 -4 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-3 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1-2 nM.

[0190] In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 140 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 135 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 130 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 125 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 100 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 75 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 50 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 40 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 30 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 20 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 10 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 9 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 8 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 7 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 6 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 5 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 4 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 3 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 2 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of about 1 nM.

[0191] In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 150 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 140 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 135 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 130 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 125 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 100 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 75 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 50 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 40 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 30 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 20 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 10 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 9 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 8 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 7 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 6 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 5 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 4 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 3 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 2 nM. In embodiments, the antibody is capable of binding DRiP with an equilibrium dissociation constant (KD) of 1 nM.

[0192] In embodiments, the DRiP protein forms part of a cell. In embodiments, the DRiP protein is expressed on the surface of a cell. In embodiments, the cell is a pancreatic cell. In embodiments, the pancreatic cell is a beta cell. In embodiments, the anti-DRiP antibody is attached to a diagnostic moiety.

[0193] A "variable light chain (VL) domain" as provided herein refers to the variable region of the light chain of an antibody, an antibody variant or fragment thereof. Likewise, the "variable heavy chain (VH) domain" as provided herein refers to the variable region of the heavy chain of an antibody, an antibody variant or fragment thereof. As described above, the variable light chain domain and the variable heavy chain domain together form the paratope, which binds an antigen (epitope). The paratope or antigen-binding site is formed at the N- terminus of an antibody, an antibody variant or fragment thereof. In embodiments, the variable light chain (VL) domain includes CDR LI, CDR L2, CDR L3 and FR LI, FR L2, FR L3 and FR L4 (framework regions) of an antibody light chain. In embodiments, the variable heavy chain (VH) domain includes CDR Hl, CDR H2, CDR H3 and FR Hl, FR H2, FR H3 and FR H4 (framework regions) of an antibody heavy chain.

[0194] The terms "CDR LI", "CDR L2" and "CDR L3" as provided herein refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable light (L) chain of an antibody or fragment thereof. In embodiments, the variable light chain includes in N-termmal to C-terminal direction a CDR LI, a CDR L2 and a CDR L3. Likewise, the terms "CDR Hl", "CDR H2" and "CDR H3" as provided herein refer to the complementarity determining regions (CDR) 1, 2, and 3 of the variable heavy (H) chain of an antibody or fragment thereof. In embodiments, the variable heavy chain includes in N-terminal to C-terminal direction a CDR Hl , a CDR H2 and a CDR H3

[0195] "Framework regions" (FRs) are variable region residues other than the CDR residues. The FRs of VH are also referred to herein as FR Hl, FR H2, FR H3 and FR H4, respectively, wherein FR Hl corresponds to FR 1 of VH, FR H2 corresponds to FR 2 of VH, FR H3 corresponds to FR 3 of VH and FR H4 corresponds to FR 4 of VH. Likewise, the FRs of VL are referred to herein as FR LI, FR L2, FR L3 and FR L4, respectively, wherein FR LI corresponds to FR 1 of VL, FR L2 corresponds to FR 2 of VL, FR L3 corresponds to FR 3 of VL and FR L4 corresponds to FR 4 of VL.

[0196] In embodiments, the variable light chain (VL) domain and a constant light chain (CL) domain form part of an antibody light chain. In embodiments, the variable heavy chain (VH) domain and a constant heavy chain (CHI) domain form part of an antibody heavy chain. In embodiments, the variable heavy' chain (VH) domain and one or more constant heavy chain (CHI, CH2, or CH3) domains form part of an antibody heavy chain. In embodiments, the variable light chain (VL) domain forms part of an antibody fragment. In embodiments, the variable heavy chain (VH) domain forms part of an antibody fragment. In embodiments, the variable light chain (VL) domain forms part of an antibody variant. In embodiments, the variable heavy chain (VH) domain forms part of an antibody variant. In embodiments, the variable light chain (VL) domain forms part of a Fab. In embodiments, the variable heavy chain (VH) domain forms part of a Fab. In embodiments, the variable light chain (VL) domain forms part of a scFv. In embodiments, the variable heavy chain (VH) domain forms part of an scFv.

ANTIBODY COMPLEXES

[0197] The anti-DRiP antibodies provided herein including embodiments thereof may bind to the N-terminus or the C-terminus of a DRiP protein provided herein including embodiments thereof thereby forming a non-covalent complex. Formation of a complex between the anti- DRiP antibody and the DRiP protein may be detected using methods and reagents well known in the biological and chemical arts for protein detection. Any of the antibodies and DRiP proteins provided herein are envisioned to form such non-covalent detectable complexes.

Thus, in another aspect is provided a complex including an anti-DRiP antibody as provided herein including embodiments thereof, wherein the antibody is non-covalently bound to the N- terminus of a DRiP protein. In embodiments, the DRiP protein includes the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 162. In embodiments, the complex is attached to a solid support. In embodiments the complex is a detection device. [0198] In another aspect is provided a complex including an anti-DRiP antibody as provided herein including embodiments thereof, wherein the antibody is non-covalently bound to the C- terminus of a DRiP protein. Tn embodiments, the DRiP protein includes the sequence of SEQ ID NO: 164. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 164. In embodiments, the complex further includes an antibody as provided herein including embodiments thereof non-covalently attached to the N-terminus of the DRiP protein. In embodiments, the complex is attached to a solid support. In embodiments, the complex is in a detection device.

[0199] In another aspect is provided a complex including an anti-DRiP antibody as provided herein including embodiments thereof, wherein the antibody is non-covalently bound to the N- terminus of a DRiP protein. In embodiments, the DRiP protein includes the sequence of SEQ ID NO: 162. In embodiments, the DRiP protein is the sequence of SEQ ID NO: 162. In embodiments, the complex is attached to a solid support. In embodiments, the complex is in a detection device.

[0200] In another aspect is provided a complex including a first anti-DRiP antibody non- covalently bound to the C-terminus of a DRiP protein and a second anti-DRiP antibody non- covalently bound to the N-terminus of the DRiP protein, wherein the first anti-DRiP antibody is an antibody as provided herein including embodiments thereof and wherein the second anti- DRiP antibody is an antibody as provided herein including embodiments thereof. In embodiments, the first anti-DRiP antibody is attached to a solid support. In embodiments, the second anti-DRiP antibody is attached to a detectable moiety. In embodiments, the detectable moiety is bovine serum albumin (BSA) or Horseradish peroxidase (HRP). In embodiments, the detectable moiety is a bovine serum albumin (BSA) protein. In embodiments, the detectable moiety is horseradish peroxidase (HRP). In embodiments, the complex is in a detection device.

[0201] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 15 and a light chain variable domain sequence of SEQ ID NO: 16, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 158. [0202] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 15 and a light chain variable domain sequence of SEQ ID NO: 16, wherein the antibody is non -covalently bound to a DRiP protein of SEQ ID NO: 159.

[0203] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 15 and a light chain variable domain sequence of SEQ ID NO: 16, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 162.

[0204] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 15 and a light chain variable domain sequence of SEQ ID NO: 16, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 153.

[0205] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 15 and a light chain variable domain sequence of SEQ ID NO: 16, wherein the antibody is non-covalently bound to amino acid residues 1-20 of a DRiP protein of SEQ ID NO: 158.

[0206] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain vanable domain sequence of SEQ ID NO: 15 and a light chain variable domain sequence of SEQ ID NO: 16, wherein the antibody is non-covalently bound to amino acid residues 1-20 of a DRiP protein of SEQ ID NO: 159.

[0207] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:31 and a light chain variable domain sequence of SEQ ID NO:32, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 158.

[0208] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:31 and a light chain variable domain sequence of SEQ ID NO: 32, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 159. [0209] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:3I and a light chain variable domain sequence of SEQ ID NO:32, wherein the antibody is non -covalently bound to a DRiP protein of SEQ ID NO: 162.

[0210] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:31 and a light chain variable domain sequence of SEQ ID NO: 32, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 153.

[0211] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:31 and a light chain variable domain sequence of SEQ ID NO: 32, wherein the antibody is non-covalently bound to amino acid residues 1-20 of a DRiP protein of SEQ ID NO: 158.

[0212] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:31 and a light chain variable domain sequence of SEQ ID NO: 32, wherein the antibody is non-covalently bound to amino acid residues 1-20 of a DRiP protein of SEQ ID NO: 159.

[0213] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain vanable domain sequence of SEQ ID NO:47 and a light chain variable domain sequence of SEQ ID NO:48, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 158.

[0214] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:47 and a light chain variable domain sequence of SEQ ID NO:48, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 159.

[0215] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:47 and a light chain variable domain sequence of SEQ ID NO:48, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 162. [0216] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:47 and a light chain variable domain sequence of SEQ ID NO:48, wherein the antibody is non -covalently bound to a DRiP protein of SEQ ID NO: 153.

[0217] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:47 and a light chain variable domain sequence of SEQ ID NO:48, wherein the antibody is non-covalently bound to amino acid residues 1-20 of a DRiP protein of SEQ ID NO: 158.

[0218] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:47 and a light chain variable domain sequence of SEQ ID NO:48, wherein the antibody is non-covalently bound to amino acid residues 1-20 of a DRiP protein of SEQ ID NO: 159.

[0219] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:63 and a light chain variable domain sequence of SEQ ID NO: 64, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 158.

[0220] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain vanable domain sequence of SEQ ID NO:63 and a light chain variable domain sequence of SEQ ID NO: 64, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 159.

[0221] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:63 and a light chain variable domain sequence of SEQ ID NO:64, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 163.

[0222] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:63 and a light chain variable domain sequence of SEQ ID NO: 64, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 154. [0223] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:63 and a light chain variable domain sequence of SEQ ID NO:64, wherein the antibody is non -covalently bound to amino acid residues 28-43 of a DRiP protein of SEQ ID NO: 158.

[0224] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:63 and a light chain variable domain sequence of SEQ ID NO: 64, wherein the antibody is non-covalently bound to amino acid residues 28-43 of a DRiP protein of SEQ ID NO: 159.

[0225] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:79 and a light chain variable domain sequence of SEQ ID NO: 80, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 158.

[0226] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:79 and a light chain variable domain sequence of SEQ ID NO: 80, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 159.

[0227] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain vanable domain sequence of SEQ ID NO:79 and a light chain variable domain sequence of SEQ ID NO: 80, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 163.

[0228] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:79 and a light chain variable domain sequence of SEQ ID NO: 80, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 154.

[0229] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:79 and a light chain variable domain sequence of SEQ ID NO: 80, wherein the antibody is non-covalently bound to amino acid residues 28-43 of a DRiP protein of SEQ ID NO: 158. [0230] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:79 and a light chain variable domain sequence of SEQ ID NO: 80, wherein the antibody is non -covalently bound to amino acid residues 28-43 of a DRiP protein of SEQ ID NO: 159.

[0231] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:95 and a light chain variable domain sequence of SEQ ID NO: 96, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 158.

[0232] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:95 and a light chain variable domain sequence of SEQ ID NO: 96, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 159.

[0233] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:95 and a light chain variable domain sequence of SEQ ID NO: 96, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 165.

[0234] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain vanable domain sequence of SEQ ID NO:95 and a light chain variable domain sequence of SEQ ID NO: 96, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 155.

[0235] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO:95 and a light chain variable domain sequence of SEQ ID NO:96, wherein the antibody is non-covalently bound to ammo acid residues 1-13 of a DRiP protein of SEQ ID NO: 158.

[0236] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 95 and a light chain variable domain sequence of SEQ ID NO:96, wherein the antibody is non-covalently bound to amino acid residues 1-13 of a DRiP protein of SEQ ID NO: 159. [0237] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 113 and a light chain vanable domain sequence of SEQ ID NO:1 14, wherein the antibody is non -covalently bound to a DRiP protein of SEQ ID NO: 158.

[0238] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 113 and a light chain variable domain sequence of SEQ ID NO: 114, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 159.

[0239] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 113 and a light chain variable domain sequence of SEQ ID NO: 114, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 165.

[0240] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 113 and a light chain variable domain sequence of SEQ ID NO: 114, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 155.

[0241] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain vanable domain sequence of SEQ ID NO: 113 and a light chain vanable domain sequence of SEQ ID NO: 114, wherein the antibody is non-covalently bound to amino acid residues 1-13 of a DRiP protein of SEQ ID NO:158.

[0242] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 113 and a light chain variable domain sequence of SEQ ID NO: 114, wherein the antibody is non-covalently bound to ammo acid residues 1-13 of a DRiP protein of SEQ ID NO:159.

[0243] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 131 and a light chain variable domain sequence of SEQ ID NO: 132, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 158. [0244] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 131 and a light chain vanable domain sequence of SEQ ID NO: 132, wherein the antibody is non -covalently bound to a DRiP protein of SEQ ID NO: 159.

[0245] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 131 and a light chain variable domain sequence of SEQ ID NO: 132, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 165.

[0246] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 131 and a light chain variable domain sequence of SEQ ID NO: 132, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 155.

[0247] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 131 and a light chain variable domain sequence of SEQ ID NO: 132, wherein the antibody is non-covalently bound to amino acid residues 1-13 of a DRiP protein of SEQ ID NO:158.

[0248] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain vanable domain sequence of SEQ ID NO: 131 and a light chain vanable domain sequence of SEQ ID NO: 132, wherein the antibody is non-covalently bound to amino acid residues 1-13 of a DRiP protein of SEQ ID NO:159.

[0249] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 149 and a light chain variable domain sequence of SEQ ID NO: 150, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 158.

[0250] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 149 and a light chain variable domain sequence of SEQ ID NO: 150, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 159. [0251] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 149 and a light chain vanable domain sequence of SEQ ID NO: 150, wherein the antibody is non -covalently bound to a DRiP protein of SEQ ID NO: 165.

[0252] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 149 and a light chain variable domain sequence of SEQ ID NO: 150, wherein the antibody is non-covalently bound to a DRiP protein of SEQ ID NO: 155.

[0253] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 149 and a light chain variable domain sequence of SEQ ID NO: 150, wherein the antibody is non-covalently bound to amino acid residues 1-13 of a DRiP protein of SEQ ID NO:158.

[0254] In one embodiment, the complex includes an anti-DRiP antibody having a heavy chain variable domain sequence of SEQ ID NO: 149 and a light chain variable domain sequence of SEQ ID NO: 150, wherein the antibody is non-covalently bound to amino acid residues 1-13 of a DRiP protein of SEQ ID NO:159.

NUCLEIC ACID COMPOSITIONS

[0255] The compositions provided herein include nucleic acid molecules encoding the anti- DRiP antibodies or portions thereof provided herein including embodiments thereof. The antibodies encoded by the isolated nucleic acid provided herein are described in detail throughout this application (including the description above and in the examples section). Thus, in an aspect is provided an isolated nucleic acid encoding an anti-DRiP antibody as provided herein including embodiments thereof.

CELL COMPOSITIONS

[0256] The compositions provided herein include cells that express the anti-DRiP antibodies or poritons thereof provided herein including embodiments thereof, or a nucleic acid as provided herein including embodiments thereof. The antibodies and nucleic acids expressed by the cells provided herein are described in detail throughout this application (including the description above and in the examples section). Thus, in an aspect is provided a cell including an anti-DRiP antibody as provided herein including embodiments thereof, or a nucleic acid as provided herein including embodiments thereof.

METHODS

[0257] The DRiP proteins provided herein including embodiments thereof may be used for immunization purposes to form specific anti DRiP antibodies. Any of the DRiP proteins provided herein including embodiments thereof may be used for the methods of forming antibodies capable of binding to the N-terminus or C-terminus of a DriP protein provided herein. In an aspect is provided a method of forming an antibody capable of binding to a DRiP protein, the method including immunizing a mammal with a peptide including the sequence of SEQ ID NO:153, SEQ ID NO:154, SEQ ID NOT55, SEQ ID NO: 162, SEQ ID NO: 163, or SEQ ID NO: 165. In embodiments, the peptide further includes an adjuvant moiety covalently attached to the N-terminus or C-terminus of the peptide. In embodiments, the peptide further includes an adjuvant moiety covalently attached to the N-terminus of the peptide. In embodiments, the peptide further includes an adjuvant moiety covalently attached to the C- terminus of the peptide.

[0258] In another aspect is provided a method of forming an antibody capable of binding to the N-termmus of a DRiP protein, the method including immunizing a mammal with a peptide including the sequence of SEQ ID NO: 153. In embodiments, the peptide is the sequence of SEQ ID NO: 153. In embodiments, the peptide includes the sequence of SEQ ID NO: 153 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide includes the sequence of SEQ ID NO: 153 and an adjuvant conjugated to the C-termmus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 153 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 153 and an adjuvant conjugated to the C-terminus of the peptide. Any of the DRiP proteins provided herein including embodiments thereof may be used for the methods of forming antibodies capable of binding to the N-terminus or C-terminus of a DriP protein provided herein.

[0259] In another aspect is provided a method of forming an antibody capable of binding to the C-terminus of a DRiP protein, the method including immunizing a mammal with a peptide including the sequence of SEQ ID NO: 154. In embodiments, the peptide is the sequence of SEQ ID NO: 154. In embodiments, the peptide includes the sequence of SEQ ID NO: 154 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide includes the sequence of SEQ ID NO: 154 and an adjuvant conjugated to the C-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 154 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 154 and an adjuvant conjugated to the C-terminus of the peptide.

[0260] In another aspect is provided a method of forming an antibody capable of binding to the N-terminus of a DRiP protein, the method including immunizing a mammal with a peptide including the sequence of SEQ ID NO: 155. In embodiments, the peptide is the sequence of SEQ ID NO: 155. In embodiments, the peptide includes the sequence of SEQ ID NO: 155 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide includes the sequence of SEQ ID NO: 155 and an adjuvant conjugated to the C-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 155 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 155 and an adjuvant conjugated to the C-terminus of the peptide.

[0261] In another aspect is provided a method of forming an antibody capable of binding to the N-termmus of a DRiP protein, the method including immunizing a mammal with a peptide including the sequence of SEQ ID NO: 162. In embodiments, the peptide is the sequence of SEQ ID NO: 162. In embodiments, the peptide includes the sequence of SEQ ID NO: 162 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide includes the sequence of SEQ ID NO: 162 and an adjuvant conjugated to the C-termmus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 162 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 162 and an adjuvant conjugated to the C-terminus of the peptide.

[0262] In another aspect is provided a method of forming an antibody capable of binding to the C-terminus of a DRiP protein, the method including immunizing a mammal with a peptide including the sequence of SEQ ID NO: 163. In embodiments, the peptide is the sequence of SEQ ID NO: 163. In embodiments, the peptide includes the sequence of SEQ ID NO: 163 and an adjuvant conjugated to the N-tenninus of the peptide. In embodiments, the peptide includes the sequence of SEQ ID NO: 163 and an adjuvant conjugated to the C-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 163 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 163 and an adjuvant conjugated to the C-terminus of the peptide.

[0263] In another aspect is provided a method of forming an antibody capable of binding to the N-terminus of a DRiP protein, the method including immunizing a mammal with a peptide including the sequence of SEQ ID NO: 165. In embodiments, the peptide is the sequence of SEQ ID NO: 165. In embodiments, the peptide includes the sequence of SEQ ID NO: 165 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide includes the sequence of SEQ ID NO: 165 and an adjuvant conjugated to the C-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 165 and an adjuvant conjugated to the N-terminus of the peptide. In embodiments, the peptide has the sequence of SEQ ID NO: 165 and an adjuvant conjugated to the C-terminus of the peptide.

[0264] In another aspect is provided a method of detecting a DRiP-expressing cell, the method including (i) contacting a DRiP-expressing cell with an antibody as provided herein including embodiments thereof; (ii) and detecting binding of the antibody to a DRiP protein expressed by the cell. Any method known in the biological and chemical arts useful for protein detection may be used to the methods of detecting a DRiP-expressing cell (e.g., ELISA, sandwich ELISA, immunohistochemistry, protein immuniprecipation).

[0265] In embodiments, the antibody is attached to a detectable moiety. In embodiments, the detectable moiety is bovine serum albumin (BSA) or Horseradish peroxidase (HRP). In embodiments, the detectable moiety is a bovine serum albumin (BSA) protein. In embodiments, the detectable moiety is horseradish peroxidase (HRP). In embodiments, the DRiP-expressing cell is in a biological sample. In embodiments, the the biological sample is whole blood, blood fractions or products, tissue, cultured cells, or pancreatic cells. In embodiments, the biological sample is whole blood. In embodiments, the biological sample is blood fractions or products. In embodiments, the biological sample is blood fractions. In embodiments, the biological sample is blood products. In embodiments, the biological sample is tissue. In embodiments, the biological sample is cultured cells. In embodiments, the biological sample is pancreatic cells. [0266] In another aspect is provided a method of detecting a DRiP-expressing cell in a human subject having or being at risk of developing diabetes, the method including: (i) obtaining a biological sample from a human subject having or being at risk of developing diabetes; (ii) contacting the biological sample with an anti-DRiP antibody as provided herein including embodiments thereof; and (ii) detecting binding of the antibody to a DRiP protein in the sample, thereby detecting a DRiP-expressing cell in the subject.

[0267] In embodiments, the method further includes after the detecting of step (ii) administering to the subject an effective amount of a diabetes treatment. In embodiments, diabetes is type I diabetes and the DRiP protein includes the sequence of SEQ ID NO: 158. In embodiments, diabetes is type 1 diabetes and the DRiP protein is the sequence of SEQ ID NO: 158. In embodiments, diabetes is type I diabetes and the DRiP protein includes the sequence of SEQ ID NO: 159. In embodiments, diabetes is type 1 diabetes and the DRiP protein is the sequence of SEQ ID NO: 159.

[0268] In another aspect is provided a method of diagnosing and treating diabetes in a human subject in need thereof, the method including: (i) obtaining a biological sample from a human subject; (ii) detecting whether a DRiP protein is present in the sample by contacting the sample with an antibody as provided herein including embodiments thereof; (iii) diagnosing the human subject with diabetes when a detectable complex is formed by the DRiP protein and the antibody; and (iv) administering to the diagnosed human subject an effective amount of a diabetes treatment.

[0269] Any diabetes treatments known in the art are contemplated for the methods provided herein. Non limiting exmaples of diabetes treatements include a biguanide, a thiazolidinedione, a sulfonylurea, an amylin analogue, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, a glucagon-like peptide-1 (GLP-1) receptor agonist, a dipeptidyl peptidase- 4 (DPP-4) inhibitor, leptin, donislecel (Lantidra), teplizumab (Tzield), otelixizumab, or rituximab (Rituxan). Thus, in embodiments, the diabetes treatment includes a biguanide, a thiazolidinedione, a sulfonylurea, an amylin analogue, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, a glucagon-like peptide-1 (GLP-1) receptor agonist, a dipeptidyl peptidase- 4 (DPP-4) inhibitor, leptin, donislecel (Lantidra), teplizumab (Tzield), otelixizumab, or rituximab (Rituxan). [0270] In embodiments, the diabetes treatment includes a biguanide. In embodiments, the biguanide is metformin (Glucophage).

[0271] In embodiments, the diabetes treatment includes a thiazohdinedione. In embodiments, the thiazohdinedione is pioglitazone (Actos), rosiglitazone (Avandia), lobeglitazone (Duvie). In embodiments, the thiazohdinedione is pioglitazone (Actos). In embodiments, the thiazohdinedione is rosiglitazone (Avandia). In embodiments, the thiazohdinedione is lobeglitazone (Duvie).

[0272] In embodiments, the diabetes treatment is a sulfonylurea. In embodiments, the sulfonylurea is acetohexamide (Dymelor), carbutamide (Glucidoral), chlorpropamide, glycyclamide, metahexamide, tolazamide, tolbutamide, glibenclamide, glibomuride (Glutril), gliclazide (Diamicron), glipizide (Glucotrol), gliquidone (Glurenorm), glisoxepide, glyclopyramide (Deamelin-S), or glimepiride. In embodiments, the sulfonylurea is acetohexamide (Dymelor). In embodiments, the sulfonylurea is carbutamide (Glucidoral). In embodiments, the sulfonylurea is chlorpropamide. In embodiments, the sulfonylurea is glycyclamide. In embodiments, the sulfonylurea is metahexamide. In embodiments, the sulfonylurea is tolazamide. In embodiments, the sulfonylurea is tolbutamide. In embodiments, the sulfonylurea is glibenclamide. In embodiments, the sulfonylurea is glibomuride (Glutril), gliclazide (Diamicron). In embodiments, the sulfonylurea is glipizide (Glucotrol). In embodiments, the sulfonylurea is gliquidone (Glurenorm). In embodiments, the sulfonylurea is glisoxepide. In embodiments, the sulfonylurea is glyclopyramide (Deamelin-S). In embodiments, the sulfonylurea is glimepiride.

[0273] In embodiments, the diabetes treatment includes an amylin analogue. In embodiments, the amylin analogue is pramlintide.

[0274] In embodiments, the diabetes treatment includes a sodium-glucose co-transporter 2 (SGLT2) inhibitor. In embodiments, the SGLT2 inhibitor is bexagliflozin (Brenzavvy), canagliflozin (Invokana), dapagliflozin (Farxiga or Forxiga), empagliflozin (Jardiance), ertughflozin (Steglatro), ipraghflozin (Suglat), luseoghflozin (Lusefi), remoghflozm etabonate, sergliflozin etabonate, sotagliflozin (Inpefa or Zynquista), or tofogliflozin. In embodiments, the SGLT2 inhibitor is bexagliflozin (Brenzavvy). In embodiments, the SGLT2 inhibitor is canagliflozin (Invokana). In embodiments, the SGLT2 inhibitor is dapagliflozin (Farxiga or Forxiga). In embodiments, the SGLT2 inhibitor is empagliflozin (Jardiance). In embodiments, the SGLT2 inhibitor is ertughflozin (Steglatro). In embodiments, the SGLT2 inhibitor is ipragliflozin (Suglat). In embodiments, the SGLT2 inhibitor is luseogliflozin (Lusefi). In embodiments, the SGLT2 inhibitor is remogliflozin etabonate. In embodiments, the SGLT2 inhibitor is sergliflozin etabonate. In embodiments, the SGLT2 inhibitor is sotagliflozin (Inpefa or Zynquista). In embodiments, the SGLT2 inhibitor is tofogliflozin.

[0275] In embodiments, the diabetes treatment includes a glucagon-like peptide-I (GLP-1) receptor agonist. In embodiments, the GLP-1 receptor agonist is exenatide (Byetta or Bydureon), liraglutide (Victoza or Saxenda), albiglutide (Eperzan or Tanzeum), dulaglutide (Trulicity), lixisenatide (Lyxumia or Adlyxin), semaglutide (Ozempic, Wegovy. or Rybelsus), or tirzepatide (Mounjaro). In embodiments, the GLP-1 receptor agonist is exenatide (Byetta or Bydureon). In embodiments, the GLP-1 receptor agonist is liraglutide (Victoza or Saxenda). In embodiments, the GLP-1 receptor agonist is albiglutide (Eperzan or Tanzeum). In embodiments, the GLP-1 receptor agonist is dulaglutide (Trulicity). In embodiments, the GLP-1 receptor agonist is lixisenatide (Lyxumia or Adlyxin). In embodiments, the GLP-1 receptor agonist is semaglutide (Ozempic, Wegovy, or Rybelsus). In embodiments, the GLP-1 receptor agonist is tirzepatide (Mounjaro).

[0276] In embodiments, the diabetes treatment includes a dipeptidyl peptidase-4 (DPP -4) inhibitor. In embodiments, the DPP-4 inhibitor is sitagliptin (Januvia), vildagliptin (Galvus), saxagliptin (Onglyza), linagliptin (Tradjenta), gemigliptin (Zemiglo), anagliptin (Suiny), teneligliptin (Tenelia), alogliptin (Nesma or Vipidia), trelagliptin (Zafatek), omarigliptm, evogliptin (Suganon or Evodine), gosogliptin (Saterex), dutogliptin, or berberine In embodiments, the DPP-4 inhibitor is sitagliptin (Januvia). In embodiments, the DPP -4 inhibitor is vildagliptin (Galvus). In embodiments, the DPP-4 inhibitor is saxagliptin (Onglyza). In embodiments, the DPP-4 inhibitor is linagliptin (Tradjenta). In embodiments, the DPP-4 inhibitor is gemigliptin (Zemiglo). In embodiments, the DPP-4 inhibitor is anagliptin (Suiny). In embodiments, the DPP-4 inhibitor is teneligliptin (Tenelia). In embodiments, the DPP-4 inhibitor is alogliptin (Nesina or Vipidia). In embodiments, the DPP- 4 inhibitor is trelagliptin (Zafatek). In embodiments, the DPP-4 inhibitor is omarigliptin. In embodiments, the DPP-4 inhibitor is evogliptin (Suganon or Evodine). In embodiments, the DPP -4 inhibitor is gosogliptin (Saterex). In embodiments, the DPP-4 inhibitor is dutogliptin. In embodiments, the DPP-4 inhibitor is berberine.

[0277] In embodiments, the diabetes treatment is leptin. In embodiments, the diabetes treatment is otelixizumab. In embodiments, the diabetes treatment is rituximab (Rituxan). In embodiments, the diabetes treatment includes donislecel (Lantidra). In embodiments, the diabetes treatment includes teplizumab (Tzield).

[0278] In embodiments, diabetes is type I diabetes and the DRiP protein includes the sequence of SEQ ID NO: 158. In embodiments, diabetes is type 1 diabetes and the DRiP protein is the sequence of SEQ ID NO: 158. In embodiments, diabetes is type I diabetes and the DRiP protein includes the sequence of SEQ ID NO: 159. In embodiments, diabetes is type 1 diabetes and the DRiP protein is the sequence of SEQ ID NO: 159.

[0279] For the methods provided herein (e.g., methods of immunizing, methods of diagnosing, method of detection) including embodiments thereof any of the DRiP proteins and peptides provided herein amy be used.

EXAMPLES

[0280] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Example 1: DRiP peptide immunization and Serum ELISA

[0281] DRiPi.20 peptide (SEQ ID NO: 155) was synthesized and conjugated to bovine semm albumin via thiol-coupling approach with the added C -terminal cysteine residue by the manufacture (Genscript). Peptide conjugates were dissolved in sterile PBS at 10 mg/mL and used for mouse immunization. All animal experiments were conducted under the approval of Institutional Animal Care and Use Committee of City of Hope (IUCAC #19070). To immunize mice, 100 mg of peptide conjugates emulsified with complete Freund’s adjuvants (Sigma Aldrich) were subcutaneously injected into each Balb/c mouse (The Jackson Laboratory). Three weeks later, mice received three subcutaneous injections with 100 mg of peptide conjugates emulsified with incomplete Freund’s adjuvants (Sigma Aldrich) in a two-week interval. Three days before spleen harvests for plasma cell isolation, 10 mg of peptide conjugates were injected via tail veins.

[0282] Mouse sera were prepared by sampling blood from cheeks and spinning blood down at 15,000 x g for 20 minutes at 4 °C. Sera were diluted in PBS containing 1% BSA for ELISA. Fifty microliter of synthetic DRiPi-9 peptide (SEQ ID NO: 156) diluted in carbonate/bicarbonate buffer, pH 9.6 at 10 mg/mL were added into micro-wells and incubated at 4 °C overnight. Wells were washed with PBS containing 0.1% Tween 20 (PBST) three times and blocked with 200 mL of PBS containing 1% BSA. After incubation at room temperature for 1 h and wash with PBST three times, 50 mL of diluted sera were added into wells and incubated at room temperature for 1 hr. After wash, 50 mL of 1: 10,000 diluted goat anti-mouse IgG.Fc-HRP (Jackson ImmunoResearch) were added into wells and incubated at room temperature for 1 hr. After wash six times, 50 mL L of TMB substrates (Thermo Fisher Scientific) were added into wells for color development. The reactions were stopped by adding 50 mL L of IN HC1. Wells were read at optical density 450 nm with a Synergy 4 microplate reader (Biotek). All ten mice showed significant antibodies responses against synthetic DRiPi-9 peptide (SEQ ID NO: 156; FIG. 1).

Example 2: Analysis of DRiP peptide structure

[0283] Crystal screens were set up and conditions were identified that produced crystals. The conditions were optimized and Fab/peptide crystals suitable for diffraction studies were grown. A full diffraction data was collected, the data was reduced, and the structure was determined by molecular replacement (using the fab of 4ioi). Several rounds of modeling and refinement were conducted. Unmodelled electron density consistent with the DRiP peptide was clear and the peptide was subsequently modeled (FIG. 8).

[0284] The structure (FIG. 8) shows the N-terminus of the peptide is buried between the light and heavy chains. The methionine side chain of the DRiP peptide docks into a cavity lined with the side chains of Tyr39, Ala 84, Phel03 of the light chain and Trp47 of the heavv chain. Tyr3 of the Drip peptide is also buried in the hydrophobic cavity backing a hydrogen bind to the nitrogen of the indole ring of Tr 47. The phenyl ring of the Tyr3 of the DRiP peptide also makes contact with the methionine. The side chains from several residues from the Fab including Glu35, Thr99 and Asp 104 of the heavy chain and Tyr41 of the light chain participate in a hydrogen bond network that coordinates the amide nitrogen of Gly 2 in the DRiP peptide. Other favorable interactions between the peptide and the Fab include the ‘pi stacking’ of His6 in the DRiP peptide and Tyr37 of the light chain and Leu 7 of the DRiP peptide and Leu99 of the Fab light chain.

[0285] While the biophysics and crystal structure clearly show the initial mAbs specifically bind to the DRiP peptide, the anti-DRiP mAbs failed to stain diseased beta cells. We hypothesize that this could reflect posttranslational modification. Specifically, we hypothesize the methionine is clipped off or oxidized in the cellular samples. Either would effectively vitiate binding.

[0286] Based on this hypothesis, we sought a different immunization strategy to avoid burying the N-termmal methionine. Rather than conjugation to the C-termmus of the peptide to attach the adjuvant, we conjugated the adjuvant to the N-terminus. Mice were subsequently immunized, titered and B-cells were isolated. Individual B-cells were screened using the BL and several hits were identified. The mAbs were made and characterized. Example 3: Immunohistochemistry experiments

[0287] We generated a fully murine version of DRiPV-7 in order to use an anti-murine secondary antibody for detection in immunohistochemistry experiments. The murine DRiPV-7 had a heavy chain with the sequence of SEQ ID NO: 194 and a light chain with the sequence of SEQ ID NO: 195.

[0288] As demonstrated in FIG. 14, pancreatic tissue was stained with: Mouse monoclonal anti DRiP v2#7 (white; 20 pg/m, 1:50 dilution); Somatostatin (top and middle panel) or Glucagon (bottom panel) (blue); Insulin (red); and Hoechst (green). DRiP staining is detected in the islet, not in exocrine tissue (top panel). Blocking the mouse monoclonal anti DRiP v2#7 with the immunization peptide results is no or non-specific staining (middle and bottom panel), indicating good antibody specificity. Top panel is not blocked with immunization peptide. Islet is indicated by hormone staining.

[0289] FIG. 15 shows pancreatic tissue stained with: Mouse monoclonal anti DRiP v2#7 (white; 20 pg/m, 1 :50 dilution); Somatostatin (blue); Insulin (red); and Hoechst (green). Overlap of DRiP and insulin staining shows that DRiP is detected in beta cells; and DRiP staining outside insulin area shows that some DRiP is detected in non-beta cells (top panel). Staining of DRiP and somatostatin do not overlap showing that DRiP is not expressed in delta cells. Image is zoomed in to show detailed single beta and delta cells

[0290] FIG. 16 shows pancreatic tissue from human donors stained with: Mouse monoclonal anti DRiP v2#7 (white); Somatostatin (blue); Insulin (red); and Hoechst (green). DRiP staining is similar between different pancreas donors: Hul036 (top panel) and Hui 151 (botom panel). No DRiP staining is detected in delta cells.

[0291] FIG. 17 shows pancreatic tissue from human donors stained with: Mouse monoclonal anti DRiP v2#7 (white); Glucagon (blue); Insulin (red); and Hoechst (green). DRiP staining is similar between different pancreas donors: Hul036 (top panel) and Hui 151 (botom panel). DRiP staining is detected in beta cells. Overlap of DRiP staining with Glucagon staining suggests there is some DRiP detected in a subset of alpha cells. INFORMAL SEQUENCE LISTING

[0292] TABLE 1. CDR sequences and sequences of variable heavy and variable light chain domains of antibodies provided herein

[0293] TABLE 2. Sequences of exemplary DRiP peptides provided herein

[0294] TABLE 3. Exemplary CDR and FR sequences of anti -DRiP antibodies provided herein

P EMBODIMENTS

[0295] P Embodiment 1. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2, and a CDR H3 as set forth in SEQ ID NO:3; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:4, a CDR L2 as set forth in SEQ ID NO:5 and a CDR L3 as set forth in SEQ ID NO:6.

[0296] P Embodiment 2. The anti-DRiP antibody of P Embodiment 1, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 15.

[0297] P Embodiment 3. The anti-DRiP antibody of P Embodiment 1 or 2, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 16.

[0298] P Embodiment 4. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 17, a CDR H2 as set forth in SEQ ID NOHS, and a CDR H3 as set forth in SEQ ID NO: 19; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:20, a CDR L2 as set forth in SEQ ID NO:21 and a CDR L3 as set forth in SEQ ID NO:22.

[0299] P Embodiment 5. The anti-DRiP antibody of P Embodiment 4, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:31.

[0300] P Embodiment 6. The anti-DRiP antibody of P Embodiment 4 or 5, wherein said light chain variable domain comprises the sequence of SEQ ID NO:32.

[0301] P Embodiment 7. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:33, a CDR H2 as set forth in SEQ ID NO: 34, and a CDR H3 as set forth in SEQ ID NO:35; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:36, a CDR L2 as set forth in SEQ ID NO:37 and a CDR L3 as set forth in SEQ ID NO:38.

[0302] P Embodiment 8. The anti-DRiP antibody of P Embodiment 7, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:47.

[0303] P Embodiment 9. The anti-DRiP antibody of P Embodiment 7 or 8, wherein said light chain vanable domain compnses the sequence of SEQ ID NO:48.

[0304] P Embodiment 10. The anti-DRiP antibody of any one of P Embodiments 1 -9, wherein said antibody binds a DRiP protein.

[0305] P Embodiment 11. The anti-DRiP antibody of any one of P Embodiments 1-10, wherein said antibody binds the N-terminus of a DRiP protein.

[0306] P Embodiment 12. The anti-DRiP antibody of any one of P Embodiments 10-11, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159.

[0307] P Embodiment 13. The anti-DRiP antibody of any one of P Embodiments 10-12, wherein said anti-DRiP antibody binds to amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158 or SEQ ID NO: 159.

[0308] P Embodiment 14. The anti-DRiP antibody of any one of P Embodiments 1-13, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 162.

[0309] P Embodiment 15. A complex comprising an anti-DRiP antibody of any one of P Embodiments 1-14 said antibody non-covalently bound to the N-terminus of a DRiP protein.

[0310] P Embodiment 1 . The complex of P Embodiment 15, wherein said DRiP protein comprises the sequence of SEQ ID NO: 162.

[0311] P Embodiment 17. The complex of P Embodiment 15 or 16, wherein said complex is attached to a solid support.

[0312] P Embodiment 18. The complex of any one of P Embodiments 15-17, wherein said complex is in a detection device. [0313] P Embodiment 19. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:49, a CDR H2 as set forth in SEQ ID NO: 50, and a CDR H3 as set forth in SEQ ID NO:51; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:52, a CDR L2 as set forth in SEQ ID NO:53 and a CDR L3 as set forth in SEQ ID NO: 54.

[0314] P Embodiment 20. The anti-DRiP antibody of P Embodiment 19, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:63.

[0315] P Embodiment 21. The anti-DRiP antibody of P Embodiment 19 or 20, wherein said light chain variable domain comprises the sequence of SEQ ID NO:64.

[0316] P Embodiment 22. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain vanable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:65, a CDR H2 as set forth in SEQ ID NO: 66, and a CDR H3 as set forth in SEQ ID NO:67; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:68, a CDR L2 as set forth in SEQ ID NO:69 and a CDR L3 as set forth in SEQ ID NO:70.

[0317] P Embodiment 23. The anti-DRiP antibody of P Embodiment 22, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:79.

[0318] P Embodiment 24. The anti-DRiP antibody of P Embodiment 22 or 23, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 80.

[0319] P Embodiment 25. The anti-DRiP antibody of any one of P Embodiments 19-24, wherein said antibody binds a DRIP protein.

[0320] P Embodiment 26. The anti-DRiP antibody of any one of P Embodiments 19-25, wherein said antibody binds the C-terminus of a DRiP protein.

[0321] P Embodiment 27. The anti-DRiP antibody of any one of P Embodiments 25-26, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159. [0322] P Embodiment 28. The anti-DRiP antibody of any one of P Embodiments 19-27, wherein said anti-DRiP antibody binds to amino acid residues corresponding to positions 29- 43 of SEQ ID NO: 158 or SEQ ID NO: 159

[0323] P Embodiment 29. The anti-DRiP antibody of any one of P Embodiments 19-26, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 163.

[0324] P Embodiment 30. A complex comprising an anti-DRiP antibody of any one of P Embodiments 19-29 said antibody non-covalently bound to the C-terminus of a DRiP protein.

[0325] P Embodiment 31. The complex of P Embodiment 30, wherein said DRiP protein comprises the sequence of SEQ ID NO: 164.

[0326] P Embodiment 32. The complex of any one of P Embodiments 30-31, wherein said complex further comprises an antibody of any one of P Embodiments 1-14 non-covalently attached to the N-terminus of said DRiP protein.

[0327] P Embodiment 33. The complex of any one of P Embodiments 30-32, wherein said complex is attached to a solid support.

[0328] P Embodiment 34. The complex of any one of P Embodiments 30-33, wherein said complex is in a detection device.

[0329] P Embodiment 35. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR H1 as set forth in SEQ ID NO:81, a CDR H2 as set forth in SEQ ID NO: 82, and a CDR H3 as set forth in SEQ ID NO:83; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 84, a CDR L2 as set forth in SEQ ID NO: 85 and a CDR L3 as set forth in SEQ ID NO: 86.

[0330] P Embodiment 36. The anti-DRiP antibody of P Embodiment 35, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:95.

[0331] P Embodiment 37. The anti-DRiP antibody of P Embodiment 35 or 36, wherein said light chain variable domain comprises the sequence of SEQ ID NO:96. [0332] P Embodiment 38. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:99, a CDR H2 as set forth in SEQ ID NO: 100, and a CDR H3 as set forth in SEQ ID NO: 101; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 102, a CDR L2 as set forth in SEQ ID NO: 103 and a CDR L3 as set forth in SEQ ID NO: 104.

[0333] P Embodiment 39. The anti-DRiP antibody of P Embodiment 38, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 113.

[0334] P Embodiment 40. The anti-DRiP antibody of P Embodiment 38 or 39, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 114.

[0335] P Embodiment 41. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 117, a CDR H2 as set forth in SEQ ID NO: 118, and a CDR H3 as set forth in SEQ ID NO: 119; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 120, a CDR L2 as set forth in SEQ ID NO: 121 and a CDR L3 as set forth in SEQ ID NO: 122.

[0336] P Embodiment 42. The anti-DRiP antibody of P Embodiment 41, wherein said heavy chain vanable domain compnses the sequence of SEQ ID NO: 131.

[0337] P Embodiment 43. The anti-DRiP antibody of P Embodiment 41 or 42, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 132.

[0338] P Embodiment 44. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 135, a CDR H2 as set forth in SEQ ID NO: 136, and a CDR H3 as set forth in SEQ ID NO: 137; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 138, a CDR L2 as set forth in SEQ ID NO: 139 and a CDR L3 as set forth in SEQ ID NO: 140.

[0339] P Embodiment 45. The anti-DRiP antibody of P Embodiment 44, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 149. [0340] P Embodiment 46. The anti-DRiP antibody of P Embodiment 44 or 45, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 150.

[0341] P Embodiment 47. The anti-DRiP antibody of any one of P Embodiments 35-46, wherein said antibody binds a DRiP protein.

[0342] P Embodiment 48. The anti-DRiP antibody of any one of P Embodiments 35-47, wherein said antibody binds the N-terminus of a DRiP protein.

[0343] P Embodiment 49. The anti-DRiP antibody of any one of P Embodiments 47-48, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159.

[0344] P Embodiment 50. The anti-DRiP antibody of any one of P Embodiments 47-49, wherein said anti-DRiP antibody binds to amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158 or SEQ ID NO: 159.

[0345] P Embodiment The anti-DRiP antibody of any one of P Embodiments 35-50, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 155 or SEQ ID NO: 165.

[0346] P Embodiment 52. A complex comprising an anti-DRiP antibody of any one of P Embodiments 35-51 said antibody non-covalently bound to the N-termmus of a DRiP protein.

[0347] P Embodiment 53. The complex of P Embodiment 52, wherein said DRiP protein comprises the sequence of SEQ ID NO: 162.

[0348] P Embodiment 54. The complex of P Embodiment 52 or 53, wherein said complex is attached to a solid support.

[0349] P Embodiment 55. The complex of any one of P Embodiments 52-54, wherein said complex is in a detection device.

[0350] P Embodiment 56. The anti-DRIP antibody of any one of P Embodiments 10-12, 25-27, or 47-49, wherein said DRiP protein forms part of a cell.

[0351] P Embodiment 57. The anti-DRiP antibody of P Embodiment 56, wherein said DRiP protein is expressed on the surface of a cell. [0352] P Embodiment 58. The anti-DRiP antibody of P Embodiment 56 or 57. wherein said cell is a pancreatic cell.

[0353] P Embodiment 59. The anti-DRiP antibody of P Embodiment 58, wherein said pancreatic cell is a beta cell.

[0354] P Embodiment 60. The anti-DRiP antibody of any one of P Embodiments 1 -46, wherein said anti-DRiP antibody is atached to a diagnostic moiety.

[0355] P Embodiment 61. An isolated nucleic acid encoding an anti-DRiP antibody of any one of P Embodiments 1-46.

[0356] P Embodiment 62. A cell comprising an anti-DRiP antibody of any one of P Embodiments 1-60, or a nucleic acid of P Embodiment 61.

[0357] P Embodiment 63. A method of forming an antibody capable of binding to a DRiP protein, said method comprising immunizing a mammal with a peptide comprising the sequence of SEQ ID NO:153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO:162, SEQ ID NO: 164, or SEQ ID NO: 165.

[0358] P Embodiment 64 . The method of P Embodiment 63, wherein said peptide further comprises an adjuvant moiety covalently atached to the N-terminus or C-terminus of said peptide.

[0359] P Embodiment 65. The method of P Embodiment 63 or 64, wherein: (i) said peptide comprises the sequence of SEQ ID NO: 162 and an adjuvant conjugated to the N-terminus of said peptide; (h) said peptide comprises the sequence of SEQ ID NO: 164 and an adjuvant conjugated to the N terminus of said peptide; or (iii) said peptide comprises the sequence of SEQ ID NO: 165 and an adjuvant conjugated to the C-terminus of said peptide.

[0360] P Embodiment 66. A method of detecting a DRiP-expressing cell, said method comprising (i) contacting a DRiP-expressing cell with an antibody of any one of P Embodiments 1-14, 19-29, 35-51 or 56-60; (n) and detecting binding of said antibody to a DRiP protein expressed by said cell.

[0361] P Embodiment 67. The method of P Embodiment 66, wherein said antibody is atached to a detectable moiety. [0362] P Embodiment 68. The method of P Embodiment 66 or 67, wherein said DRiP- expressing cell is in a biological sample.

[0363] P Embodiment 69. The method of any one of P Embodiments 66-68, wherein the biological sample is whole blood, blood fractions or products, tissue, cultured cells, or pancreatic cells.

[0364] P Embodiment 70. A complex comprising a first anti-DRiP antibody non-covalently bound to the C-terminus of a DRiP protein and a second anti-DRiP antibody non-covalently bound to the N-terminus of said DRiP protein, wherein said first anti-DRiP antibody is an antibody of any one of P Embodiments 19-24 and wherein said second anti-DRiP antibody is an antibody of any one of P Embodiments 1-9.

[0365] P Embodiment 71. The complex of P Embodiment 70, wherein said first anti-DRiP antibody is attached to a solid support.

[0366] P Embodiment 72. The complex of P Embodiment 70 or 71, wherein said second anti-DRiP antibody is attached to a detectable moiety.

[0367] P Embodiment 73. The complex of any one of P Embodiments 70-72, wherein said complex is in a detection device.

[0368] P Embodiment 74. A method of detecting a DRiP-expressing cell in a human subject having or being at risk of developing diabetes, said method comprising: (i) obtaining a biological sample from a human subject having or being at risk of developing diabetes; (ii) contacting said biological sample with an anti-DRiP antibody of any one of P Embodiments 1 - 14, 19-29, or 35-51; and (ii) detecting binding of said antibody to a DRiP protein in said sample, thereby detecting a DRiP-expressing cell in said subject.

[0369] P Embodiment 75. The method of P Embodiment 74, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 and wherein diabetes is type I diabetes.

[0370] P Embodiment 76. The method of P Embodiment 74, wherein said DRiP protein comprises the sequence of SEQ ID NO: 159 and wherein diabetes is type I diabetes .

[0371] P Embodiment 77. A method of diagnosing and treating diabetes in a human subject in need thereof, said method comprising: (i) obtaining a biological sample from a human subject; (ii) detecting whether a DRiP protein is present in said sample by contacting said sample with an antibody of any one of P Embodiments 1-14 or 19-29; (hi) diagnosing said human subject with diabetes when a detectable complex is formed by said DRiP protein and said antibody; and (iv) administering to said diagnosed human subject an effective amount of a diabetes treatment.

[0372] P Embodiment 78. The method of P Embodiment 77, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 and wherein diabetes is type I diabetes.

[0373] P Embodiment 79. The method of P Embodiment 77, wherein said DRiP protein comprises the sequence of SEQ ID NO: 159 and wherein diabetes is type I diabetes.

EMBODIMENTS

[0374] Embodiment 1. An anti-DRiP antibody comprising a heavy chain vanable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR H1 as set forth in SEQ ID NO: 17, a CDR H2 as set forth in SEQ ID NO: 18, and a CDR H3 as set forth in SEQ ID NO: 19; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:20, a CDR L2 as set forth in SEQ ID NO:21 and a CDR L3 as set forth in SEQ ID NO:22.

[0375] Embodiment 2. The anti-DRiP antibody of Embodiment 1, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:31.

[0376] Embodiment 3. The anti-DRiP antibody of Embodiment 1 or 2, wherein said light chain variable domain comprises the sequence of SEQ ID NO:32.

[0377] Embodiment 4. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:1, a CDR H2 as set forth in SEQ ID NO:2, and a CDR H3 as set forth in SEQ ID NO:3; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:4, a CDR L2 as set forth in SEQ ID NO:5 and a CDR L3 as set forth in SEQ ID NO:6.

[0378] Embodiment 5. The anti-DRiP antibody of Embodiment 4, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 15. The anti-DRiP antibody of Embodiment 4, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:31.

[0379] Embodiment 6. The anti-DRiP antibody of Embodiment 4 or 5, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 16.The anti-DRiP antibody of Embodiment 4 or 5, wherein said light chain variable domain comprises the sequence of SEQ ID NO:32.

[0380] Embodiment 7. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain vanable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:33, a CDR H2 as set forth in SEQ ID NO: 34, and a CDR H3 as set forth in SEQ ID NO:35; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:36, a CDR L2 as set forth in SEQ ID NO:37 and a CDR L3 as set forth in SEQ ID NO:38.

[0381] Embodiment 8. The anti-DRiP antibody of Embodiment 7, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:47.

[0382] Embodiment 9. The anti-DRiP antibody of Embodiment 7 or 8, wherein said light chain variable domain comprises the sequence of SEQ ID NO:48.

[0383] Embodiment 10. The anti-DRiP antibody of any one of Embodiments 1-9, wherein said antibody binds a DRiP protein.

[0384] Embodiment 11. The anti-DRiP antibody of any one of Embodiments 1-10, wherein said antibody binds the N-terminus of a DRiP protein.

[0385] Embodiment 12. The anti-DRiP antibody of any one of Embodiments 10-11, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159.

[0386] Embodiment 13. The anti-DRiP antibody of any one of Embodiments 10-12, wherein said anti-DRiP antibody binds to amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158 or SEQ ID NO: 159.

[0387] Embodiment 14. The anti-DRiP antibody of any one of Embodiments 1-13, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 162. [0388] Embodiment 15. A complex comprising an anti-DRiP antibody of any one of Embodiments 1-14 said antibody non-covalently bound to the N-terminus of a DRiP protein.

[0389] Embodiment 16. The complex of Embodiment 15, wherein said DRiP protein comprises the sequence of SEQ ID NO: 162.

[0390] Embodiment 17. The complex of Embodiment 15 or 16, wherein said complex is attached to a solid support.

[0391] Embodiment 18. The complex of any one of Embodiments 15-17, wherein said complex is in a detection device.

[0392] Embodiment 19. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:49, a CDR H2 as set forth in SEQ ID NO: 50, and a CDR H3 as set forth in SEQ ID NO:51; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:52, a CDR L2 as set forth in SEQ ID NO:53 and a CDR L3 as set forth in SEQ ID NO: 54.

[0393] Embodiment 20. The anti-DRiP antibody of Embodiment 19, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 63.

[0394] Embodiment 21. The anti-DRiP antibody of Embodiment 19 or 20, wherein said light chain variable domain comprises the sequence of SEQ ID NO:64.

[0395] Embodiment 22. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain vanable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:65, a CDR H2 as set forth in SEQ ID NO: 66, and a CDR H3 as set forth in SEQ ID NO:67; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:68, a CDR L2 as set forth in SEQ ID NO:69 and a CDR L3 as set forth in SEQ ID NO:70.

[0396] Embodiment 23. The anti-DRiP antibody of Embodiment 22, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 79.

[0397] Embodiment 24. The anti-DRiP antibody of Embodiment 22 or 23, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 80. [0398] Embodiment 25. The anti-DRiP antibody of any one of Embodiments 19-24, wherein said antibody binds a DRiP protein.

[0399] Embodiment 26. The anti-DRiP antibody of any one of Embodiments 19-25, wherein said antibody binds the C-terminus of a DRiP protein.

[0400] Embodiment 27. The anti-DRiP antibody of any one of Embodiments 25-26, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159.

[0401] Embodiment 28. The anti-DRiP antibody of any one of Embodiments 19-27, wherein said anti-DRiP antibody binds to amino acid residues corresponding to positions 29- 43 of SEQ ID NO:158 or SEQ ID NO 159.

[0402] Embodiment 29. The anti-DRiP antibody of any one of Embodiments 19-26, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 163.

[0403] Embodiment 30. A complex comprising an anti-DRiP antibody of any one of Embodiments 19-29 said antibody non-covalently bound to the C-terminus of a DRiP protein.

[0404] Embodiment 31. The complex of Embodiment 30, wherein said DRiP protein comprises the sequence of SEQ ID NO: 164.

[0405] Embodiment 32. The complex of any one of Embodiments 30-31, wherein said complex further comprises an antibody of any one of Embodiments 1-14 non-covalently attached to the N-terminus of said DRiP protein.

[0406] Embodiment 33. The complex of any one of Embodiments 30-32, wherein said complex is attached to a solid support.

[0407] Embodiment 34. The complex of any one of Embodiments 30-33, wherein said complex is in a detection device.

[0408] Embodiment 35. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR H1 as set forth in SEQ ID NO:81, a CDRH2 as set forth in SEQ ID NO: 82, and a CDR EI3 as set forth in SEQ ID NO:83; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 84, a CDR L2 as set forth in SEQ ID NO: 85 and a CDR L3 as set forth in SEQ ID NO: 86.

[0409] Embodiment 36. The anti-DRiP antibody of Embodiment 35, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 95.

[0410] Embodiment 37. The anti-DRiP antibody of Embodiment 35 or 36, wherein said light chain variable domain comprises the sequence of SEQ ID NO:96.

[0411] Embodiment 38. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:99, a CDR H2 as set forth in SEQ ID NO: 100, and a CDR H3 as set forth in SEQ ID NO: 101; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 102, a CDR L2 as set forth in SEQ ID NO: 103 and a CDR L3 as set forth in SEQ ID NO: 104.

[0412] Embodiment 39. The anti-DRiP antibody of Embodiment 38, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 113.

[0413] Embodiment 40. The anti-DRiP antibody of Embodiment 38 or 39, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 114.

[0414] Embodiment 41. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 117, a CDR H2 as set forth in SEQ ID NO: 11 , and a CDR H3 as set forth in SEQ ID NO: 1 19; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 120, a CDR L2 as set forth in SEQ ID NO: 121 and a CDR L3 as set forth in SEQ ID NO: 122.

[0415] Embodiment 42. The anti-DRiP antibody of Embodiment 41, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 131.

[0416] Embodiment 43. The anti-DRiP antibody of Embodiment 41 or 42, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 132.

[0417] Embodiment 44. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy' chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 135, a CDR H2 as set forth in SEQ ID NO: 136, and a CDR H3 as set forth in SEQ ID NO: 137; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 138, a CDR L2 as set forth in SEQ ID NO: 139 and a CDR L3 as set forth in SEQ ID NO: 140.

[0418] Embodiment 45. The anti-DRiP antibody of Embodiment 44, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 149.

[0419] Embodiment 46. The anti-DRiP antibody of Embodiment 44 or 45, wherein said light chain vanable domain compnses the sequence of SEQ ID NO: 150.

[0420] Embodiment 47. The anti-DRiP antibody of any one of Embodiments 35-46, wherein said antibody binds a DRiP protein.

[0421] Embodiment 48. The anti-DRiP antibody of any one of Embodiments 35-47, wherein said antibody binds the N-terminus of a DRiP protein.

[0422] Embodiment 49. The anti-DRiP antibody of any one of Embodiments 47-48, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159.

[0423] Embodiment 50. The anti-DRiP antibody of any one of Embodiments 47-49, wherein said anti-DRiP antibody binds to amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158 or SEQ ID NO: 159.

[0424] Embodiment The anti-DRiP antibody of any one of Embodiments 35-50, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 155 or SEQ ID NO: 165.

[0425] Embodiment 52. A complex comprising an anti-DRiP antibody of any one of Embodiments 35-51, said antibody non-covalently bound to the N-terminus of a DRiP protein.

[0426] Embodiment 53. The complex of Embodiment 52, wherein said DRiP protein comprises the sequence of SEQ ID NO: 162.

[0427] Embodiment 54. The complex of Embodiment 52 or 53, wherein said complex is attached to a solid support.

[0428] Embodiment 55. The complex of any one of Embodiments 52-54, wherein said complex is in a detection device. [0429] Embodiment 56. The anti-DRIP antibody of any one of Embodiments 10-12, 25- 27, or 47-49, wherein said DRiP protein forms part of a cell.

[0430] Embodiment 57. The anti-DRiP antibody of Embodiment 56, wherein said DRiP protein is expressed on the surface of a cell.

[0431] Embodiment 58. The anti-DRiP antibody of Embodiment 56 or 57, wherein said cell is a pancreatic cell.

[0432] Embodiment 59. The anti-DRiP antibody of Embodiment 58, wherein said pancreatic cell is a beta cell.

[0433] Embodiment 60. The anti-DRiP antibody of any one of Embodiments 1-14, 19-29, 35-51, or 56-60, wherein said anti-DRiP antibody is attached to a diagnostic moiety.

[0434] Embodiment 61. An isolated nucleic acid encoding an anti-DRiP antibody of any one of Embodiments 1-14, 19-29, 35-51, or 56-60.

[0435] Embodiment 62. A cell comprising an anti-DRiP antibody of any one of Embodiments 1-14, 19-29, 35-51, or 56-60, or a nucleic acid of Embodiment 61.

[0436] Embodiment 63. A method of forming an antibody capable of binding to a DRiP protein, said method comprising immunizing a mammal with a peptide comprising the sequence of SEQ ID NO:153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO:162, SEQ ID NO: 164, or SEQ ID NO: 165.

[0437] Embodiment 64. The method of Embodiment 63, wherein said peptide further comprises an adjuvant moiety covalently attached to the N-terminus or C-terminus of said peptide.

[0438] Embodiment 65. The method of Embodiment 63 or 64, wherein: (i) said peptide comprises the sequence of SEQ ID NO: 162 and an adjuvant conjugated to the N-terminus of said peptide; (ii) said peptide comprises the sequence of SEQ ID NO: 164 and an adjuvant conjugated to the N terminus of said peptide; or (iii) said peptide comprises the sequence of SEQ ID NO: 165 and an adjuvant conjugated to the C-terminus of said peptide. [0439] Embodiment 66. A method of detecting a DRiP-expressing cell, said method comprising (i) contacting a DRiP-expressing cell with an antibody of any one of Embodiments 1 -14, 19-29, 35-51 or 56-60; (ii) and detecting binding of said antibody to a DRiP protein expressed by said cell.

[0440] Embodiment 67. The method of Embodiment 66, wherein said antibody is attached to a detectable moiety.

[0441] Embodiment 68. The method of Embodiment 66 or 67, wherein said DRiP- expressing cell is in a biological sample.

[0442] Embodiment 69. The method of any one of Embodiments 66-68, wherein the biological sample is whole blood, blood fractions or products, tissue, cultured cells, or pancreatic cells.

[0443] Embodiment 70. A complex comprising a first anti-DRiP antibody non-covalently bound to the C-terminus of a DRiP protein and a second anti-DRiP antibody non-covalently bound to the N-terminus of said DRiP protein, wherein said first anti-DRiP antibody is an antibody of any one of Embodiments 19-24 and wherein said second anti-DRiP antibody is an antibody of any one of Embodiments 1-9.

[0444] Embodiment 71. The complex of Embodiment 70, wherein said first anti-DRiP antibody is attached to a solid support.

[0445] Embodiment 72. The complex of Embodiment 70 or 71, wherein said second anti- DRiP antibody is attached to a detectable moiety.

[0446] Embodiment 73. The complex of any one of Embodiments 70-72, wherein said complex is in a detection device.

[0447] Embodiment 74. A method of detecting a DRiP-expressing cell in a human subject having or being at risk of developing diabetes, said method comprising: (i) obtaining a biological sample from a human subject having or being at risk of developing diabetes; (ii) contacting said biological sample with an anti-DRiP antibody of any one of Embodiments 1- 14, 19-29, or 35-51; and (ii) detecting binding of said antibody to a DRiP protein in said sample, thereby detecting a DRiP-expressing cell in said subject. [0448] Embodiment 75. The method of Embodiment 74, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 and wherein diabetes is type I diabetes.

[0449] Embodiment 76. The method of Embodiment 74, wherein said DRiP protein comprises the sequence of SEQ ID NO: 159 and wherein diabetes is type I diabetes . [0450] Embodiment 77. A method of diagnosing and treating diabetes in a human subject in need thereof, said method comprising: (i) obtaining a biological sample from a human subject; (ii) detecting whether a DRiP protein is present in said sample by contacting said sample with an antibody of any one of Embodiments 1-14 or 19-29; (hi) diagnosing said human subject with diabetes when a detectable complex is formed by said DRiP protein and said antibody; and (iv) administering to said diagnosed human subject an effective amount of a diabetes treatment.

[0451] Embodiment 78. The method of Embodiment 77, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 and wherein diabetes is type I diabetes.

[0452] Embodiment 79. The method of Embodiment 77, wherein said DRiP protein comprises the sequence of SEQ ID NO: 159 and wherein diabetes is type I diabetes.

Claims

WHAT IS CLAIMED IS:

1. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 17, a CDR H2 as set forth in SEQ ID NO: 18, and a CDR H3 as set forth in SEQ ID NO: 19; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:20, a CDR L2 as set forth in SEQ ID NO:21 and a CDR L3 as set forth in SEQ ID NO:22.

2. The anti-DRiP antibody of claim 1, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:31.

3. The anti-DRiP antibody of claim 1, wherein said light chain variable domain comprises the sequence of SEQ ID NO:32.

4. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NOT, a CDR H2 as set forth in SEQ ID NO:2, and a CDR H3 as set forth in SEQ ID NO:3; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:4, a CDR L2 as set forth in SEQ ID NO:5 and a CDR L3 as set forth in SEQ ID NO:6.

5. The anti-DRiP antibody of claim 4, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 15.

6. The anti-DRiP antibody of claim 4, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 16.

7. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:33, a CDR H2 as set forth in SEQ ID NO:34, and a CDR H3 as set forth in SEQ ID NO: 35; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:36, a CDR L2 as set forth in SEQ ID NO:37 and a CDR L3 as set forth in SEQ ID NO:38.

8. The anti-DRiP antibody of claim 7, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:47.

9. The anti-DRiP antibody of claim 7, wherein said light chain variable domain comprises the sequence of SEQ ID NO:48.

10. The anti-DRiP antibody of any one of claims 1, 4, or 7, wherein said antibody binds a DRiP protein.

11. The anti-DRiP antibody of any one of claims 1, 4, or 7, wherein said antibody binds the N-terminus of a DRiP protein.

12. The anti-DRiP antibody of claim 10, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159.

13. The anti-DRiP antibody of claim 10, wherein said anti-DRiP antibody binds to amino acid residues corresponding to positions 1-20 of SEQ ID NO: 158 or SEQ ID NO: 159.

14. The anti-DRiP antibody of any one of claims 1, 4, or 7, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 162.

15. A complex comprising an anti-DRiP antibody of any one of claims 1, 4 or 7, said antibody non-covalently bound to the N-terminus of a DRiP protein.

16. The complex of claim 15, wherein said DRiP protein comprises the sequence of SEQ ID NO: 162.

17. The complex of claim 15, wherein said complex is attached to a solid support.

18. The complex of claim 15, wherein said complex is in a detection device.

19. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:49, a CDR H2 as set forth in SEQ ID NO:50, and a CDR H3 as set forth in SEQ ID NO:51; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:52, a CDR L2 as set forth in SEQ ID NO:53 and a CDR L3 as set forth in SEQ ID NO:54.

20. The anti-DRiP antibody of claim 19, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:63.

21. The anti-DRiP antibody of claim 19, wherein said light chain variable domain comprises the sequence of SEQ ID NO:64.

22. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NO:65, a CDR H2 as set forth in SEQ ID NO:66, and a CDR H3 as set forth in SEQ ID NO: 67; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:68, a CDR L2 as set forth in SEQ ID NO:69 and a CDR L3 as set forth in SEQ ID NO:70.

23. The anti-DRiP antibody of claim 22, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:79.

24. The anti-DRiP antibody of claim 22, wherein said light chain variable domain comprises the sequence of SEQ ID NO:80.

25. The anti-DRiP antibody of claim 19 or 22, wherein said antibody binds a DRiP protein.

26. The anti-DRiP antibody of claim 19 or 22, wherein said antibody binds the C-terminus of a DRiP protein.

27. The anti-DRiP antibody of claim 25, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159.

28. The anti-DRiP antibody of claim 19, wherein said anti-DRiP antibody binds to ammo acid residues corresponding to positions 29-43 of SEQ ID NO: 158 or SEQ ID NO: 159.

29. The anti-DRiP antibody of claim 19, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 163.

30. A complex comprising an anti-DRiP antibody of claim 19 or 22, said antibody non-covalently bound to the C-terminus of a DRiP protein.

31. The complex of claim 30, wherein said DRiP protein comprises the sequence of SEQ ID NO: 164.

32. The complex of claim 30, wherein said complex further comprises an antibody of any one of claims 1, 4 or 7 non-covalently attached to the N-terminus of said DRiP protein.

33. The complex of claim 30, wherein said complex is attached to a solid support.

34. The complex of claim 30, wherein said complex is in a detection device.

35. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 81, a CDR H2 as set forth in SEQ ID NO: 82, and a CDR H3 as set forth in SEQ ID NO: 83; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 84, a CDR L2 as set forth in SEQ ID NO: 85 and a CDR L3 as set forth in SEQ ID NO:86.

36. The anti-DRiP antibody of claim 35, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:95.

37. The anti-DRiP antibody of claim 35, wherein said light chain vanable domain comprises the sequence of SEQ ID NO:96.

38. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain vanable domain, wherein said heavy chain variable domain compnses a CDR Hl as set forth in SEQ ID NO: 99, a CDR H2 as set forth in SEQ ID NO: 100, and a CDR H3 as set forth in SEQ ID NO: 101; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO: 102, a CDR L2 as set forth in SEQ ID NO: 103 and a CDR L3 as set forth in SEQ ID NO: 104.

39. The anti-DRiP antibody of claim 38, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 113.

40. The anti-DRiP antibody of claim 38, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 114.

41. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 117, a CDR H2 as set forth in SEQ ID NO: 118, and a CDR H3 as set forth in SEQ ID NO: 119; and wherein said light chain vanable domain comprises a CDR LI as set forth in SEQ ID NO: 120, a CDR L2 as set forth in SEQ ID NO: 121 and a CDR L3 as set forth in SEQ ID NO: 122.

42. The anti-DRiP antibody of claim 41, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO:13L

43. The anti-DRiP antibody of claim 41, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 132.

44. An anti-DRiP antibody comprising a heavy chain variable domain and a light chain variable domain, wherein said heavy chain variable domain comprises a CDR Hl as set forth in SEQ ID NO: 135, a CDR H2 as set forth in SEQ ID NO: 136, and a CDR H3 as set forth in SEQ ID NO: 137; and wherein said light chain variable domain comprises a CDR LI as set forth in SEQ ID NO:138, a CDR L2 as set forth in SEQ ID NO:139 and a CDR L3 as set forth in SEQ ID NO: 140.

45. The anti-DRiP antibody of claim 44, wherein said heavy chain variable domain comprises the sequence of SEQ ID NO: 149.

46. The anti-DRiP antibody of claim 44, wherein said light chain variable domain comprises the sequence of SEQ ID NO: 150.

47. The anti-DRiP antibody of any one of claims 35, 38, 41 , or 44, wherein said antibody binds a DRiP protein.

48. The anti-DRiP antibody of any one of claims 35, 38, 41, or 44, wherein said antibody binds the N-terminus of a DRiP protein.

49. The anti-DRiP antibody of claim 47, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 or SEQ ID NO: 159.

50. The anti-DRiP antibody of claim 47, wherein said anti-DRiP antibody binds to amino acid residues corresponding to positions 1-13 of SEQ ID NO: 158 or SEQ ID NO: 159.

51. The anti-DRiP antibody of claim 35, wherein said antibody binds a peptide comprising the sequence of SEQ ID NO: 155 or SEQ ID NO: 165.

52. A complex comprising an anti-DRiP antibody of any one of claims 35, 38, 41, or 44, said antibody non-covalently bound to the N-terminus of a DRiP protein.

53. The complex of claim 52, wherein said DRiP protein comprises the sequence of SEQ ID NO: 162.

54. The complex of claim 52, wherein said complex is attached to a solid support.

55. The complex of claim 52, wherein said complex is in a detection device.

56. The anti-DRIP antibody of claim 10, wherein said DRiP protein forms part of a cell.

57. The anti-DRiP antibody of claim 56, wherein said DRiP protein is expressed on the surface of a cell.

58. The anti-DRiP antibody of claim 56, wherein said cell is a pancreatic cell.

59. The anti-DRiP antibody of claim 58, wherein said pancreatic cell is a beta cell.

60. The anti-DRiP antibody of claim 1, wherein said anti-DRiP antibody is attached to a diagnostic moiety.

61. An isolated nucleic acid encoding an anti-DRiP antibody of any one of claims 1, 4, 7, 19, 22, 35, 38, 41, or 44.

62. A cell comprising an anti-DRiP antibody of any one of claims 1, 4, 7, 19, 22, 35, 38, 41, or 44, or a nucleic acid of claim 61.

63. A method of forming an antibody capable of binding to a DRiP protein, said method comprising immunizing a mammal with a peptide comprising the sequence of SEQ ID NO:153, SEQ ID NO: 154, SEQ ID NO: 155, SEQ ID NO:162, SEQ ID NO: 164, or SEQ ID NO: 165.

64 . The method of claim 63, wherein said peptide further comprises an adjuvant moiety covalently attached to the N-terminus or C-terminus of said peptide.

65. The method of claim 63, wherein: (i) said peptide comprises the sequence of SEQ ID NO: 162 and an adjuvant conjugated to the N-terminus of said peptide; (ii) said peptide comprises the sequence of SEQ ID NO: 164 and an adjuvant conjugated to the N terminus of said peptide; or (iii) said peptide comprises the sequence of SEQ ID NO: 165 and an adjuvant conjugated to the C-terminus of said peptide.

66. A method of detecting a DRiP-expressing cell, said method comprising (i) contacting a DRiP-expressing cell with an antibody of any one of claims 1, 4, 7, 19, 22, 35, 38, 41 , or 44; (ii) and detecting binding of said antibody to a DRiP protein expressed by said cell.

67. The method of claim 66, wherein said antibody is attached to a detectable moiety.

68. The method of claim 66, wherein said DRiP-expressing cell is in a biological sample.

69. The method of claim 66, wherein the biological sample is whole blood, blood fractions or products, tissue, cultured cells, or pancreatic cells.

70. A complex comprising a first anti-DRiP antibody non-covalently bound to the C-terminus of a DRiP protein and a second anti-DRiP antibody non-covalently bound to the N-terminus of said DRiP protein, wherein said first anti-DRiP antibody is an antibody of claim 19 or 22 and wherein said second anti-DRiP antibody is an antibody of any one of claims 1, 4 or 7.

71. The complex of claim 70, wherein said first anti-DRiP antibody is attached to a solid support.

72. The complex of claim 70, wherein said second anti-DRiP antibody is attached to a detectable moiety.

73. The complex of claim 70, wherein said complex is in a detection device.

74. A method of detecting a DRiP-expressing cell in a human subject having or being at nsk of developing diabetes, said method comprising:

(i) obtaining a biological sample from a human subject having or being at risk of developing diabetes;

(ii) contacting said biological sample with an anti-DRiP antibody of any one of claims 1, 4, 7, 19, 22, 35, 38, 41, or 44; and (ii) detecting binding of said antibody to a DRiP protein in said sample, thereby detecting a DRiP-expressing cell in said subject.

75. The method of claim 74, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 and wherein diabetes is type I diabetes.

76. The method of claim 74, wherein said DRiP protein comprises the sequence of SEQ ID NO: 159 and wherein diabetes is type I diabetes.

77. A method of diagnosing and treating diabetes in a human subject in need thereof, said method comprising:

(i) obtaining a biological sample from a human subject;

(ii) detecting whether a DRiP protein is present in said sample by contacting said sample with an antibody of any one of claims 1, 4, 7, 19, 22, 35, 38, 41, or 44;

(iii) diagnosing said human subject with diabetes when a detectable complex is formed by said DRiP protein and said antibody; and

(iv) administering to said diagnosed human subject an effective amount of a diabetes treatment.

78. The method of claim 77, wherein said DRiP protein comprises the sequence of SEQ ID NO: 158 and wherein diabetes is type I diabetes.

79. The method of claim 77, wherein said DRiP protein comprises the sequence of SEQ ID NO: 159 and wherein diabetes is type I diabetes.