IGFR-L1 ANTIBODIES AND USES THEREOF

Abstract

The present invention provides novel IGFR-L1 antibodies for targeting the extracellular domain of the native IGFR-L1 protein, which are envisaged for use as medicines, in particular for the treatment of diabetes and related disorders, and cancer.

Description

[Technical field]

[0001] This application contains a Sequence Listing in computer readable format, which is incorporated herein by reference.

[0002] Technical Field The present invention provides novel structure-specific (e.g., conformation-specific) IGFR-L1 antibodies for specifically targeting the extracellular domain of non-denatured IGFR-L1 protein, and methods and uses based thereon (e.g., therapeutic methods and immunoprecipitation methods).The novel IGFR-L1 antibodies of the present invention are envisaged for use as medicines and / or in therapy, in particular for the treatment of diabetes and related disorders (e.g., hyperinsulinemia, insulin resistance and related disorders, etc.).The novel IGFR-L1 antibodies of the present invention are also envisaged for use in various immunoprecipitation assays, for example, immunoprecipitation assays for which domain-specific peptide antibodies from the prior art are not suitable. [Background technology]

[0003] background Insulin / insulin-like growth factors (IGFs) constitute a network of ligands, cell surface receptors and binding proteins involved in the regulation of multiple physiological and pathological processes. Insulin / IGFs play important developmental and metabolic roles at all stages of life. Insulin / IGF signaling also contributes to the regulation of lifespan, while dysregulation of signaling has been implicated in tumorigenesis. Although the insulin receptor (InsR) and IGF-1 receptor (IGF1R) share most of their downstream cytoplasmic mediators, most experimental and clinical evidence is consistent with the view that InsR activation (mainly by insulin) primarily leads to metabolic activities, whereas IGF1R activation (mainly by IGF-1 or IGF-2) leads to proliferation and differentiation events (Sarfstein R and Werner H Endocrinology. 2013 May;154(5):1672-9 (Non-Patent Document 1); Siddle KJ Mol Endocrinol. 2011 Jun 17;47(1):R1-10 (Non-Patent Document 2)).

[0004] InsR and IGF1R belong to a family of transmembrane tyrosine kinase-containing receptors. In their mature form, they exist as heterotetramers composed of two extracellular α-subunits and two transmembrane β-subunits that possess tyrosine kinase activity. Both IGF receptors and insulin receptors show a high degree of homology (84% in the tyrosine kinase domain, 45%-65% in the ligand-binding domain, and more than 50% in the overall amino acid sequence). In addition, the receptors display a striking similarity in genomic organization (Sarfstein R and Werner H, supra (Non-Patent Document 1); Arnalez F and Helman L. Hematol Oncol Clin North Am. 2012 Jun;26(3):527-42 (Non-Patent Document 3)).

[0005] There is also a "hybrid" receptor (IRαβ linked to IGF1Rαβ) that is composed of half an insulin receptor and half an IGF receptor. The hybrid binds IGF with an affinity similar to that of the IGFR, but binds insulin with a substantially lower affinity than the InsR. It is unclear whether the hybrid receptor has an entirely different physiological role (Sarfstein R and Werner H, supra (Non-Patent Document 1); Arnalez F and Helman L., supra (Non-Patent Document 3)).

[0006] The insulin receptor exists in two splice variant isoforms as a result of alternative splicing of the sequence encoded by exon 11; the "B" isoform recognizes only insulin, whereas the "A" isoform, which is the isoform most commonly expressed by tumors, recognizes both insulin and IGF1 and 2. Both isoforms are differentially expressed during development, with InsR-A being preferentially expressed in fetal tissues and InsR-B being preferentially expressed in adult tissues, particularly liver, muscle and adipocytes. IGF1R exhibits the opposite expression pattern, being absent from liver, present at low levels in adipose tissue and at high levels in brain. In addition, consistent with its potent anti-apoptotic, pro-survival role, IGF1R is overexpressed in most tumors and malignant cells (Pollak M Nat Rev Cancer. 2012 Feb 16;12(3):159-69 (Non-Patent Document 4); Sarfstein R and Werner H, supra (Non-Patent Document 1); Siddle K, supra (Non-Patent Document 2)).

[0007] IGF1 and IGF2 can be expressed in an endocrine, paracrine or autocrine manner, the latter being more common in transformed cells. The liver is their primary site of production. Insulin production, in contrast, is restricted to pancreatic β-cells. Insulin and IGF bind with high affinity to their specific receptors and with lower affinity to non-cognate receptors, except for IGF2, which also binds with high affinity to InsR-A (Pollak M, supra (Non-Patent Document 4); Siddle K, supra (Non-Patent Document 2)).

[0008] Ligand binding induces conformational changes in the structure of InsR and IGF1R, activating their intrinsic tyrosine kinase activity. Although insulin and IGFs have completely different physiological roles, they utilize the same signaling pathways. Downstream signaling of InsR and IGF1R is transmitted largely through the MAPK / Ras-Raf-Erk, phosphatidylinositol-3-kinase / AKT / mTOR (PI3K / AKT) and Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathways. Ultimately, activation of IGF1R results in increased cell proliferation and decreased apoptosis, whereas activation of InsR by insulin binding promotes storage and synthesis of lipids, proteins and carbohydrates and inhibits their degradation and release into circulation. The initial step by which insulin increases energy storage or utilization involves regulated glucose transport into cells, mediated by the facilitative glucose transporter Glut4 (Chang et al. Mol Med. 2004 Jul-Dec; 10(7-12): 65-71.). Insulin expression is restricted to specialized pancreatic β-cells and, under normal circumstances, is tightly regulated by circulating glucose levels. Insulin-stimulated glucose uptake by classical insulin-sensitive organs (liver, muscle, and adipose tissue) reduces circulating glucose levels. Thus, β-cells are glucose "thermostats," sensing glucose and releasing insulin to maintain physiological glucose levels within a relatively narrow range. Disruption of the delicately balanced InsR signaling pathway leads to uncontrolled or abnormal insulin secretion, dysregulated blood glucose levels, and ultimately to the destruction or loss of function of pancreatic beta cells, a condition commonly known as diabetes (Pollak M, supra (Non-Patent Document 4); Siddle K, supra (Non-Patent Document 2); Sarfstein R and Werner H, supra (Non-Patent Document 1); Arnalez F and Helman L., supra (Non-Patent Document 3)).

[0009] Diabetes mellitus, affecting 8.3% of the world's adult population and increasing at an alarming rate, is one of the most common diseases of our time. The number of people with diabetes mellitus is projected to increase from 382 million in 2013 to 592 million in 2035, representing a net increase of 55%. The predominant type is type 2 diabetes (T2D), accounting for nearly 90% of all diabetes cases (Hameed et al. World J Diabetes. 2015 May 15; 6(4): 598-612).

[0010] Type 1 diabetes (T1D) is an autoimmune disorder that affects millions of people worldwide and results from organ-specific immune destruction of insulin-producing beta cells in the islets of Langerhans within the pancreas. When these cells are destroyed, type 1 diabetes patients lose blood glucose control, which can result in both acute disease (e.g., ketoacidosis and severe hypoglycemia) and secondary complications (including heart disease, blindness, and renal failure). Type 1 diabetes is thought to develop as a result of a combination of genetic predisposition, poorly understood environmental factors, and stochastic events, although the precise immunological, genetic, and physiological events that control disease onset and progression continue to be elucidated.

[0011] Early type 2 diabetes (T2D) is caused by insulin resistance in classical insulin target organs (i.e., reduced glucose uptake by normal insulin target cells, often induced by excess caloric intake), leading to hyperinsulinemia. Initially, these increased insulin levels are sufficient to overcome insulin resistance and avoid hyperglycemia. However, hyperglycemia eventually results not only from increased insulin resistance but also from reduced insulin output by pancreatic β cells.

[0012] Control of blood glucose levels is the primary goal of diabetes treatment. T1D is usually managed by administration of insulin as well as dietary modification and exercise. However, the requirement for lifelong nutritional intake followed by insulin injections can significantly reduce the patient's quality of life. Furthermore, the appropriate dosage and timing of insulin injections can be challenging. Cure or prevention of T1D is greatly hampered by the lack of biomarkers that reliably correlate with the pathogenic process, resulting in severely reduced beta cell numbers at the time of diagnosis. The goal of most clinical trials for type 1 diabetes today is to improve functional residual beta cell mass, ideally through induction of immune tolerance, while preserving a protective immune response. Of course, this would hardly "cure" the disease due to the profound beta cell destruction prior to treatment. A reliable biomarker, preferably expressed at disease onset, would therefore be highly desirable. Other methods have focused on transplanting either the pancreas or pancreatic beta cells to restore insulin secretion function. However, this approach is hampered by a shortage of donor organs. In addition to insulin, other non-insulin treatments, including synthetic hypoglycemic agents, are available for T2D; however, these are often limited in terms of their practical effectiveness, ease of administration, and may induce adverse reactions.

[0013] Safety concerns and adverse effects of available diabetes medications, as well as the lack of durable remission of the disease with any agent tested to date, have stimulated interest in specific interventions that may modulate the disease.

[0014] It is an object of the present invention to address the needs in the prior art. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Sarfstein R and Werner H Endocrinology. 2013 May;154(5):1672-9 [Non-Patent Document 2] Siddle KJ Mol Endocrinol. 2011 Jun 17;47(1):R1-10 [Non-Patent Document 3] Arnalez F and Helman L. Hematol Oncol Clin North Am. 2012 Jun;26(3):527-42 [Non-Patent Document 4] Pollak M Nat Rev Cancer. 2012 Feb 16;12(3):159-69 [Non-Patent Document 5] Chang et al. Mol Med. 2004 Jul-Dec; 10(7-12): 65-71. [Non-Patent Document 6] Hameed et al. World J Diabetes. 2015 May 15; 6(4): 598-612 Summary of the Invention

[0016] overview The present invention provides an antibody that binds to the extracellular domain of a non-denatured (e.g., folded or partially folded) receptor protein (IGFR-L1 protein) comprising the amino acid sequence of SEQ ID NO:1, preferably to a native epitope within the IGFR-L1 protein, wherein binding by said antibody to the non-denatured IGFR-L1 protein is characterized by: (a) An aliquot of lysate from Min6 cells (ATCC CRL-11506) was (i) 5 min at ambient temperature in a buffer suitable for SDS-PAGE of proteins; (ii) a buffer suitable for SDS-PAGE of proteins and a reducing agent for 5 min at ambient temperature; and (iii) A buffer suitable for SDS-PAGE of proteins and a reducing agent at 95°C for 5 min. incubating separately with each of (b) subjecting said aliquot to SDS-PAGE; (c) Western blotting of SDS-PAGE gels; (d) incubating the Western blot membrane with said antibody; is determinable (e.g., determined) according to wherein the antibody detects only aliquot (i); Concerning antibodies.

[0017] The present invention further comprises: (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:5, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:7, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:9, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:15, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:17, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:19; (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:25, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:27, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:29, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:35, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:37, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:39; (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:45, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:47, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:49, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:55, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:57, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:59; (d) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:65, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:67, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:69, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:75, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:77, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:79; (e) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:85, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:87, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:89, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:95, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:97, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:99; (f) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:105, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:107, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:109, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:115, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:117, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:119; (g) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:125, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:127, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:129, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:135, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:137, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:139; (h) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:145, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:147, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:149, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:155, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:157, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:159; (i) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:165, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:167, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:169, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:175, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:177, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:179; (j) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:185, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:187, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:189, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:195, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:197, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:199; (k) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:205, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:207, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:209, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:215, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:217, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:219; (l) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:225, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:227, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:229, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:235, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:237, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:239; or (m) an antibody that binds to the same epitope in human PRDX4 (peroxiredoxin-4, e.g., UniProtKB-Q13162) protein as the epitope bound by any one of the antibodies (a) to (l); The present invention relates to an antibody,

[0018] The present invention further relates to the use of the antibodies of the invention in methods for treating diabetes.

[0019] Overview of the Sequence Listing As described herein, and unless otherwise indicated, references are made to UniProtKB Accession Numbers (available at https: / / www.uniprot.org / news / 2021 / 04 / 07 / release, e.g., UniProt release 2021_02, published on April 7, 2021).

[0020] As described herein, unless otherwise indicated, references are made to NCBI GenBank Accession Numbers (available at https: / / www.ncbi.nlm.nih.gov / genbank / release / current / , e.g., Release 243.0, published on April 15, 2021).

[0021] SEQ ID NO:1 is the amino acid sequence of human endosome / lysosome-associated apoptosis and autophagy regulator 1 (ELAPOR1), referred to interchangeably herein as "IGFR-L1," and corresponds, for example, to UniProtKB Accession Number: Q6UXG2-1. The extracellular domain of the IGFR-L1 protein corresponds to amino acids 1-910 of SEQ ID NO:1.

[0022] SEQ ID NOs:2-241 are the amino acid sequences of the chains and specific regions of twelve novel exemplary antibodies (Abs) of the present invention (i.e., AB-1, AB-2, AB-3, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11 and AB-12), with Table 1 showing the correspondence between specific SEQ ID NOs and specific heavy chain regions and Table 2 showing the correspondence between specific SEQ ID NOs and specific light chain regions.

[0023] Table 1 shows the correspondence between particular SEQ ID NOs and particular heavy chain regions. C "- heavy chain, "L"- leader sequence, C H + tail region of the heavy chain including the Fc region, "HFR" - framework region of the heavy chain, "CDR-H" - complementarity determining region of the heavy chain).

[0024] [Table 1]

[0025] Table 2 shows the correspondence between particular SEQ ID NOs and particular light chain regions ("L C "-light chain, "L"-leader sequence or "C L " - the tail region of the light chain containing the constant region, "LFR" - the framework region of the light chain, "CDR-L" - the complementarity determining region of the light chain).

[0026] [Table 2]

[0027] SEQ ID NO:242 is an amino acid sequence representing an exemplary comparative epitope sequence from WO2017042242 (SEQ ID NO:3 therein) used to generate comparative domain-specific peptide AB as used herein (see, e.g., Figures 1-2).

[0028] SEQ ID NO:243 is an amino acid sequence representing another exemplary comparative epitope sequence from WO2017042242 (SEQ ID NO:4 therein) used to generate comparative domain-specific peptide AB as used herein (see, e.g., Figures 1-2).

[0029] SEQ ID NO:244 is an amino acid sequence representing yet another exemplary comparative epitope sequence of the present invention derived from WO2017042242 (SEQ ID NO:6 therein) used to generate comparative domain-specific peptide AB as used herein (see, e.g., Figures 1-2). [Brief description of the drawings]

[0030] The invention will be better understood by reference to the detailed description when considered in conjunction with the non-limiting examples and the accompanying drawings, which illustrate aspects of the method of the invention.

[0031] [Figure 1] Comparison of the novel structure-specific monoclonal antibodies (AB) of the present invention with domain-specific peptides AB from the prior art under non-denaturing conditions (no DTT, ambient / room temperature) and denaturing conditions (+DTT or +DTT and +95°C). Structure-specific AB detects proteins under non-denaturing conditions in SDS gels after Western blotting, whereas peptides AB only detect denatured proteins. Sequence ID NOs from which domain-specific peptides AB were generated from patent application WO2017042242 are provided. [Diagram 2]Western blotting showing a comparison of the novel structure-specific monoclonal antibodies (AB) of the present invention with domain-specific peptide ABs from the prior art on InsR / IGF1R activation and activation of downstream signaling proteins. The structure-specific ABs activate p-InsR / IGF1R, p-IRS1 and p-AKT in a dose-dependent manner, whereas the domain-specific peptide antibodies have no effect or an inhibitory effect on InsR / IGF1R pathway activation. [Figure 3-1] Western blotting of AB-1 to AB-12 of the present invention. [Figure 3-2] This is a continuation of Figure 3-1. [Figure 4-1] ELISA measurement of AB-1 to AB-12 of the present invention. [Figure 4-2] This is a continuation of Figure 4-1. [Figure 5-1] Measurement of the affinity Kd of antibodies AB-1 to AB-12 of the present invention. [Figure 5-2] This is a continuation of Figure 5-1. [Figure 5-3] This is a continuation of Figure 5-2. [Figure 5-4] This is a continuation of Figure 5-3. [Figure 5-5] This is a continuation of Figure 5-4. [Figure 5-6] This is a continuation of Figure 5-5. [Figure 6A] Sequence analysis of the light chains of AB-1 to AB-12 of the present invention. A. mbed-like clustering guide tree. [Figure 6B-1] B. Sequence alignment of the light chains of AB-1 to AB-12 of the present invention. [Figure 6B-2] This is a continuation of Figure 6B-1. [Figure 6C] Sequence analysis of the light chains of AB-1 to AB-12 of the present invention. C. Percent Identity Matrix-Generated by Clustal2.1. [Figure 7A] Sequence analysis of the heavy chains of AB-1 to AB-12 of the present invention. A. mbed-like clustering guide tree. [Figure 7B-1] B. Sequence alignment of the heavy chains of AB-1 to AB-12 of the present invention. [Figure 7B-2] This is a continuation of Figure 7B-1. [Figure 7C] Sequence analysis of the heavy chains of AB-1 to AB-12 of the present invention. C. Percent identity matrix - generated by Clustal2.1. [Figure 8-1] FIG. 13 is a preparation of Min6 cells and Western blotting of AB-1 to AB-12 of the present invention, showing that the ABs can regulate insulin receptor sensitization. [Figure 8-2] See description of Figure 8-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] Detailed Description The present inventors have produced and characterized a novel structure-specific IGFR-L1 antibody for specifically targeting the extracellular domain of non-denatured IGFR-L1 protein (SEQ ID NO:1).This is particularly advantageous because it leads to a new therapeutic method for treating diabetes, preventing or reversing insulin resistance, reversing the dysfunction / dedifferentiation of pancreatic islet cells, and / or increasing the number of pancreatic beta cells.Therefore, it is envisioned that the novel structure-specific IGFR-L1 antibody as described herein defines a new group of diabetic patients in that it is uniquely different from known domain-specific peptide AB and can be used in diabetic patients to prevent or reverse insulin resistance, reverse the dedifferentiation of pancreatic islet cells, and / or increase the number of pancreatic beta cells. Moreover, the novel structure-specific ABs of the present invention are capable of detecting their target proteins under non-denaturing conditions, for example in SDS gels after Western blotting, whereas the peptide ABs known from the prior art are only capable of detecting denatured proteins; moreover, the structure-specific ABs are capable of activating p-InsR / IGF1R, p-IRS1 and p-AKT in a dose-dependent manner, whereas the known domain-specific peptide antibodies have no effect or an inhibitory effect on InsR / IGF1R pathway activation. Therefore, the novel structure-specific ABs of the present invention represent a novel and unique IGFR-L1 antibody class. This is particularly advantageous since the new antibodies of the present invention are suitable for use in immunoprecipitation methods, for which the domain-specific peptide antibodies from the prior art are not suitable.

[0033] The present inventors have pioneered the elucidation of the function of the human KIAA1324 gene, which encodes an IGFR-like receptor (SEQ ID NO:1) as described herein. The protein product of KIAA1324, previously called UPF0577 protein KIAA1324 or estrogen-induced gene 121 (EIG121) protein, is commonly known as a cancer marker, but the present inventors were the first to attribute a crucial role to the protein in metabolism. The terms "IGFR-like receptor", "IGF-like receptor"; "IGF3 receptor", "IGF3R", "ELAPOR1", "endosome / lysosome-associated apoptosis and autophagy regulator 1", "inceptor", and "IGFR-L1" are used interchangeably herein and refer to, for example, endosome / lysosome-associated apoptosis and autophagy regulator 1, having UniProtKB Accession Number: Q6UXG2.

[0034] In some aspects, the present invention provides an antibody that binds to the extracellular domain of a folded or partially folded receptor protein comprising the amino acid sequence of SEQ ID NO:1, preferably to a native epitope within the IGFR-L1 protein, wherein binding by said antibody to said folded or partially folded IGFR-L1 protein is characterized by: (a) An aliquot of lysate from Min6 cells (ATCC CRL-11506) was (i) 5 min at ambient temperature in a buffer suitable for SDS-PAGE of proteins; (ii) a buffer suitable for SDS-PAGE of proteins and a reducing agent for 5 min at ambient temperature; and (iii) A buffer suitable for SDS-PAGE of proteins and a reducing agent at 95°C for 5 min. incubating separately with each of (b) subjecting said aliquot to SDS-PAGE; (c) Western blotting of SDS-PAGE gels; (d) incubating the Western blot membrane with said antibody; is determinable (e.g., determined) according to wherein the antibody detects only aliquot (i); Concerning antibodies.

[0035] In some further aspects of the invention, step (a) comprises: subjecting an aliquot of lysate from Min6 cells (ATCC CRL-11506) to (i) 50 mM Tris-HCl pH=6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, no buffer, no thiol agent, for 5 min at ambient temperature; (ii) 50 mM Tris-HCl pH=6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, 20 mM DTT, for 5 min at ambient temperature, and (iii) 50 mM Tris-HCl pH=6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, 20 mM DTT, 95° C. for 5 min Incubate separately with each of the following:

[0036] In some aspects of the invention, the antibodies of the invention can increase or decrease or modulate or inhibit binding of one or more growth factors (e.g., insulin) or similar ligands, morphogens, homo-oligomerization partners, hetero-oligomerization partners, and / or di-oligomerization partners to receptor proteins and / or other receptors.

[0037] In some aspects of the invention, the antibodies of the invention are capable of increasing the binding of insulin to the insulin receptor (InsR).

[0038] In some aspects of the invention, the antibodies of the invention are capable of modulating the binding of insulin to the insulin receptor (InsR).

[0039] In some aspects of the present invention, all 12 antibodies are made using a specific method against the native extracellular domain of IGFR-L1 / inceptor (see examples disclosed herein). The interceptor indirectly binds to the insulin receptor complex at the plasma membrane and mediates the internalization and thus desensitization of the activated insulin receptor complex. Therefore, when insulin-producing beta cells are incubated with any one of the 12 antibodies, the antibody binds to the extracellular domain of the interceptor and thus inhibits its interaction with the activated insulin receptor complex. Thus, the insulin receptor is not desensitized and insulin signal activation is enhanced and / or prolonged (Figure 8). In other words, the interceptor Ak of ​​the present invention binds to the interceptor (which may all have different paratopes, i.e. epitopes), thereby inhibiting the interceptor from efficiently integrating with the activated insulin receptor complex. Thus, the insulin receptor remains longer at the plasma membrane and is activated longer without being efficiently desensitized. This is supported for all 12 novel Aks of the present invention (p-IR / IGF1R) by FIG. 8, which provides a unifying feature for all Aks of the present invention in addition to their unique production methods.

[0040] In some aspects of the invention, the antibodies of the invention are capable of increasing InsR-mediated signaling.

[0041] In some aspects of the invention, the antibodies of the invention are capable of increasing phosphorylation of InsR, IRS1 and / or AKT and / or MEK and / or MAP kinase.

[0042] In some aspects of the invention, the antibodies of the invention are capable of binding to the receptor protein with a Kd of 10 nM or less, preferably 6 nM or less, more preferably 5 nM or less, and even more preferably 3 nM or less.

[0043] In some aspects, the antibodies of the present invention can be obtained by immunizing a rodent with proteoliposomes containing the receptor protein.

[0044] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (a) an antibody comprising a heavy chain having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO:2, and a light chain having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO:12.

[0045] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (b) an antibody comprising a heavy chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:22, and a light chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:32.

[0046] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (c) an antibody comprising a heavy chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:42, and a light chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:52.

[0047] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (d) an antibody comprising a heavy chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:62, and a light chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:72.

[0048] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (e) an antibody comprising a heavy chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:82, and a light chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:92.

[0049] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (f) an antibody comprising a heavy chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:102, and a light chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:112.

[0050] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (g) an antibody comprising a heavy chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:122, and a light chain having an amino acid sequence that is at least 85% identical to the amino acid sequence set forth in SEQ ID NO:132.

[0051] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (h) an antibody comprising a heavy chain having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO:142, and a light chain having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO:152.

[0052] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (i) an antibody comprising a heavy chain having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO:162, and a light chain having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO:172.

[0053] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (j) an antibody comprising a heavy chain having an amino acid sequence at least 85% identical to the amino acid sequence set forth in SEQ ID NO:182, and a light chain having an amino acid sequence at least 85% identical to the amino acid sequence set forth in SEQ ID NO:192.

[0054] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (k) an antibody comprising a heavy chain having an amino acid sequence at least 85% identical to the amino acid sequence set forth in SEQ ID NO:202, and a light chain having an amino acid sequence at least 85% identical to the amino acid sequence set forth in SEQ ID NO:212.

[0055] In some aspects of the invention, the antibodies of the invention have the following structural characteristics: (l) an antibody comprising a heavy chain having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO:222, and a light chain having an amino acid sequence that has at least 85% identity to the amino acid sequence set forth in SEQ ID NO:232.

[0056] In some aspects of the present invention, the antibodies of the present invention have the following structural features: (m) an antibody that binds to the same epitope in an receptor protein as the epitope bound by any one of antibodies (a) to (l) as defined herein.

[0057] In some aspects of the invention, an antibody of the invention has the following structural features: (a) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 19-140 of SEQ ID NO:2, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 28-136 of SEQ ID NO:12.

[0058] In some aspects of the invention, an antibody of the invention has the following structural characteristics: (b) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 62-177 of SEQ ID NO:22, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 48-162 of SEQ ID NO:32.

[0059] In some aspects of the invention, an antibody of the invention has the following structural characteristics: (c) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20-136 of SEQ ID NO:42, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 39-153 of SEQ ID NO:52.

[0060] In some aspects of the invention, an antibody of the invention has the following structural features: (d) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20-141 of SEQ ID NO:62, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 40-148 of SEQ ID NO:72.

[0061] In some aspects of the invention, an antibody of the invention has the following structural features: (e) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 58-175 of SEQ ID NO:82, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 21-129 of SEQ ID NO:92.

[0062] In some aspects of the invention, an antibody of the invention has the following structural features: (f) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 54-171 of SEQ ID NO:102, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 55-163 of SEQ ID NO:112.

[0063] In some aspects of the invention, an antibody of the invention has the following structural features: (g) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 19-139 of SEQ ID NO:122, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 45-156 of SEQ ID NO:132.

[0064] In some aspects of the invention, an antibody of the invention has the following structural features: (h) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20-139 of SEQ ID NO:142, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 40-148 of SEQ ID NO:152.

[0065] In some aspects of the invention, an antibody of the invention has the following structural features: (i) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20-133 of SEQ ID NO:162, and a light chain variable region having an amino acid sequence that is at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 40-148 of SEQ ID NO:172.

[0066] In some aspects of the invention, an antibody of the invention has the following structural features: (j) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 54-175 of SEQ ID NO:182, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 38-149 of SEQ ID NO:192.

[0067] In some aspects of the invention, an antibody of the invention has the following structural features: (k) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 55-170 of SEQ ID NO:202, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 21-135 of SEQ ID NO:212.

[0068] In some aspects of the invention, an antibody of the invention has the following structural features: (l) an antibody comprising a heavy chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20-144 of SEQ ID NO:222, and a light chain variable region having an amino acid sequence at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 52-165 of SEQ ID NO:232.

[0069] In some aspects of the present invention, the antibodies of the present invention have the following structural features: (m) an antibody that binds to the same epitope in the receptor protein as the epitope bound by any one of antibodies (a) to (l).

[0070] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (a) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:5, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:7, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:9, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:15, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:17, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:19.

[0071] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (b) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:25, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:27, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:29, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:35, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:37, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:39.

[0072] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (c) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:45, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:47, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:49, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:55, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:57, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:59.

[0073] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (d) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:65, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:67, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:69, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:75, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:77, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:79.

[0074] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (e) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:85, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:87, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:89, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:95, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:97, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:99.

[0075] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (f) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:105, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:107, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:109, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:115, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:117, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:119.

[0076] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (g) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:125, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:127, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:129, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:135, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:137, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:139.

[0077] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (h) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:145, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:147, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:149, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:155, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:157, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:159.

[0078] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (i) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:165, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:167, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:169, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:175, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:177, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:179.

[0079] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (j) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:185, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:187, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:189, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:195, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:197, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:199.

[0080] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (k) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:205, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:207, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:209, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:215, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:217, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:219.

[0081] In some aspects of the invention, an antibody of the invention has one or more of the following structural features: (l) an antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:225, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:227, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:229, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO:235, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO:237, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO:239.

[0082] In some aspects of the invention, the antibodies of the invention have one or more of the following structural features: (m) an antibody that binds to the same epitope in human PRDX4 protein as the epitope bound by any one of antibodies (a) to (l).

[0083] In some aspects of the invention, the antibodies of the invention are for use as pharmaceuticals and / or in therapy.

[0084] In some aspects of the invention, the antibodies of the invention are for use in methods for treating diabetes and / or hyperinsulinemia.

[0085] In some aspects of the invention, diabetes includes type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome or glucose tolerance or hyperinsulinemia.

[0086] In some aspects of the invention, the antibodies of the invention are for use in methods of preventing or reversing insulin resistance.

[0087] In some aspects of the invention, the antibodies of the invention are for use in methods of reversing pancreatic islet cell dysfunction / dedifferentiation.

[0088] In some aspects of the invention, the antibodies of the invention are for use in methods of increasing the number of pancreatic beta cells.

[0089] In some aspects of the invention, the natural / independent selection / generation of two individual clones (e.g., clones corresponding to AB-2 and AB-11) with conserved variable chain sequences but differences in the Fc chain highlights the highly conserved / available epitopes / coepitopes / antigens and their importance in regulating receptor structure / function; the importance of the Fc domain sequence and its alterations, mutations and / or chemical modifications, e.g., PEGylation, glycosylation, etc., to optimize antibody stability and bioavailability.

[0090] Also encompassed by the term "IGFR-like receptor" are functional variants of the IGFR-like receptors disclosed herein that have threshold sequence identity or sequence homology to the IGFR-like receptors described herein, said functional variants being contemplated to have at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5% or 100% sequence identity to SEQ ID NO:1.

[0091] It is further envisaged that said functional variant preferably exhibits the same properties as the UPF0577 protein KIAA1324, i.e. inhibits or reduces InsR and / or IGF1R mediated signalling, in particular (i) Akt phosphorylation and / or (ii) AMPK phosphorylation and / or (iii) mTOR phosphorylation, as assessable by routine methods presented in the accompanying examples.

[0092] The term "% identity" or "% sequence identity" as used herein refers to the percentage of pairwise identical residues, relative to the number of residues in the longer of the two sequences, following (homologous) alignment of the sequence of the polypeptide of the invention with the sequence in question. The percent identity is determined by dividing the number of identical residues by the total number of residues and multiplying the result by 100.

[0093] The term "homology" is used herein in its ordinary sense and includes not only identical amino acids, but also amino acids that are considered conservative substitutions (e.g., replacement of a glutamic acid residue with an aspartic acid residue) at equivalent positions in the linear amino acid sequences of the two proteins. Preferably, the amino acid sequences shown in SEQ ID NO:182 or 192 are preferred as "reference sequences."

[0094] SEQ ID NO:1 shows the human UPF0577 protein KIAA1324, also referred to herein as an IGFR-like receptor.

[0095] The terms "reference sequence" and "wild type sequence" (of IGFR-like receptor) are used interchangeably herein. Alternatively, the amino acid sequence having SWISS-PROT / UniProt Data Bank Accession Number Q6UXG2 (entry version 95 of July 22, 2015) can be used as a reference sequence.

[0096] The percentage of sequence homology or sequence identity can be determined, for example, herein using BLASTP version blastp 2.2.5 (November 16, 2002; see Altschul, SF et al. (1997) Nucl. Acids Res. 25, 3389-3402). In this embodiment, the percentage of homology is based on the alignment of the entire polypeptide sequence, including the propeptide sequence, preferably using the wild-type protein scaffold as a reference for pairwise comparison (matrix: BLOSUM 62; gap cost: 11.1). It is calculated as the percentage of the number of "positives" (homologous amino acids) shown as a result of the BLASTP program output divided by the total number of amino acids selected by the program for alignment.

[0097] In the context of the present invention, the phrase "position corresponding to another position" (e.g., region, fragment, nucleotide or amino acid position, etc.) is based on the convention of numbering according to the number of nucleotides or amino acid positions and then aligning the sequences so that the percentage of sequence identity is maximized. Not all positions within a given "corresponding region" need to be identical, so non-matching positions within a corresponding region may be considered as "corresponding positions". Thus, as used herein, reference to an "amino acid position corresponding to amino acid position [X]" of a specified protein sequence represents a reference to the amino acid position of the specified protein sequence as well as a reference to the collection of equivalent positions in other recognized proteins and structural analogs and families. The same may be applied mutatis mutandis to the phrase "sequence corresponding to a sequence". That is, reference to a sequence "corresponding to" a specified protein sequence [X] represents a reference to the sequence of the specified protein sequence as well as a reference to the collection of equivalent sequences in other recognized proteins and structural analogs and families.

[0098] The term "InsR" or "IR" refers to the insulin receptor and generally includes both the IR-A isoform (also known as the "short isoform") and the IR-B isoform (also known as the "long isoform"). InsR occurs as a tetramer of two α chains carrying the insulin-binding region and two β chains carrying the kinase domain linked by disulfide bonds. InsR is a receptor tyrosine kinase that is activated by the binding of insulin, IGF-1, and IGF-2, ultimately directing signal transduction through the MAPK / Ras-Raf-Erk pathway, the phosphatidylinositol-3-kinase / AKT / mTOR (PI3K / AKT) pathway, and / or the Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway. More precisely, ligand binding to the α-chain of the InsR ectodomain induces conformational changes within the receptor leading to autophosphorylation of various tyrosine residues within the intracellular tyrosine kinase domain of the β-chain, which in turn leads to recruitment and phosphorylation of several intracellular substrates, including insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins acts as a docking protein for other signaling proteins containing Src homology 2 domains (SH2 domains), including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRS proteins leads to the activation of two major signaling pathways: the PI3K-AKT / PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates the expression of several genes and cooperates with the PI3K pathway to control cell growth and differentiation. PI3K binding to phosphotyrosines on IRS1 and subsequent PI3K activation leads to phosphorylation and activation of AKT, AMPK and mTOR, signaling pathways that regulate metabolism and integrate signals from insulin. InsR activation by ligand binding also triggers the Ras / RAF / MAP2K / MAPK pathway through phosphorylation of IRS1 and recruitment of GRB2 / SOS, which is primarily involved in mediating cell growth, survival and insulin cellular differentiation.

[0099] An example of an InsR is the human InsR having Uniprot Acc. No. P06213 (entry version 216 of 22 July 2015) and variants thereof. The insulin receptor in the context of the present invention is preferably capable of inducing (i) AKT phosphorylation and / or (ii) AMPK phosphorylation and / or (iii) mTOR phosphorylation upon binding of its ligand, in particular insulin.

[0100] The term "IGF-receptor 1" or "IGF1R" or "IGFRI" is used herein to refer to insulin-like growth factor 1 receptor tyrosine kinase. IGF1R binds with high affinity to IGF1 and with lower affinity to IGF2 and insulin (INS). Ligand binding activates the receptor kinase, leading to receptor autophosphorylation and phosphorylation of multiple substrates, including insulin-receptor substrates (IRS1 / 2), Shc and 14-3-3 proteins, ultimately leading to activation of three major signaling pathways: the PI3K-AKT / PKB pathway, the Ras-MAPK pathway, and the JAK / STAT pathway. Activated IGF1R is involved in the control of cell growth and survival. Thus, although InsR and IGF1R feed into similar signaling pathways, InsR-mediated signaling preferentially regulates metabolism, whereas IGF1R signaling is involved in cell growth and survival.

[0101] An example of an IGF1R is the human IGF1R having Uniprot Acc. No. P08069 (entry version 185 of 22 July 2015) and variants thereof. IGF1R in the context of the present invention is preferably capable of inducing (i) AKT phosphorylation and / or (ii) AMPK phosphorylation and / or (iii) mTOR phosphorylation upon binding of its ligand, in particular IGF1.

[0102] The term "IGF1" or "IGFI" refers to insulin-like growth factor I, a protein structurally and functionally related to insulin but with higher growth-promoting activity. An example is human IGF1 having Uniprot Acc. No. P05019 (entry version 186 of July 22, 2015). "IGF1" in the context of the present invention is preferably capable of binding to the IGF1 receptor and inducing IGF1R signaling, as described elsewhere herein.

[0103] The terms "IGF2R" or "IGF2R" or "IGFRII" are used herein to refer to the insulin-like growth factor 2 / mannose-6-phosphate (IGF-2 / M6P) receptor. IGF2R is a single transmembrane protein composed of a large extracytoplasmic (i.e., extracellular) domain, a single transmembrane region, and a short cytoplasmic tail that lacks intrinsic catalytic activity. The receptor binds IGF-2 with higher affinity than IGF-1, but not insulin. IGF2R has been reported to interact with lysosomal enzymes and a variety of other M6P-containing ligands through distinct sites to regulate extracellular IGF-2 concentrations, thereby regulating signaling through the growth stimulatory IGF-1 receptor pathway.

[0104] An example of an IGF2R is the human IGF2R having Uniprot Acc. No. P11717 (entry version 174 of July 22, 2015) and variants thereof.

[0105] The term "IGF2" or "IGFII" refers to insulin-like growth factor II. An example is human IGF2 and its variants having Uniprot Acc. No. P01344 (entry version 199 of July 22, 2015). "IGF2" in the context of the present invention is preferably capable of binding to the IGF2 receptor.

[0106] As used herein, a variant or orthologue of the human KIAA1324 gene is envisaged to encode an IGFR-like receptor or a functional variant thereof, i.e. preferably capable of inhibiting or reducing InsR and / or IGF1R mediated signalling, in particular (i) AKT phosphorylation and / or (ii) AMPK phosphorylation and / or (iii) mTOR phosphorylation, and having at least about 60%, 65%, 70%, 75%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5% or 100% sequence identity with the human KIAA1324 gene (NCBI Gene ID 57535, updated on 15 July 2015), i.e. sequence identity with the coding sequence of the human KIAA1324 gene as shown in SEQ ID NO:7. The coding sequence of the human KIAA1324 gene (NG_032763.1) is represented by nucleotides 222..374, 47932..48052, 50537..50729, 57904..58051, 58526..58606, 59512..59617, 59726..59875, 71083..71171, 74215..74392, 75104..75232, 76106..76108, 77105..77109, 78104..78107, 79106..79109, 80105..80106, 80105..80107, 80105..80109, 80106 ... This is obtained by concatenating 5630..75720, 77404..77509, 77764..77901, 78649..78912, 80459..80632, 83512..83692, 84017..84113, 84611..84712, 85892..86018, 86097..86275, 86773..86938, 88982..89050.

[0107] As used herein, the term "isolated DNA sequence" refers to a DNA molecule that has been purified or substantially purified from endogenous materials, including other nucleic acid sequences, proteins, peptides, lipids, etc., that are naturally present in the cell and / or organism from which the DNA sequence is derived, and includes not only DNA purified by standard purification techniques, but also DNA prepared by recombinant techniques and that are chemically synthesized.

[0108] As used herein, the term "folded or partially folded" can mean having a 3D or tertiary structure, with or without post-translational modifications, such as one or more alpha helices, turns, unfolded elements, intrinsically disordered elements, coil-coil elements, beta sheets and / or their individual structural elements.

[0109] As used herein, the term "tertiary structure" may mean having the three-dimensional shape of a polypeptide in space, including one or more protein secondary structures and / or protein domains, with or without post-translational modifications, for example, one or more alpha helices, turns, unfolded elements, intrinsically disordered elements, coil-coil elements, beta sheets and / or their individual structural elements.

[0110] As used herein, the term "morphogen" may refer to a substance that directs the pattern of tissue development through its non-uniform distribution during morphogenesis or pattern formation.

[0111] As used herein, the term "homo-oligomerization partner" may refer to identical monomers contained within a polymer or a protein complex (eg, a protein complex that includes an acceptor protein).

[0112] As used herein, the term "hetero-oligomerization partner" may refer to non-identical monomers comprised within a polymer or a protein complex (eg, a protein complex that includes an acceptor protein).

[0113] As used herein, the term "dimerization or oligomerization partner" can refer to identical or non-identical monomers comprised within a dimer or oligomer (eg, a protein complex that includes an receptor protein).

[0114] vector The nucleic acids of the invention may also be in the form of, present in and / or part of a vector.

[0115] The term "vector" refers to a nucleic acid molecule used as a vehicle to transfer (foreign) genetic material into a host cell, and includes, but is not limited to, plasmids, viruses, cosmids, and artificial chromosomes, such as bacterial artificial chromosomes (BAC) and yeast artificial chromosomes (YAC). In general, engineered vectors contain an origin of replication, a multiple cloning site, and a selection marker. The vector itself is generally a DNA sequence that contains a nucleotide sequence, usually an insert (transgene) and a larger sequence that serves as the "backbone" of the vector. A vector may contain additional elements, besides the transgene insert and backbone, including genetic regulatory elements, genetic markers, antibiotic resistance, reporter genes, targeting sequences, or protein purification tags. In particular, expression vectors (expression constructs), which generally contain genetic regulatory sequences in addition to the transgene, for the expression of the transgene in a host cell, are envisaged within the context of the present invention.

[0116] An expression vector is generally a vector that is capable of providing expression of an antibody of the invention in vitro and / or in vivo (i.e., in a suitable host cell, host organism and / or expression system). One of skill in the art will readily appreciate that the selection of a particular vector will depend, for example, on the host cell, the intended copy number of the vector, whether transient or stable expression of the antibody of the invention is envisaged, etc.

[0117] "Transient expression" results from the introduction of a non-autoreplicative nucleic acid (e.g., a linear or non-linear DNA or RNA molecule) or vector into a recipient host cell. Expression of the transgene occurs through the transient expression of the introduced sequence.

[0118] However, "stable expression" of a nucleic acid sequence as described herein is often preferred, and can be achieved either by stably integrating the nucleic acid sequence into the genome of the host cell, or by introducing into the host cell a vector containing a nucleic acid sequence of the invention and capable of autonomous replication.

[0119] The vectors provided herein are specifically contemplated to contain genetic regulatory elements operably linked to a DNA sequence encoding an antibody of the invention.

[0120] The term "genetic regulatory element" refers to a DNA sequence required for the expression of a functionally linked coding sequence in a particular host organism. The term "genetic regulatory element" includes other elements that can control gene expression, including controllable transcriptional promoters, operators, enhancers, silencers, transcription terminators, 5' and 3' untranslated regions that interact with host cell proteins to carry out transcription and translation, and start and stop codons. The exact nature of the regulatory regions required for gene expression can vary from organism to organism. Genetic regulatory elements for prokaryotes include, for example, promoters, optionally operator sequences, and ribosome binding sites (RBS), while genetic regulatory elements for eukaryotic cells include promoters, polyadenylation (poly-A) signals, and enhancers.

[0121] A genetic regulatory element is considered to be "operably linked" to a gene to be expressed, i.e., placed in a functional relationship with the gene. For example, a promoter or enhancer is "operably linked" to a coding nucleic acid sequence if it affects the transcription of that sequence. "Operably linked" DNA sequences may be contiguous or non-contiguous. Linking is typically accomplished by ligation at convenient restriction sites or by synthetic oligonucleotide adaptors or linkers.

[0122] host cell Further provided herein are host cells (eg, recombinant and / or isolated host cells) that contain a vector as described herein.

[0123] A variety of host cells can be used to express the nucleic acid sequence encoding the antibody as described herein. The host cells can be prepared using genetic engineering methods known in the art. The process of introducing a vector into a recipient host cell is also referred to hereinafter as "transformation" or "transfection". These terms are used interchangeably herein.

[0124] Transformation of host cells typically involves opening transient pores or "holes" in the cell wall and / or cell membrane that allow for uptake of materials. Examples of transformation protocols involve the use of calcium phosphate, electroporation, cell squeezing, dendrimers, liposomes, cationic polymers such as DEAE-dextran or polyethyleneimine, sonoporation, optical transfection, impalefection, nanoparticles (gene guns), magnetofection, particle bombardment, alkaline cations (cesium, lithium), enzymatic digestion, agitation with glass beads, viral vectors, etc. The choice of method generally depends on the type of cell to be transformed, the vector to be introduced into the cell, and the conditions under which the transformation is to be performed.

[0125] As used herein, the term "host cell" refers to any cell or cell culture that acts as a recipient for a vector or isolated nucleic acid sequence encoding an Ab as described herein. Suitable host cells include prokaryotic or eukaryotic cells, including, but not limited to, bacteria, yeast cells, fungal cells, plant cells, and animal cells, such as insect cells and mammalian cells, e.g., murine, rat, macaque, or human.

[0126] For example, Abs can be produced in bacteria. In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for the IGFR-like receptors of the present invention. Examples include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces hosts such as K. lactis, K. fragilis (ATCC 12424), K. bulgaricus (ATCC 16045), K. wickeramii (ATCC 24178), K. waltii (ATCC 56500), K. drosophilarum (ATCC 36906), K. thermotolerans, and K. marxianus; Yarrowia (EP 402 226); Pichia pastoris (EP 183 070); Candida; Trichoderma reesia (EP 244 234); Neurospora crassa; Schwanniomyces, such as Schwanniomyces occidentalis; and filamentous fungi, such as Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts, such as A. nidulans and A. niger.

[0127] Suitable host cells for the expression of the glycosylated antibody constructs of the present invention may also be derived from multicellular organisms. Examples of invertebrate cells include plants and insect cells. Numerous baculovirus strains and variants and corresponding permissive insect host cells have been identified from hosts such as Spodoptera frugiperda (caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster (fruit fly) and Bombyx mori. Various virus strains for transfection are publicly available, such as the L-1 variant of Autographa californica NPV and the Bm-5 strain of Bombyx mori NPV.

[0128] Plant cell cultures of cotton, corn, potato, soybean, petunia, tomato, Arabidopsis, and tobacco can also be used as hosts. Cloning and expression vectors useful in the production of proteins in plant cell culture are known to those of skill in the art.

[0129] Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 cells or 293 cells subcloned to grow in suspension culture); baby hamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovary cells / -DHFR (CHO), mouse Sertoli cells (TM4); monkey kidney cells (CVI ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat hepatocytes (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human hepatocytes (Hep G2,1413 8065); mouse mammary tumor (MMT 060562, ATCC CCL5 1); TRI cells; MRC 5 cells; FS4 cells; and human hepatoma cells (Hep G2).

[0130] antibody The antibodies provided herein preferably exhibit the desired biological activity, i.e., specifically bind to the extracellular domain of a non-denatured receptor protein as described herein. "Increase" refers to the increase in the respective signal in the presence of the antibody compared to the absence of the antibody in the respective detection method used to detect and / or quantify the increase.

[0131] As is well known in the art, an antibody is an immunoglobulin molecule capable of specifically binding to a target (epitope) through at least one epitope recognition site located in its variable region. The term "antibody" as used herein includes monoclonal and polyclonal antibodies, as well as their (naturally occurring or synthetic) fragments or variants, including fusion proteins, multimeric assemblies (e.g., IgG dimers, etc.), including antibody moieties with antigen-binding fragments of the required specificity, and any other modified configuration of an antibody that contains an antigen-binding site or fragment (epitope recognition site) of the required specificity. Examples include dAbs, nanobodies, affibodies, Fab, Fab', F(ab'), including scFvs linked to CH3 domains. 2 , Fv, single chain Fv (scFv), diabodies, and minibodies. It will be understood that other antibody frameworks or scaffolds comprising an "antigen binding site" can be used in accordance with the present invention. Thus, the term "antibody" also includes these scaffolds. The mentioned scaffolds include, for example, non-immunoglobulin-based antibodies and scaffolds onto which the CDRs of an antibody can be grafted. Such scaffolds include, for example, anticalins, avimers, affilins, etc.

[0132] The antibody may be a chimeric antibody (or an antigen-binding variant or fragment thereof). The term "chimeric antibody" refers to antibodies in which portions of the heavy and / or light chains are identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chains are identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, and to fragments of such antibodies.

[0133] The antibody may be a humanized antibody (or an antigen-binding variant or fragment thereof). The term "humanized antibody" refers to an antibody that contains minimal sequence derived from a non-human antibody. Generally, humanized antibodies are human immunoglobulins that comprise residues from a hypervariable region of an immunoglobulin derived from a non-human species such as mouse, rat, rabbit or non-human primate (the "donor antibody") grafted onto a human immunoglobulin (the "recipient antibody"). In some cases, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or the donor antibody. This modification is made to further refine antibody performance. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.

[0134] The antibody may be a human antibody. A "human antibody" is an antibody that possesses an amino acid sequence that corresponds to that of an antibody produced by a human and / or has been produced using any of the techniques for producing human antibodies. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries (Hoogenboom and Winter, J. MoI Biol, 227:381 (1991); Marks et al, J. MoI Biol, 222:581 (1991)). Also, methods described in Cole et al, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol, 147(l):86-95 (1991) are available for the preparation of human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol, 5: 368-374 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenomice, that have been engineered to produce such antibodies in response to antigen challenge but whose endogenous loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 for XENOMOUSE™ technology). See also, e.g., Li et al, Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) for human antibodies made via human B cell hybridoma technology.

[0135] chemical modification Antibodies or antigen-binding variants or fragments thereof used in accordance with the present invention may be modified. Exemplary modifications contemplated in the context of the present invention include, for example, chemical modifications as described below.

[0136] Generally, any type of modification is contemplated as long as it does not destroy the ability of the antibody or antigen-binding variant or fragment thereof to specifically bind to the extracellular domain of the native receptor protein as described elsewhere herein.

[0137] Possible chemical modifications of antibodies or antigen-binding variants or fragments thereof include acylation or acetylation of the amino terminus or amidation or esterification of the carboxy terminus, or both. Modifications can also affect the amino groups in the side chains of lysine or the hydroxyl groups of threonine. Other suitable modifications include, for example, extension of amino groups with polypeptide chains of various lengths (e.g., XTEN technology or PASylation®), N-glycosylation, O-glycosylation, and chemical conjugation of carbohydrates such as hydroxyethyl starch (e.g., HESylation®) or polysialic acid (e.g., PolyXen® technology). Chemical modifications such as alkylation (e.g., methylation, propylation, butylation), arylation and etherification are possible and are also envisioned.

[0138] The antibodies of the present invention specifically bind to the extracellular domain of the native receptor protein comprising the amino acid sequence of SEQ ID NO:1, preferably to a native epitope within the IGFR-L1 protein, i.e., they do not exhibit cross-reactivity to non-target molecules such as InsR, IGF1R and IGF2R.

[0139] The term "epitope" generally refers to a site on an antigen to which a binding domain, such as an antibody or immunoglobulin or a derivative or fragment of an antibody or immunoglobulin, specifically binds. An "epitope" is antigenic, and therefore the term epitope is sometimes also referred to herein as an "antigen structure" or "antigenic determinant". Thus, the binding domain is an "antigen interaction site". Said binding / interaction is also understood to define "specific recognition". The term "epitope" encompasses linear epitopes and conformational epitopes. A linear epitope is a contiguous epitope contained within a primary amino acid sequence, typically comprising at least 3 or at least 4, more commonly at least 5 or at least 6 or at least 7, e.g., about 8 to about 10 amino acids in a unique sequence. A conformational epitope is formed by non-contiguous amino acids juxtaposed by protein folding. Methods for determining the three-dimensional structure of an epitope include, but are not limited to, X-ray crystallography, two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy and site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy.

[0140] The terms "polypeptide" and "protein" may be used interchangeably herein.

[0141] specific binding The terms "bind" and "recognize" are used interchangeably herein in all grammatical forms.

[0142] The term "specifically binds" generally indicates that a binding agent, particularly an antibody, binds to its intended target (i.e., to the extracellular domain of a non-modified receptor protein as described herein) with higher affinity than its non-target molecule. Non-target molecules include IGF receptors, particularly human IGF1R with Uniprot Acc. No. P08069 (Entry version 185 of July 22, 2015), human IGF2R with Uniprot Acc. No. P11717 (Entry version 174 of July 22, 2015), and human InsR with Uniprot Acc. No. P06213 (Entry version 216 of July 22, 2015); as well as functional variants thereof. Preferably, the affinity of an agonist or antagonist will be at least about 5-fold, preferably 10-fold, more preferably 25-fold, even more preferably 50-fold, and most preferably 100-fold or more greater for the target molecule than its affinity for the non-target molecule. Preferred antibodies have a molecular weight of at least about 10 7 M -1 , preferably about 10 8 M -1 ~about 10 9 M -1 , about 10 9 M -1 ~about 10 10 M -1 , or about 10 10 M -1 ~about 10 12 M -1 It binds with an affinity of

[0143] Preferably, the term "specifically binds" therefore indicates that an antagonist or agonist, such as an antibody, binds exclusively to its intended target (ie, an IGFR-like receptor).

[0144] treatment It is assumed that the IGFR-like receptor antibody of the present invention is particularly useful in the treatment and diagnosis of diabetes.As used herein, "diabetes" refers to a broad class of disorders characterized by abnormal insulin production and glucose tolerance, and generally includes type 1 and type 2 diabetes (also called juvenile and adult onset, respectively), gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, and impaired glucose tolerance.Diabetes results from the deficiency or dysfunction of insulin-producing β-cells, alone or in combination with insulin resistance.

[0145] The term "metabolic syndrome" includes abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, low high density lipoprotein (HDL) and / or high low density lipoprotein (LDL) levels, which are further associated with the risk of developing cardiovascular disease, including type 2 diabetes and / or coronary heart disease.

[0146] The terms "β cells," "beta cells," and "islet cells" are used interchangeably herein and refer to pancreatic β cells, located in the islets of Langerhans, whose primary function is to store and release insulin.

[0147] Defective insulin secretion underlies all forms of diabetes mellitus. Destruction of β-cells contributes to type 1 diabetes (T1D), whereas both reduced β-cell mass and loss of secretory function are involved in type 2 diabetes (T2D). Emerging results suggest that functional defects involving dedifferentiation of mature β-cells to a more progenitor-like state may be an important driver of abnormal secretion in T2D.

[0148] It is contemplated that the antagonists and agonists of the present invention can be advantageously used in suppressing the dedifferentiation of β-cells and / or reversing the loss of function of β-cells.The antagonists and agonists described herein are therefore contemplated for use as pharmaceuticals.In particular, the antagonists and agonists are intended for use in methods for the prophylactic and / or therapeutic treatment of diabetes.

[0149] Type 1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM) and juvenile diabetes. The terms are used interchangeably herein. This form accounts for 5-10% of diabetes and is believed to be due to cellular autoimmune destruction of pancreatic β cells, resulting in little or no insulin secretion. The IGFR-like receptor antagonists and agonists provided herein may be capable of suppressing or even reversing β cell dedifferentiation and / or loss of function. Thus, the present invention is envisioned to open up new possibilities for preventive or regenerative therapy of T1D.

[0150] Type 2 diabetes, also referred to as adult-onset diabetes, accounts for approximately 90-95% of all diabetes. Insulin resistance in target tissues and a relative deficiency in insulin secretion from pancreatic β cells are the primary features of type 2 diabetes (T2D). Insulin resistance is used herein to describe a condition characterized by impaired insulin response of target cells leading to hyperglycemia. Pancreatic β cells in the pancreas then increase production of insulin, leading to hyperinsulinemia. Without being bound to a particular theory, it is contemplated that the IGFR-like receptors described herein act as scavengers for either insulin or insulin receptor. For example, IGFR-like receptors can bind to insulin receptors, leading to their internalization (insulin receptor scavenger). IGFR-like receptors can also bind to insulin, leading to its internalization and potentially lysosomal degradation (insulin scavenger). Inhibiting these IGFR-like receptor functions with the aid of antagonists as described herein can increase InsR and / or IGF1R mediated signaling, thereby restoring insulin sensitivity.

[0151] patient The term "patient" or "subject" as used herein refers to a human or non-human animal, generally a mammal. In particular, a mammal, such as rabbit, mouse, rat, guinea pig, hamster, dog, cat, pig, cow, goat, sheep, horse, monkey, ape or preferably human, is envisaged. Thus, the methods, uses and compounds described herein are generally applicable to both human and animal diseases.

[0152] treatment The term "treatment" in all its grammatical forms includes therapeutic or prophylactic treatment. "Therapeutic or prophylactic treatment" includes prophylactic treatment aimed at completely preventing clinical and / or pathological signs, or therapeutic treatment aimed at improving or ameliorating clinical and / or pathological signs of disease. Thus, the term "treatment" also includes the amelioration or prevention of diabetes.

[0153] In the context of the present invention, the term "therapeutic effect" generally refers to the desired or beneficial effects of treatment, such as the improvement or amelioration of disease symptoms. The term "sign" of a disease is used herein to describe its perceptible manifestation, and includes both clinical signs, hereafter defined as indicators of a disease (i.e., symptoms) that can be detected during a physical examination and / or are perceptible by the patient, and pathological signs, meaning the manifestation of a disease at the cellular and molecular level. The therapeutic effect of treatment with the IGFR-like antibody of the present invention can be evaluated using routine methods in the art, for example, by measuring insulin and / or glucose levels in a patient's blood sample. Additionally or alternatively, it is also possible to evaluate the overall impression (e.g., health, well-being) of each patient, which will also assist the skilled practitioner in assessing whether the therapeutic effect has been exerted. The skilled practitioner will be aware of numerous other techniques suitable for observing the therapeutic effect of the compounds of the present invention.

[0154] dose Preferably, a therapeutically effective amount of a compound as described herein is administered. By "therapeutically effective amount" is meant an amount of a compound as described herein that exerts a therapeutic effect. The exact dose of the IGFR-like receptor antibody of the present invention will depend on the purpose of the treatment (e.g., maintaining remission or treating acute exacerbations of the disease) and will be ascertained by one of ordinary skill in the art using known techniques. Adjustments may be necessary to the route of administration, age, weight, overall health, sex, diet, time of administration, drug interactions and severity of the condition, and will be ascertained by one of ordinary skill in the art with routine experimentation.

[0155] Administration A variety of routes are applicable for administration of the compounds according to the invention, including but not limited to oral, topical, transdermal, subcutaneous, intravenous, intraperitoneal, intramuscular or intraocular, however, any other route may be readily selected by the skilled artisan, if desired.

[0156] composition It is contemplated that the IGFR-like antibodies of the present invention will be administered in the form of a pharmaceutical composition.

[0157] The term "pharmaceutical composition" refers in particular to a composition suitable for administration to humans, i.e., a composition that is preferably sterile and / or contains pharma- ceutically acceptable components. However, compositions suitable for administration to non-human animals are also contemplated herein. Preferably, the pharmaceutical composition comprises an IGFR-like antibody of the present invention together with one or more pharmaceutical excipients. The term "excipient" includes a bulking agent, a binder, a disintegrant, a coating agent, an adsorbent, an anti-adherent, a glidant, a preservative, an antioxidant, a flavoring agent, a coloring agent, a sweetener, a solvent, a cosolvent, a buffer, a chelating agent, a viscosity imparting agent, a surfactant, a diluent, a humectant, a carrier, a diluent, a preservative, an emulsifier, a stabilizer, or an osmolality adjusting agent. The pharmaceutical compositions of the present invention can be formulated in various forms, e.g., solid, liquid, gaseous or lyophilized, including, among others, ointments, creams, transdermal patches, gels, powders, tablets, solutions, aerosols, granules, pills, suspensions, emulsions, capsules, syrups, solutions, elixirs, extracts, tinctures or liquid extracts, or any form particularly suited to the desired method of administration.

[0158] The pharmaceutical composition of the present invention may further comprise one or more additional active substances.Preferably, said active substances are therapeutically effective for treating the diseases described herein and are present in the composition in a therapeutically effective amount.Examples include, but are not limited to, metformin, sulfonylurea, meglitinide, thiazolidinedione, DPP-4 inhibitor, GLP-1 receptor agonist, SGLT2 inhibitor, insulin and insulin derivatives (insulin glulisine, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin isophane), and combinations thereof.

[0159] In view of the above, the present invention therefore also provides pharmaceutical compositions comprising one or more IGFR-L1 antibodies of the invention, said pharmaceutical compositions being intended in particular for use in methods for the therapeutic and / or prophylactic treatment of diabetes.

[0160] kit Also provided herein is a kit. The kit may be a kit of two or more parts, and preferably comprises the IGFR-like receptor antibody of the present invention in a therapeutically effective amount and in a pharma-ceutically acceptable form. The components of the kit may be contained in a container or vial. It is envisaged that the kit may comprise additional agents useful in the treatment of diabetes, as described elsewhere herein. Exemplary additional agents include, but are not limited to, metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, insulin and insulin derivatives (insulin glulisine, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin isophane), and combinations thereof.

[0161] The IGFR-like antibody of the invention and the additional agent may be administered to the patient simultaneously or sequentially.

[0162] The present invention is also characterized by the following: 1. An antibody (e.g., an antigen-binding portion thereof) that binds to the extracellular domain of a non-denatured (e.g., native) receptor protein comprising the amino acid sequence of SEQ ID NO:1, preferably to a native epitope within the IGFR-L1 protein, and more preferably, binding by the antibody to the non-denatured IGFR-L1 protein is as follows: (a) An aliquot of lysate from Min6 cells (ATCC CRL-11506) was (i) 5 min at ambient temperature in a buffer suitable for SDS-PAGE of proteins; (ii) a buffer suitable for SDS-PAGE of proteins and a reducing agent for 5 min at ambient temperature; and (iii) A buffer suitable for SDS-PAGE of proteins and a reducing agent at 95°C for 5 min. incubating separately with each of (b) subjecting said aliquot to SDS-PAGE; (c) Western blotting of SDS-PAGE gels; (d) incubating the Western blot membrane with said antibody; is determinable (e.g., determined) according to wherein the antibody detects only aliquot (i); antibody.

[0163] 2. An antibody that binds to the extracellular domain of a folded (e.g., native) or partially folded (e.g., having 3D and / or tertiary structure, with or without post-translational modifications, e.g., one or more alpha helices, turns, unfolded elements, intrinsically disordered elements, coil-coil elements, beta sheets and / or their individual structural elements) receptor protein comprising the amino acid sequence of SEQ ID NO:1, preferably to a native epitope within the IGFR-L1 protein, wherein binding by said antibody to said folded or partially folded IGFR-L1 protein is as follows: (a) An aliquot of lysate from Min6 cells (ATCC CRL-11506) was (i) 5 min at ambient temperature in a buffer suitable for SDS-PAGE of proteins; (ii) a buffer suitable for SDS-PAGE of proteins and a reducing agent for 5 min at ambient temperature; and (iii) A buffer suitable for SDS-PAGE of proteins and a reducing agent at 95°C for 5 min. incubating separately with each of (b) subjecting said aliquot to SDS-PAGE; (c) Western blotting of SDS-PAGE gels; (d) incubating the Western blot membrane with said antibody; is determinable (e.g., determined) according to wherein the antibody detects only aliquot (i); antibody.

[0164] 3. The antibody of any one of the preceding claims, wherein said partial folding is performed using SDS treatment according to any one of the preceding claims.

[0165] 4. Step (a) (a) An aliquot of lysate from Min6 cells (ATCC CRL-11506) was (i) 50 mM Tris-HCl pH=6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, no buffer, no thiol agent, for 5 min at ambient temperature; (ii) 50 mM Tris-HCl pH=6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, 20 mM DTT, for 5 min at ambient temperature, and (iii) 50 mM Tris-HCl pH=6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, 20 mM DTT, 95° C. for 5 min Incubate separately with each of The antibody of any one of the preceding claims.

[0166] 5. An antibody of any one of the preceding items which increases or decreases or modulates or inhibits binding of one or more growth factors (e.g., insulin) or similar ligands, morphogens, homo-oligomerization partners, hetero-oligomerization partners, and / or di-oligomerization partners to receptor proteins and / or other receptors (e.g., InsR).

[0167] 6. The antibody of any one of the preceding items, which increases or decreases or modulates or inhibits the binding of insulin to an insulin receptor (e.g., InsR).

[0168] 7. The antibody of any one of the preceding items, which increases binding of insulin to the insulin receptor (e.g., InsR).

[0169] 8. An antibody of any one of the preceding items, which increases insulin receptor sensitivity.

[0170] 9. The antibody of any one of the preceding items, which modulates insulin receptor sensitivity.

[0171] 10. The antibody of any one of the preceding items, which modulates insulin on- and off-rate binding kinetics and / or de- and hypersensitization of the InsR kinase domain.

[0172] 11. The antibody of any one of the preceding items, wherein the antibody increases InsR-mediated signaling, preferably said increase is compared to a control antibody of the same class and / or subtype.

[0173] 12. The antibody of any one of the preceding items, wherein the antibody increases phosphorylation of InsR, IRS1 and / or AKT and / or MEK and / or MAP kinase, preferably wherein said increase is compared to a control antibody of the same class and / or subtype.

[0174] 13. The antibody of any one of the preceding items, wherein the extracellular domain ranges from amino acids 1-910 of SEQ ID NO:1, and preferably, the extracellular domain ranges from amino acids 42-910 of SEQ ID NO:1 (e.g., lacking the signaling peptide having amino acids 1-41 of SEQ ID NO:1).

[0175] 14. The antibody of any one of the preceding items which binds to the receptor protein with a Kd of 10 nM or less, preferably 6 nM or less, more preferably 5 nM or less, even more preferably 3 nM or less.

[0176] 15. The antibody of any one of the preceding items, which is producible by immunizing a rodent with proteoliposomes containing the receptor protein.

[0177] 16. (a) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:2, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:12; (b) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:22, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:32; (c) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:42, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:52; (d) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:62, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:72; (e) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:82, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:92; (f) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:102, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:112; (g) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:122, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:132; (h) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:142, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:152; (i) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:162, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:172; (j) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:182, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:192; (k) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:202, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:212; (l) an antibody comprising a heavy chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:222, and a light chain having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:232; or (m) an antibody that binds to the same epitope in the receptor protein as that bound by any one of the antibodies (a) to (l); The antibody of any one of the preceding items,

[0178] 17. (a) an antibody comprising a heavy chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 19-140 of SEQ ID NO:2, and a light chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 28-136 of SEQ ID NO:12; (b) an antibody comprising a heavy chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 62-177 of SEQ ID NO:22, and a light chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 48-162 of SEQ ID NO:32; (c) an antibody comprising a heavy chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20-136 of SEQ ID NO:42, and a light chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 39-153 of SEQ ID NO:52; (d) an antibody comprising a heavy chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20 to 141 of SEQ ID NO:62, and a light chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 40 to 148 of SEQ ID NO:72; (e) an antibody comprising a heavy chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 58-175 of SEQ ID NO:82, and a light chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 21-129 of SEQ ID NO:92; (f) an antibody comprising a heavy chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 54-171 of SEQ ID NO:102, and a light chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 55-163 of SEQ ID NO:112; (g) an antibody comprising a heavy chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 19-139 of SEQ ID NO:122, and a light chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 45-156 of SEQ ID NO:132; (h) an antibody comprising a heavy chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20 to 139 of SEQ ID NO:142, and a light chain variable region having an amino acid sequence at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 40 to 148 of SEQ ID NO:152; (i) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 20 to 133 of SEQ ID NO:162, and a light chain variable region having an amino acid sequence that is at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 40 to 148 of SEQ ID NO:172; (j) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 54-175 of SEQ ID NO:182, and a light chain variable region having an amino acid sequence that is at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to amino acids 38-149 of SEQ ID NO:192; (k) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 25% identical (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) to amino acids 55-170 of SEQ ID NO:202, and a light chain variable region having an amino acid sequence that is at least 25% identical (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) to amino acids 21-135 of SEQ ID NO:212; (l) an antibody comprising a heavy chain variable region having an amino acid sequence that is at least 25% identical (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) to amino acids 20 to 144 of SEQ ID NO:222, and a light chain variable region having an amino acid sequence that is at least 25% identical (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) to amino acids 52 to 165 of SEQ ID NO:232; or (m) an antibody that binds to the same epitope in the receptor protein as that bound by any one of the antibodies (a) to (l); The antibody of any one of the preceding items,

[0179] 18. The antibody of any one of the preceding items, wherein the variable region comprises or consists of seven amino acid regions, four of which are corresponding framework regions (e.g., HFRs and / or LFRs, e.g., as depicted in Table 1 and / or Table 2 herein), and three of which are corresponding CDRs (which may also be referred to herein as "hypervariable regions"), e.g., as depicted in Table 1 and / or Table 2 herein.

[0180] 19. (a) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:5, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:7, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:9; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:15; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:17; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:19; an antibody; (b) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:25, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:27, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:29; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:35; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:37; a light chain variable region comprising a light chain having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:39; an antibody; (c) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:45, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:47, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:49; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:55; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:57; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:59; an antibody; (d) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:65, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:67, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:69; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:75; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:77; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:79; an antibody; (e) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:85, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:87, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:89; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:95; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:97; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in NO:99; an antibody; (f) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:105, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:107, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:109; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:115; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:117; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:119; an antibody; (g) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:125, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:127, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:129; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:135; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:137; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:139; an antibody; (h) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:145, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:147, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:149; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:155; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:157; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:159; an antibody; (i) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:165, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:167, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:169; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:175; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:177; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:179; an antibody; (j) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:185, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:187, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:189; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:195; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:197; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:199; an antibody; (k) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:205, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:207, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:209; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:215; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:217; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:219; an antibody; (l) a heavy chain CDR1 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:225, a heavy chain CDR2 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:227, and a heavy chain variable region comprising a heavy chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:229; a light chain CDR1 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:235; a light chain CDR2 having an amino acid sequence that has at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:237; a light chain variable region comprising a light chain CDR3 having an amino acid sequence having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:239; an antibody; or (m) an antibody that binds to the same epitope in human peroxiredoxin-4 protein (PRDX4, e.g., having UniProtKB Accession Number: Q13162) as the epitope bound by any one of the antibodies (a) to (l); The antibody of any one of the preceding items,

[0181] 20. The antibody of any one of the preceding items, comprising one or more amino acid sequences having at least 25% (e.g., at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to any of the amino acid sequences set forth in SEQ ID NOs:2-241.

[0182] 21. The antibody of any one of the preceding items, comprising one or more of the following: i) one or more H C (heavy chain) and / or L C (light chain) leader sequence (L), e.g., as depicted in Table 1 and / or Table 2 herein; ii) one or more framework regions HFR1 and / or LFR1, e.g., as depicted in Table 1 and / or Table 2 herein; iii) one or more framework regions HFR2 and / or LFR2, e.g., as depicted in Table 1 and / or Table 2 herein; iv) one or more framework regions HFR3 and / or LFR3, e.g., as depicted in Table 1 and / or Table 2 herein; v) one or more framework regions HFR4 and / or LFR4, e.g., as depicted in Table 1 and / or Table 2 herein; and / or vi) one or more tail regions, e.g., H L (heavy chain constant region) and / or C L (light chain constant), e.g., as depicted in Table 1 and / or Table 2 herein.

[0183] 22. The antibody of any one of the preceding items, comprising one or more of the following features: i) SEQ ID NO: 182 (e.g., H of AB-10) C (I) at a position corresponding to position 104 of the amino acid sequence of (I) above, which is preferably part of the heavy chain CDR2 region; ii) SEQ ID NO: 182 (e.g., H of AB-10) C the amino acid T at a position corresponding to position 111 of the amino acid sequence of iii) SEQ ID NO: 192 (e.g., L of AB-10) C the amino acid T at a position corresponding to position 137 of the amino acid sequence (A) of (A), which is preferably part of the light chain CDR3 region; iv) a heavy chain having an amino acid sequence at least 72% (e.g., at least 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:1; v) a light chain having an amino acid sequence at least 59% (e.g., at least 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:12; vi) SEQ ID a light chain variable region comprising a light chain CDR1 (e.g., CDR-L1) having an amino acid sequence having at least 50% (e.g., at least 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in NO:15; vii) SEQ ID a light chain variable region comprising a light chain CDR2 (e.g., CDR-L2) having an amino acid sequence having at least 50% (e.g., at least 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:17; viii) SEQ ID a light chain variable region comprising a light chain CDR3 (e.g., CDR-L3) having an amino acid sequence having at least 50% (e.g., at least 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in SEQ ID NO:19; ix) SEQ ID a heavy chain variable region comprising a heavy chain CDR1 (e.g., CDR-H1) having an amino acid sequence having at least 50% (e.g., at least 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in NO:5; x) SEQ ID a heavy chain variable region comprising a heavy chain CDR2 (e.g., CDR-H2) having an amino acid sequence having at least 50% (e.g., at least 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in NO:7; xi) SEQ ID A heavy chain variable region comprising a heavy chain CDR3 (e.g., CDR-H3) having an amino acid sequence having at least 50% (e.g., at least 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identity to the amino acid sequence set forth in NO:9.

[0184] 23. The antibody of any one of the preceding items, comprising one or more (e.g., 2-469) conservative amino acid substitutions (e.g., exemplary or preferred) of the original amino acids in accordance with Table 3 below: [Table 3] TIFF2024529411000004.tif247150TIFF2024529411000005.tif77150

[0185] 24. The antibody of any one of the preceding items which is a monoclonal antibody.

[0186] 25. The antibody of any one of the preceding items, which is chimeric, humanized or human.

[0187] 26. The antibody of any one of the preceding items, coupled to a labeling group and / or a protein tag, and / or comprising one or more substitutions with non-naturally occurring amino acids.

[0188] 27. The antibody of any one of the preceding items, which is obtainable by a hybridoma (e.g., is a recombinant antibody).

[0189] 28. The antibody of any one of the preceding items, for use as a medicament and / or in therapy.

[0190] 29. The antibody of any one of the preceding items for use in a method for treating diabetes and / or cancer.

[0191] 30. The antibody for use of any one of the preceding items, wherein diabetes includes type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, or glucose tolerance.

[0192] 31. The antibody of any one of the preceding items for use in a method of preventing or reversing insulin resistance.

[0193] 32. The antibody of any one of the preceding items, for use in a method of reversing pancreatic islet cell dedifferentiation and / or dysfunction.

[0194] 33. The antibody of any one of the preceding items for use in a method of increasing the number of pancreatic beta cells.

[0195] 34. An antibody according to any one of the preceding items, obtainable by hybridoma and / or by any other suitable mammalian cell expression system.

[0196] 35. An antibody according to any one of the preceding items, which is capable of specifically binding to the ectodomain within SEQ ID NO:1.

[0197] 36. The antibody according to any one of the preceding items, selected from the group consisting of AB-1, AB-2, AB-3, AB-4, AB-5, AB-5, AB-6, AB-7, AB-8, AB-9, AB-10, AB-11 and AB-12, preferably AB-2 and AB-11, or a group corresponding thereto.

[0198] 37. An antibody according to any one of the preceding items, selected from the group consisting of AB-2 and AB-11 or a group corresponding thereto, wherein said AB-2 and AB-11 are obtainable from two individual clones having conserved (e.g., identical) variable chain sequences according to any one of the preceding items but having differences (e.g., non-identical sequences) in the fragment crystallizable region (i.e., Fc region or tail region).

[0199] 38. An antibody according to any one of the preceding items, which is AB-10.

[0200] 39. An antibody according to any one of the preceding items, which is AB-11.

[0201] 40. An antibody according to any one of the preceding items, which is AB-2.

[0202] 41. The tail region is post-translationally modified (e.g., glycosylation, e.g., N- and O-linked glycosylation, glycosylation, cysteinylation and sulfation; chain trimmed, e.g., C-terminal lysine clipping; amino acid modification, e.g., cyclization (e.g., to N-terminal pyroglutamic acid), deamidation, oxidation, isomerization and carbamylation; disulfide scrambling of the hinge region interchain disulfide bond, PEGylation, methylation, acetylation and / or phosphorylation, etc.), preferably wherein the tail region is (i) an Fc and C polypeptide according to any one of the preceding items; H ; and / or C by any one of the preceding items L An antibody according to any one of the preceding items,

[0203] 42. A multimeric assembly of antibodies (e.g., an IgG dimer) comprising one or more antibodies according to any one of the preceding items.

[0204] 43. The epitope, epitope, co-epitope or antigen of an antibody according to any one of the preceding items, preferably fragments and / or isolated receptor ectodomains as well as complete receptors in cell membranes and / or receptors in detergent micelles or mixed micelles are screened, obtained using one or more of the following: epitope mapping, cryo-electron microscopy, protein crystallization, chemical cross-linking, mass spectrometry, HDX exchange mass spectrometry, NMR and other suitable structural techniques, phage display and / or similar methods.

[0205] 44. A hybridoma that produces a monoclonal antibody according to any one of the preceding items.

[0206] 45. A nucleic acid encoding an antibody according to any one of the preceding items.

[0207] 46. ​​An expression vector comprising at least one nucleic acid molecule according to any one of the preceding items.

[0208] 47. A bispecific molecule comprising the antibody of any one of the preceding items linked to a molecule having a second binding specificity, wherein the second binding specificity is different from the binding specificity of the antibody.

[0209] 48. An immunoconjugate comprising an antibody of any one of the preceding items linked to a second agent, wherein said second agent is different from said antibody.

[0210] 49. A host cell (e.g., a recombinant host cell, e.g., an isolated recombinant host cell) comprising a vector and / or nucleic acid according to any one of the preceding items, preferably said host cell being transformed with said vector and / or nucleic acid, more preferably said host cell being a heterologous host cell, and most preferably said host cell being a non-human host cell.

[0211] 50. A composition comprising an antibody, a hybridoma, a nucleic acid, an expression vector, a bispecific molecule, an immunoconjugate, a host cell, a multimeric assembly according to any one of the preceding items.

[0212] 51. A composition according to any one of the preceding items, which is a pharmaceutical or diagnostic composition.

[0213] 52. A method for the production of an antibody according to any one of the preceding items, comprising culturing a host cell according to any one of the preceding items under conditions allowing the synthesis of said antibody, and recovering said antibody or an antigen-binding portion thereof from said culture.

[0214] 53. The method according to any one of the preceding items, wherein the antibody is a monoclonal or polyclonal antibody.

[0215] 54. A method for treating, ameliorating, preventing or diagnosing diabetes, comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of an antibody, bispecific molecule, multimeric assembly of antibodies or immunoconjugate according to any one of the preceding items to treat diabetes.

[0216] 55. The method according to any one of the preceding items, wherein said diabetes comprises type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome or glucose tolerance.

[0217] 56. A method for preventing or reversing insulin resistance, comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of an antibody, bispecific molecule, multimeric assembly of antibodies, or immunoconjugate according to any one of the preceding items to prevent or reverse insulin resistance.

[0218] 57. A method for reversing dysfunction and / or dedifferentiation of pancreatic islet cells, comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of an antibody, bispecific molecule, multimeric assembly of antibodies or immunoconjugate according to any one of the preceding items to reverse dysfunction and / or dedifferentiation of said pancreatic islet cells.

[0219] 58. A method for increasing the number of pancreatic beta cells, comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of an antibody, bispecific molecule, multimeric assembly of antibodies, or immunoconjugate according to any one of the preceding items to increase the number of pancreatic beta cells.

[0220] 59. A method according to any one of the preceding items, which is an in vitro, ex vivo or in vivo method or a combination thereof.

[0221] 60. A kit comprising an antibody, a hybridoma, a nucleic acid, an expression vector, a bispecific molecule, an immunoconjugate, a host cell, a multimeric assembly of antibodies or a composition according to any one of the preceding items, and optionally including instructions for use of said kit.

[0222] 61. An antibody, hybridoma, nucleic acid, expression vector, bispecific molecule, immunoconjugate, host cell, multimeric assembly of antibodies or composition according to any one of the preceding items for use as a medicament and / or in therapy.

[0223] 62. An antibody, hybridoma, nucleic acid, expression vector, bispecific molecule, immunoconjugate, host cell, multimeric assembly of antibodies or composition according to any one of the preceding items for use in one or more of the following methods: i) methods for the treatment, amelioration, prevention, or diagnosis of diabetes or related disorders (e.g., hyperinsulinemia, insulin resistance, and related disorders); ii) methods of preventing or reversing insulin resistance; iii) methods of reversing pancreatic islet cell dysfunction / dedifferentiation; iv) methods for increasing the number of pancreatic beta cells; v) methods for the production or preparation of antibodies; vi) methods for immunizing non-human animals; vii) methods for the preparation of hybridomas; viii) methods for immunoprecipitation (e.g., "pull-down" assays) and / or methods for identification of epitopes or co-epitopes or antigens using one or more of the following: epitope mapping, cryo-electron microscopy, protein crystallization, chemical cross-linking, mass spectrometry, HDX exchange mass spectrometry, NMR and other suitable structural techniques, phage display and / or similar methods; ix) By any one of the preceding paragraphs; x) Any one of (i) to (viii), which is in vitro, ex vivo or in vivo.

[0224] 63. Use of an antibody, hybridoma, nucleic acid, expression vector, bispecific molecule (e.g., recombinant protein), immunoconjugate, host cell, multimeric assembly of antibodies or fragments thereof, or composition according to any one of the preceding items for one or more of the following: i) treating diabetes and / or related disorders (e.g., hyperinsulinemia, insulin resistance and related disorders); ii) preventing or reversing insulin resistance; iii) reversing pancreatic islet cell dysfunction and / or dedifferentiation; iv) increasing the number of pancreatic beta cells; v) production or preparation of antibodies; vi) immunizing a non-human animal; vii) preparation of hybridomas; viii) identification of epitopes or co-epitopes or antigens using immunoprecipitation (e.g., "pull-down" assays) and / or one or more of the following: epitope mapping, cryo-electron microscopy, protein crystallization, chemical cross-linking, mass spectrometry, HDX exchange mass spectrometry, NMR and other suitable structural techniques, phage display and / or similar methods; ix) By any one of the preceding paragraphs; x) Any one of (i) to (ix), which is in vitro, ex vivo or in vivo.

[0225] 64. The method or use according to any one of the preceding items, wherein said diabetes comprises type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome or glucose tolerance.

[0226] 65. A method of immunoprecipitation (e.g., IP or "pull-down" assay) comprising contacting an antibody of any one of the preceding items with a specific substance (e.g., a polypeptide, e.g., a recombinant polypeptide) from / in solution.

[0227] As used herein, it should be noted that the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a reagent" includes one or more of such various reagents, and reference to "the method" includes reference to equivalent steps and methods known to those skilled in the art that can be modified or substituted for the methods described herein.

[0228] Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain without undue routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0229] The term "and / or" whenever used herein includes the meaning of "and", "or" and "all or any other combination of the elements connected by said term".

[0230] The terms "about" or "approximately" as used herein mean within 20%, preferably within 10%, and more preferably within 5% of a given value or range. However, the terms also include numbers, for example, "about 20" includes 20.

[0231] The terms "less than" or "greater than" are inclusive of numerals. For example, less than 20 means less than or equal to. Similarly, more than or greater than means more than or equal to, or greater than or equal to, respectively.

[0232] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", as well as variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integers or steps or group of integers or steps. As used herein, the term "comprising" can be replaced with the terms "containing" or "including", or, as sometimes used herein, with the term "having".

[0233] As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[0234] It is to be understood that this invention is not limited to the particular methodology, protocols, materials, reagents, and substances, etc. described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined only by the claims.

[0235] All publications and patents cited throughout the document herein, whether supra or infra, including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc., are hereby incorporated by reference in their entirety. Nothing herein should be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. To the extent that the material incorporated by reference is inconsistent or inconsistent with the present specification, the present specification will take precedence over any such material.

[0236] A still further understanding of the present invention and its advantages will be gained from the following examples, which are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way. EXAMPLES

[0237] material and method Western blot (e.g., as shown in Figures 2-3 herein) Min6 cells were lysed (50 mM Tris-HCl, 150 mM NaCl, 2 mM EDTA, 1% NP-40, pH 8.0) and mixed (4:1) with loading buffer (250 mM Tris-HCl, 12.5 mM ethylenediaminetetraacetic acid, 10% sodium dodecyl sulfate, 25% glycerol). 20 mM DTT and heating (95 deg, 5 min) were added, if necessary. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of Min6 cell lysates was performed on NuPAGE gels (4–12% Bis-Tris gels, and MOPS buffer, Invitrogen). For western blotting, 0.45 μm Immobilon-P PVDF membranes (Millipore) were used. Membrane blocking was performed with 5% (w / v) milk (Carl Roth, Germany) in TBST (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, and 0.05% Tween 20) for 1 hour at room temperature. Monoclonal rat anti-IGFR1 antibody (1ug / mL in TBST + 5% (w / v) milk) was applied for 1 hour at RT, followed by three subsequent washes in TBST. Secondary antibody peroxidase-conjugated mouse anti-rat (isotype specific; in TBST + 5% milk) was incubated with the membrane for 1 hour at RT. After three washes with TBST, the HRP reaction was developed using West Femto substrate (Thermo Fisher Scientific) and detected using a LAS-3000 Imaging System (Fuji).

[0238] Electrochemiluminescence-ELISA (e.g., as shown in Figure 4 herein) Antigen (1ug) was passively adsorbed onto the electrode surface (1 hour, 23°C) and the remaining sites on the surface were blocked with 0.2% porcine gelatin (1 hour, 23°C). The surface was then washed three times with HBS (25mM HEPES, 150mM NaCl, pH 7.25). For initial screening, the supernatants harvested from hybridoma cultures were diluted 10-fold and 100-fold with 0.2% porcine gelatin solution.

[0239] Antibody affinity K d Measurement (e.g., as shown in FIG. 5 herein) K of antibody affinities for AB1 to AB-12 according to standard protocols d Measurements were performed. Briefly, for affinity measurements, a porcine gelatin solution containing the desired concentration of purified rat monoclonal anti-IGFR1 was added to each well. Binding was performed for 2 hours at 23°C. The plate was then washed 3 times with HBS solution and a solution of isotype-specific secondary anti-rat detection antibody (1 μg / mL) was added and incubated (23°C, 1 hour). The wells were washed 3 times with HBS and reading buffer (MSD detergent-free reading buffer) was added. Data were acquired with a SECTOR Imager 6000 chemiluminescence reader. Background was determined from binding of the secondary antibody to the antigen. Recorded data were analyzed using the GraphPad Prism 6.0 software using the one-site specific binding algorithm.

[0240] Sequence alignments (e.g., as shown in Figures 6-7 herein) Alignments were performed using EMBL's Clustal Omega web service (https: / / www.ebi.ac.uk / Tools / msa / clustalo / ) using standard conditions, i.e., with a valid mbed-like clustering guide tree and mbed-like clustering iterations.

[0241] Example 1: Comparison of the unique and superior properties of the novel structure-specific monoclonal antibodies (AB) of the present invention with those of domain-specific peptide ABs from the prior art Methods (e.g., as used in Figure 1): Min6 cells were lysed in mild lysis buffer and proteins were quantified using BCA assay. Min6 lysates were used in three different ways for sample preparation: a) Min6 lysate + 4x Laemmli buffer without β-ME. No DTT was added and samples were not heat denatured. B) Min6 lysate + 4x Laemmli buffer without β-ME. DTT was added to the loading dye. Samples were not heat denatured. C) Min6 lysate + 4x Laemmli buffer without β-ME. DTT was added to the loading dye. Samples were heat denatured at 95°C for 10 minutes. Samples were then loaded onto a 10% SDS gel for separation and Western blot analysis was performed. Primary antibodies were used at 1:1000 dilution in milk blocking solution overnight at 4°C. Respective secondary antibodies were added and signals were developed.

[0242] Results (as in FIG. 1): The structure-specific AB of the present invention (exemplified by AB-2) detects proteins under non-denaturing conditions in SDS gels after Western blotting, whereas peptide AB from the prior art detects only denatured proteins (e.g., FIG. 1).

[0243] Method (e.g., as used in Figure 2): Min6 cells were cultured in 6-well plates until they reached 80% confluency. On the day of the experiment, cells were treated with AB and its respective isotype control at two different concentrations (final concentrations 0.1 μg / ml and 1.0 μg / ml in complete DMEM medium) for 15 min in a 37°C incubator. Cells were gently washed with ice-cold PBS and lysed in cold lysis buffer containing protease and phosphatase inhibitor cocktail (1:100). Cell lysates were collected in Eppendorf tubes and incubated for 20-30 min on a rotor in a cold room to facilitate proper lysis of cells. Cell lysates were centrifuged at maximum speed to remove cell debris. Supernatants were collected in new tubes and protein was quantified using the BCA assay. 15-20 μg protein was loaded onto a 10% SDS gel for WB analysis.

[0244] Results (as in Figure 2): The novel structure-specific ABs of the present invention activate p-InsR / IGF1R, p-IRS1 and p-AKT in a dose-dependent manner, whereas domain-specific peptide antibodies from the prior art have no effect or an inhibitory effect on InsR / IGF1R pathway activation.

[0245] Example 2: Novel antibodies can modulate (e.g., increase) insulin receptor sensitivity Methods: Min6 cells were prepared as shown in FIG. 8 (see also Example 1 for details) followed by Western blotting as described in Example 1 above.

[0246] Result (as shown in Figure 8): All twelve antibodies of the present invention were generated using a specific method against the native extracellular domain of IGFR-L1 / inceptor. The receptor indirectly binds to the insulin receptor complex at the plasma membrane and mediates the internalization and thus desensitization of the activated insulin receptor complex. Therefore, when insulin-producing beta cells are incubated with any of the twelve antibodies of the present invention, the antibody binds to the extracellular domain of the receptor and thus inhibits its interaction with the activated insulin receptor complex. Thus, the insulin receptor is not desensitized and insulin signal activation is enhanced and / or prolonged (Figure 8). In other words, the receptor Ak of ​​the present invention binds to the receptor (which may all have different paratopes, i.e. epitopes), thereby inhibiting the receptor from efficiently integrating with the activated insulin receptor complex. Thus, the insulin receptor remains longer at the plasma membrane and is activated longer without being efficiently desensitized. This is supported for all 12 novel Aks of the present invention (p-IR / IGF1R) by FIG. 8, which provides a unifying feature for all Aks of the present invention in addition to their unique production methods.

[0247] Those skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the results and advantages described, as well as those inherent herein. Moreover, it will be readily apparent to those skilled in the art that various substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The compositions, methods, procedures, treatments, molecules, and specific compounds described herein are presently representative of certain embodiments, are exemplary, and are not intended to limit the scope of the invention. Modifications therein and other uses will occur to those skilled in the art, and are encompassed within the spirit of the invention as defined by the claims. The listing or discussion of a previously published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0248] The present invention illustratively described herein may be suitably practiced in the absence of any element or elements, or any limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising", "including", "containing" and the like are to be interpreted expansively and without limitation. Furthermore, the terms and expressions used herein are used as terms of description, not of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the invention claimed. Thus, although the present invention has been specifically disclosed by exemplary embodiments and optional features, it should be understood that modifications and variations of the invention embodied herein may be resorted to by those skilled in the art, and such modifications and variations are considered to be within the scope of the present invention.

[0249] The present invention has been described broadly and generically herein. Each of the subspecies and subgeneric groupings falling within the scope of the generic disclosure also form part of the present invention. This includes the generic description of the invention, subject to any proviso or negative limitation that removes any subject matter from the genus, whether or not the excised material is specifically recited herein.

[0250] Other embodiments are within the scope of the following claims. Additionally, when features or aspects of the invention are described in terms of a Markush group, those skilled in the art will recognize that the invention is also described thereby in terms of any individual members or subgroups of members of the Markush group.

Claims

**Claim 1** An antibody that binds to the extracellular domain of an Inceptor protein comprising the amino acid sequence of SEQ ID NO:1, folded (e.g., native) or partially folded (e.g., having a tertiary structure with or without post-translational modifications), preferably to a native epitope within the IGFR-L1 protein, wherein the binding of the antibody to the folded or partially folded IGFR-L1 protein is as follows: (a) An aliquot of the lysate from Min6 cells (ATCC CRL-11506) is (i) incubated separately for 5 minutes at ambient temperature with a buffer suitable for SDS-PAGE of proteins, (ii) incubated separately for 5 minutes at ambient temperature with a buffer suitable for SDS-PAGE of proteins and a reducing agent, and (iii) incubated separately for 5 minutes at 95°C with a buffer suitable for SDS-PAGE of proteins and a reducing agent ; (b) subjecting the aliquot to SDS-PAGE; (c) Western blotting the SDS-PAGE gel; (d) incubating the Western blot membrane with the antibody and is determinable (e.g., determined) accordingly, wherein the antibody detects only aliquot (i), antibody. **Claim 2** wherein step (a) is (a) An aliquot of the lysate from Min6 cells (ATCC CRL-11506) is (i) incubated separately for 5 minutes at ambient temperature with 50 mM Tris-HCl pH = 6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, buffer, without thiol agent, (ii) incubated separately for 5 minutes at ambient temperature with 50 mM Tris-HCl pH = 6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, 20 mM DTT, and (iii) incubated separately for 5 minutes at 95°C with 50 mM Tris-HCl pH = 6.8, 2.5 mM EDTA, 2% (w / v) SDS and 5% (v / v) glycerol, 20 mM DTT ; The antibody according to claim 1, comprising **Claim 3** The antibody according to claim 1, which increases, decreases, modulates or inhibits the binding of one or more growth factors (e.g., insulin) or similar ligands, morphogens, homo-oligomerization partners, hetero-oligomerization partners, and / or dimerization or oligomerization partners to the receptor protein and / or other receptors, preferably increases or modulates insulin receptor sensitization.

4. The antibody according to claim 1 or 2, which increases InsR-mediated signal transduction.

5. The antibody according to claim 1 or 2, which increases the phosphorylation of InsR, IRS1 and / or AKT.

6. The antibody according to claim 1 or 2, wherein the extracellular domain ranges from amino acids 1 to 910 of SEQ ID NO: 1, preferably, the extracellular domain ranges from amino acids 42 to 910 of SEQ ID NO:

1.

7. The antibody according to claim 1 or 2, which binds to the receptor protein with a Kd of 10 nM or less, preferably 6 nM or less, more preferably 5 nM or less, even more preferably 3 nM or less.

8. The antibody according to claim 1 or 2, which can be produced by immunizing a rodent with proteoliposomes containing the receptor protein.

9. An antibody comprising: (a) a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 19 to 140 of SEQ ID NO: 2, and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 28 to 136 of SEQ ID NO: 12; An antibody comprising: (b) a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 62 to 177 of SEQ ID NO: 22, and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 48 to 162 of SEQ ID NO: 32; An antibody comprising: (c) a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 20 to 136 of SEQ ID NO: 42, and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 39 to 153 of SEQ ID NO: 52; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 20 to 141 of SEQ ID NO: 62 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 40 to 148 of SEQ ID NO: 72; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 58 to 175 of SEQ ID NO: 82 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 21 to 129 of SEQ ID NO: 92; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 54 to 171 of SEQ ID NO: 102 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 55 to 163 of SEQ ID NO: 112; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 19 to 139 of SEQ ID NO: 122 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 45 to 156 of SEQ ID NO: 132; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 20 to 139 of SEQ ID NO: 142 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 40 to 148 of SEQ ID NO: 152; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 20 to 133 of SEQ ID NO: 162 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 40 to 148 of SEQ ID NO: 172; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 54 to 175 of SEQ ID NO: 182 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 38 to 149 of SEQ ID NO: 192; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 55 to 170 of SEQ ID NO: 202 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 21 to 135 of SEQ ID NO: 212; An antibody comprising a heavy chain variable region having an amino acid sequence with at least 85% identity to amino acids 20 to 144 of SEQ ID NO: 222 and a light chain variable region having an amino acid sequence with at least 85% identity to amino acids 52 to 165 of SEQ ID NO: 232; or An antibody that binds to the same epitope as the epitope in the interceptor protein to which any one of antibodies (a) to (l) binds The antibody according to claim 1 or 2.

10. An antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as shown in SEQ ID NO: 5, a heavy chain CDR2 having the amino acid sequence as shown in SEQ ID NO: 7, and a heavy chain CDR3 having the amino acid sequence as shown in SEQ ID NO: 9, and A light chain variable region comprising a light chain CDR1 having the amino acid sequence as shown in SEQ ID NO: 15, a light chain CDR2 having the amino acid sequence as shown in SEQ ID NO: 17, and a light chain CDR3 having the amino acid sequence as shown in SEQ ID NO: 19 ; An antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as shown in SEQ ID NO: 25, a heavy chain CDR2 having the amino acid sequence as shown in SEQ ID NO: 27, and a heavy chain CDR3 having the amino acid sequence as shown in SEQ ID NO: 29, and A light chain variable region comprising a light chain CDR1 having the amino acid sequence as shown in SEQ ID NO: 35, a light chain CDR2 having the amino acid sequence as shown in SEQ ID NO: 37, and a light chain CDR3 having the amino acid sequence as shown in SEQ ID NO: 39 ; An antibody comprising a heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as shown in SEQ ID NO: 45, a heavy chain CDR2 having the amino acid sequence as shown in SEQ ID NO: 47, and a heavy chain CDR3 having the amino acid sequence as shown in SEQ ID NO: 49, and A light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 55, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 57, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 59, and an antibody comprising the same; (d) A heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 65, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 67, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 69, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 75, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 77, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 79, and an antibody comprising the same; (e) A heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 85, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 87, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 89, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 95, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 97, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 99, and an antibody comprising the same; (f) A heavy chain variable region comprising a heavy chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 105, a heavy chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 107, and a heavy chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 109, and a light chain variable region comprising a light chain CDR1 having the amino acid sequence as set forth in SEQ ID NO: 115, a light chain CDR2 having the amino acid sequence as set forth in SEQ ID NO: 117, and a light chain CDR3 having the amino acid sequence as set forth in SEQ ID NO: 119, and an antibody comprising the same; (g) A heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 125, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 127, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 129, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 135, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 137, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 139 An antibody comprising; (h) A heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 145, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 147, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 149, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 155, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 157, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 159 An antibody comprising; (i) A heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 165, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 167, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 169, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 175, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 177, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 179 An antibody comprising; (j) A heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 185, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 187, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 189, and A light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 195, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 197, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 199, and an antibody comprising the same; (k) A heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 205, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 207, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 209, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 215, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 217, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 219 an antibody comprising the same; (l) A heavy chain variable region comprising a heavy chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 225, a heavy chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 227, and a heavy chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 229, and a light chain variable region comprising a light chain CDR1 having an amino acid sequence as shown in SEQ ID NO: 235, a light chain CDR2 having an amino acid sequence as shown in SEQ ID NO: 237, and a light chain CDR3 having an amino acid sequence as shown in SEQ ID NO: 239 an antibody comprising the same; or (m) An antibody that binds to the same epitope as the epitope in the human PRDX4 protein to which any one of the antibodies (a) to (l) binds The antibody according to claim 1 or 2, which is such an antibody.

11. The antibody according to claim 1 or 2, which is for use as a medicament and / or in therapy.

12. i) For treating diabetes, hyperinsulinemia and / or insulin resistance and / or cancer; and / or ii) For use in a method for immunoprecipitation The antibody according to claim 1 or 2, which is for use in such a method.

13. The antibody for use according to claim 12, wherein the diabetes includes type 1 diabetes, type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome or glucose tolerance.

14. The antibody according to claim 1 or 2, which is for use in a method of preventing or reversing insulin resistance.

15. The antibody according to claim 1 or 2, which is for use in a method of reversing pancreatic islet cell dysfunction and / or dedifferentiation.

16. The antibody according to claim 1 or 2, which is for use in a method of increasing the number of pancreatic beta cells.

Images