Antibodies against receptor for advanced glycation end products (RAGE) and uses thereof

Abstract

Disclosed herein are antibodies against the receptor for advanced glycation end products (RAGE) and methods of using said antibodies.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 280,999, filed November 18, 2021, which is incorporated herein by reference in its entirety.

[0002] (Technical field) The present disclosure relates to anti-RAGE antibodies and fragments thereof, antibody formulations, administration regimens and methods of use thereof. Anti-RAGE antibodies and fragments thereof may be used in the treatment and diagnosis of certain cancers, inflammatory conditions, and / or other conditions associated with increased expression or abnormal function of RAGE. [Background technology]

[0003] The receptor for advanced glycation end products (RAGE or AGER, see SEQ ID NO: 1 or 23) is a multi-ligand receptor expressed on several cell types, including immune cells such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and mesenchymal stromal cells. Expression of RAGE is increased in tumor immune cell infiltrates, and RAGE is also overexpressed in several tumor cell types.

[0004] RAGE also acts like a master switch from acute to chronic inflammatory responses. When activated by one of several known ligands, it primes cells for anti-apoptotic activity and tumor cell proliferation. Activated RAGE forms a feed-forward loop that enhances the expression of itself and several known activating ligands.

[0005] Known ligands for RAGE include those belonging to the damage-associated molecular patterns (DAMPs), including high-mobility group box 1 (HMGB1), S100 calcium-binding proteins, amyloid fibrils, nucleic acid scaffolds, etc. Other ligands include those of the extracellular signal-regulated kinase (Erk, also known as mitogen-activated protein kinase or MAPK) pathway and those involved in the control of cell migration.

[0006] The chronic inflammatory state caused by RAGE activation creates an immunosuppressive environment by several mechanisms. These mechanisms include the expression and activation of inflammatory molecules such as tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and matrix metalloproteinases (MMPs). RAGE also acts directly to suppress the activity of antitumor lymphocytes by contact. RAGE activity recruits immunosuppressive cells such as MDSCs and TAMs, promoting tumor infiltration.

[0007] The present disclosure describes novel antibodies that bind to RAGE and can be used in therapeutic and / or diagnostic methods. Summary of the Invention [Means for solving the problem]

[0008] The present disclosure is based in part on antibodies against RAGE. The disclosure also provides antibodies as therapeutic and diagnostic agents for use in targeting pathologies associated with RAGE expression and / or activity. And the disclosure provides methods, compositions, kits, and articles of manufacture related to RAGE.

[0009] The present disclosure provides binding molecules, particularly antibodies, that specifically bind to RAGE; representative anti-RAGE antibodies of the present disclosure may comprise at least one of the antibody variable region amino acid sequences set forth in SEQ ID NOs: 2, 3, 10, and 11, or individual CDRs thereof, or associated CDR sequences, as defined in more detail below.

[0010] Specifically, the disclosure provides antibodies that bind to RAGE, more specifically monoclonal antibodies that bind to the V and / or C1 domains of RAGE. The disclosure also provides RAGE binding fragments that are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 2, 3, 10, 11.

[0011] Included in the present disclosure are anti-RAGE antibodies that specifically bind RAGE and comprise a light chain variable region having an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 3 and 11, or a RAGE binding fragment of an antibody comprising said sequence or a homologous variant thereof. Also included in the present disclosure are anti-RAGE antibodies that specifically bind RAGE and comprise an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the CDRs (as identified herein) contained in SEQ ID NOs: 3 or 11.

[0012] Also included are anti-RAGE antibodies and fragments thereof that specifically bind RAGE and that comprise a heavy chain variable region having an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 2 and 10, or that are RAGE binding fragments of antibodies comprising said sequences or homologous variants thereof. The present disclosure also includes anti-RAGE antibodies that specifically bind RAGE and that comprise an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the CDRs (as identified herein) contained in SEQ ID NOs: 2 or 10.

[0013] The anti-RAGE antibodies of the present disclosure include the above-mentioned anti-RAGE antibodies or fragments thereof, or RAGE-binding fragments or homologous variants thereof, selected from the group consisting of chimeric antibodies, CDR-grafted antibodies or humanized antibodies, single-chain antibodies, fusion proteins, and human antibodies.

[0014] In certain embodiments, an antibody or antibody fragment that binds to RAGE (SEQ ID NO: 1) or a fragment thereof is provided, wherein the antibody or fragment thereof comprises a variable domain comprising a heavy chain (VH) consisting of the amino acid sequence of SEQ ID NO: 2 or 10 and a light chain (VL) consisting of the amino acid sequence of SEQ ID NO: 3 or 11.

[0015] In certain embodiments, an antibody or antibody fragment that binds to RAGE is provided, wherein the antibody or fragment thereof comprises a variable domain comprising at least one, two, three, four, five or six of the following complementarity determining region (CDR) sequences: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or 12; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5 or 13; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6 or 14. In certain embodiments, the antibody or fragment thereof further comprises a CDR-L1 consisting of the amino acid sequence of SEQ ID NO: 7 or 15; CDR-L2 consisting of the amino acid sequence of SEQ ID NO: 8 or 16; and CDR-L3 consisting of the amino acid sequence of SEQ ID NO: 9 or 17. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising at least one, two, three, four, five or six complementarity determining region (CDR) sequences consisting of an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 4-9 or 12-17.

[0016] In certain embodiments, an antibody or antibody fragment that binds to RAGE or a fragment thereof is provided, wherein the antibody or fragment thereof comprises a variable domain comprising CDR sequences comprising the amino acid sequence of CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or 12; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5 or 13; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6 or 14. In certain embodiments, the antibody or fragment thereof further comprises a CDR-L1 consisting of the amino acid sequence of SEQ ID NO: 7 or 15; CDR-L2 consisting of the amino acid sequence of SEQ ID NO: 8 or 16; and CDR-L3 consisting of the amino acid sequence of SEQ ID NO: 9 or 17. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising CDR sequences comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 4-9 or 12-17.

[0017] In one embodiment, an antibody or antibody fragment that binds to RAGE or a fragment thereof is provided, wherein the antibody comprises a VH consisting of the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the antibody or fragment thereof further comprises a VL consisting of the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the antibody comprises a VH consisting of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 2, and / or a VL consisting of an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:3. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising at least one CDR sequence comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of SEQ ID NOs: 4-9.

[0018] In one embodiment, an antibody or antibody fragment that binds RAGE or a fragment thereof is provided, comprising a VH comprising the amino acid sequence of SEQ ID NO: 10. In certain embodiments, the antibody or fragment thereof further comprises a VH comprising the amino acid sequence of SEQ ID NO: 10 and a VL comprising the amino acid sequence of SEQ ID NO: 11. In certain embodiments, the antibody comprises a VH comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 10, and / or a VL comprising an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 11. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising at least one CDR sequence comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of SEQ ID NOs: 12-17.

[0019] In one embodiment, an antibody or antibody fragment that binds to RAGE or a fragment thereof is provided, wherein the antibody or fragment thereof: (1) CDR-H1 comprising the amino acid sequence of SEQ ID NO:4; (2) CDR-H2 comprising the amino acid sequence of SEQ ID NO:5; (3) CDR-H3 comprising the amino acid sequence of SEQ ID NO:6; (4) CDR-L1 comprising the amino acid sequence of SEQ ID NO:7; (5) CDR-L2 comprising the amino acid sequence of SEQ ID NO:8; and (6) CDR-L3 comprising the amino acid sequence of SEQ ID NO:9; Includes.

[0020] In certain embodiments, the antibody or antibody fragment comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 4-9.

[0021] In one embodiment, an antibody or fragment thereof that binds to RAGE is provided, the antibody or fragment thereof comprising: (1) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12; (2) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13; (3) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 14; (4) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 15; (5) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (6) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 17 Includes.

[0022] In certain embodiments, the antibody or antibody fragment comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of SEQ ID NOs: 12-17.

[0023] In certain embodiments, an antibody or antibody fragment that binds to RAGE is provided, the antibody or fragment thereof comprising: (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:10; or (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:11.

[0024] In one embodiment, an antibody or antibody fragment that binds to RAGE or a fragment thereof is provided, wherein the antibody or fragment thereof comprises the VH sequence of SEQ ID NO: 2 and the VL sequence of SEQ ID NO: 3. In another embodiment, an antibody or antibody fragment that binds to RAGE or a fragment thereof is provided, wherein the antibody or fragment thereof comprises the VH sequence of SEQ ID NO: 10 and the VL sequence of SEQ ID NO: 11.

[0025] In certain embodiments, an antibody or antibody fragment is provided which binds to RAGE or a fragment thereof, the antibody binding to an epitope within a fragment of RAGE. In certain embodiments, an antibody or antibody fragment is provided which binds to RAGE or a fragment thereof, the antibody binding to an epitope within a fragment of RAGE comprising the V and / or C1 domain of the human RAGE amino acid sequence of SEQ ID NO: 1. The V domain of human RAGE comprises amino acids 23-116 of SEQ ID NO: 1 (also provided as SEQ ID NO: 18), the C1 domain comprises amino acids 124-221 of SEQ ID NO: 1 (also provided as SEQ ID NO: 19) and the C2 domain comprises amino acids 227-317 of SEQ ID NO: 20 (also provided as SEQ ID NO: 20).

[0026] In one embodiment, the anti-RAGE antibody is a monoclonal antibody. In a particular embodiment, the anti-RAGE antibody is humanized. In a particular embodiment, the anti-RAGE antibody is a human antibody. In one embodiment, at least a portion of the framework sequences of the anti-RAGE antibody are human consensus framework sequences or human germline sequences. In one embodiment, the antibody is an antibody fragment selected from a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment.

[0027] In one embodiment, a nucleic acid is provided that encodes any of the above anti-RAGE antibodies and or fragments thereof. In one embodiment, a vector is provided that comprises the nucleic acid. In one embodiment, the vector is an expression vector. In one embodiment, a host cell is provided that comprises the vector. In one embodiment, the host cell is eukaryotic. In another embodiment, the host cell is mammalian. In yet another embodiment, the host cell is prokaryotic. In one embodiment, a method of making an anti-RAGE antibody and or fragment thereof is provided, the method comprising culturing a host cell under conditions suitable for expression of a nucleic acid encoding the antibody and isolating the antibody. In one embodiment, the method further comprises recovering the anti-RAGE antibody and fragment thereof from the host cell. In a particular embodiment, a composition is provided that comprises any of the anti-RAGE antibodies and or fragments thereof described herein. In one embodiment, the composition further comprises a pharma- ceutically acceptable carrier.

[0028] In one aspect, provided herein is a pharmaceutical composition comprising an anti-RAGE antibody or fragment thereof. In certain embodiments, the composition is suitable for subcutaneous administration. In certain embodiments, the composition is suitable for intravenous administration. In certain embodiments, the viscosity of the composition is less than about 10 cP at 25° C. In other embodiments, the viscosity of the composition is less than about 20 cP at 25° C., including, but not limited to, about 15 cP, about 16 cP, about 17 cP, about 18 cP, and about 19 cP. Anti-RAGE antibodies known in the art or described herein may be incorporated into the composition.

[0029] In one aspect, provided herein is a subcutaneous administration device comprising an anti-RAGE antibody or fragment thereof, or a composition comprising an anti-RAGE antibody or fragment thereof, as described herein, hi certain embodiments, the device is for delivering a fixed dose of antibody in the range of about 200 to about 1200 mg to an individual.

[0030] In one aspect, the disclosure relates to a method of inhibiting RAGE-mediated activation of the Erk / MAPK pathway or the p53 pathway in a subject, the method comprising administering to the subject an effective amount of any of the anti-RAGE antibodies and fragments thereof described herein. In another aspect, the disclosure relates to a method of reducing at least one of chronic inflammation, immune suppression, cancer / tumor cell migration, cancer / tumor cell infiltration, suppressive immune cell infiltration into tumors, tumor-promoting immune cell infiltration, cancer / tumor growth, liver injury and fibrosis, ocular neovascularization, respiratory disease, infection, and / or cancer / tumor progression in a subject, the method comprising administering to the subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0031] In one aspect, the disclosure relates to a method of inhibiting RAGE-mediated activation of the Erk / MAPK pathway or the p53 pathway in a subject, the method comprising administering to the subject an effective amount of any of the anti-RAGE antibodies and fragments thereof described herein. In another aspect, the disclosure relates to a method of increasing at least one of CD8+ T cell infiltration, M1 TAM infiltration or M2 to M1 TAM polarization, NKT cells, NK cells, CD8+ anti-tumor memory cells, increased M1 function (such as increased production of IL-27), the method comprising administering to the subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0032] In one aspect, the present disclosure relates to a method of inhibiting RAGE activity to prevent and / or treat cancer, such as cancers characterized by high angiogenesis, including, but not limited to, colon cancer and renal cancer, comprising administering to a subject an effective amount of any of the anti-RAGE antibodies and or fragments thereof described herein.

[0033] In another aspect, the disclosure relates to a method of inhibiting RAGE activity to alter the tumor microenvironment, including, but not limited to, inhibiting angiogenesis to tumors, inhibiting tumor growth, inhibiting or reducing expression of growth and / or inflammatory factors in tumors, reducing monocytic myeloid derived suppressor cells (MDSCs), reducing inflammatory monocytes (iMonos), reducing M2 tumor associated macrophages (M2 TAMs), increasing M1 macrophages and M1 macrophage signaling, increasing M1 / M2 macrophage tumor infiltration and / or signaling, increasing M2 to M1 polarization, and / or promoting T cell activity and infiltration into tumors, comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0034] In another aspect, the disclosure relates to a method of inhibiting RAGE activity to prevent the development of chronic inflammation, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies and fragments thereof described herein. In a related aspect, the disclosure relates to a method of inhibiting RAGE activity to maintain an acute inflammatory state, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0035] In another aspect, the present disclosure relates to a method for inhibiting RAGE activity to prevent liver damage and / or fibrosis, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0036] In another aspect, the present disclosure relates to a method for inhibiting RAGE activity to prevent neovascularization in the eye, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0037] In another aspect, the present disclosure relates to a method for inhibiting RAGE activity to prevent respiratory disease and / or the onset of respiratory disease, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0038] In another aspect, the present disclosure relates to a method for inhibiting RAGE activity to prevent infection and / or the onset of an infection, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0039] In one aspect, the present disclosure relates to a method of treating cancer, including but not limited to cancers characterized by high angiogenesis, such as colon cancer and renal cancer, comprising administering to a subject an effective amount of any of the anti-RAGE antibodies described herein.

[0040] In another aspect, a method of altering the tumor microenvironment to, for example, but not limited to, inhibit angiogenesis into a tumor, inhibit tumor growth, inhibit or reduce expression of growth factors in a tumor, reduce or alter the infiltration and / or activity of myeloid cell types, reduce or alter the infiltration and / or activity of mesenchymal / stromal cell types, and / or promote T cell activity and infiltration into a tumor, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0041] In another aspect, the disclosure relates to a method of preventing the development of chronic inflammation, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In a related aspect, the disclosure relates to a method of maintaining an acute inflammatory state, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0042] In another aspect, the present disclosure relates to a method for preventing liver damage and / or fibrosis, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0043] In another aspect, the present disclosure relates to a method of preventing neovascularization in the eye, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0044] In another aspect, the present disclosure relates to a method for preventing respiratory diseases and / or the onset of respiratory diseases, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0045] In another aspect, the present disclosure relates to a method for preventing respiratory diseases and / or the onset of respiratory diseases, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein.

[0046] In certain embodiments, the methods described herein further comprise administering to the subject an effective amount of a second pharmaceutical agent, where the anti-RAGE antibody or fragment thereof is the first pharmaceutical agent. In some embodiments, the second pharmaceutical agent is a vaccine, such as a vaccine against an infectious agent. In some embodiments, the second pharmaceutical agent is a biologic cancer therapeutic agent. Exemplary biologic cancer therapeutic agents include, but are not limited to, antibodies, cytokines, hematopoietic growth factors, cancer vaccines, Bacillus Calmette-Guerin, oncolytic viruses, gene therapy, adoptive T cell transfer therapy, and chimeric antigen receptor modified cells. Exemplary antibodies include, but are not limited to, antibodies that bind to PD-1, PD-L1, CTLA-4, GITIR, LAIR-1, TIGIT, CD73, OX40, TLR2, TLR4, TLR7, TLR8, TLR9, EP2 receptor, EP4 receptor, VEGF, CD20, CD52, EGF, and HER-2. Also included are small molecule compounds that target, for example, S100 family ligands, HBGB1, NFκB, TGF-BetaIDO, TDO, ARG1, ARG2, iNOS, TLR2, TLR4, TLR7, TLR8, TLR9, PDE5, P2X7, P2Y11, A2A receptor, A2A receptor, A2B receptor, CD39, CD73, COX2, EP2 receptor, EP4 receptor, CXCR1, CXCR2, CXCR4, CCR2, CCR5, ALK5, BRAF, RON, CSF1, PI3Kγ, PI3Kδ, CSF receptor 1, and those that are also targeted by antibodies.

[0047] In certain embodiments, the subject or individual is a human.

[0048] In one aspect, the present disclosure relates to a method of detecting RAGE protein in a sample suspected of containing RAGE protein, the method comprising: (a) contacting the sample with an anti-RAGE antibody or fragment thereof described herein; and (b) detecting formation of a complex between the anti-RAGE antibody or fragment thereof and the RAGE protein. In one embodiment, the anti-RAGE antibody or fragment thereof is detectably labeled.

[0049] Any embodiment described herein or any combination thereof applies to any and all anti-RAGE antibodies or fragments thereof, methods and uses of the present disclosure described herein.

[0050] The antibody or fragment thereof of the present application comprises a heavy chain constant region, such as an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. Additionally, the antibody may comprise a light chain constant region, either a kappa light chain constant region or a lambda light chain constant region. In particular, the antibody comprises a kappa light chain constant region. Alternatively, the antibody portion may be, for example, a Fab fragment or a single chain Fv fragment. Substitution of amino acid residues in the Fc portion to alter the effector functions of the antibody is known in the art (U.S. Pat. Nos. 5,648,260; 5,624,821). The Fc portion of the antibody mediates several important effector functions, such as cytokine induction, ADCC, phagocytosis, complement-dependent cytotoxicity (CDC), half-life / clearance rate of the antibody and antigen-antibody complex, etc. In some cases, these effector functions are desirable for a therapeutic antibody, but in other cases they may be unnecessary or even deleterious. Certain human IgG isotypes, particularly IgG1 and IgG3, mediate ADCC and CDC via binding to FcγR and complement C1q, respectively. The neonatal Fc receptor (FcRn) is a key component determining the circulating half-life of an antibody. In yet another embodiment, at least one amino acid residue is substituted in the constant region of the antibody, e.g., the Fc region of the antibody, such that the effector function of the antibody is altered.

[0051] These and other objects, features and advantages of the present disclosure will become more apparent from the following specification taken in conjunction with the accompanying description, claims and drawings.

[0052] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. The patent or application file contains at least one drawing of color. Copies of this patent or patent application publication containing color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief description of the drawings]

[0053] [Figure 1A] Figures 1A and B show the binding and cross-reactivity of antibodies of the disclosure to human and mouse RAGE protein by flow cytometry: Figure 1A shows binding to human RAGE protein. [Figure 1B] Figures 1A and B show the binding and cross-reactivity of antibodies of the disclosure to human and mouse RAGE protein by flow cytometry, and Figure 1B shows binding to mouse RAGE protein. [Figure 2A] Figures 2A-2C show mapping of binding sites of antibodies of the disclosure to RAGE protein domains: Figure 2A is a schematic diagram of the RAGE protein showing domains V, C1, C2. [Figure 2B] Figures 2A-2C show binding site mapping of antibodies of the disclosure to RAGE protein domains. Figure 2B is a bar graph showing the interaction of antibodies of the disclosure with RAGE domains V, C1 and C2. [Figure 2C] Figures 2A-2C show mapping of binding sites of antibodies of the disclosure to RAGE protein domains. Figure 2C is a schematic showing the binding sites of several exemplary antibodies of the disclosure to specific RAGE domains. [Figure 3A] 3A-C-3 show the effect of anti-RAGE antibodies of the present disclosure on various cellular functions, including cell migration (FIG. 3A). Specifically, migration of THP-1 cells (a human acute monocytic leukemia line) to AGE-BSA was measured. [Figure 3B] Figures 3A-C-3 show the effect of anti-RAGE antibodies of the present disclosure on various cellular functions including cell migration (Figure 3A) and Figure 3B shows that anti-RAGE antibodies of the present disclosure inhibit basal levels of NFκB signaling in a mouse melanoma cell line. [Figure 3C-1] Figures 3A-C-3 show the effect of anti-RAGE antibodies of the present disclosure on various cellular functions including cell migration (Figure 3A), and Figure 3C-1 shows that antibodies of the present disclosure inhibit binding of S100A8 / 9 to monocytes and granulocytes. [Figure 3C-2] Figures 3A-C-3 show the effect of anti-RAGE antibodies of the present disclosure on various cellular functions including cell migration (Figure 3A), and Figure 3C-2 shows that antibodies of the present disclosure inhibit binding of S100A8 / 9 to monocytes. [Figure 3C-3] Figures 3A-C-3 show the effect of anti-RAGE antibodies of the present disclosure on various cellular functions including cell migration (Figure 3A), and Figure 3C-3 shows that antibodies of the present disclosure inhibit binding of S100A8 / 9 to granulocytes. [Figure 4] FIG. 4 shows the effect of anti-RAGE antibodies of the present disclosure on Erk signaling. [Figure 5A] Figures 5A-5E show the binding of specific anti-RAGE antibody RFT01 in human colon adenocarcinoma cell lines. Figure 5A shows the binding of RFT01 antibody to stage III cells. [Figure 5B] Figures 5A-5E show the binding of specific anti-RAGE antibody RFT01 in human colon adenocarcinoma cell lines, and Figure 5B shows the binding of RFT01 antibody to stage IV cells. [Figure 5C] Figures 5A-5E show binding of specific anti-RAGE antibody RFT01 in human colon adenocarcinoma cell lines, and Figure 5C shows quantification of RAGE antibody infiltrated cells from Figures 5A and 5B. [Figure 5D] Figures 5A-5E show the binding of specific anti-RAGE antibody RFT01 in human colon cancer adenocarcinoma cell lines, and Figure 5D shows the binding of RFT01 anti-RAGE antibody in human colon cancer myeloid cells. [Figure 5E] Figures 5A-5E show the binding of specific anti-RAGE antibody RFT01 in human colon cancer adenocarcinoma cell lines. Figure 5E shows the binding of RFT01 anti-RAGE antibody in human colon cancer lymphoid cells. [Figure 6A] FIG. 6A shows the effect of RS15 treatment on tumor-infiltrating myeloid cell populations in syngeneic animal models CT26 and Colon26. [Figure 6B] FIG. 6B shows the corresponding shift in tumor cytokine profile in Colon26 tumors toward a less immunosuppressive microenvironment. [Figure 7] FIG. 7 shows that RAGE (RS15) treatment of CT26 tumor-bearing mice increases tumor-infiltrating T cells by FACS analysis of tumor-infiltrating lymphocyte populations. [Figure 8A] Figures 8A and 8B show that RFT01 treatment inhibits tumor growth. Figure 8A shows that CT26 tumor growth is inhibited in a syngeneic mouse model (specifically, the murine colon cancer cell line CT26 implanted in BALB / C mice). [Figure 8B] Figures 8A and 8B show that RFT01 treatment inhibits tumor growth. Figure 8B shows that administration of RFT01 starting with 100 mm3 tumors reduced Colon26 tumor volume over time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] definition In order to facilitate understanding of the principles and features of various embodiments of the present disclosure, various exemplary embodiments are described below. Although exemplary embodiments of the present disclosure are described in detail, it should be understood that other embodiments are also envisioned. Therefore, it is not intended that the present disclosure be limited in scope to the details of the structure and arrangement of the components described in the following description or examples. The present disclosure is capable of other embodiments and of being implemented or carried out in various ways. Also, in describing exemplary embodiments, specific terms will be used for the sake of clarity.

[0055] It should also be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, a reference to a component is also intended to include a composition of multiple components. A reference to a composition that includes a component with "a" is intended to include the other components in addition to the named component. In other words, "a" or "an" means "at least one" or "one or more."

[0056] As used herein, the term "and / or" can mean "and," can mean "or," can mean "exclusive-or," can mean "one," can mean "some but not all," can mean "neither," or can mean "both."

[0057] Moreover, in describing the exemplary embodiments, terminology is used for the sake of clarity, and each term is intended to be accorded its broadest meaning as understood by one of ordinary skill in the art and to encompass all technical equivalents that operate in a similar manner to accomplish a similar purpose.

[0058] Ranges may be expressed herein as "about" or "substantially" from one particular value and / or to another particular value. When such a range is expressed, other exemplary embodiments include from the one particular value and / or to the other particular value. Furthermore, the term "about" means within an acceptable error range for a particular value, as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within an acceptable standard deviation, as practiced in the art. Alternatively, "about" may mean within a range of ±20%, ±10%, ±5%, or ±1% of a given value. Alternatively, particularly with respect to biological systems or methods, the term may mean within an order of magnitude, such as within 2-fold of a value. When specific values ​​are described in this application and claims, unless otherwise specified, the term "about" is implicit, and in this context means within an acceptable error range for the particular value. In some embodiments, and unless otherwise specified, the term "about" means up to ±10% of a given value.

[0059] Similarly, as used herein, "substantially free" or "substantially pure" of something, and similar characterizations can include both being "at least substantially free" or "at least substantially pure" of something, and being "completely free" or "completely pure" of something.

[0060] "Comprising" or "containing" or "including" means that at least the named compound, element, particle, or method step is present in a composition or article or method, but does not exclude the presence of other compounds, materials, particles, or method steps, even if those other compounds, materials, particles, or method steps have the same function as the one named.

[0061] Throughout this specification, various components may be specified to have specific values ​​or parameters, but these items are provided as example embodiments. Indeed, many equivalent parameters, sizes, ranges, and / or values ​​may be implemented, and the example embodiments are not intended to limit the various aspects and concepts of the present disclosure. The terms "first," "second," and similar terms, "primary," "secondary," and similar terms do not denote any order, quantity, or importance, but rather are used to distinguish one element from another.

[0062] It should be noted that terms such as "specifically," "preferably," "typically," "generally," and "often" are not utilized herein to limit the scope of the claims or to imply that a particular feature is critical, essential, or even critical to the structure or function of the claimed subject matter. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present disclosure. It should also be noted that terms such as "substantially" and "about" are utilized herein to convey the inherent degree of uncertainty that may result from any quantitative comparison, value, measurement, or other representation.

[0063] The dimensions and values ​​disclosed herein should not be understood to be strictly limited to the exact numerical values ​​recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as "50 mm" is intended to mean "about 50 mm."

[0064] It should also be understood that the recitation of one or more method steps does not exclude the presence of additional or intervening method steps between those steps expressly identified.Similarly, it should also be understood that the recitation of one or more components in a composition does not exclude the presence of additional components other than those expressly identified components.

[0065] The materials described below as constituting various elements of the present disclosure are intended to be exemplary and not limiting. Many suitable materials that perform the same or similar functions as the materials described herein are intended to be encompassed within the scope of the present disclosure. Such other materials not described herein may include, for example, but are not limited to, materials developed later over time. Any dimensions depicted in the various figures are for illustrative purposes only and are not intended to be limiting. Other dimensions and proportions are contemplated and intended to be within the scope of the present disclosure.

[0066] As used herein, the term "subject" or "patient" or "individual" refers to a mammal, including, but not limited to, domestic animals (e.g., cows, sheep, cats, dogs, horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject is a human.

[0067] As used herein, the term "sample" refers to anything that may contain an analyte for which an analyte assay is desired. A sample may be a biological sample, such as a biological fluid or biological tissue. Examples of biological fluids include blood, serum, plasma, saliva, sputum, ocular lens fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, percutaneous exudate, pharyngeal exudate, bronchoalveolar lavage fluid, tracheal aspirate, cerebrospinal fluid, semen, cervical mucus, vaginal or urethral secretions, amniotic fluid, and the like. A biological tissue usually comprises a collection of cells of a particular type together with their intercellular substances that form one of the structural materials of human, animal, plant, bacterial, fungal, or viral structures, including connective tissue, epithelial tissue, muscle tissue, and nervous tissue. Examples of biological tissue also include organs, tumors, lymph nodes, arteries, and individual cells. A sample can be used as obtained directly from a source or after pretreatment to alter its properties.

[0068] As used herein, the term "specifically binds" refers to the binding specificity of a specific binding pair. Recognition by an antibody of a particular target in the presence of other potential targets is one characteristic of such binding.

[0069] As used herein, the term "combination" of an anti-RAGE antibody and at least a second pharmacoactive ingredient means at least two, although any desired combination of compounds can be delivered simultaneously or sequentially (e.g., within a 24-hour period). When used to treat various diseases, it is contemplated that the compositions and methods of the present disclosure can be utilized with other therapeutic methods / medications suitable for the same or similar diseases. Such other therapeutic methods / medications can be co-administered (simultaneously or sequentially) to produce additive or synergistic effects. The appropriate therapeutically effective amount of each agent can be reduced due to additive or synergistic effects.

[0070] Within the meaning of this disclosure, the term "co-administration" is used to refer to the administration of a composition according to the present disclosure and another therapeutic agent either simultaneously in one composition, or simultaneously in different compositions, or sequentially (e.g., within a 24 hour period).

[0071] The term "treatment" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the appearance of at least one clinical or subclinical symptom of the condition, disorder, or condition that has developed in a subject who may be afflicted with or susceptible to the condition, disorder, or condition, but who has not yet experienced or displayed a clinical or subclinical symptom of the condition, disorder, or condition; or (2) (in the case of maintenance therapy) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying, or at least one clinical or subclinical symptom thereof; or (3) palliating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof. The benefit to a subject being treated is either statistically significant or at least perceptible to the patient or physician.

[0072] As used herein, the term "therapeutically effective" or "effective" as applied to a dose or amount refers to the amount of a compound or pharmaceutical composition that, when administered to a subject for treating (e.g., preventing or ameliorating) a condition, disorder, or pathology, is sufficient to effect such therapeutic or prophylactic result. A "therapeutically effective amount" will vary depending on the compound or bacterium or analog administered, as well as the disease and its severity, and the age, weight, physical condition, and responsiveness of the mammal being treated.

[0073] The phrase "pharmaceutical acceptable" as used in connection with the compositions of the present disclosure refers to molecular entities and other components of the composition that are physiologically tolerable and typically do not cause adverse reactions when administered to a mammal (e.g., a human). As used herein, in some embodiments, the term "pharmaceutical acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in mammals, or even humans.

[0074] The term "pharmaceutical formulation" or "pharmaceutical composition" refers to a formulation in a form such that the biological activity of the active ingredient contained therein is effective, and which does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0075] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water or aqueous solutions, saline solutions, and aqueous solutions of dextrose and glycerol are particularly employed as carriers for injectable solutions. Alternatively, the carrier can be a solid dosage form carrier, including, but not limited to, one or more of a binder (for compressed tablets), a lubricant, an encapsulating agent, a flavoring agent, and a coloring agent. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by EW Martin.

[0076] The terms "anti-RAGE antibody," "anti-RAGE," "RAGE antibody" or "antibody that binds RAGE" refer to an antibody that can bind RAGE (e.g., human RAGE having the amino acid sequence set forth in SEQ ID NO: 1) with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting RAGE. In one embodiment, the extent of binding of the anti-RAGE antibody to unrelated, non-RAGE proteins is less than about 10% of the binding of the antibody to RAGE as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds PCSK9 has an affinity of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 M) In certain embodiments, the anti-RAGE antibody binds to an epitope of RAGE that is conserved among RAGE from different species.

[0077] The term "antibody" as used herein is used in the broadest sense and includes various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) and antibody fragments, so long as they exhibit the desired antigen-binding activity. An antibody broadly refers to an immunoglobulin (Ig) molecule, which comprises four polypeptide chains, two heavy (H) chains and two light (L) chains, or a functional fragment, mutant, variant, or derivative thereof that retains the essential epitope-binding function of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art, and non-limiting embodiments thereof are described below. An antibody is said to be "capable of binding" a molecule if it is capable of specifically reacting with the molecule to bind the molecule to the antibody. As used herein, the term "fragment" should be understood to mean an antigen-binding fragment, such as a RAGE-binding antibody fragment.

[0078] An "antigen-binding portion" or "antigen-binding fragment" of an antibody (or simply "antibody portion" or "antibody fragment") refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to an antigen bound by the intact antibody (e.g., one or more fragments of an antibody that retain the ability to specifically bind to an antigen). Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), heavy-chain only antibodies (HCAbs), and multispecific antibodies formed from antibody fragments. Papain digestion of an antibody produces two identical antigen-binding fragments called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, so named because of its amenability to crystallization. Pepsin treatment yields the F(ab')2 fragment, which has two antigen-binding sites and is capable of cross-linking antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Such antibody embodiments may be in a bispecific, dual or multispecific format and specifically bind to one or more different antigens. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains, (ii) a F(ab')2 fragment, a bivalent fragment consisting of two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fd fragment consisting of the VH and CH1 domains, (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment comprising a single variable domain (WO 90 / 05144 A1, which is incorporated herein by reference), and (vi) an isolated complementarity determining region (CDR). Furthermore, the two domains of the Fv fragment, VL and VH, are encoded by separate genes, but can be linked using recombinant methods by a synthetic linker that allows the VL and VH regions to be produced as a single protein chain (known as single-chain Fv (scFv)) that pairs to form a monovalent molecule. Such single-chain antibodies are also intended to be encompassed by the term "antigen-binding portion" of an antibody. Other forms of single-chain antibodies, such as diabodies, are also included.

[0079] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, and at least one other portion of the heavy and / or light chain (including the remainder) is derived from a different source or species.

[0080] The "class" of an antibody refers to the type of constant domain or region possessed by its heavy chain. There are five major classes of antibodies: e.g., IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, etc. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0081] The term "diabody" refers to antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with complementary domains on another chain, forming two antigen-binding sites. Diabodies may be bivalent and / or bispecific. Diabodies are described in more detail, for example, in EP 404,097, WO 1993 / 01161, Hudson et al., Nat. Med. 9:129-134, 2003, and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993. Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134. 2003.

[0082] The term "epitope" or "antigenic determinant" includes any polypeptide determinant capable of specific binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitopic determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and in certain embodiments may have specific three-dimensional structural characteristics, and / or specific charge characteristics. An epitope is the region of an antigen that is bound by an antibody. In certain embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules.

[0083] "Fab" fragments contain the heavy and light chain variable domains, and further contain the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residues of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments that have the hinge cysteines between them. Other chemical bonds of antibody fragments are known.

[0084] The term "Fc region" as used herein defines a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions.

[0085] "Framework" or "FR" refers to variable domain residues other than the complementarity determining region (CDR) residues. The FR of a variable domain typically consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the CDR and FR sequences typically appear in a VH (or VL) as follows: FR1-CDRH1 (CDRL1)-FR2-CDRH2 (CDRL2)-FR3-CDRH3 (CDRL3)-FR4.

[0086] As used herein, the terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or an antibody having a heavy chain that includes an Fc region as defined herein.

[0087] An "Fv" is the minimum antibody fragment that contains a complete antigen-binding site. In one embodiment, a two-chain Fv species consists of a dimer of one heavy-chain variable domain and one light-chain variable domain in tight non-covalent association. In a single-chain Fv (scFv) species, one heavy-chain and one light-chain variable domain can be covalently linked by a flexible peptide linker such that the light and heavy chains can associate in a "dimeric" structure similar to that in the two-chain Fv species. It is in this structure that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for an antigen) has the ability to recognize and bind antigen, albeit with a lower affinity than the entire binding site.

[0088] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of the cells into which the exogenous nucleic acid has been introduced. Host cells include "transformants" and "transformed cells," and include the primary transformed cell and its progeny, regardless of the number of transfers. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Included herein are mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell.

[0089] A "human antibody" is an antibody having an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, or from a non-human source that utilizes a human antibody repertoire or other human antibody coding sequence. The human antibodies of the present disclosure may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs, particularly CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of other mammalian species, such as mouse, have been grafted onto human framework sequences.

[0090] A "humanized" antibody refers to an antibody that contains heavy and light chain variable region sequences from a non-human species (e.g., mouse), but in which at least a portion of the VH and / or VL sequences have been modified to be more "human-like", i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences have been introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequences. A humanized antibody may contain amino acid residues of non-human CDRs and amino acid residues of human FRs. In certain embodiments, a humanized antibody will contain substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally contain at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has been subjected to humanization. A humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab', F(ab')2, FabC, Fv), in which all or substantially all of the CDR regions correspond to a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are human immunoglobulin consensus sequences. In particular, a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. In some embodiments, a humanized antibody comprises both a light chain and at least the variable domain of a heavy chain. The antibody may also comprise the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. In some embodiments, a humanized antibody comprises only a humanized light chain. In some embodiments, a humanized antibody comprises only a humanized heavy chain. In specific embodiments, a humanized antibody comprises only a humanized variable domain of a light chain and / or a humanized heavy chain. The humanized antibody can be selected from any class of immunoglobulins, including IgY, IgM, IgG, IgD, IgA, and IgE, and any isotype, including but not limited to IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4.A humanized antibody may comprise sequences from one or more isotypes, and the particular constant domain may be selected to optimize the desired effector functions using techniques well known in the art. The framework and CDR regions of a humanized antibody need not correspond exactly to the parental sequences, for example, the donor antibody CDR or consensus framework may be mutated by substitution, insertion and / or deletion of at least one amino acid residue such that the CDR or framework residue at that site does not correspond to either the donor antibody or the consensus framework. However, in certain embodiments, such mutations will not be extensive. Usually, at least 50%, 55%, 60%, 65%, 70%, 75% or 80%, particularly at least 85%, more particularly at least 90%, and especially at least 95% of the humanized antibody residues will correspond to those of the parental FR and CDR sequences. Thus, disclosed herein are humanized antibodies in which at least one of the CDRs corresponds to one of SEQ ID NOs: 4-9 and 12-17.

[0091] The term "CDR-grafted antibody" refers to an antibody that contains the heavy and light chain variable region sequences of one species but in which one or more of the sequences of the VH and / or VL CDR regions have been replaced with CDR sequences of another species, such as an antibody comprising murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) have been replaced with human CDR sequences.

[0092] An "immunoconjugate" is an antibody bound to one or more heterologous molecules, including, but not limited to, a cytotoxic agent.

[0093] An "isolated" antibody is one that has been separated from a component of its natural environment. In some embodiments, the antibody is purified to greater than 95% or 99% purity, for example, as measured by, but not limited to, electrophoretic methods (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic methods (e.g., ion exchange or reverse phase HPLC). An isolated antibody is substantially free of other antibodies having different antigen specificity (e.g., an isolated antibody that specifically binds human RAGE is substantially free of antibodies that specifically bind antigens other than human RAGE). However, an isolated antibody that specifically binds human RAGE may have cross-reactivity to other antigens, such as RAGE molecules of other species.

[0094] An "isolated" nucleic acid refers to a nucleic acid molecule that is separated from a component of its natural environment. Isolated nucleic acid includes a nucleic acid molecule contained within a cell that normally contains the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its native chromosomal location.

[0095] "Isolated nucleic acid encoding an anti-RAGE antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including nucleic acid molecules in a single vector or separate vectors, and in one or more locations in a host cell.

[0096] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies; that is, the individual antibodies comprising the population are identical and / or bind to the same epitope, except for variant antibodies that may, for example, contain naturally occurring mutations or arise during the manufacture of a monoclonal antibody preparation, in which such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure may be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or a portion of the human immunoglobulin loci, and such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0097] "Naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. Naked antibodies may be present in pharmaceutical formulations.

[0098] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a light chain variable domain or light chain variable domain, followed by a constant light chain (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0099] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment over the entire length of the sequences being compared.

[0100] As used herein, the term "polynucleotide" refers to a polymer of two or more nucleotides, either ribonucleotides or deoxynucleotides, or a modified form of either type of nucleotide. The term includes single- and double-stranded forms of DNA, but particularly double-stranded DNA.

[0101] As used herein, the term "isolated polynucleotide" refers to a polynucleotide (e.g., of genomic, cDNA, or synthetic origin, or any combination thereof) that, by virtue of its origin, is not associated with all or a portion of a polynucleotide with which it is found in nature, is operably linked to a polynucleotide with which it is not naturally linked, or does not occur in nature as part of a larger sequence.

[0102] As used herein, the term "polypeptide" refers to a polymeric chain of amino acids. The terms "peptide" and "protein" are used interchangeably with the term polypeptide and also refer to a polymeric chain of amino acids. The term "polypeptide" includes native or artificial proteins, protein fragments, and polypeptide analogs of protein sequences. Polypeptides may be monomeric or polymeric.

[0103] The term "isolated protein" or "isolated polypeptide" refers to a protein or polypeptide that, by reason of its origin or source, is not associated with naturally associated components with which it is natively associated, is substantially free of other proteins from the same species, is expressed by cells from a different species, or is not naturally occurring. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system other than the cell in which it is naturally derived would be "separated" from naturally associated components. A protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well known in the art.

[0104] The term "variable region" or "variable domain" refers to the heavy or light chain domain of an antibody that is involved in binding the antibody to an antigen. The heavy and light chain variable domains (VH and VL, respectively) of native antibodies generally have a similar structure, with each domain containing four conserved framework regions (FR) and three hypervariable regions called complementarity determining regions (CDRs) (see, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a particular antigen may be isolated by screening a library of complementary VL or VH domains, respectively, with a VH or VL domain from an antibody that binds to the antigen.

[0105] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures and vectors that are integrated into the genome of a host cell into which they are introduced. Certain vectors are capable of directing the expression of a nucleic acid to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0106] In accordance with the present disclosure there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art, such techniques being fully explained in the literature. See, for example, Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (referred to herein as "Sambrook et al., 1989"); DNA Cloning: A Practical Approach, Volumes I and II (ed. D. N. Glover, 1985); Oligonucleotide Synthesis (ed. M. J. Gait, 1984); Nucleic Acid Hybridization (eds. B. D. Hames & S. J. Higgins, 1985); Transcription and Translation (eds. B. D. Hames & S. J. Higgins, 1984); Animal Cell Culture (eds. R. I. Freshney, 1984); Immobilized Cells and Enzymes (IRL Press, (1986)); B. Perbal, A Practical Guide To Molecular Cloning (1984); F. M. Ausubel et al., (eds.), Current Protocols in Molecular Biology, See, e.g., John Wiley & Sons, Inc. (1994).

[0107] Compositions and methods The structure of human RAGE has been determined in its ligand-bound (binding to human S100A6) and unliganded forms. RAGE has an extracellular domain, a transmembrane domain, and a short cytoplasmic portion. Homology with other proteins has led to the model that RAGE has several extracellular domains. These extracellular domains, similar to immunoglobulins, have been named the V domain, C1 domain, and C2 domain (named for their homology to the V and C domains of immunoglobulins). The V domain is located at the N-terminus and binds several ligands such as S100 (specifically S100B, S100A1, S100A2, S100A4, S100A5, S100A6, S100A7, S100A8 / 9, S100A11, S100A12, S100A13, and S100P) and AGEs. Monoclonal antibodies that bind to the V-like domain of RAGE compete for binding of different ligands, including but not limited to S100b, HMGB1, and amyloid-β, suggesting that these ligands also bind to RAGE through the same domain. RAGE has two domains with homology to the C2 domain of immunoglobulins, one of which is designated C1. Several ligands that bind to this domain have been described, including S100A12 (also called ENRAGE or calgranulin C) and amyloid-β peptide aggregates. The second C2-like domain is designated C2. The ligand for RAGE, S100A6, binds to the C2 domain. Human RAGE also has a signal peptide. The overall structure of human RAGE is generally believed to be a signal peptide (amino acids 1-22 of SEQ ID NO:1; also shown in SEQ ID NO:21), followed by three immunoglobulin-like domains, including an Ig-like V-type domain (amino acids 23-116 of SEQ ID NO:1; also shown in SEQ ID NO:18) and two Ig-like C2 type 1 / 2 domains (amino acids 124-221 of SEQ ID NO:1; also referred to as the C1 domain and shown in SEQ ID NO:19; and amino acids 227-317 of SEQ ID NO:1; also referred to as the C2 domain and shown in SEQ ID NO:20), a single transmembrane domain (amino acids 343-363 of SEQ ID NO:1), and a short cytoplasmic tail (amino acids 364-404 of SEQ ID NO:1; also shown in SEQ ID NO:22).Human RAGE comprises both a membrane-bound and a soluble form derived from the V, C1 and C2 extracellular domains.

[0108] RAGE is a target for other indications that exhibit inflammation-driven pathologies that cause tissue dysfunction through inflammation induction, amplification, and neovascularization, including atherosclerosis, psoriasis, diabetic retinopathy, diabetic neuropathy, nephropathy, and Alzheimer's disease.

[0109] RAGE polymorphisms are also associated with some disease indications.Autoimmune disease indications include, but are not limited to, type 1 diabetes, psoriasis, and rheumatoid arthritis.Vascular disease indications include, but are not limited to, atherosclerosis, sporadic abdominal aortic aneurysm, and diabetic microvascular dermopathy.Oncological indications include, but are not limited to, gastric cancer.

[0110] Expression of RAGE correlates with poor prognosis, survival, stage, and metastasis in human tumors. Specifically, high expression of RAGE has been associated in the literature with poor clinical outcomes in certain cancer types, including, but not limited to, gastric, breast, and renal cancers.

[0111] Experiments have been performed to examine the effects of knocking out RAGE in various animal models. For example, RAGE knockout mice have been shown to be resistant to CAC (colitis-associated carcinogenesis). RAGE knockout mice are resistant to DMBA / TPA-induced skin carcinogenesis, a common model of chemical-induced skin carcinogenesis using DMBA and 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor initiators and promoters, respectively. RAGE knockout mice also show delayed mutant Ras-driven pancreatic carcinogenesis. RAGE knockout mice showed reduced growth of orthotopic polyoma middle T oncoprotein (PyMT) breast cancers. Other investigators have shown that RAGE knockout mice, when orthotopically transplanted with the GL261 glioma cell line, have an increased survival time, possibly as a result of reduced tumor inflammation and angiogenesis mediated by TAMs and microglia. Still others have shown that tumor-suppressing antigen-presenting cell (APC) mutant mice have reduced intestinal tumor incidence and size in comparison to RAGE knockout mice. Furthermore, transgenic mice with Kras mutant models of pancreatic ductal cancer showed carcinogenesis when crossed with RAGE knockout mice. In an orthotopic breast cancer model, transgenic mice overexpressing the RAGE ligand S100a7a15 were administered either soluble RAGE or a RAGE neutralizing antibody. As a result, inhibition of RAGE reduced tumor growth, lung metastasis, angiogenesis (CD31), and TAM recruitment (f4 / 80).

[0112] In a syngeneic animal model, injection of RAGE-transfected MC-38 tumor cells into the portal vein increased tumor burden compared with controls. In another syngeneic animal model, injection of CT26 tumor cells into the portal vein and treatment with soluble RAGE reduced tumor burden in the liver.

[0113] RAGE inhibition was also effective in xenograft models, suggesting a non-immune-mediated mechanism. For example, siRAGE-transfected MDA-MB-231 cells implanted into the mammary fat pad of NOD / SCID mice followed by intratumoral injection of S100A8 / 9 showed reduced lung metastasis. Single progeny clone 2 of MBA-MD-231 injected intracardially in nude mice showed significantly reduced metastatic potential when treated with a RAGE-neutralizing antibody.

[0114] In one aspect, the present disclosure is based in part on experimental and clinical results obtained with anti-RAGE antibodies, which show that the anti-RAGE antibodies of the present disclosure can inhibit Erk / MAPK signaling, inhibit cancer cell motility and invasiveness, promote T cell infiltration into tumor cells, alter the tumor microenvironment, and inhibit tumor growth.

[0115] A. Exemplary Anti-RAGE Antibodies In one aspect, the disclosure provides isolated antibodies or fragments thereof that bind to RAGE, such as human RAGE isoforms. In certain embodiments, the anti-RAGE antibodies or fragments thereof modulate RAGE activity. Any of the antibodies or fragments thereof described herein can specifically bind to RAGE and epitopes of RAGE, including but not limited to the specific domains of RAGE discussed herein.

[0116] In certain embodiments, the anti-RAGE antibody or fragment thereof binds to at least one domain of RAGE, such as, for example, but not limited to, the V and / or C1 domain of human RAGE. In certain embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of RAGE, including, for example, but not limited to, an epitope found in the V and / or C1 domain of human RAGE.

[0117] In certain embodiments, the anti-RAGE antibody or fragment thereof binds to an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to at least a portion of SEQ ID NO: 1. This portion may be contained in any, at least one, at least two or all of the V, C1 and / or C2 domains of human RAGE. In certain embodiments, the anti-RAGE antibody or fragment thereof binds to an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to at least a portion of the V and / or C1 domains of human RAGE. In certain embodiments, the anti-RAGE antibody or fragment thereof binds to an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to at least a portion of SEQ ID NOs: 18, 19, and / or 20.

[0118] In one aspect, the disclosure provides an antibody or antibody fragment that binds to RAGE (e.g., SEQ ID NO:1) or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof comprises a variable domain comprising a heavy chain (VH) comprising the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:10 and a light chain (VL) comprising the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:11. In certain embodiments, the antibody or fragment thereof comprises a VH domain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:2 or 10. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising a VL domain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:3 or 11. In certain embodiments, the sequence identity is to the full-length sequences disclosed herein.

[0119] In one embodiment, an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof) is provided, wherein said antibody or fragment thereof comprises a VH consisting of the amino acid sequence of SEQ ID NO:2. In certain embodiments, the antibody or fragment thereof further comprises a VL consisting of the amino acid sequence of SEQ ID NO:3. In certain embodiments, the antibody or fragment thereof comprises a VH consisting of the amino acid sequence of SEQ ID NO:2 and a VL consisting of the amino acid sequence of SEQ ID NO:3. In certain embodiments, the antibody or fragment thereof comprises a VH domain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:2. In certain embodiments, the antibody or fragment thereof comprises a VL domain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:3. In certain embodiments, the sequence identity is to the full-length sequences disclosed herein.

[0120] In one embodiment, an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof) is provided, wherein the antibody or fragment thereof comprises a VH consisting of the amino acid sequence of SEQ ID NO: 10. In a particular embodiment, the antibody or fragment thereof further comprises a VL comprising the amino acid sequence of SEQ ID NO: 11. In a particular embodiment, the antibody or fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 10 and a VL comprising the amino acid sequence of SEQ ID NO: 11. In a particular embodiment, the antibody or fragment thereof comprises a variable domain comprising a heavy chain (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 10. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising a light chain (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:11.

[0121] In certain embodiments, an antibody or antibody fragment is provided that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof comprises a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 2, or SEQ ID NO: 10. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity contains substitutions (e.g. conservative substitutions), insertions or deletions with respect to the reference sequence, but an anti-RAGE antibody or fragment thereof comprising that sequence retains the ability to bind to RAGE (e.g. SEQ ID NO: 1).

[0122] In certain embodiments, an antibody or antibody fragment is provided that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof comprises a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 3, or SEQ ID NO: 11. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity comprises substitutions (e.g. conservative substitutions), insertions or deletions with respect to the reference sequence, but an anti-RAGE antibody comprising that sequence retains the ability to bind to RAGE (e.g. SEQ ID NO: 1).

[0123] In one embodiment, an antibody or antibody fragment is provided which binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein said antibody or fragment thereof comprises a VH sequence of SEQ ID NO: 2 and a VL sequence of SEQ ID NO: 3. In one embodiment, an antibody or antibody fragment is provided which binds to RAGE or a fragment thereof, wherein said antibody comprises a VH sequence of SEQ ID NO: 10 and a VL sequence of SEQ ID NO: 11.

[0124] In certain embodiments, an antibody or antibody fragment is provided that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof comprises a variable domain comprising at least one, two, three, four, five or six complementarity determining region (CDR) sequences, including CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or 12; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5 or 13; and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6 or 14. In certain embodiments, the antibody or fragment thereof further comprises CDR-L1 comprising the amino acid sequence of SEQ ID NO: 7 or 15; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 8 or 16; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 9 or 17. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising at least one, two, three, four, five or CDR sequences comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 4-9 or 12-17.

[0125] In certain embodiments, an antibody or fragment thereof is provided that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof comprises a variable domain comprising six CDR sequences, including a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5 or 13, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6 or 14. In certain embodiments, the antibody or fragment thereof further comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 7 or 15, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 8 or 16, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 9 or 17. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising six CDR sequences comprising amino acid sequences that are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 4-9 or 12-17.

[0126] In one aspect, the disclosure provides an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof) comprising at least one, at least two, or all three VH CDR sequences selected from (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 12, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5 or SEQ ID NO: 13, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6 or SEQ ID NO: 14. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising at least one, at least two, or all three VH CDR sequences comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 4-6 or 12-14.

[0127] In one aspect, the disclosure provides an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof) comprising at least one, at least two, or all three VL CDR sequences selected from (a) CDR-L1 comprising the amino acid sequence of SEQ ID NO:7 or SEQ ID NO:15, (b) CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or SEQ ID NO:16, and (c) CDR-L3 comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:17. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising at least one, at least two, or all three VL CDR sequences that comprise an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs:7-9 or 15-17.

[0128] In another aspect, the disclosure provides an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), comprising: (a) a VH domain that comprises at least one, at least two, or all three VH CDR sequences selected from (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:12; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:13; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:6 or SEQ ID NO:14; and (b) a VL domain that comprises at least one, at least two, or all three VL CDR sequences selected from (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO:7 or SEQ ID NO:15; (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO:8 or SEQ ID NO:16; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:17. In certain embodiments, the antibody or fragment thereof comprises a variable domain comprising at least one, at least two, or all three VH and VL CDR sequences consisting of an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to any of SEQ ID NOs: 4-9 or 12-17.

[0129] In certain embodiments, an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof) is provided, wherein the antibody or fragment thereof has (i) a CDR-H1 having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:4 or SEQ ID NO:12, and (ii) a CDR-H1 having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:13. and (iii) a CDR-H3 having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:6 or SEQ ID NO:14. In certain embodiments, a CDR-H1, CDR-H2, or CDR-H3 sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions, but an anti-RAGE antibody or fragment thereof comprising that sequence retains the ability to bind to RAGE (e.g., SEQ ID NO: 1).

[0130] In certain embodiments, an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof) is provided, wherein the antibody or fragment thereof has (i) a CDR-L1 that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:7 or SEQ ID NO:15, and (ii) a CDR-L1 that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:8 or SEQ ID NO:16. and (iii) a CDR-L3 having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:17. In certain embodiments, a CDR-L1, CDR-L2, or CDR-L3 sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions, but an anti-RAGE antibody or fragment thereof comprising that sequence retains the ability to bind to RAGE (e.g., SEQ ID NO: 1).

[0131] In one embodiment, there is provided an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof: (1) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (2) CDR-H2 comprising the amino acid sequence of SEQ ID NO:5; and (3) CDR-H3 comprising the amino acid sequence of SEQ ID NO:6; and (4) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 7; and (5) CDR-L2 comprising the amino acid sequence of SEQ ID NO:8; and (6) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 9; Includes.

[0132] In certain embodiments, the antibody or antibody fragment comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of SEQ ID NOs:4-9.

[0133] In one embodiment, there is provided an antibody or antibody fragment that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof: (1) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 12; (2) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13; and (3) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 14; and (4) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 15; and (5) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (6) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 17; Includes.

[0134] In certain embodiments, the antibody or antibody fragment comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to any of SEQ ID NOs: 12-17.

[0135] In one embodiment, an antibody or fragment thereof is provided that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof comprises at least one CDR comprising an amino acid sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16 and SEQ ID NO:17.

[0136] In one embodiment, an antibody or fragment thereof is provided that binds to RAGE or a fragment thereof (including homologous variants of RAGE and fragments thereof), wherein the antibody or fragment thereof comprises at least one CDR having an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16 and SEQ ID NO:17.

[0137] In another aspect, an anti-RAGE antibody or fragment thereof is provided, wherein the antibody or fragment thereof comprises a VH as in any of the embodiments provided above and a VL as in any of the embodiments provided above.

[0138] In another aspect, an anti-RAGE antibody or fragment thereof is provided, wherein said antibody or fragment thereof comprises any CDR as in any of the embodiments above. In another aspect, an anti-RAGE antibody or fragment thereof is provided, wherein said antibody or fragment thereof comprises any CDR-H1, CDR-H2 or CDR-H3 as in any of the embodiments provided above, and any CDR-L1, CDR-L2 or CDR-L3 as in any of the embodiments provided above.

[0139] In another aspect, the anti-RAGE antibody or fragment thereof comprises a post-translational modification.

[0140] In certain embodiments, an antibody or antibody fragment that binds to RAGE or a fragment thereof is provided, wherein the antibody or fragment thereof binds to an epitope within a fragment of RAGE. In certain embodiments, an antibody or antibody fragment that binds to RAGE or a fragment thereof is provided, wherein the antibody binds to an epitope within a fragment of RAGE comprising the V and / or C1 domain of the human RAGE amino acid sequence of SEQ ID NO: 1. In certain embodiments, the antibody or fragment thereof binds to an epitope with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to RAGE and / or a fragment thereof, including but not limited to fragments comprising the V and / or C1 domain of human RAGE.

[0141] In certain embodiments, the anti-RAGE antibody is a monoclonal antibody. In certain embodiments, the anti-RAGE antibody is a chimeric antibody. In certain embodiments, the anti-RAGE antibody is a humanized antibody. In certain embodiments, the anti-RAGE antibody is a human antibody. In certain embodiments, at least a portion of the framework sequences of the anti-RAGE antibody are human consensus framework sequences. In one embodiment, the antibody is a RAGE binding antibody fragment selected from a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment. In some embodiments, the RAGE binding antibody or fragment thereof disclosed herein is an antibody or variant thereof comprising one or more CDRs selected from SEQ ID NOs: 4-9 and 12-17, and which binds to human RAGE.

[0142] In any of the above embodiments, the anti-RAGE antibody or fragment thereof is capable of binding to a target selected from RAGE molecules. In any of the above embodiments, the anti-RAGE antibody or fragment thereof is capable of binding to human RAGE. In any of the above embodiments, the anti-RAGE antibody or fragment thereof is capable of binding to mouse or rat RAGE.

[0143] In any of the above embodiments, the anti-RAGE antibody or fragment thereof is capable of modulating, in particular neutralizing, the biological function of a target selected from the RAGE molecule, In any of the above embodiments, the anti-RAGE antibody or fragment thereof modulates, in particular inhibits, the ability of RAGE to bind to at least one of its ligands.

[0144] In any of the above embodiments, the anti-RAGE antibody or fragment thereof comprises a linker polypeptide or an immunoglobulin constant domain.

[0145] In any of the above embodiments, the anti-RAGE antibody or fragment thereof is selected from the group consisting of an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab', a F(ab')2, an Fv, a disulfide-linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, a dual variable domain immunoglobulin, a heavy chain antibody (HCAb), and a bispecific antibody.

[0146] In any of the above embodiments, the anti-RAGE antibody or fragment thereof comprises an immunoglobulin heavy chain constant domain selected from the group consisting of a human IgM constant domain, a human IgG1 constant domain, a human IgG2 constant domain, a human IgG3 constant domain, a human IgG4 constant domain, a human IgE constant domain, a human IgD constant domain, a human IgA1 constant domain, a human IgA2 constant domain, a human IgY constant domain, and a corresponding mutated domain.

[0147] In any of the above embodiments, the anti-RAGE antibody or fragment thereof is present as an immune complex and is coupled to an immune adhesion molecule (such as, but not limited to, a radiolabel (e.g., 3 H, 14 C. 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I,177 Lu, 166 Ho, and 153 The therapeutic agent may further comprise an agent selected from the group consisting of an imaging agent (including, but not limited to, Sm), an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, and biotin), a therapeutic agent, and a cytotoxic agent. Exemplary therapeutic or cytotoxic agents include antimetabolites, alkylating agents, antibiotics, growth factors, cytokines, antiangiogenic agents, antimitotic agents, anthracyclines, toxins, and apoptotic agents.

[0148] In one aspect, the disclosure provides an isolated CDR of an antibody as described herein.

[0149] In another aspect, the disclosure provides an isolated binding protein that specifically interacts with at least one epitope of the RAGE protein and / or a homologous variant of that epitope having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to RAGE. In a related aspect, the isolated binding protein is an antibody or antigen-binding fragment thereof. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a VH and a VL domain and / or at least one CDR.

[0150] In one aspect, a nucleic acid is provided encoding any of the above anti-RAGE antibodies or fragments thereof. In one embodiment, a vector is provided comprising the nucleic acid. In one embodiment, the vector is an expression vector. In one embodiment, a host cell is provided comprising the vector. In another embodiment, a host cell transformed with the vector is provided. In one embodiment, the host cell is eukaryotic (such as, but not limited to, a protist cell, an animal cell, a plant cell, a fungal cell, a mammalian cell, an avian cell, an insect cell, a HEK cell, a CHO cell, a COS cell, and a yeast cell). In another embodiment, the host cell is mammalian. In yet another embodiment, the host cell is a prokaryotic cell.

[0151] In one aspect, the present disclosure provides a hybridoma cell line that produces an anti-RAGE antibody or antigen-binding fragment thereof. In certain embodiments, the hybridoma is selected from the group consisting of mouse, human, rat, ovine, porcine, bovine, caprine, and equine hybridomas. In certain embodiments, the hybridoma cell line produces an anti-RAGE antibody or antigen-binding fragment thereof (e.g., a monoclonal antibody) that specifically binds to at least one epitope of a RAGE protein.

[0152] In one embodiment, a method of making an anti-RAGE antibody or fragment thereof is provided, the method comprising culturing a host cell under conditions suitable for expression of nucleic acid encoding the antibody and isolating the antibody. In certain embodiments, the method further comprises recovering the anti-RAGE antibody from the host cell.

[0153] In one aspect, a pharmaceutical composition is provided comprising an anti-RAGE antibody or fragment thereof as described herein. In certain embodiments, the composition is suitable for subcutaneous administration. In certain embodiments, the composition is suitable for intravenous administration. In certain embodiments, the viscosity of the composition is less than about 10 cP at 25° C. In other embodiments, the viscosity of the composition is less than about 20 cP at 25° C., such as, but not limited to, about 15 cP, about 16 cP, about 17 cP, about 18 cP, and about 19 cP. Any anti-RAGE antibody known in the art or described herein may be formulated in the composition. In certain embodiments, the composition comprises a pharma- ceutically acceptable carrier, such as, but not limited to, a polymeric carrier. In certain embodiments, the composition may further comprise one or more of albumin, sucrose, trehalose, lactitol, gelatin, hydroxypropyl-β-cyclodextrin, methoxypolyethylene glycol and polyethylene glycol, arginine, and Tween.

[0154] In certain embodiments, the composition may further comprise an adjuvant.

[0155] In certain embodiments, the compositions may further comprise additional agents, for example, but not limited to, therapeutic agents, imaging agents, cytotoxic agents, angiogenesis inhibitors; kinase inhibitors; costimulatory molecule blockers; adhesion molecule blockers; anti-cytokine antibodies or functional fragments thereof; methotrexate; cyclosporine; rapamycin; FK506; detectable labels or reporters; TNF antagonists; anti-rheumatic agents; muscle relaxants, narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blocking agents, antibacterial agents, antipsoriatic agents, corticosteroids, anabolic steroids, erythropoietin, immune agents, immunoglobulins, immunosuppressants, growth hormones, hormone replacement agents, radiopharmaceuticals, antidepressants, antipsychotics, stimulants, asthma medications, beta agonists, inhaled steroids, epinephrine or analogs, cytokines, and cytokine antagonists. Further examples are latrepirdine, anti-Aβ antibodies, beta-secretase inhibitors, tau modulators, cognitive enhancers such as 5-HT6 antagonists, cholesterinase inhibitors (e.g. tactrine, donepezil, rivastigmine or galantamine), partial NMDA receptor blockers (e.g. memantine), glycosaminoglycan mimetics (e.g. tramiprosate), inhibitors or allosteric modulators of gamma secretase (e.g. R-flurbiprofen), luteinizing hormone blocking gonadotropin releasing hormone agonists (e.g. leuprorelin), serotonin 5-HT1A receptor antagonists, chelating agents, neuroselective L-type calcium channel blockers, immunomodulators. blocking agents, amyloid fibril formation inhibitors or amyloid protein deposition inhibitors (e.g., M266), another antibody (e.g., bapineuzumab), 5-HT1a receptor antagonists, PDE4 inhibitors, histaminergic agents, advanced glycation end products receptor protein, PARP stimulators, serotonin 6 receptor antagonists, 5-HT4 receptor agonists, human steroids, glucose uptake enhancers that promote neuronal metabolism, selective CB1 antagonists, benzodiazepine receptor partial agonists, amyloid beta production antagonists or inhibitors, amyloid beta deposition inhibitors, NNRα7 partial antagonists, PDE4 targeted therapeutics, RNA translation inhibitors, muscarinic agonists, nerve growth factor (NGF) receptor agonists, and gene therapy modulators.

[0156] In one aspect, there is provided a subcutaneous administration device comprising an anti-RAGE antibody or a composition comprising an anti-RAGE antibody or fragment thereof as described herein, hi certain embodiments, the device is for delivering a dose ranging from about 10 to about 1200 mg of antibody per administration to an individual.

[0157] B. Therapeutic and / or Diagnostic Methods In one aspect, the disclosure relates to a method of inhibiting binding of RAGE to an Erk / MAPK pathway protein in a subject, the method comprising administering to the subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In another aspect, the disclosure relates to a method of reducing at least one of chronic inflammation, immune suppression, cancer / tumor cell migration, cancer / tumor cell infiltration, suppressive immune cell infiltration into tumors, tumor-promoting immune cell infiltration, cancer / tumor growth, liver injury and fibrosis, ocular neovascularization, respiratory disease, infection, and / or cancer / tumor progression in a subject, the method comprising administering to the subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO: 1), including but not limited to, an epitope present in the V and / or C1 domain of human RAGE protein (e.g., SEQ ID NOs: 19 and / or 20).

[0158] In one aspect, the disclosure relates to a method of inhibiting RAGE activity to prevent and / or treat cancer, such as, for example, but not limited to, cancers characterized by high angiogenesis, such as colon cancer and renal cancer, comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), such as, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0159] In another aspect, the disclosure relates to a method of inhibiting RAGE activity to alter the tumor microenvironment, such as, but not limited to, inhibiting angiogenesis to tumors, inhibiting tumor growth, inhibiting or reducing expression of growth factors in tumors, reducing or altering the infiltration and / or activity of cell types of myeloid lineage, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein to reduce or alter the infiltration and / or activity of cell types of mesenchymal / stromal lineage, and / or promote T cell activity and infiltration into the tumor. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or at least one of the amino acid sequences having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NO: 19 and / or 20).

[0160] In another aspect, the disclosure relates to a method of inhibiting RAGE activity to prevent the development of chronic inflammation, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In a related aspect, the disclosure relates to a method of inhibiting RAGE activity to maintain an acute inflammatory state, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NO: 19 and / or 20).

[0161] In another aspect, the disclosure relates to a method of inhibiting RAGE activity to prevent liver injury and / or fibrosis, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17, and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0162] In another aspect, the disclosure relates to a method of inhibiting RAGE activity to prevent neovascularization in the eye, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0163] In another aspect, the disclosure relates to a method of inhibiting RAGE activity to prevent respiratory disease and / or onset of respiratory disease, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20). In some embodiments, the respiratory disease is allergic airway inflammation (AAI) and asthma, pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), acute lung injury, pneumonia, cystic fibrosis, and bronchopulmonary dysplasia.

[0164] In another aspect, the disclosure relates to a method of inhibiting RAGE activity to prevent infection and / or onset of an infection, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17, and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs: 19 and / or 20). In some embodiments, the infection is the result of infection by one or more of a virus, bacteria, fungus, prion, parasite, etc.

[0165] In one aspect, the disclosure relates to a method of treating a disease or disorder, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17, and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0166] In one aspect, the disclosure relates to a method of treating cancer, such as cancers characterized by high angiogenesis, such as, but not limited to, colon cancer and renal cancer, comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), such as, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0167] In some embodiments, the cancer is selected from the group consisting of leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, hairy cell leukemia), adrenocortical carcinoma, anal carcinoma, astrocytoma, Kaposi's sarcoma, lymphoma (e.g., AIDS-related lymphoma, primary central nervous system lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, cutaneous T-cell lymphoma, mycosis fungoides), skin cancer (e.g., skin cancer (basal cell carcinoma) , melanoma, Merkel cell carcinoma), bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, carcinoma, cancer of unknown primary site, central nervous system cancer, cervical cancer, chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, myeloblastoma, Ewing's sarcoma, extracranial germ cell tumor, extracranial germ cell tumor, extrapyramidal germ cell tumor, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma, gallbladder cancer, stomach cancer, gastrointestinal cal tinoid tumor, gastrointestinal stromal tumor, germ cell tumor, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, hypopharyngeal cancer, pancreatic islet cell tumor, renal cell carcinoma, laryngeal cancer, lip and oral cavity cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), malignant mesothelioma, oral cancer, multiple myeloma, myelodysplastic syndrome, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid adenocarcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, primary peritoneal cancer, prostate cancer, colorectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., rhabdomyosarcoma, hemangioma, Ewing's sarcoma, Kaposi's sarcoma, osteosarcoma, uterine sarcoma, soft tissue sarcoma), Sézary syndrome, squamous cell carcinoma, testicular cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor.

[0168] In some embodiments, the cancer is colorectal cancer. Four distinct consensus molecular subtypes (CMS): CMS1 (MSI-immunotype, 14%): hypermutated, microsatellite unstable, strong immune activation; CMS2 (canonical, 37%): epithelial, chromosomal instability, significant WNT and MYC signal activation; CMS3 (metabolic, 13%): epithelial, obvious metabolic disorder; and CMS4 (mesenchymal, 23%): Shows prominent transforming growth factor-β activation, stromal invasion, and angiogenesis There is. CRC samples with mixed characteristics (13%) likely represent a transitional phenotype or intratumoral heterogeneity. In some embodiments, the anti-RAGE antibodies disclosed herein are used to treat CRC in combination with biologic immunotherapy customized for CMS of CRC.

[0169] In another aspect, the disclosure relates to a method of altering the tumor microenvironment, such as, but not limited to, inhibiting angiogenesis into a tumor, inhibiting tumor growth, inhibiting or reducing expression of growth factors in a tumor, reducing or altering infiltration and / or activity of myeloid cell types, reducing or altering infiltration and / or activity of mesenchymal / stromal cell types, and / or promoting T cell activity and infiltration into a tumor, comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NO: 19 and / or 20).

[0170] In another aspect, the disclosure relates to a method of preventing the development of chronic inflammation, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In a related aspect, the disclosure relates to maintaining an acute inflammatory state, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17, and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NOs: 19 and / or 20).

[0171] In another aspect, the disclosure relates to a method of preventing liver injury and / or fibrosis, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17, and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0172] In another aspect, the disclosure relates to a method of preventing neovascularization in the eye, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0173] In another aspect, the disclosure relates to a method of preventing respiratory disease and / or onset of respiratory disease, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20). In some embodiments, the respiratory disease is allergic airway inflammation (AAI) and asthma, pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), acute lung injury, pneumonia, cystic fibrosis, and bronchopulmonary dysplasia.

[0174] In another aspect, the disclosure relates to a method of preventing an infectious disease and / or the onset of an infectious disease, the method comprising administering to a subject an effective amount of any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs: 19 and / or 20). In some embodiments, the infectious disease is the result of infection with one or more of a virus, bacteria, fungus, prion, parasite, etc.

[0175] In another aspect, the disclosure provides a method of reducing human RAGE activity comprising contacting human RAGE with any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0176] In another aspect, the disclosure provides a method of reducing human RAGE binding to at least one ligand selected from Erk, S100b, AGE, HMGB1 (amphoterin), S100A12 (EN-RAGE), S100A7 (psoriasin), S100P, S100A8 / A9 complex (calprotectin), amyloid-β-protein, Mac-1, phosphatidylserine, and S100A4, comprising administering to a subject in need thereof any of the anti-RAGE antibodies or fragments thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NO: 19 and / or 20).

[0177] In another aspect, the disclosure provides a method of treating a subject for a disorder associated with RAGE activity comprising administering any of the anti-RAGE antibodies or fragments thereof described herein, alone or in combination with other therapeutic agents. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0178] In another aspect, the disclosure provides a method for reducing RAGE activity in a subject suffering from a disorder in which RAGE activity is detrimental, comprising administering to the subject any of the anti-RAGE antibodies or fragments thereof described herein, alone or in combination with other therapeutic agents. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs:2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs:2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of human RAGE protein (e.g., SEQ ID NO:1), including, but not limited to, an epitope present in the V and / or C1 domains of human RAGE protein (e.g., SEQ ID NOs:19 and / or 20).

[0179] In certain embodiments, the methods described herein further comprise administering to the subject an effective amount of a second pharmaceutical or therapeutic agent, and the anti-RAGE antibody or fragment thereof is the first pharmaceutical or therapeutic agent. In one embodiment, the second pharmaceutical or therapeutic agent is a cancer therapeutic agent. In certain embodiments, the subject or individual is a human. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NOs: 19 and / or 20).

[0180] In one aspect, the present disclosure relates to a method of detecting RAGE protein in a sample suspected of containing RAGE protein, the method comprising the steps of: (a) contacting the sample with an anti-RAGE antibody or fragment thereof described herein; and (b) detecting formation of a complex between the anti-RAGE antibody or fragment thereof and the RAGE protein. In one embodiment, the anti-RAGE antibody or fragment thereof is detectably labeled.

[0181] The present disclosure also provides new diagnostic tests for characterizing an individual's risk of developing or having a disease or condition characterized by high levels of RAGE, as well as for identifying subjects with high levels of RAGE who will respond or are likely to respond to a particular treatment or therapeutic agent to reduce RAGE levels. Yet other diagnostic tests include monitoring the levels of RAGE during treatment.

[0182] In certain embodiments, the methods described herein include identifying a subject who will respond to anti-RAGE antibody treatment, and include determining the level of RAGE in a sample from the subject using an antibody described herein, and comparing the level of RAGE to a comparable sample obtained from the general population or a selected population of human subjects. The level may also be compared to the level of RAGE in the subject before starting anti-RAGE antibody treatment. Such a comparison characterizes the subject's response to anti-RAGE antibody treatment.

[0183] In certain embodiments, the methods described herein include identifying a subject who will respond to treatment for a disease or condition characterized by high levels of RAGE (such as, for example, but not limited to, cancer, chronic inflammation, cancer / tumor cell migration, cancer / tumor cell infiltration, tumor suppressive immune cell infiltration, tumor promoting immune cell infiltration, cancer / tumor growth, liver injury and fibrosis, ocular neovascularization, respiratory disease, infectious disease, cancer / tumor progression, and / or a devascularized tumor microenvironment), and include determining the level of RAGE in a sample from the subject using an antibody described herein and comparing the level of RAGE to a comparable sample from the general population or a selected population of human subjects. The level may also be compared to the level of RAGE in the subject before initiating anti-RAGE antibody treatment. Such a comparison characterizes the subject's response to anti-RAGE antibody treatment.

[0184] The present disclosure also provides a method of monitoring the status of RAGE levels in a subject over time, the method comprising determining the level of RAGE in a sample taken from the subject at an initial time point and in a corresponding sample taken from the subject at a subsequent time point. An increase in the level of RAGE from the sample taken at the subsequent time point compared to the initial time point indicates that the subject is at increased risk of having or developing a RAGE-associated condition or disorder in the future. A decrease in the level of RAGE from the sample taken at the subsequent time point compared to the initial time point indicates that the subject is at reduced risk of having or developing a RAGE-associated condition or disorder in the future.

[0185] In another embodiment, the disclosure provides a method of evaluating a treatment in a subject having or suspected of having a condition or disease associated with elevated levels of RAGE, the method comprising determining the level of RAGE in a sample taken from the subject prior to treatment and a corresponding sample taken from the subject during or after treatment. A decrease in the level of RAGE in the sample taken after or during treatment compared to the level of RAGE in the sample taken prior to treatment indicates a positive effect of the treatment on the RAGE-associated disease or condition in the subject.

[0186] In one aspect, the present disclosure provides a method for diagnosing a condition or disease associated with high levels of RAGE in a subject, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying the subject as (i) having a condition or disease associated with high levels of RAGE when the subject's RAGE level is equal to or greater than the RAGE level of the comparison sample, or (ii) not having a condition or disease associated with high levels of RAGE when the subject's RAGE level is less than the RAGE level of the comparison sample; The present invention provides a method comprising:

[0187] In another aspect, the present disclosure provides a method for detecting a condition or disease associated with high levels of RAGE in a subject, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying the subject as (i) having a condition or disease associated with high levels of RAGE when the subject's RAGE level is equal to or greater than the RAGE level of the comparison sample, or (ii) not having a condition or disease associated with high levels of RAGE when the subject's RAGE level is less than the RAGE level of the comparison sample; The present invention provides a method comprising:

[0188] In one aspect, the disclosure provides a method for classifying a subject as having or not having a condition or disease associated with high levels of RAGE, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying the subject as (i) having a condition or disease associated with high levels of RAGE when the subject's RAGE level is equal to or greater than the RAGE level of the comparison sample, or (ii) not having a condition or disease associated with high levels of RAGE when the subject's RAGE level is less than the RAGE level of the comparison sample; The present invention provides a method comprising:

[0189] In another aspect, the present disclosure provides a method of monitoring a condition or disease associated with high levels of RAGE in a subject, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected human population; and c) (i) identifying the subject as having or continuing to have a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) identifying the subject as not having, or no longer having, a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is less than the level of RAGE in the comparable sample; The present invention provides a method comprising:

[0190] In one aspect, the disclosure provides a method of selecting subjects for clinical trials of anti-RAGE antibody therapeutic compositions and / or methods, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying the subject as (i) suitable for clinical trials if the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) not suitable for clinical trials if the level of RAGE in the subject is less than the level of RAGE in the comparable sample; The present invention provides a method comprising:

[0191] In one aspect, the present disclosure provides a method of treating and / or preventing a condition or disease associated with high levels of RAGE in a subject, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected human population; c) (i) identifying the subject as suitable for treatment of elevated levels of RAGE or having a condition or disease associated with elevated levels of RAGE when the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) identifying the subject as not suitable for treatment of elevated levels of RAGE or not having a condition or disease associated with elevated levels of RAGE when the level of RAGE in the subject is less than the level of RAGE in the comparable sample; and d) if the subject has or is suitable for treatment of a condition or disease associated with elevated levels of RAGE, utilizing an appropriate therapeutic and / or prophylactic composition and / or method; The present invention provides a method comprising:

[0192] In another aspect, the present disclosure provides a method for predicting a risk of developing a condition or disease associated with high levels of RAGE in a subject, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying the subject as (i) having or at risk for developing a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) not having or at risk for developing a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is less than the level of RAGE in the comparable sample; The present invention provides a method comprising:

[0193] In one aspect, the disclosure provides a method of predicting a subject's response to treatment for a condition or disease associated with an elevated level of RAGE in the subject, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected human population; c) identifying the subject as (i) at risk for having or developing a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) not at risk for having or developing a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is less than the level of RAGE in the comparable sample; and (d) predicting a response to treatment for severe or fatal GVHD in the subject based on the identifying step; The present invention provides a method comprising:

[0194] In one aspect, the present disclosure provides a method for monitoring the likelihood of developing a condition or disease associated with high levels of RAGE in a subject, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying the subject as (i) at risk for having or developing a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) not at risk for having or developing a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is less than the level of RAGE in the comparable sample; The present invention provides a method comprising:

[0195] In another aspect, the present disclosure provides a method for monitoring the success and / or effectiveness of treatment and / or prophylaxis in a subject having or likely to develop a condition or disease associated with high levels of RAGE, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying (i) the treatment and / or prevention as successful when the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) the treatment and / or prevention as not successful when the level of RAGE in the subject is less than the level of RAGE in the comparable sample; Optionally, steps a, b, and / or c may be repeated during and after a course of treatment and / or prevention.

[0196] In one aspect, the disclosure provides a method of selecting a subject for treatment and / or prevention of a condition or disease associated with high levels of RAGE, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying the subject as (i) suitable for the treatment and / or prevention if the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) not suitable for the treatment and / or prevention if the level of RAGE in the subject is less than the level of RAGE in the comparable sample; Optionally, steps a, b, and / or c may be repeated during and after a course of treatment and / or prevention.

[0197] In a related aspect, the disclosure provides a method for prognosis of a condition or disease associated with high levels of RAGE, comprising: a) measuring the level of RAGE in a sample obtained from a subject; b) comparing the RAGE levels obtained from the subject with the RAGE levels in comparable samples obtained from the general population or a selected population of human subjects; and c) identifying the subject as (i) likely to develop a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is equal to or greater than the level of RAGE in the comparable sample, or (ii) not likely to develop a condition or disease associated with high levels of RAGE when the level of RAGE in the subject is less than the level of RAGE in the comparable sample; The present invention provides a method comprising:

[0198] In any of the above embodiments, steps (b) and / or (c) may be performed by a computer.

[0199] In any of the above methods, step (a) further comprises obtaining a blood sample from the subject and then isolating RAGE. In any of the above methods, step (b) further comprises obtaining a blood sample from a member of the general population or a selected population and then isolating RAGE.

[0200] In any of the above methods, steps (a) and / or (b) may further comprise determining the level of RAGE in the sample.

[0201] In any of the preceding methods, determining the level of RAGE further comprises isolating nucleic acid and / or protein from the sample.

[0202] In any of the above methods, the method further comprises treating and / or preventing a subject determined to have, or to be at risk for, a condition or disease associated with elevated levels of RAGE.

[0203] In one embodiment of any of the above methods, the treatment is prophylactic and includes administration of a suitable prophylactically effective pharmaceutical composition and / or use of a suitable prophylactically effective method. In one embodiment, the prophylactic treatment includes an immunosuppressant, an anti-inflammatory, a cytotoxic, an immunomodulatory agent, etc. In other embodiments, the prophylactic treatment includes at least one anti-RAGE antibody or fragment thereof described herein. In yet other embodiments, the prophylactic treatment includes a therapeutic agent and at least one anti-RAGE antibody or fragment thereof described herein. In some embodiments, the anti-RAGE antibody or fragment thereof includes at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NO: 19 and / or 20).

[0204] In one embodiment of any of the above methods, the treatment comprises the administration of a suitable therapeutically effective pharmaceutical composition and / or the use of a suitable therapeutically effective method. In one embodiment, the therapeutically effective composition comprises a cancer therapeutic agent and / or an immunomodulatory therapy (e.g., but not limited to, checkpoint inhibitors such as nivolumab and pembrolizumab, anti-cancer agents that induce immunogenic cell death (ICD), such as platinum compounds, taxanes, and alkylating agents (e.g., oxaliplatin, paclitaxel, and cyclophosphamide, respectively), VEGF pathway and vascular targeting antibodies and tyrosine kinase inhibitors (TKIs), such as bevacizumab and sunitinib, respectively, antimetabolites, such as 5-fluorouracil and gemcitabine, antibody therapies that involve ADCC responses, such as cetuximab and trastuzumab). In another embodiment, the therapeutically effective method comprises the use of high doses of steroids (e.g., corticosteroids) and / or the use of immunosuppressive therapy and / or the use of a cancer therapeutic agent. In other embodiments, the therapeutic treatment comprises at least one anti-RAGE antibody or fragment thereof as described herein. In yet other embodiments, the therapeutic treatment comprises a therapeutic agent and at least one anti-RAGE antibody or fragment thereof as described herein. In some embodiments, the anti-RAGE antibody or fragment thereof comprises at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibody or fragment thereof binds to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NOs: 19 and / or 20).

[0205] The treatment and / or prophylaxis of a subject having or at risk of having a condition and / or disease associated with high levels of RAGE may be administered to the subject via any suitable route of administration. The effective amount or dose of such treatment and / or prophylaxis administered should be sufficient to provide a therapeutic or prophylactic response in the subject in a reasonable time frame. For example, the dose of an immunosuppressant should be sufficient to reduce the level of RAGE and reduce the symptoms of such a condition and / or disease. The dosage is determined by the efficacy of the particular active agent and the condition of the subject (e.g., human), as well as the body weight of the subject (e.g., human) to be treated.

[0206] Any of the embodiments described herein, or combinations thereof, apply to any and all of the anti-RAGE antibodies, methods and uses of the present disclosure described herein. In some embodiments, the anti-RAGE antibodies and fragments thereof comprise at least one of the amino acid sequences of SEQ ID NOs: 2-17 and / or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequences of SEQ ID NOs: 2-17. In some embodiments, the anti-RAGE antibodies or fragments thereof bind to at least one epitope of the human RAGE protein (e.g., SEQ ID NO: 1), including, but not limited to, an epitope present in the V and / or C1 domains of the human RAGE protein (e.g., SEQ ID NOs: 19 and / or 20).

[0207] It is also contemplated that the isolated RAGE-interacting antibody or fragment thereof of the present application may be a glycosylated binding protein, where the antibody or antigen-binding portion thereof comprises one or more carbohydrate residues. Nascent in vivo protein production may undergo further processes known as post-translational modifications. In particular, sugar (glycosyl) residues may be added enzymatically, a process known as glycosylation. Proteins with the resulting oligosaccharide side chains are known as glycosylated proteins or glycoproteins. Protein glycosylation depends on the amino acid sequence of the protein of interest and the host cell in which the protein is expressed. Different organisms may produce different glycosylation enzymes (e.g., glycosyltransferases and glycosidases) and may be able to utilize different substrates (nucleotide sugars). Due to such factors, the glycosylation pattern of a protein and the composition of glycosyl residues may vary depending on the host system in which a particular protein is expressed. Glycosyl residues useful in the present disclosure may include, but are not limited to, glucose, galactose, mannose, fucose, n-acetylglucosamine, and sialic acid.

[0208] The antibody or fragment thereof of the present application comprises a heavy chain constant region, such as an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. Additionally, the antibody may comprise a light chain constant region, either a kappa light chain constant region or a lambda light chain constant region. In particular, the antibody comprises a kappa light chain constant region. Alternatively, the antibody portion may be, for example, a Fab fragment or a single chain Fv fragment. Substitution of amino acid residues in the Fc portion to alter the effector functions of the antibody is known in the art (U.S. Pat. Nos. 5,648,260 and 5,624,821). The Fc portion of the antibody mediates several important effector functions, such as, for example, cytokine induction, ADCC, phagocytosis, complement-dependent cytotoxicity (CDC), and half-life / clearance rate of the antibody and antigen-antibody complex. While these effector functions may be desirable for therapeutic antibodies, they may be unnecessary or even harmful depending on the therapeutic purpose. Certain human IgG isotypes, particularly IgG1 and IgG3, mediate ADCC and CDC via binding to Fcγ receptors and complement C1q, respectively. The neonatal Fc receptor (FcRn) is a key component determining the circulating half-life of an antibody. In yet another embodiment, at least one amino acid residue is substituted in the constant region of the antibody, e.g., the Fc region of the antibody, such that the effector function of the antibody is altered.

[0209] It is contemplated that when used to treat various diseases, the compositions and methods of the present disclosure may be combined with other therapeutic agents suitable for the same or similar disease. Also, two or more embodiments of the present disclosure may also be co-administered to produce additive or synergistic effects. When co-administered with a second therapeutic agent, the embodiments of the present disclosure and the second therapeutic agent may be simultaneous or sequential (in any order). The appropriate therapeutically effective dosage of each agent may be reduced due to additive or synergistic effects.

[0210] As a non-limiting example, the present disclosure can be combined with other therapies that block inflammation (e.g., via blockade of IL1, INFα / β, IL6, TNF, IL13, IL23, etc.).

[0211] The compositions and methods of the disclosure can also be administered in combination with anti-tumor antibodies or antibodies directed against pathogenic antigens or allergens.

[0212] The compositions and methods of the present disclosure can be combined with other immunomodulatory therapies, such as, for example, therapeutic vaccines (including but not limited to, GVAX, DC-based vaccines, etc.), checkpoint inhibitors (including but not limited to, agents that inhibit CTLA4, PD1, LAG3, TIM3, etc.), or activators (including but not limited to, agents that enhance 41BB, OX40, etc.). The inhibitory treatments of the present disclosure can also be combined with other treatments capable of modulating the function or stability of antigen-free or antigen-loaded natural killer T cells, including but not limited to, CD1d, CD1d fusion proteins, CD1d dimers, or large polymers of CD1d, CD1d-chimeric antigen receptors (CD1d-CARs), or any of the other of the five known CD1 isomers currently present in humans (CD1a, CD1b, CD1c, CD1e), in any of the forms or formulations described above, alone or in combination with other agents.

[0213] The therapeutic methods of the present disclosure can be combined with additional immunotherapy and treatment. For example, when used to treat cancer, the anti-RAGE antibody or fragment thereof of the present disclosure can be used in combination with conventional cancer treatments, such as surgery, radiation therapy, chemotherapy, or a combination thereof, depending on the type of tumor, the patient's condition, other health issues, and various factors. In some aspects, other therapeutic agents useful in combination cancer therapy with the inhibitors of the present disclosure include antiangiogenic agents. Many antiangiogenic agents have been identified and are known in the art, including, for example, the following: TNP-470, platelet factor 4, thrombospondin-1, tissue inhibitor of metalloproteinases (TIMP1 and TIMP2), prolactin (16-Kd fragment), angiostatin (38-Kd fragment of plasminogen), endostatin, bFGF soluble receptor, transforming growth factor beta, interferon alpha, soluble KDR and FLT-1 receptor, and placental proferin-related protein. In one embodiment, the anti-RAGE antibodies or fragments thereof of the present disclosure may be used with anti-VEGF antibodies, VEGF variants, soluble VEGF receptor fragments, aptamers capable of blocking VEGF or VEGFR, neutralizing anti-VEGFR antibodies, inhibitors of VEGFR tyrosine kinase, and any combination thereof (e.g., anti-hVEGF antibody A4.6.1, bevacizumab or ranibizumab).

[0214] Non-limiting examples of chemotherapeutic compounds that may be used in the combination therapy of the present disclosure include, for example, aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramnustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea , idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin Examples of agents that may be used include rituximab, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine.

[0215] These chemotherapeutic compounds may be classified according to their mechanism of action into, for example, the following groups: antimetabolites / anticancer drugs such as pyrimidine analogues (5-fluorouracil, floxuridine, capecitabine, gemcitabine, and cytarabine) and purine analogues, folate antagonists and related inhibitors (mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine (cladribine)); natural products such as vinca alkaloids (vinblastine, vincristine, and vinorelbine), taxanes (paclitaxel, docetaxel, , vincristine, vinblastine, nocodazole, epothilones and navelbine, epipodophyllotoxins (etoposide, teniposide), DNA damaging agents (actinomycin, amsacrine, anthracyclines, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, hexamethylphenylamine oxaliplatin, ifosfamide, melphalan, mercury, mycobacterium purpura ... Antibiotics such as tomycin, mitoxantrone, nitrosoureas, plicamycin, procarbazine, taxol, taxotere, teniposide, triethylenethiophosphoramide, and etoposide (VP16); dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), and mitomycin; enzymes (cells that do not have the ability to metabolize L-asparagine systemically and synthesize asparagine) L-asparaginase, which strips asparagine from the blood; antiplatelet agents; antiproliferative / anti-exacerbating alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and its analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkylsulfonates-busulfan, nitrosoureas (carmustine (BCNU) and its analogs, streptozocin), and trazeneth-dacarbazine (DTIC); antiproliferative / anti-exacerbating antimetabolites such as folic acid analogs (methotrexate);Platinum complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogues (estrogens, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytics (tissue plasminogen activator, streptokinase and urokinase, etc.), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab, counterstimulants; secretory inhibitors (bleverdin); immunosuppressants (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); antiangiogenic compounds (e.g. TNP-470, geniste angiotensin receptor antagonists; nitric oxide donors; antisense oligonucleotides; antibodies (trastuzumab); cell cycle inhibitors and differentiation inducers (tretinoin); mTOR inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin and mitoxantrone, topotecan, irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone and prenisolone); growth factor signaling kinase inhibitors, mitochondrial dysfunction inducers and caspase activators, and chromatin disruptors.

[0216] The composition of the present disclosure can include carriers and / or excipients. The excipients and / or carriers must be "acceptable" in the sense of being compatible with other ingredients of the formulation and not harmful to the recipient. Therapeutic acceptable excipients and carriers are well known in the art and are described, for example, in Remington: The Science and Practice of Pharmacy. Lippincott Williams & Wilkins (AR Gennaro edit. 2005). The choice of pharmaceutical excipients and carriers can be selected taking into account the intended route of administration and standard pharmaceutical practice. Those skilled in the art can prepare suitable solutions.

[0217] In one embodiment of any of the compositions of the present disclosure, the composition is formulated for delivery by routes such as oral, topical, rectal, mucosal, sublingual, nasal, nasal / intragastric, parenteral, intraperitoneal, intradermal, transdermal, intrathecal, intranasal, and intratracheal.In one embodiment of any of the compositions of the present disclosure, the composition is in the form of a liquid, foam, cream, spray, powder, or gel.In one embodiment of any of the compositions of the present disclosure, the composition comprises a buffer (e.g., sodium bicarbonate).

[0218] The administration of the compounds and compositions in the disclosed methods can be accomplished by any method known in the art. Non-limiting examples of useful delivery routes include oral, rectal, colonic (by enema), and naso / gastric oral administration, as well as parenteral, intraperitoneal, intradermal, intravenous, subcutaneous, transdermal, intrathecal, nasal, and intratracheal administration. The active agent may be systemic after administration, or may be localized by topical administration, intrathecal administration, or the use of an implant that acts to retain the active dose at the implantation site. The carrier material must be non-toxic to the subject / patient.

[0219] Useful dosages of the compounds and formulations of the present disclosure vary widely depending on the nature of the disease, the patient's medical history, the frequency of administration, the method of administration, clearance of the drug from the host, etc. A higher initial dosage may be administered followed by a lower maintenance dosage. Administration may be as infrequent as once a week or once every other week, or may be divided into smaller doses and administered daily, semi-weekly, etc., to maintain an effective dosage level. It is envisioned that a range of doses will be effective to achieve a therapeutic effect. While the compounds of the present disclosure can be used in therapy as such, it may be preferable to administer them in a pharmaceutical formulation, e.g., in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. The excipient, diluent, and / or carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Therapeutically acceptable excipients, diluents and carriers are well known in the art and are described, for example, in Remington: The Science and Practice of Pharmacy. Lippincott Williams & Wilkins (AR Gennaro edit. 2005). The choice of pharmaceutical excipients, diluents and carriers can be selected having regard to the intended route of administration and standard pharmaceutical practice.

[0220] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizing agents, thickening agents, stabilizers, and preservatives.

[0221] The solutions or suspensions may contain any of the following components in any combination: a sterile diluent, for example, water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, for example, benzyl alcohol and methylparabens; antioxidants, for example, ascorbic acid and sodium bisulfite; chelating agents, for example, ethylenediaminetetraacetic acid (EDTA); buffers, for example, acetates, citrates, and phosphates; and osmotic adjusters, for example, sodium chloride or glucose.

[0222] In cases where a drug exhibits insufficient solubility, methods of solubilizing the drug may be used. These methods are known in the art and include, but are not limited to, the use of cosolvents such as dimethylsulfoxide (DMSO), the use of surfactants such as TWEEN® 80, or dissolution in aqueous sodium bicarbonate. Pharmaceutically acceptable derivatives of drugs may also be used to formulate effective pharmaceutical compositions.

[0223] The compositions may contain, together with the active agent, for example and without limitation: diluents such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; lubricants such as magnesium stearate, calcium stearate, and talc; and binders such as natural gums such as starch, acacia gum, gelatin, glucose, molasses, polyvinylpyrrolidone, cellulose and its derivatives, povidone, crospovidone, and other such binders known in the art. Liquid pharma- ceutically administrable compositions may be prepared, for example, by dissolving, dispersing, or otherwise mixing the active agent as defined above and optional pharmaceutical adjuvants in a carrier such as, for example and without limitation, water, saline, aqueous dextrose, glycerol, glycol, ethanol, and the like, thereby forming a solution or suspension. If desired, the pharmaceutical composition to be administered may contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents, etc., such as acetates, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents. Actual methods for preparing such dosage forms are known in the art or will be apparent to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975). In any event, the composition or formulation to be administered will contain a quantity of the active agent sufficient to alleviate the symptoms in the subject to be treated.

[0224] The active agents or pharma- ceutically acceptable derivatives may be prepared with carriers that protect the agent against rapid elimination from the body, such as time-release formulations or coatings. The compositions may contain other active agents to obtain desired combinations of properties.

[0225] Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously, and is often contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients include, by way of example and without limitation, water, saline, dextrose, glycerol, or ethanol. In addition, if desired, the pharmaceutical composition to be administered may contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0226] Implantation of a slow-release or sustained-release system such that a constant level of dosage is maintained (e.g., U.S. Pat. No. 3,710,795) is also contemplated herein. Briefly, the anti-RAGE antibodies disclosed herein are administered to a subject in need of treatment with a solid internal matrix (e.g., polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate), It is surrounded by an outer polymeric membrane (e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / vinyloxyethanol copolymers) that is insoluble in body fluids. The drug diffuses through the outer polymeric membrane in a step that controls the release rate. The percentage of active drug contained in such parenteral compositions is highly dependent on their specific nature, the activity of the drug, and the needs of the subject.

[0227] The lyophilized powders can be reconstituted for administration as solutions, emulsions, and other mixtures, or can be formulated as solids or gels. Sterile lyophilized powders are prepared by dissolving the agent provided herein or a pharma- ceutically acceptable derivative thereof in a suitable solvent. The solvent may contain excipients that improve the stability or other pharmacological components of the powder or the reconstituted solution prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The solvent may also contain a buffer, typically around neutral pH, such as citrate, sodium or potassium phosphate, or other such buffers known in the art. The solution is then sterile filtered and lyophilized under standard conditions known in the art to obtain the desired formulation. Generally, the resulting solution is apportioned into vials for lyophilization. Each vial may contain, by way of example and not limitation, a single dose (10-1000 mg, e.g., 10-500 mg) or multiple doses of drug. The lyophilized powder can be stored under appropriate conditions, such as at about 4° C. to room temperature. Reconstitution of the lyophilized powder with water for injection provides a formulation for parenteral administration. Precise amounts will depend on the drug selected. Such amounts can be empirically determined.

[0228] The composition of the present invention or its pharma- ceutically acceptable derivatives may be formulated as an aerosol, for example, for inhalation or nasal application. These formulations may be used alone or in combination with an inert carrier such as lactose, in the form of an aerosol or solution for nebulizers, or as fine powder for pneumoperitoneum. In such cases, the particles of the formulation have, by way of example and not limitation, a diameter of less than about 50 microns, for example less than about 10 microns.

[0229] kit In one aspect, the present disclosure provides a kit for diagnosing and / or detecting a condition or disease associated with high levels of RAGE in a subject, said kit comprising an antibody directed to RAGE, said antibody being usable to determine the expression level of RAGE. The kit may also comprise a detection means. The kit may further optionally comprise a control antibody.

[0230] In some embodiments, these kits include a detection reagent that specifically binds to RAGE (e.g., SEQ ID NO:1) and fragments thereof. The kits typically include, but are not limited to, an antibody that specifically binds to a polypeptide of the disclosure, such as, but not limited to, RAGE and fragments thereof, and a label to detect the presence of the probe. The kits may include multiple antibodies specific for a polypeptide of the disclosure. The kits may further include a control antibody to provide a control level of the protein, and / or other standards or controls. The antibody is optionally detectably labeled.

[0231] The kit may contain in separate containers the antibody (already bound to a solid matrix or packaged separately with reagents for binding to the matrix), control formulations (positive and / or negative), and / or a detectable label, such as fluorescein, green fluorescent protein, rhodamine, cyanine dyes, Alexa dyes, luciferase, radiolabels, etc. Instructions for carrying out the assay may also be included in the kit. The assay may be in the form of, for example, but not limited to, a sandwich ELISA or a protein-antibody array.

[0232] Reagents for detecting the biomarkers of the present disclosure can be immobilized on a solid matrix, such as a porous strip, to form at least one biomarker detection site. The measurement or detection area of ​​the porous strip can include multiple sites containing antibodies. The test strip can include sites for negative and / or positive controls. Alternatively, the control sites can be located on a strip separate from the test strip. Optionally, different detection sites can contain different amounts of immobilized antibody, for example, a higher amount at the first detection site and a lower amount at subsequent sites. Upon addition of sample, the number of sites that display a detectable signal can quantitatively indicate the amount of biomarker present in the sample. The detection sites can be configured in any suitably detectable shape, typically in the shape of a bar or dot spanning the width of the test strip.

[0233] The kit may further include a means for isolating or purifying the protein, as well as positive and negative controls. The kit may also include a notice associated therewith, in a format prescribed by a government agency regulating the manufacture, use, or sale of diagnostic kits. Detailed instructions for use, storage, and troubleshooting may also be provided with the kit. The kit may also optionally be provided in a suitable housing useful for robotic manipulation in a high throughput environment.

[0234] The components of the kit may be provided as a dry powder. When reagents and / or components are provided as a dry powder, the powder can be reconstituted by the addition of a suitable solvent. It is also envisioned that the solvent may be provided in another container. The container will generally include at least one vial, test tube, flask, bottle, syringe, and / or other container means into which the solvent may be placed and optionally dispensed. The kit may also include a second container means for containing a sterile pharma- ceutically acceptable buffer and / or other solvent.

[0235] Where more than one component is included in the kit, the kit will typically also contain a second, third or more additional containers into which the additional components may be separately placed, although combinations of various components may be contained in the containers.

[0236] Such kits may also include components that preserve or maintain the protein, such as reagents that protect against protein degradation. Any of the compositions or reagents described herein may be a component of the kit.

[0237] In some embodiments, the kit further comprises an apparatus for withdrawing a blood sample from a subject, hi other embodiments, the kit further comprises instructions for using the withdrawal apparatus and / or the reagents included in the kit.

[0238] [Example] Example 1: Generation of anti-RAGE antibodies Mouse antibodies against the purified extracellular domain of human RAGE were generated in BALB / c mice using a 28-day Rapid Immunization Multiple Sites (RIMMS) protocol followed by one boost. Hybridomas were generated from fusions of spleen cells and lymphocytes from immunized mice with the mouse myeloma cell line NS1. Hybridoma clones were first assessed by ELISA using hybridoma clone supernatants against the purified extracellular domain (ECD) of human RAGE. ELISA-positive clone supernatants were then examined for IgG binding to human RAGE-transfected cells by flow cytometry (Figure 1A). ELISA- and flow-positive clones were subcloned and assessed for IgG expression, RAGE binding by ELISA and flow cytometry, and RAGE inhibitory activity in vitro. Cross-reactivity of mouse antibodies against human RAGE was assessed by flow cytometric binding of the subclones to cells transfected with mouse RAGE (Figure 1B). The results confirmed that three subclones bound to mouse RAGE and cross-reacted with human RAGE.

[0239] Example 2 Determination of antibody binding to RAGE protein domains The extracellular part of the RAGE protein has three domains similar to the IgG family. The three domains are V, C1, and C2 (variable, constant 1, constant 2). RS07 binds the V domain and RS15 binds the V-C1 domain (Figure 2B). In this exemplary embodiment, a RAGE construct is used that includes the V-C1-C2 construct, which starts immediately after the native signal sequence, at amino acid residue 23 of SEQ ID NO:1 (AQNITA···). The C1-C2 construct starts at amino acid residue 117 of SEQ ID NO:1 (VYQIPG···) and the C2 construct starts at amino acid residue 249 of SEQ ID NO:1 (VAPGG···). The results of the mapping experiment are shown in Figure 2B and summarized in Figure 2C. The domains were predicted from Genbank and from the crystal structure. To map antibody binding to individual RAGE domains, the IL2 signal sequence was cloned into pEGFP-N2 into which a portion of RAGE was cloned in frame with the IL2 signal sequence (IL2ss) at the 5' end and in frame with eGFP at the 3' end. In addition to the extracellular portion of RAGE, all constructs contain the transmembrane and C-terminal regions of RAGE, so that the GFP signal is present intracellularly and the IL2ss ensures that the V, C1, and / or C2 motifs of RAGE are present extracellularly and accessible to antibodies. The ABC construct in FIG. 2B contains the V, C1, and C2 domains and starts at amino acid residue 23 of SEQ ID NO:1. The BC construct in FIG. 2B contains the C1 and C2 domains and starts at amino acid residue 116 of SEQ ID NO:1. The C construct in FIG. 2B contains the C2 domain and starts at amino acid residue 246 of SEQ ID NO:1.

[0240] Example 3 In vitro activity of antibodies Yusou The human cell line THP-1 was used to test the inhibition of cell migration or chemotaxis of RAGE antibody clones. Several clones, including RS15 but not RS07, inhibited the ability of THP-1 cells to migrate towards the RAGE ligand AGE-BSA (advanced glycation end products-BSA, Figure 3A). Figure 3B shows that RS7 and RS15 inhibit basal levels of NFκB signaling in the mouse melanoma line B16F10. Figures 3C-1 to 3C-3 show that the RAGE antibody RS15 inhibits the binding of S100A8 / 9 to monocytes and granulocytes. Here, the binding of labeled S100A8 / 9 (Alexafluor-488) to human peripheral blood cells (ACK preps) from healthy donors was detected by flow cytometry.

[0241] Erk Signaling The ability of RAGE antibody clones to inhibit basal Erk activation levels (phosphorylated Erk) was assessed using human THP-1 cells. Several clones, including both RS07 and RS15, inhibited activated Erk levels (Figure 4).

[0242] RAGE human tumor expression Using flow cytometry, RAGE expression was detected in two human colon cancer samples using RS15, also referred to as RFT01 (Figure 5A). Analysis of specific cell types showed that RAGE was expressed in multiple myeloid and lymphoid lineages infiltrating the tumor samples (Figures 5B and 5C, respectively). Figure 5D shows the effect of anti-RAGE binding in stage III and stage IV colon cancer myeloid cells. As can be seen in Figure 5D, RAGE-expressing MDSCs suppress T cell activation and proliferation, RAGE inhibition promotes M1 macrophage-associated cytokine production, and RAGE binds to CD11b, leading to the formation of inflammatory foci and the accumulation of myeloid cells. Cells were identified by the following markers in Table 1:

[0243] [Table 1]

[0244] Figure 5E shows the effect of anti-RAGE binding in stage III and stage IV colon cancer lymphocytes. Notably, stage IV cancers had a higher percentage of RAGE+ infiltrating cells in all cell types. MDSCs and inflammation were found to be mediated by downregulation of the ζ chain of T cell and NK cell activating receptors. Cancers were identified by the following markers in Table 2:

[0245] [Table 2]

[0246] Example 4 In vivo activity of antibodies RF101 treatment - Composition of tumor-infiltrating immune cells The in vivo effects of RFT01 treatment were evaluated in two mouse syngeneic models of colon cancer, CT26 and Colon-26. RS15 treatment of CT26 tumor-bearing mice and Colon-26 (Colon-26 adenocarcinoma) tumors resulted in a decrease in potentially immunoinhibitory myeloid populations infiltrating the tumors (Figure 6A), specifically, a decrease in total myeloid cells, M-MSDCs, and M2_TAMs in CT26 tumor-bearing mice, and a decrease in M-MSDCs, iMonos, and an increase in M1 TAMs in Colon-26 mice and Colon-26 tumors. Furthermore, RS15 treatment was shown to affect myeloid-related cytokines in Colon-26 tumors (Figure 6B). Specifically, IL27, IL17A, IFNβ, IL1β, and IL10 were increased, and TGFβ and CCL2 were decreased. IL27 is predominantly expressed by APCs, including macrophages and dendritic cells, and exerts antitumor activity through direct and indirect mechanisms, including stimulation of NK cells and inhibition of angiogenesis. IL17A promotes CD8+ T cell cytotoxicity, and IL17 levels are increased in RAGE knockout mice. IFNβ is known to promote an anti-inflammatory state. IL1β is a marker of M1-activated macrophages. IL10 is stimulated by IL27 and is known to be anti-inflammatory, but immune stimulatory or suppressive depending on the antigenic environment. TGFβ promotes a protumor microenvironment and is associated with CMS4 type of colorectal cancer. Finally, CCL2 is expressed by monocytes, macrophages, and dendritic cells, and is associated with cachexia, recruitment of macrophages and other immune cells to tumors, and also contributes to tumor angiogenesis and growth.

[0247] RFT01 treatment also increased the number of T cells infiltrating the tumor (Figure 7), indicating a possible immune response against the tumor. 3 ) had increased numbers of CD3+ T cells and late-stage tumors (median tumor size 3300 mm 3) had increased numbers of CD8+ T cells. Increased CD3+ T cell infiltration in early tumors was likely due to reduced RAGE-mediated immunosuppression of MDSCs and TAMs and inflammation. Increased CD8+ cytotoxic T cells suggested improved immune responses against tumors, possibly mediated by reduced MDSC and TAM immunosuppression and inflammation.

[0248] RF101-tumor growth inhibition Treatment of RT-PCR in CT26 tumor-bearing mice resulted in 78% tumor growth inhibition (Figure 8A). Figure 8B shows that the Colon-26 tumors were 100 mm 3 1 shows that RFT01 was administered intravenously at 10 mg / kg twice weekly starting at 0.5 mg / kg, resulting in a reduction in tumor volume over time.

[0249] [Table 3-1]

[0250] [Table 3-2]

[0251] Unless otherwise indicated, all numerical values ​​expressing the amounts of ingredients, properties such as molecular weights, reaction conditions, and the like used in the specification and claims should be understood to be modified in all instances by the term "about". As used herein, the terms "about" and "approximately" mean within 10-15%, preferably within 5-10%. Thus, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of, at the very least, the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0252] The terms "a," "an," "the," and similar reference words used in the context of describing the present invention (particularly in the context of the claims that follow) shall be construed to include both the singular and the plural, unless otherwise indicated to the contrary or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method for individually referring to each individual value falling within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually set forth herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any examples or exemplary language (e.g., "such as") used herein are merely intended to better illustrate the invention and do not limit the scope of the claimed invention. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0253] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that for reasons of convenience and / or patentability, one or more members of a group may be included in or deleted from a group. When such inclusion or deletion is made, the specification shall be deemed to include the group as modified so as to satisfy all Markush group descriptions used in the appended claims.

[0254] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of skill in the art upon reading the foregoing description. The inventors anticipate that such variations will be adopted by those of skill in the art, and the inventors intend that the invention be practiced other than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, combinations of the above-described elements in all possible variations thereof are encompassed by the present invention unless otherwise stated herein or clearly contradicted by context.

[0255] Certain embodiments disclosed herein may be further limited in the claims using the phrase "consisting of" or "consisting essentially of." When used in the claims, whether as filed or added by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the claim to those materials or steps specified and that do not materially affect the basic and novel characteristics. An embodiment of the invention so claimed is operative as essentially or explicitly described herein.

[0256] Additionally, throughout this application, there are numerous references to patents and printed publications, each of which is individually incorporated herein by reference in its entirety.

[0257] Finally, it should be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the invention may be utilized in accordance with the teachings herein. Thus, the invention is not limited to that precisely as shown and described.

[0258] (Additional Note) (Appendix 1) An antibody specific to the V and / or C1 domain of the receptor for advanced glycation end products (RAGE), wherein at least one of the complementarity determining regions (CDRs) has an amino acid sequence of any one of SEQ ID NOs: 4 to 9 or 12 to 17.

[0259] (Appendix 2) A specific antibody against the V and / or C1 domain of RAGE, wherein the variable heavy (VH) region of the antibody has the amino acid sequence of SEQ ID NO: 2 or 10.

[0260] (Appendix 3) A specific antibody against the V and / or C1 domain of RAGE, wherein the variable light chain (VL) region of the antibody has the amino acid sequence of SEQ ID NO: 3 or 11.

[0261] (Appendix 4) The antibody according to any one of claims 1 to 3, which is a monoclonal antibody.

[0262] (Appendix 5) The antibody according to any one of appendix 1 to 3, which is a chimeric antibody.

[0263] (Appendix 6) The antibody according to any one of appendix 1 to 3, which is a humanized antibody.

[0264] (Appendix 7) The antibody according to any one of appendix 1 to 3, which is an antigen-binding antibody fragment.

[0265] (Appendix 8) 8. The antibody of claim 7, wherein the antigen-binding antibody fragment is a Fab, Fab', F(ab')2, Fv, disulfide-linked Fv, scFv, single domain antibody, diabody, multispecific antibody, dual specific antibody, dual variable domain immunoglobulin, heavy chain antibody (HCAb), or bispecific antibody.

[0266] (Appendix 9) An antibody described in Appendix 1, comprising CDRs of SEQ ID NOs: 4, 5 and 6.

[0267] (Appendix 10) 2. An antibody described in Appendix 1, comprising CDRs of SEQ ID NOs: 7, 8 and 9.

[0268] (Appendix 11) An antibody described in Appendix 1, comprising CDRs of SEQ ID NOs: 12, 13 and 14.

[0269] (Appendix 12) An antibody described in Appendix 1, comprising CDRs of SEQ ID NOs: 15, 16 and 17.

[0270] (Appendix 13) 4. The antibody of claim 2 or 3, comprising a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 3.

[0271] (Appendix 14) 4. The antibody of claim 2 or 3, comprising a VH of SEQ ID NO: 10 and a VL of SEQ ID NO: 11.

[0272] (Appendix 15) A pharmaceutical composition comprising the antibody according to any one of claims 1 to 14.

[0273] (Appendix 16) A method for inhibiting RAGE activity, comprising administering an effective amount of the antibody according to any one of claims 1 to 14 or the pharmaceutical composition according to claim 15 to a subject in need of inhibition of RAGE activity.

[0274] (Appendix 17) 17. The method of claim 16, wherein inhibiting RAGE activity comprises treating cancer in the subject.

[0275] (Appendix 18) 17. The method of claim 16, wherein treating cancer comprises altering the tumor microenvironment, inhibiting angiogenesis to the tumor, inhibiting tumor growth, inhibiting or reducing expression of growth and / or inflammatory factors in the tumor, reducing monocytic myeloid-derived suppressor cells (MDSCs), reducing inflammatory monocytes (iMonos), reducing M2 tumor-associated macrophages (M2 TAMs), increasing M1 macrophages and M1 macrophage signaling, increasing M1 / M2 macrophage tumor infiltration and / or signaling, increasing M2 to M1 polarization, and / or promoting T cell activity and infiltration into the tumor.

[0276] (Appendix 19) 17. The method of claim 16, wherein inhibiting RAGE activity comprises reducing inflammation in the subject.

[0277] (Appendix 20) 20. The method of claim 19, wherein the inflammation is chronic inflammation or acute inflammation.

[0278] (Appendix 21) 21. The method of claim 20, wherein the chronic inflammation is the result of an autoimmune disease.

[0279] (Appendix 22) 17. The method of claim 16, wherein inhibiting RAGE activity comprises preventing or treating liver injury and / or fibrosis.

[0280] (Appendix 23) 17. The method of claim 16, wherein inhibiting RAGE activity comprises preventing or treating neovascularization in the eye.

[0281] (Appendix 24) 17. The method of claim 16, wherein inhibiting RAGE activity comprises preventing or treating a respiratory disease.

[0282] (Appendix 25) 17. The method of claim 16, wherein inhibiting RAGE activity comprises preventing or treating an infection.

[0283] (Appendix 26) 26. The method of any one of claims 16 to 25, further comprising administering an effective amount of a second medicament.

[0284] (Appendix 27) 27. The method of claim 26, wherein the method treats cancer and the second medicament is an immune checkpoint inhibitor.

[0285] (Appendix 28) 28. The method of claim 27, wherein the immune checkpoint inhibitor comprises an antibody against PD-1 or PDL-1.

[0286] (Appendix 29) 27. The method of claim 26, wherein the second medicament is a vaccine.

[0287] (Appendix 30) 18. The method of claim 17, wherein the cancer is colorectal cancer.

[0288] (Appendix 31) 1. A method for detecting a RAGE protein in a biological sample, comprising: contacting the sample with an anti-RAGE antibody according to any one of claims 1 to 14; and detecting the formation of a complex between said antibody and a RAGE protein in said sample; A method comprising:

Claims

1. A specific antibody against the V and / or C1 domain of the receptor for advanced glycation end products (RAGE), said antibody comprising: a) the amino acid sequences of SEQ ID NOs: 4, 5 and 6; b) the amino acid sequences of SEQ ID NOs: 7, 8 and 9; c) the amino acid sequences of SEQ ID NOs: 12, 13 and 14, or d) the amino acid sequences of SEQ ID NOs: 15, 16 and 17; An antibody comprising a complementarity determining region (CDR) comprising:

2. The antibody described in claim 1, wherein the variable heavy chain (VH) region of the antibody has the amino acid sequence of SEQ ID NO: 2 or 10.

3. The antibody described in claim 1, wherein the variable light chain (VL) region of the antibody has the amino acid sequence of SEQ ID NO: 3 or 11.

4. The antibody of claim 1, which is a monoclonal antibody.

5. The antibody of claim 1, which is a chimeric antibody.

6. The antibody of claim 1, which is a humanized antibody.

7. The antibody of claim 1 which is an antigen-binding antibody fragment.

8. The antigen-binding antibody fragments include Fab, Fab', F(ab') ２ 8. The antibody of claim 7, which is a Fv, a disulfide-linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, a dual variable domain immunoglobulin, a heavy chain antibody (HCAb), or a bispecific antibody.

9. The antibody of claim 1, comprising CDRs of SEQ ID NOs: 4, 5 and 6.

10. The antibody of claim 1, comprising CDRs of SEQ ID NOs: 7, 8 and 9.

11. The antibody of claim 1, comprising CDRs of SEQ ID NOs: 12, 13 and 14.

12. The antibody of claim 1, comprising CDRs of SEQ ID NOs: 15, 16 and 17.

13. The antibody of claim 2 or 3, comprising a VH of SEQ ID NO: 2 and a VL of SEQ ID NO:

3.

14. The antibody of claim 2 or 3, comprising a VH of SEQ ID NO: 10 and a VL of SEQ ID NO:

11.

15. A pharmaceutical composition comprising the antibody according to any one of claims 1 to 3 and 9 to 12.

16. A pharmaceutical composition for inhibiting RAGE activity, comprising the antibody of any one of claims 1 to 3 and 9 to 12, wherein an effective amount of the pharmaceutical composition is administered to a subject in need of inhibition of RAGE activity.

17. 17. The pharmaceutical composition of claim 16, wherein inhibiting RAGE activity comprises treating cancer in the subject.

18. 17. The pharmaceutical composition of claim 16, wherein treating cancer comprises altering the tumor microenvironment, inhibiting angiogenesis to tumors, inhibiting tumor growth, inhibiting or reducing expression of growth and / or inflammatory factors in tumors, reducing monocytic myeloid-derived suppressor cells (MDSCs), reducing inflammatory monocytes (iMonos), reducing M2 tumor-associated macrophages (M2 TAMs), increasing M1 macrophages and M1 macrophage signaling, increasing M1 / M2 macrophage tumor infiltration and / or signaling, increasing M2 to M1 polarization, and / or promoting T cell activity and infiltration into tumors.

19. 17. The pharmaceutical composition of claim 16, wherein inhibiting RAGE activity comprises reducing inflammation in the subject.

20. 20. The pharmaceutical composition of claim 19, wherein the inflammation is chronic inflammation or acute inflammation.

21. 21. The pharmaceutical composition of claim 20, wherein the chronic inflammation is the result of an autoimmune disease.

22. 17. The pharmaceutical composition of claim 16, wherein inhibiting RAGE activity comprises preventing or treating liver injury and / or fibrosis.

23. 17. The pharmaceutical composition of claim 16, wherein inhibiting RAGE activity comprises preventing or treating neovascularization in the eye.

24. 17. The pharmaceutical composition of claim 16, wherein inhibiting RAGE activity comprises preventing or treating a respiratory disease.

25. 17. The pharmaceutical composition of claim 16, wherein inhibiting RAGE activity comprises preventing or treating an infection.

26. 17. The pharmaceutical composition of claim 16, further comprising an effective amount of a second medicament.

27. 27. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition is for treating cancer and the second medicament is an immune checkpoint inhibitor.

28. The pharmaceutical composition of claim 27, wherein the immune checkpoint inhibitor comprises an antibody against PD-1 or PDL-1.

29. 27. The pharmaceutical composition of claim 26, wherein the second medicament is a vaccine.

30. The pharmaceutical composition of claim 17, wherein the cancer is colon cancer.

31. 1. A method for detecting a RAGE protein in a biological sample, comprising: contacting the sample with an anti-RAGE antibody according to any one of claims 1 to 3; and detecting the formation of a complex between said antibody and a RAGE protein in said sample; A method comprising:

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