TW201805303A - IP-10 antibodies and their uses - Google Patents

Abstract

The present invention provides isolated monoclonal antibodies, particularly human antibodies, that bind to IP-10 with high affinity, inhibit the binding of IP-10 to its receptor, inhibit IP-10-induced calcium flux and inhibit IP-10-induced cell migration. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The invention also provides methods for inhibiting IP-10 activity using the antibodies of the invention, including methods for treating various inflammatory and autoimmune diseases.

Description

IP-10 antibody and use thereof

The present invention relates to a monoclonal antibody that binds to interferon gamma-inducible protein 10 (IP-10). In particular, the present invention relates to modified IP-10 antibodies that exhibit improved stability and activity compared to unmodified antibodies.

Interferon gamma-inducible protein 10 (IP-10) (also known as CXCL10) is a 10 kDa chemokine (Luster, originally identified based on the expression of the IP-10 gene in cells treated with interferon gamma (IFN-γ). AD et al. (1985) Nature 315 : 672-676). IP-10 exhibits homology to chemotactically active proteins (such as platelet factor 4 and beta-clooglobulin) and mitogen-active proteins (such as connective tissue-activating peptide III) (Luster, AD et al. (1987) Proc. Natl. Acad. Sci. USA 84 : 2868-2871). IP-10 is secreted by various cells (including endothelial cells, mononuclear cells, fibroblasts, and keratinocytes) in response to IFN-γ (Luster, AD and Ravetch, JV (1987) J. Exp. Med. 166 :1084 -1097). IP-10 also displays cutaneous hyperphages and endothelial cells present in delayed allergic (DTH) responses in human skin (Kaplan, G. et al. (1987) J. Exp. Med. 166 :1098-1108) . Although initially identified based on IFN-γ induction, IP-10 can also be induced by IFN-α (eg, in dendritic cells) (Padovan, E. et al., (2002 ) J. Leukoc. Biol . 71 :669 -676). IP-10 performance can also be induced by stimuli (eg, IFN-γ, viruses, and lipopolysaccharides) in cells of the central nervous system (eg, astrocytes and microglia) (Vanguri, R. and Farber, JM (1994) J Immunol. 152 : 1411-1418; Ren, LQ et al. (1998) Brain Res. Mol. Brain Res . 59 : 256-263). The immunobiology of IP-10 is reviewed in Neville, LF et al. (1997) Cytokine Growth Factor Rev. 8 : 207-219. The receptor for IP-10 has been identified as CXCR3 (7 transmembrane receptor) (Loetscher, M. et al., (1996) J. Exp. Med. 184 : 963-969). CXCR3 has been shown to be expressed on activated T lymphocytes, but is expressed on resting T lymphocytes as well as B lymphocytes, mononuclear spheres or granules (Loetscher, M. et al., supra). It has been shown that stimulation with TGF-β1 upregulates CXCR3 expression on NK cells (Inngjerdingen, M. et al. (2001) Blood 97 :367-375). Two other ligands for CXCR3 have also been identified: MIG (Loetscher, M. et al., supra) and ITAC (Cole, KE et al. (1998) J. Exp. Med . 187 : 2009-2021). It has been shown that the combination of IP-10 to CXCR3 mediates calcium mobilization and chemotaxis in activated T cells (Loetscher, M. et al., supra). Chemotactic and intracellular calcium mobilization was also induced by binding of IP-10 to CXCR3 on activated NK cells (Maghazachi, AA et al. (1997) FASEB J. 11 : 765-774). Within the thymus, IP-10 has been shown to be a chemoattractant for TCRαβ ⁺ CD8 ⁺ T cells, TCR αβ ⁺ T cells, and NK cells (Romagnani, P. et al. (2001) Blood 97 : 601-607). IP-10 or its receptor CXCR3 has been identified in a variety of different inflammatory and autoimmune conditions, including multiple sclerosis (see, for example, Sorensen, TL et al. (1999) J. Clin. Invest. 103 :807-815 Rheumatoid arthritis (see, eg, Patel, DD et al. (2001) Clin. Immunol. 98 : 39-45), ulcerative colitis (see, for example, Uguccioni, M. et al. (1999) Am. J. Pathol 155 :331-336), hepatitis (see, for example, Narumi, S. et al. (1997) J. Immunol. 158 : 5536-5544), bone marrow damage (see, for example, McTigue, DM et al. (1998) J. Neurosci. Res . 53: 368-376; Gonzalez et al., 2003.Exp Neurol 184:.. 456-463 ), systemic lupus erythematosus (see, for example Narumi, S. et al. (2000) Cytokine 12: 1561-1565) , transplant rejection (See, for example, Zhang, Z. et al. (2002) J. Immunol. 168 : 3205-3212), Sjogren's syndrome (see, for example, Ogawa, N. et al. (2002) Arthritis Rheum . 46 : 2730-2741 ). Antibodies that bind to IP-10 to treat such conditions are known in the art, for example as set forth in WO2005/058815. However, there is a continuing need for improved therapeutic agents (e.g., antibodies) that inhibit IP-10 activity, particularly agents useful in humans.

The present invention provides for the binding of interferon gamma-inducible protein 10 (IP-10) (also known as CXCL10, such as human IP-10) and has optimized physical stability and improved functional characteristics compared to previously described anti-IP-10 antibodies. Individual antibodies (eg, human monoclonal antibodies) are isolated. In particular, the present invention relates to a modified form of the antibody IP10.1 (WO 2005/058815, also known as antibody 6A5) which exhibits significantly improved stability and activity compared to unmodified antibodies. In particular, it has been shown that by altering the heavy chain CDR domain of antibody IP10.1, the modified antibody exhibits higher thermal stability and thermoreversibility (eg, the first melting temperature is 70.2 ° C (TM1 of IP10.1 is 64) °C) and the thermal reversibility at 73 ° C is 41.2% higher thermal stability and thermal reversibility). At the same time, it has been surprisingly observed that modified antibodies exhibit at least a 50-fold improvement in binding affinity to human IP-10 compared to unmodified antibodies and improve other functional features including, for example, blocking binding to their target cells (eg, Cells expressing CXCR3 (CXCR3/300.19) and intestinal epithelial cells (KM12SM) increased at least 5-fold in exogenous IP-10 and inhibited endogenous IP-10 regulation by hPBMC stimulated with IFNα/γ Increases IL-6 secretion by at least a factor of 6 and increases at least 4-fold efficacy in inhibiting endogenous IP-10-mediated IL-12p40 secretion by hPBMC stimulated with IFNγ/LPS, and in pharmacokinetics/ Increased efficacy of pharmacodynamics (PK/PD) by at least 150 times). Other modified functional features exhibited by the modified antibodies described herein as compared to their unmodified counterparts include: (a) an increase in inhibition of endogenous IP-10-mediated IL-12p40 secretion by hPBMC (eg improved by at least 4 times) efficacy; (b) increased inhibition of IL-6 and IL-12p40 in blood (colitis model); (c) increased inhibition of free IP-10, eg up to 10 days; Decrease the frequency of human CXCR3+ NK cells in mouse spleens; (e) increase (eg improve at least 8-fold) efficacy in inhibiting IP-10-induced calcium flux in mice in CXCR3/300.19 cells; (f) increase cells a decrease in circulating concentration of interleukin; and/or (g) an increase (eg, at least a 2-fold improvement in body serum clearance (CLT)). In addition, modified antibodies (eg, antibody IP10.1) lack substantial cross-reactivity with human MIG, human ITAC, or mouse IP-10. The increased stability of the modified antibodies and the combination of binding/biological activity are surprising in particular in terms of the criticality of the CDR regions for antibody function. Thus, the antibodies of the invention exhibit improved physical properties (i.e., thermal and chemical stability) as well as improved functional characteristics (e.g., binding affinity and efficacy to human IP-10) as compared to antibody IP10.1. In a specific embodiment, the isolated monoclonal antibody (eg, a human antibody) or antigen binding portion thereof comprises a heavy chain and a light chain variable region, wherein the heavy chain CDR1, CDR2 and CDR3 regions are from SEQ ID NO: 16, a heavy chain variable region of 40, 52, 64, 76, 88, 100, 112, 124, 136 or 148, such as the CDR1, CDR2 and CDR3 sequences from SEQ ID NO: 16 (eg, SEQ ID NO: 13 respectively) , as stated in 14 and 15). In another embodiment, the light chain CDR1, CDR2 and CDR3 regions are derived from the light chain variable region of SEQ ID NO: 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142 or 154 For example, the CDR1, CDR2 and CDR3 sequences from SEQ ID NO: 22 (e.g., as set forth in SEQ ID NOs: 19, 20, and 21, respectively). In still another embodiment, the heavy chain variable region comprises an amino acid sequence of SEQ ID NO: 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136 or 148, and/or light The chain variable region comprises the amino acid sequence of SEQ ID NO: 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142 or 154 (e.g., the amine of SEQ ID NO: 16 and/or 22) a base acid sequence), or comprising SEQ ID NO: 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136 or 148 and/or SEQ ID NO: 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142 or 154 sequences having at least 95% amino acid identity (eg, sequences having at least 95% amino acid identity to SEQ ID NO: 16 and/or 22, respectively) ). Alternatively, the heavy chain variable region comprises a consensus amino acid sequence as set forth in SEQ ID NO: 166, 167 or 168. In another embodiment, the heavy and light chain CDR1, CDR2 and CDR3 regions comprise the following amino acid sequences, respectively: (a) SEQ ID NOs: 13, 14 and 15 and SEQ ID NOs: 19, 20 and 21; b) SEQ ID NOs: 25, 26 and 27 and SEQ ID NOs: 31, 32 and 33; (c) SEQ ID NOs: 37, 38 and 39 and SEQ ID NOs: 43, 44 and 45; (d) SEQ ID NO: 49, 50 and 51 and SEQ ID NO: 55, 56 and 57; (e) SEQ ID NO: 61, 62 and 63 and SEQ ID NO: 67, 68 and 69; (f) SEQ ID NO: 73, 74 and 75 and SEQ ID NOs: 79, 80 and 81; (g) SEQ ID NOs: 85, 86 and 87 and SEQ ID NOs: 91, 92 and 93; (h) SEQ ID NOs: 97, 98 and 99 and SEQ ID NOs: 103, 104 and 105; (i) SEQ ID NOs: 109, 110 and 111 and SEQ ID NOs: 115, 116 and 117; (j) SEQ ID NOs: 121, 122 and 123 and SEQ ID NO: 127, 128 and 129; (k) SEQ ID NO: 133, 134 and 135 and SEQ ID NO: 139, 140 and 141; or (l) SEQ ID NO: 145, 146 and 147 and SEQ ID NO: 152, 152 And 153. The antibodies (or antigen binding portions thereof) set forth herein can be used in a variety of applications, including inhibition of inflammatory or autoimmune responses mediated by activated T cells or NK cells, inhibition of viruses or bacteria involved in undesirable IP-10 activity. Infection and detection of IP-10 protein. In a specific embodiment, human IP-10 comprises a polypeptide having the amino acid sequence set forth in SEQ ID NO: 157 (GenBank Accession No. NP_001556); CXCR3 comprises an amine having the amino acid set forth in SEQ ID NO: 158 Polypeptide of the base acid sequence (GenBank Accession No. NP_001495); Rhesus macaque IP-10 includes a polypeptide having the amino acid sequence as set forth in SEQ ID NO: 159 (GenBank Accession No. AAK95955); Mouse IP-10 Included is a polypeptide having the amino acid sequence as set forth in SEQ ID NO: 160 (GenBank Accession No. NP_067249); human MIG comprises a polypeptide having the amino acid sequence as set forth in SEQ ID NO: 161 (Genebank Accession) No. NP_002407); and/or human ITAC includes a polypeptide having the amino acid sequence as set forth in SEQ ID NO: 162 (GenBank Accession No. NP_005400). In another embodiment, the antibody or antigen binding portion thereof additionally exhibits at least one of the following properties: (a) inhibiting binding of IP-10 to CXCR3; (b) inhibiting IP-10 induced calcium flux; (c) Inhibition of IP-10-induced cell migration; (d) Cross-reactivity with rhesus IP-10; (e) No cross-reactivity with mouse IP-10; (f) No cross-reactivity with human MIG; and/or (g Does not cross-react with human ITAC. For example, an antibody or antigen binding portion thereof exhibits at least two of properties (a), (b), (c), (d), (e), (f), and (g). Alternatively, the antibody or antigen-binding portion thereof exhibits at least three of properties (a), (b), (c), (d), (e), (f), and (g), or exhibits properties (a), At least four, five, six or all seven of (b), (c), (d), (e), (f) and (g). In another embodiment, the antibody or antigen-binding portion 1 × 10 ^-9 M or K _D of less (e.g., 1 × 10 ^-10 M or less, or K _D of 1 × 10 ^-11 M or less K _D ) binds to human IP-10. In yet another embodiment, the antibody or antigen binding portion thereof binds to human IP-10 of SISNQP (SEQ ID NO: 163), VNPRSLEKL (SEQ ID NO: 164) and/or IIPASQFCPRVEIIA (SEQ ID NO: 165) Amino acid residue. An antibody of the invention may be a full length antibody of, for example, an IgGl, IgG2 or IgG4 isotype (e.g., IgGl isotype), optionally having a serine to valerine mutation in the hinge region of the heavy chain constant region (corresponding to position 241) Position, as described in Angal et al. (1993) Mol. Immunol . 30 : 105-108), thereby reducing or eliminating inter-heavy chain disulfide bridge heterogeneity. In one aspect, the constant region isotype is IgG4 having a mutation (eg, S228P) at amino acid residue 228. Alternatively, the antibody can be an antibody fragment (eg, a binding fragment, such as a Fab, Fab' or Fab'2 fragment) or a single chain antibody. In another aspect, the antibody (or antigen binding portion thereof) is part of an immunoconjugate comprising a therapeutic agent (eg, a cytotoxin or a radioisotope) linked to the antibody. In another aspect, a portion of an anti-system bispecific molecule comprising a second functional moiety (eg, a second antibody) having a binding specificity different from the antibody or antigen binding portion thereof. Compositions comprising an antibody or antigen binding portion thereof, an immunoconjugate or a bispecific molecule of the invention, and optionally formulated in a pharmaceutically acceptable carrier, are also provided. Nucleic acid molecules encoding antibodies or antigen binding portions thereof (e.g., variable regions and/or CDRs), as well as expression vectors including such nucleic acids, and host cells comprising such expression vectors are also provided. Also provided are methods of making anti-IP-10 antibodies using host cells comprising such expression vectors, and such methods can comprise the steps of (i) displaying the antibody in a host cell and (ii) isolating the antibody from the host cell. In another aspect, the invention provides a method of inhibiting an inflammatory or autoimmune response mediated by activated T cells or NK cells, comprising binding a T cell or NK cell to an antibody of the invention or antigen thereof Partial contact, thereby inhibiting an inflammatory response or an autoimmune response. In still another aspect, the invention provides a method of treating an inflammatory or autoimmune disease in a subject in need thereof, comprising administering to the subject an antibody or antigen binding portion thereof of the invention, thereby treating the inflammatory disease or self of the individual Immune disease. The disease can be, for example, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), systemic lupus erythematosus, type I diabetes, inflammatory skin conditions ( For example, psoriasis, lichen planus, autoimmune thyroid disease (such as Graves' disease, Hashimoto's thyroiditis), Sjogren's syndrome, lung inflammation (such as asthma, chronic obstructive pulmonary disease) , pulmonary sarcoma, lymphocytic alveolitis, transplant rejection, bone marrow damage, brain damage (eg stroke), neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease) )), gingivitis, gene therapy-induced inflammation, angiogenic diseases, inflammatory nephropathy (eg, IgA nephropathy, membrane proliferative glomerulonephritis, rapidly progressive glomerulonephritis), and atherosclerosis. In still another aspect, the invention provides a method of treating a viral or bacterial infection involving undesired IP-10 activity in an individual in need of treatment comprising administering to the individual an antibody or antigen binding portion thereof of the invention, thereby treating the individual Viral or bacterial infection. For example, antibodies can be used to treat viral meningitis, viral encephalitis, or bacterial meningitis. Viral infections to be treated by the methods of the invention may be mediated by, for example, human immunodeficiency virus (HIV), hepatitis C virus (HCV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome (SARS) virus. In one embodiment, the method comprises administering a single dose of 30-450 mg of an anti-IP-10 antibody (or antigen binding portion thereof), for example, a single dose of antibody at the following doses: 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 Mg, 400 mg, 450 mg or 35 mg, 45 mg, 55 mg, 65 mg, 75 mg, 85 mg, 95 mg, 105 mg, 115 mg, 125 mg, 135 mg, 145 mg, 155 mg, 165 mg , 175 mg, 185 mg, 195 mg, 205 mg, 215 mg, 225 mg, 235 mg, 245 mg, 255 mg, 265 mg, 275 mg, 285 mg, 295 mg, 305 mg, 315 mg, 325 mg, 335 Dosages of mg, 345 mg, 355 mg, 365 mg, 375 mg, 385 mg, 395 mg, 405 mg, or 445 mg. In another embodiment, the antibody is administered weekly or biweekly. In yet another embodiment, the antibody is administered for a period of about 12 weeks (eg, on days 1, 15, 29, 43, 57, and 71). The antibody can be administered to the subject by any suitable means, such as by intravenous administration or subcutaneous administration. In one embodiment, the method is for treating ulcerative colitis comprising administering a single dose of about 40 mg of the antibody or antigen binding portion thereof intravenously every two weeks over a period of about 12 weeks. In yet another embodiment, the anti-IP-10 antibody is administered in a line ("front") treatment (eg, initial or first treatment). In another embodiment, the anti-IP-10 antibody is administered by second-line therapy (eg, after initial treatment with the same or different therapeutic agents, including after relapse and/or where the first treatment has failed). . The efficacy of the methods of treatment provided herein can be evaluated using any suitable means. In one embodiment, the treatment produces at least one therapeutic effect, such as a complete response, a partial response, and a stable disease. Kits comprising a pharmaceutical composition comprising an anti-IP-10 antibody (eg, IP10.44 (BMS-986184)) and a pharmaceutically acceptable carrier (in a therapeutically effective amount suitable for use in the methods described herein) are also provided . In one embodiment, the kit comprises: (a) a dose of an anti-IP-10 antibody comprising SEQ ID NOs: 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, The CDR1, CDR2 and CDR3 domains of the heavy chain variable region of the sequence set forth in 136 or 148, for example, the CDR1, CDR2 and CDR3 sequences from SEQ ID NO: 16 (eg, as set forth in SEQ ID NOs: 13, 14, and 15, respectively) CDR1, CDR2 and CDR3 structures having the light chain variable region of the sequence set forth in SEQ ID NO: 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142 or 154; a domain, such as the CDR1, CDR2 and CDR3 sequences from SEQ ID NO: 22 (eg as set forth in SEQ ID NO: 19, 20 and 21, respectively); and (b) for use in the method of the invention with anti-IP-10 Instructions for antibodies. In another embodiment, the methods comprise administering a composition, a bispecific molecule or an immunoconjugate of the invention. In another aspect, the invention provides an anti-IP-10 antibody and composition of the invention for use in the foregoing methods or for the manufacture of a medicament for use in the foregoing methods (e.g., for use in therapy) . Other features and advantages of the invention will be apparent from the description and appended claims. The contents of all of the references, gene bank entries, patents, and published patent applications, which are hereby incorporated by reference in their entireties in the entire entireties in

縮寫：IV =靜脈內；MAD =多遞增劑量；POM =機制驗證；SAD =單一遞增劑量； SC =皮下；Q2W =每隔一週 * 自劑量組S3及上文，所有劑量值皆係藉由自前一組獲得之實時PK及PD (無血清IP-10)分析所測定。每一劑量組存在AUC及Cmax帽，其不超過來自NOAEL下AUC之預定安全係數。 **在完成組S3並分析之後選擇用於組M1之MAD劑量且可包含劑量S3或更低劑量。在完成組S4並分析之後選擇用於組M2之MAD劑量且可包含劑量S4或更低劑量(除M1中所用之劑量外)。 ***若TE數據支持MAD中之SC投藥可能，則實施SC組。部分 A 用於健康參與者中之 SAD/MAD 之研究設計 ( 部分 A) 在部分A中，健康參與者經受篩選評估以測定合格性。參與者必須在自第1天之21天內完成篩選程序。可使用±2天窗口訪視來調節單位及參與者之時間表。允許參與者在第-1天早晨進入臨床設施中。健康參與者中之 SAD 之研究設計 ( 部分 A1) 每一依序SAD劑量組(S1-S7)存在8名健康雄性或雌性參與者。使每一組雙盲及隨機化。對於第一劑量組(S1)而言，投用前哨組。一名健康雄性或雌性參與者接受單一劑量之BMS-986184且1名健康雄性或雌性參與者接受匹配安慰劑。在治療第一劑量組(S1)之剩餘參與者之前24小時內由探究者及發起者評估來自該2名參與者之可用安全性數據(包含任一所報告不良事件、來自體檢之發現、任一臨床實驗室結果、生命體徵及ECG)。在第1天，使第一劑量組(S1)中之剩餘6名健康雄性或雌性參與者隨機以5:1之比率接受單一劑量之BMS-986184或匹配安慰劑。對於每一依序劑量組(S2-S7)而言，在第1天，使8名健康雄性或雌性參與者在第1天以3:1之比率隨機接受單一劑量之BMS-986184或匹配安慰劑。劑量選擇準則闡述於下文中。健康參與者中之 SAD/MAD 之研究設計 ( 部分 A) 在部分A中，健康參與者經受篩選評估以測定合格性。參與者必須在自第1天之21天內完成篩選程序。可使用±2天窗口訪視來調節單位及參與者之時間表。允許參與者在第-1天早晨進入臨床設施中。健康參與者中之 SAD 之研究設計 ( 部分 A1) 每一依序SAD劑量組(S1-S7)存在8名健康雄性或雌性參與者。使每一組雙盲及隨機化。對於第一劑量組(S1)而言，投用前哨組。一名健康雄性或雌性參與者接受單一劑量之BMS-986184且1名健康雄性或雌性參與者接受匹配安慰劑。在治療第一劑量組(S1)之剩餘參與者之前24小時內由探究者及發起者評估來自該2名參與者之可用安全性數據(包含任一所報告不良事件、來自體檢之發現、任一臨床實驗室結果、生命體徵及ECG)。在第1天，使第一劑量組(S1)中之剩餘6名健康雄性或雌性參與者隨機以5:1之比率接受單一劑量之BMS-986184或匹配安慰劑。對於每一依序劑量組(S2-S7)而言，在第1天，使8名健康雄性或雌性參與者在第1天以3:1之比率隨機接受單一劑量之BMS-986184或匹配安慰劑。劑量選擇準則闡述於表9中。表 9 ：健康參與者中之SAD研究之研究訪視示意圖(部分A1)

縮寫：CPU =臨床藥理單位； D =天； SAD =單一遞增劑量 *在D15具有任一進行中之AE/SAE之參與者應保留在室內直至解決或在臨床上並不視為顯著為止。

=研究藥物投與

=訪視天數 健康參與者中之MAD之研究設計(部分A2) 每一依序MAD劑量組(M1-M2)存在8名健康雄性或雌性參與者。在第1天，使該相同之8名健康雄性或雌性參與者在第1天以3:1之比率隨機接受BMS-986184或匹配安慰劑。使每一組雙盲及隨機化。劑量選擇準則闡述於下文中。使MAD組(M1及M2)中之參與者保持侷限於臨床設施中直至在第50天休假為止。在第50天具有任一進行中之AE或SAE之參與者應保留於研究場所直至探究者測得該等事件已解決或已視為在臨床上不顯著為止。參與者預計會返回臨床單位以用於第57、64、71、85及99天之隨訪評價。可使用±2天窗口訪視來調節單位及參與者之時間表。部分A2 MAD參與者之近似研究持續時間為最多120天。早期自研究退出之參與者需要完成預計開始於第99天之研究出院評估。可替換出於除AE外之原因而中斷之參與者。最多16名參與者計劃完成SAD研究之部分A2。在整個投藥間隔中於所選時間下實施體檢、生命體徵量測、眼部評估、12導程ECG及臨床實驗室評估。在整個研究中密切監測參與者之AE。在所選時間點下收集血樣以用於安全性及PK分析。在研究之部分A2期間自每一參與者抽取大約495 mL血液。部分A2之研究訪視示意圖呈現於表10中。表 10 ： 健康參與者中之MAD研究之研究訪視示意性(部分A2)

縮寫：CPU =臨床藥理單位； D =天；MAD =多遞增劑量

=研究藥物投與

=訪視天數 UC患者中之POM之研究設計(部分B) 在部分B中存在最多36名患有中等至嚴重UC之參與者。部分B包含3個時段：篩選期、治療期及安全性隨訪期。若期中分析在預期治療劑量下展示不充分靶咬合或若發生不耐受安全性事件，則可增加36名參與者(24名活性劑:12名安慰劑)之額外較高劑量組，若預測PK暴露遠低於與安全性發現有關之暴露範圍，則可增加36名參與者(24名活性:12名安慰劑)之較低劑量組。在PK及PD數據變得可自健康個體中之SAD/MAD研究獲得後，立即對患有UC之個體在PoM研究期間(部分B)之劑量體積及投與實施最終測定。此時修改方案以包含用於UC參與者中之PoM研究之最終劑量選擇。使參與者經受篩選評估以測定合格性。部分B中之參與者必須在自第1天之28天內完成篩選程序(隨機化)。在篩選期期間，使參與者經受體檢及醫學史、吸煙史、篩選測試程序、篩選內視鏡檢法及實驗室評估以證實由UC所致且並不由其他病因所致之活動性腸黏膜發炎。治療期 ： 在第1天，使最多36名患有UC之參與者在12週時段內每隔一週(在第1、15、29、43、57及71天)以2:1之比率隨機接受單一劑量之BMS-986184或匹配安慰劑。使部分B雙盲及隨機化。在第85天，使參與者經受內視鏡檢法。 對於在治療期期間經歷UC發作之參與者而言，應儘可能符合研究方案。若根據探究者之建議參與者接受根據研究方案不容許之療法及/或需要住院，則參與者應根據探究者之判斷進行治療且中斷研究。強烈鼓勵探究者接觸實施醫學監測以論述任何在研究期期間經歷UC發作之參與者。安全性隨訪期： 在57天內每隔一週(在第99、113及127天)進行隨訪訪視。部分B參與者之近似研究持續時間為最多177天。可替換出於除AE外之原因而中斷之參與者 。計劃使用最多72名參與者。在整個投藥間隔中在所選時間下實施體檢、生命體徵量測、12導程ECG及臨床實驗室評估。在整個研究中密切監測參與者之AE。在所選時間點下收集血樣以用於安全性及PK分析。在研究之部分B期間自每一參與者抽取大約300 mL血液。部分B之研究訪視示意圖呈現於表11中。表 11 ：UC患者中之POM研究之研究訪視示意圖(部分B)

縮寫：D =天；POM=機制驗證 * D8 ±1天

=研究藥物投與(±3天)

=訪視天數(±2天，D8 ±1天除外)

=內視鏡檢法參與者數量 在部分A中將最多72名參與者隨機化至9組中(7個SAD組及2個MAD組)。在部分A1 (SAD)中，每一組由8名參與者(6名活性: 2名安慰劑)組成。在部分 A1 (SAD)中總共治療56名參與者。若開始MAD，則在部分A2 (MAD)中治療其他16名參與者(每組6名活性: 2名安慰劑)。儘管參與者數量並非基於統計檢定力考慮，但向每一組中之6名參與者投與BMS-986184使得有80%之機率觀察到任一AE發生至少一次，該AE會在抽取試樣之群體中以24%之發病率發生。若AE之發病率為32%，則使用6名BMS-986184治療之參與者之試樣大小觀察到任一AE發生至少一次之機率為90%。在研究之部分B (POM)中，使總共36參與者隨機(24名活性: 12名安慰劑)接受自部分A2攜載之靶定治療劑量。若期中分析在預期治療劑量下展示不充分靶咬合或若發生不耐受安全性事件，則可增加36名參與者(24名活性劑:12名安慰劑)之額外較高劑量組，若預測PK暴露遠低於與安全性發現有關之暴露範圍，則可增加36名參與者(24名活性:12名安慰劑)之較低劑量組。若期中分析在預期治療劑量下展示不充分靶咬合或若發生不耐受安全性事件，則可增加36名參與者(24名活性劑:12名安慰劑)之額外較高劑量組，若預測PK暴露遠低於與安全性發現有關之暴露範圍，則可增加36名參與者(24名活性:12名安慰劑)之較低劑量組。 研究終點定義 將第一參與者簽署研究特定性知情同意書之日期定義為研究起點。在簽署研究特定性知情同意書(ICF)時，可考慮招募參與者。將最後參與者完成出院程序或最後隨訪訪視之日期定義為研究終點。研究設計之科學原理 存在若干原因以經由FIH研究在NHV中來開始研發BMS-986184。在用於患有UC之參與者之前，其容許使用增量及逐漸劑量遞增之較安全研發路徑。其將精確確立治療窗口，且評價寬範圍之劑量(30 mg至最高大約450 mg，靜脈內及可能皮下)以更佳地告知治療指數。在單一劑量之後於健康參與者中在不存在疾病效應下及不影響經活化免疫系統下評估免疫阻抑及感染。在健康參與者中完成SAD及MAD之後，使用患有UC之參與者實施重複投藥。劑量論證 並無先前臨床經歷可用，選擇用於FIH研究之劑量係基於預測之PK暴露、自非臨床研究確立之PK/TE (亦即血清中之游離IP-10)關係及自動物毒理學研究確立之安全邊際。簡言之，使用PK模型來估計人類PK參數，從而解決猴中之非線性PK且隨後外延至人類。使用預測之人類PK參數來估計Cmax及AUC以計算在FIH研究中所測試劑量範圍中之安全邊際。使用PK/PD模型估計相應PD反應，從而探究在FIH中所測試劑量範圍中BMS-986184濃度與血清中游離IP-10之間之關係。使用所預測PD反應來提供各別劑量值下之預期靶咬合，從而測定適當劑量範圍以完全探究PK與靶咬合之間之關係。 為解決自非線性數據外推至人類之轉變不確定性，可基於安全性、耐受性及實時PK/PD分析來連續調節各組之劑量值及數量。固定SAD中之前2個劑量值(30 mg及75 mg)。可基於PK/PD分析來調節部分A中之剩餘劑量值及部分B中之整個劑量範圍以達到各別劑量組之預期PK暴露及游離IP-10。另外，所選SAD劑量組中之預期PK暴露將不超過在NOAEL下自Cmax及AUC估計之預定安全係數以確保研究參與者之安全性。 健康參與者中之SAD之劑量選擇論證(部分A1) 在部分A1中，使用安全性、PK及TE數據作出劑量遞增決定。在測定後續劑量組之劑量遞增之前由探究者及發起者評估來自當前劑量組之可用安全性數據(包含任一所報告不良事件、來自體檢之發現、眼部檢查、任一臨床實驗室結果、生命體徵及ECG)。並不將參與者隨機化至後續劑量組中，直至所有參與者中直至第15天來自當前劑量值之安全性數據由探究者及發起者加以評審且測得顯示安全性及耐受性為止。分別固定部分A1中之第一及第二劑量組(S1及S2) (30 mg及75 mg)。對於除SAD組2外之剩餘劑量組(S3-S5)而言，藉由在先前劑量組中基於實時PK/PD分析使用累積數據(除安全性評價外)所確立之PK/PD關係來引導劑量選擇。部分A1 SAD中之預期預留劑量範圍為30 mg至最高大約450 mg。 在部分A1 (研究之SAD部分)中，考慮源於靶調介之藥物處置之潛在非線性PK，選擇覆蓋寬範圍暴露之劑量範圍以描述PK與靶咬合(亦即血清中自基線之游離IP-10減少)之間之定量關係，且確立人類中之充分安全邊際以使得能夠進行患者研究。因在猴模型中觀察到TMDD，故選擇靜脈內投與途徑在FIH之單一劑量條件下進行研究以試圖更佳地描述劑量範圍下端(其中非線性最為明顯)之PK。因出於靶患者群體中之最佳順從性及便利性而期望皮下投與，故亦在研究之SAD部分中經皮下投與BMS-986184以測定皮下投與之可行性且研發擬在研究之後續部分中所測試的適當投藥方案。 在考慮來自臨床前研究之毒理學發現下來選擇擬藉由靜脈內途徑投與之起始劑量之大小。使用猴中之NOAEL劑量來計算最大推薦起始劑量(MRSD)。猴(其可視為最敏感物種)中之NOAEL為30 mg/kg/週。基於體表面積方法且考慮到NOAEL劑量之10倍安全邊際之MRSD大約為58 mg。因來自PK/PD模型之預測值指示大於此劑量下之最小藥理學活性，故MRSD並不適於測試為人類中之起始劑量。因此，將SAD中之起始劑量降至30 mg，從而血清中自基線之所預測游離IP-10減少預計為37% (表12)。自NOAEL下暴露估計之Cmax及30 mg下AUC之預期安全邊際分別為59倍及322倍。所提出劑量遞增方案預計會包括所預測有效劑量周圍之暴露。假設需要中和(如減小≥90%所定義)穩態波谷下之游離IP-10以促進患者中之預期效能，則期望達成游離IP-10在穩態波谷下之90%及95%減少之投藥方案預計分別為180 mg及300 mg，且每2週(Q2W)進行投與。因此，研究藥物之最高300 mg之單一劑量遞增應足以描述PK/PD特徵曲線之陡峭部分且可捕獲所預測有效劑量範圍。在300 mg下，自NOAEL下暴露估計之Cmax及AUC之預期安全邊際分別為6.4及13倍(表13)。 考慮到UC患者可展現較大PK以及PD可變性(因與健康個體相比之靶載量差異)，故可需要在SAD中測試大於300之劑量以提供充分安全性資訊，從而使得能夠將此化合物在UC患者中進行較長效臨床研究。為此，研究之SAD部分之最高提出劑量大約為450 mg。應注意，450 mg投與係可選的且取決於自先前SAD組所獲得之安全性、PK及TE數據。若所觀察PK及TE數據表明可在較低劑量值下達成游離IP-10在波谷下之最大阻抑，則不在SAD研究中探究所提出最高劑量。自NOAEL下暴露估計之此劑量值之Cmax及AUC之預期安全邊際分別為4倍及8倍(表12)。 30 mg至450 mg之提出劑量可確保充分描述PK/PD，同時誘發寬暴露範圍以提供充分安全性資訊，從而告知用於後續患者研究之劑量選擇。表13匯總人類中之預期暴露及基於NOAEL及LOAEL下之暴露之後續安全邊際。表12匯總在單一劑量投與之後第14天人類中之預期靶咬合。表 12 ： 在第14天(靜脈內投與) SAD中之游離IP-10之平均減少(部分A1) *在第一劑量組之後，所有剩餘劑量值皆係預留劑量且可基於實時PK/PD分析加以修改。表 13 ： SAD中之劑量範圍及安全邊際(靜脈內投與) (部分A1) *在前2個劑量組之後，所有剩餘劑量值皆係預留劑量且可基於實時PK/PD分析利用可用所觀察PK及PD數據來加以修改。所選劑量組中之預期平均AUC將不超過預定AUC值。 在向前2組投用30 mg及75 mg之後，剩餘劑量組之選擇將取決於健康個體中之所觀察PK/PD特徵。為確保劑量遞增提供預期暴露範圍以維持適當安全邊際，在對後續劑量遞增作出決定之前考慮下列因素。預測劑量值之預測平均Cmax及AUC將不超過表13中之預定值。增加連續SAD組之間之預測劑量值將不超過大約3倍增量。後續劑量組中之預測平均PK暴露(AUC(INF))將自先前劑量組中之平均 AUC(INF)增加不超過大約4倍。來自NOAEL暴露之Cmax及AUC(INF)之最小安全暴露邊際將分別維持於4倍及8倍。 SC中之劑量選擇論證 在SAD中經靜脈內投與至少2個劑量組後，實施可行性評價以決定是否經皮下投與BMS-986184。皮下投與之調配物可利用40 mg/mL之濃度。若在靜脈內投與後達成預期TE (表13)且可視為無需投與過多皮下注射即可達成，則在皮下投與後進一步測試BMS-986184 。 因BMS-986184之預期非線性PK及後續劑量依賴性生物可用性，需要適當評估匹配劑量值之絕對生物可用性。若實施，則經由皮下途徑之劑量值將與相應靜脈內劑量匹配。組S6之皮下劑量值可類似於靜脈內劑量組S2或S3，且組S7之皮下劑量值可類似於靜脈內劑量組S3或S4。基於SAD中之可用PK、TE、安全性數據且考慮部分B中所測試之潛在劑量值來選擇劑量。皮下組之預測平均Cmax及AUC將不超過在靜脈內投與後之相應劑量值下之平均Cmax及AUC。 健康參與者中之MAD之劑量選擇論證(部分A2) 在部分A2 (研究之MAD部分)中，可研究兩個劑量值以描述在多個BMS-986184投藥之後之安全性、耐受性及持續TE。在部分A2中，基於PK/PD建模利用自研究之部分A1 SAD獲得之可用安全性、PK及TE數據及部分B中之所測試潛在治療劑量值來決定MAD組(M1及M2)中之所測試劑量值以及投與途徑(靜脈內及/或皮下)。研究之MAD部分之目標在於選擇在投藥間隔中達成且維持大約50%或更大之游離IP-10減少之劑量值，同時確保來自NOAEL暴露之Cmax及AUC(INF)之安全暴露邊際分別至少為5倍及10倍。投藥間隔之選擇將取決於所觀察PK (亦即T-HALF)及PD (IP-10阻抑隨時間之維持)。當前，2週投藥間隔可視為期望的，然而，可基於所觀察PK/PD及安全性特徵來考慮1週。 對於第一劑量組(M1)而言，在評審來自前3個SAD組(S1-S3)之PK、TE及安全性數據且該數據視為可安全進行之後選擇劑量。考慮多個投藥之後之所觀察PK、TE、安全性及預期穩態PK及TE，劑量值可類似於組S2或S3。對於第二劑量組(M2)而言，在評審來自前4個SAD組(S1-S4)之PK、TE及安全性數據且該數據視為可安全進行之後選擇劑量值。表14 -表5.5.1-3圖解說明可在MAD中測試之潛在劑量值及具有安全邊際之相應PK暴露。表 14 ：MAD中之潛在劑量值及安全邊際(部分A2) *投藥方案及投與途徑意欲具有闡釋目的以提供暴露範圍及相應安全邊際。基於來自SAD中之累積數據之PK/PD建模來確定實際投藥方案及投與途徑。 UC患者中之POM之劑量選擇論證(部分B) 在PK及PD數據變得自健康參與者中之SAD/MAD研究獲得後，立即對UC患者中在POM研究期間(部分B)之劑量體積及投與實施最終測定。此時修改方案以包含用於UC患者中之POM研究之最終劑量選擇。選擇單一投藥方案以在部分B中進行測試。然而，若所觀察PD不足或劑量較低而獲得意外安全性發現，則可增加另一劑量組以包含較高劑量。使用投與途徑(靜脈內或皮下)之相同考慮、達成且維持90%或更大游離IP-10減少之能力、投藥間隔持續時間及安全暴露邊際之維持來作出決定。 治療 將研究治療定義為根據研究隨機化或治療分配意欲投與研究參與者之任一探究治療、市場化產物、安慰劑或醫學器件。 研究治療包含探究產物(IP)及非探究產物(Non-IP)。探究產物(在一些領域中亦稱為探究醫學產物)定義為在臨床研究中所測試或用作參考之活性物質或安慰劑之醫藥形式，包含已具有上市許可但不同於許可形式來使用或組裝 (調配或包裝)或用於未許可適應症或在用於獲得關於許可形式之其他資訊時之產物。用作用於預防、診斷或治療原因之支持或免除醫藥之其他醫藥(如用於給定診斷之標準護理組份)可視為非探究產物。 對於此方案而言，研究藥物包含探究產物BMS-986184-01注射(150 mg/小瓶(40 mg/mL)，3.75 mL小瓶)及相似安慰劑。 將BMS-986184-01或相似安慰劑以溶液形式經皮下或經靜脈內(取決於劑量組)投與。表 15 ：用於IMI012004之研究治療表 16 ：劑量之選擇及時刻 研究評價及程序 效能評價 僅針對部分B實施效能評價，如藉由患有中等至嚴重UC之參與者中之內視鏡檢法及組織病理學評分之改良所量測。 主要效能評價 修正 Baron 評分 使用經修正Baron來評估經由內視鏡檢法評價之黏膜疾病嚴重程度。修正Baron評分系統係具有0至4量表之內視鏡指數評分，其中較高評分指示較大嚴重程度。修正Baron評分如下：評分0指示具有可見血管圖案且不易破裂之正常平滑、閃耀黏膜；評分1指示粒狀黏膜，血管圖案不可見，不易破裂，充血；評分2指示與1相同之黏膜，但係易破裂黏膜。 內視鏡檢法及內視鏡評價 為確保品質數據及標準化，在整個試驗中於臨床地點根據探究者之判斷由同一內鏡醫師儘可能地局部實施內視鏡檢法。應在基線下(第1天)及第12週(第85天)研究訪視時投用研究藥物之前實施撓性乙狀結腸鏡檢查術或結腸鏡檢查術。基線內視鏡檢法(結腸鏡檢查術或乙狀結腸鏡檢查術)必須在隨機化28天內實施，必須歸檔，且應儘可能接近隨機化地實施。第85天內視鏡檢法(結腸鏡檢查術或乙狀結腸鏡檢查術)應在第85天訪視之前或之後不超過3天來實施。結腸鏡檢查術或乙狀結腸鏡檢查術可在基線下(第1天)及第85天實施。所實施程序(結腸鏡檢查術或乙狀結腸鏡檢查術)無需在所有時間點皆相同。應藉由局部導則所指示來篩選結腸癌且應根據探究者之判斷來實施。藉由局部讀數儀在探究者之判斷下來評估任何經實施用於評估結腸癌之生檢。 另外，藉由局部讀數儀在探究者之判斷下來評估任何經實施以獲得UC診斷之組織學證實之生檢。可使用在篩選時實施之結腸鏡檢查術程序來測定梅奧評分(Mayo Score)之內視鏡檢法子評分分量且代替乙狀結腸鏡檢查術(若實施於隨機化28天內)。 生檢應獲取自結腸直腸之最嚴重影響區域(除在基線內視鏡檢法評估中特定地靶向未受影響區域時)。若結腸及結腸之所有部分同等受影響，則應獲取直腸生檢。對於組織病理學分析而言，應較佳地使用大型鑷子獲取兩種生檢。若存在潰瘍，則生檢應指向潰瘍邊緣。 在每一內視鏡檢法期間(第1及85天)獲得內視鏡檢法影像且發送用於藉由中心內視鏡檢法讀數儀進行獨立內視鏡黏膜評分，並測定梅奧內視鏡檢法評分及修正Baron評分。來自中心讀數實驗室之詳細影像評審圖表儀概述了內視鏡程序、視訊記錄及用於視訊捕獲及傳輸內視鏡記錄之設備。對於每一參與者而言，使用可接受之儲存介質實施整個內視鏡程序之視訊記錄。藉由合格腸胃科醫生根據影像評審圖表儀以盲式整體讀取內視鏡記錄。出於測定參與者之招募合格性之目的，如9.1.2部分中所闡述，藉由探究者及藉由中心內視鏡檢法讀數儀(第3方供應商)來局部測定基線梅奧評分內視鏡子評分。僅藉由中心內視鏡讀數儀(第3方供應商)來實施所有其他內視鏡評分(基線下修正Baron評分及梅奧內視鏡子評分、第85天下之修正Baron評分)。用於試驗中之臨床終點之梅奧評分利用源自中心內視鏡檢法讀數儀之梅奧內視鏡檢法子評分。用於試驗中之臨床終點之修正Baron評分亦源自中心內視鏡檢法讀數儀。 在內視鏡檢法程序期間在投藥之前第1天及85天收集結腸組織。為確保品質數據及標準化，在第1天及第85天主要藉由由中心讀數實驗室簽約之單盲病理學家來讀取結腸組織組織病理學評分(Geboes, Modified Riley, and Robarts Histopathology Index，參見9.1.2部分)。來自中心讀數實驗室之詳細影像評審圖表儀將概述用於固定樣品轉移、處理、載玻片製備及用於組織病理學評分之載玻片數位化之組織病理學程序。由合格病理學家根據影像評審圖表儀主要以盲式來讀取內視鏡記錄。 二級效能評價 內視鏡評價 -修正Baron評分 組織病理學評價 修正 Riley 指數 修正Riley指數係考慮6種特徵[急性發炎細胞浸潤物(固有層中之嗜中性球)、隱窩膿腫、黏蛋白消耗、表面上皮完整性、慢性發炎細胞浸潤物(固有層中之圓形細胞)及隱窩構造不規則性]之組織病理學評分系統，每一特徵評級為量表0-3，其中較高評分指示較嚴重組織病況。Geboes 評分 Geboes評分係利用6點評級系統(0-5)基於構造變化、慢性發炎浸潤物、固有層嗜中性球及嗜酸性球、上皮中之嗜中性球、隱窩破壞及侵蝕或潰瘍來量測疾病活動性之組織病理學評分系統。較高等級指示較嚴重疾病活動性。 Robarts組織病理學指數 Robarts組織病理學指數(RHI)總評分介於0 (無疾病活動性)至33 (嚴重疾病活動性)之間。RHI可計算為： RHI = 1 ×慢性發炎浸潤物等級(4個等級) + 2 ×固有層嗜中性球(4個等級) + 3 ×上皮中之嗜中性球(4個等級) + 5 ×侵蝕或潰瘍(4個等級，在組合Geboes 5.1及5.2之後)；其中 慢性發炎浸潤物 0=無增加 1=輕度但明確之增加 2=中等增加 3=顯著增加 固有層嗜中性球 0=無 1=輕度但明確之增加 2=中等增加 3=顯著增加 上皮中之嗜中性球 0=無 1=涉及＜5%之隱窩 2=涉及＜50%之隱窩 3=涉及＞50%之隱窩 侵蝕或潰瘍 0=無侵蝕、潰瘍或肉芽組織 1=恢復上皮+疲勞發炎 1=可能侵蝕—病灶帶 2=明確侵蝕 3=潰瘍或肉芽組織 臨床評價 梅奧評分 使用梅奧評分來評估疾病活動性。梅奧評分系統係由以下4種疾病變量組成之複合指數(每一評分為量表0至3，其中較高評分指示較大頻率或嚴重程度)：糞便頻率、直腸出血、內視鏡檢法發現及醫師整體評價(PGA)。使用該三項來計算部分梅奧評分。納入內視鏡梅奧子分量以計算完整梅奧評分。藉由IVRS自動計算部分及總梅奧評分且可由探究者及發起者獲得。 梅奧評分介於0至12點之間且利用所有4種疾病變量，其中較高評分指示較嚴重疾病。內視鏡子評分僅包括0-3之內視鏡量表。除內視鏡子評分外，部分梅奧評分包含所有分量(直腸出血、糞便頻率、醫師整體評價)。 評審梅奧評分系統且與探究員工在探究者會議或其他論壇上一起論述為標準化探究員工之間之評級之方法。 對於糞便頻率分量而言，評分0 =參與者具有正常數量之糞便，1 =一或兩種糞便不正常，2 =三種或四種糞便不正常，3 =五種或更多種糞便不正常。 對於直腸出血分量而言，0 =在糞便中未看到血液，1 =小於一半之日排便之糞便具有血絲，2 =大部分日排便之糞便具有明顯血液，3 =排便時僅排出血液。 將PGA評分為0 =正常，1 =溫和疾病，2 =中等疾病，3 =嚴重疾病兩項式患者相關結果 (PRO) 兩項式PRO係使用來自日記之直腸出血及糞便頻率之分量作為額外效能評價之複合評分。用於梅奧評分之日記時刻 日記時刻取決於實施內視鏡檢法之時間。對於不實施內視鏡檢法之訪視(治療期第8、15、-29、43、57及71天)而言，參與者將在緊鄰每一研究訪視之前至少5天完成日記。 對於在實施基線(治療期第1及85天)內視鏡檢法時之訪視而言，參與者將在緊鄰內視鏡檢法製備之日之前至少連續5天完成日記。內視鏡檢法必須在臨床評價之前及在投藥之前3天內實施(排除腸製備及內視鏡程序天數)。 探索性效能評價 內視鏡及臨床評價 使用修正Baron評分、臨床及組織學評價來評價內視鏡、臨床及組織學緩解。結腸黏膜生檢收集 對於部分B中之所有參與者而言，需要在內視鏡檢法(作為研究之一部分)期間或在第85天之前提前結束時實施生檢。在每一內視鏡檢法時對5至6份試樣(在縮回內視鏡期間遠離30 cm之最嚴重影響結腸位點處)實施生檢。若最受影響區域潰瘍，則應自潰瘍邊緣獲得試樣。在不存在UC之任一可見病灶特性下，應在縮回內視鏡時自10 cm區域收集2份試樣。另外，在基線訪視時，應獲得每一參與者之來自未受影響區域之2份生檢試樣(若在縮回內視鏡期間存在於30 cm內)，如下文所闡述。應將1至2份生檢樣品置於提供用於研究之每一容器中。使用10%中性緩衝福爾馬林預填充福爾馬林(formalin)固定之瓶且使用RNA later溶液預填充RNA later瓶。 藥物動力學 自血清濃度對時間數據導出BMS-986184之藥物動力學。在健康參與者中針對SAD及MAD評價下列藥物動力學參數： 在健康參與者中針對部分A1 SAD評價下列藥物動力學參數。 在健康參與者中針對部分A2 MAD評價下列藥物動力學參數。 在UC患者中針對部分 B POMT評價下列藥物動力學參數。 藉由非分室方法且藉由驗證藥物動力學分析程式導出個體參與者之藥物動力學參數值。將實際時間用於分析。表 17 ：用於BMS-986184 - SAD之藥物動力學採樣時間表(部分A1)^a EOI=輸注結束，此試樣應在即將停止輸注之前(較佳地在輸注結束之前2分鐘內)獲取。若輸注結束延遲至超過標稱輸注持續時間，則此試樣之收集應亦相應延遲。表 18 ：用於BMS-986184 - MAD之藥物動力學採樣時間表(部分A2)^a EOI=輸注結束，對於遵循靜脈內投與之參與者而言，此試樣應在即將停止輸注之前(較佳地在輸注結束之前2分鐘內)獲取。若輸注結束延遲至超過標稱輸注持續時間，則此試樣之收集應亦相應延遲。表 19 ：用於BMS-986184 - POM之藥物動力學採樣時間表(部分B)^a EOI=輸注結束，對於遵循靜脈內投與之參與者而言，此試樣應在即將停止輸注之前(較佳地在輸注結束之前2分鐘內)獲取。若輸注結束延遲至超過標稱輸注持續時間，則此試樣之收集應亦相應延遲。^b 在隨訪期期間收集該等試樣。^c 應收集因不良事件而中斷之參與者之試樣。 針對BMS-986184藉由經驗證配體結合免疫分析來分析血清試樣。除非需要證實安慰劑狀態，否則並不分析自接受安慰劑之參與者收集之藥物動力學試樣。 免疫原性評價 自在計劃時間點下獲得之量測來測定BMS-986184之特異性ADA之出現。使用驗證免疫分析來分析試樣。研究終點係藉由開始藥物治療最多(且包含)最後劑量之隨訪期產生之持續性陽性ADA之發病率。 應用下列定義： 參與者之ADA狀態： ● 基線ADA陽性參與者：具有基線ADA陽性試樣之參與者 ● ADA陽性參與者：相對於基線在開始治療之後於所界定觀察時間段期間之任一時間下具有至少一種ADA陽性試樣之參與者。 ● ADA陰性參與者：在開始治療之後並無ADA陽性試樣之參與者 藥效動力學 糞便鈣衛蛋白 糞便鈣衛蛋白係IBD中之腸發炎之代用標記物，此乃因其與腸顆粒球之排泄相關。可將糞便鈣衛蛋白縱向追蹤為治療反應之標記物。高敏感性 CRP (hsCRP) hsCRP係發炎之非特異性急性期反應物標記物。hsCRP用作安全性標記且可將其縱向追蹤為治療反應之標記物。 生物標記物 靶咬合生物標記物 用於靶咬合之血清 IP-10 濃度 ( 總及游離 )( 部分 A 及 B) 在部分A中，抽取血液以用於量測血清游離及總IP-10濃度，從而評價TE。表 20 ：用於BMS-986184 - SAD之血清TE生物標記物採樣時間表(部分A1)表 21 ：BMS-986184 -MAD之TE生物標記物採樣時間表(部分A2) 在部分B中，在表9.8.1.1-3中所指示之時間下抽取血液以用於量測血清游離及總IP-10濃度，從而評價TE。將血液收集及處理之其他細節提供至實驗室程序手冊中之地點。表 22 ：BMS-986184之TE生物標記物採樣時間表-部分B (POM)組織靶咬合生物標記物 ( 部分 B) 使用結腸生檢來量測游離及總IP-10濃度以評價組織TE。藥物動力學生物標記物 ( 部分 B) 僅在部分B中於投藥前在一定時間下抽取血液以用於評價hsCRP。亦量測糞便鈣衛蛋白。探索性血清 / 血漿生物標記物 ( 部分 B) 僅在部分B中於投藥前抽取血液以用於評價可與IP-10中和或相關路徑相關之探索性血清生物標記物。探索性血清生物標記物可包含(但不限於)其他CXCR3相關趨化介素(CXCL9/MIG、 CXCL11/ITAC)、 IL-1(α、β)、IL-6、IL-10、IL-12、G-CSF、MIP-3β、IFN-γ及可與UC疾病活動性及/或黏膜癒合相關之新穎標記物。亦可進行蛋白組學描述以支持理解BMS-986184在潰瘍性結腸炎中之活性。 免疫細胞表現型分型 ( 部分 B) 僅在部分B中於投藥前抽取血液以用於免疫細胞表現型分型，其可包含(但不限於)下列標記物：CXCR3、CD3、CD4、CD56、CD16、CD45RA、CCR7。使用該等結果來評價可因抗IP-10療法而發生之藥物動力學變化及/或潛在地鑑別反應之基線預測物。 免疫組織化學 ( 部分 B) 根據標準程序，福爾馬林固定試樣之免疫組織化學可包含下列抗原：CD3、CD68、IP-10、Foxp3、細胞角質蛋白18、EpCAM、IL17及CXCR3。 基因表現描述 全血 RNA 表現 ( 部分 B) 僅在部分B中於投藥前抽取血液。該等試樣提供寬RNA描述(微陣列或RNA測序)以鑑別與發炎及/或UC疾病路徑、作用機制及BMS-986184治療反應相關之新穎藥物動力學及效能生物標記物。另外，使用該等試樣來探索在基線下可預測對BMS-986184治療之參與者之效能之基因表現。組織 RNA 表現 ( 部分 B) 處理儲存於RNA later中之結腸生檢以分離RNA。該等試樣提供寬RNA描述(微陣列或RNA測序)以鑑別與發炎及/或UC疾病路徑、作用機制及BMS-986184治療反應相關之新穎藥物動力學及效能生物標記物。另外，使用該等試樣來探索在基線下可預測對BMS-986184治療之參與者之效能之基因表現。序列表之概述 等效內容 熟習此項技術者僅使用常規實驗即可識別或能確定本文所闡述本發明具體實施例之許多等效形式。該等等效內容皆意欲涵蓋於下文申請專利範圍內。 Cross-reference to related applications The present application claims priority to U.S. Provisional Application No. 62/261,210, filed on Nov. 30, 2015, and No. 62/374,622, filed on August 12, 2016. The entire contents of any of the patents, patent applications, and references cited throughout the specification are hereby incorporated by reference. To make the invention easier to understand, certain terms are first defined. Other definitions are set forth throughout the detailed description. The terms "6A5", "antibody 6A5", "antibody IP10.1", "IP10.1" and "Eldelumab" refer to the anti-human IP-10 antibody 6A5 as set forth in WO2005/058815. The nucleotide sequence (SEQ ID NO: 5) encoding the heavy chain variable region of IP10.1 and the corresponding amino acid sequence (SEQ ID NO: 4) are shown in Figure 1A (wherein the CDR sequences are designated as SEQ ID NO, respectively) : 1, 2 and 3). The nucleotide sequence (SEQ ID NO: 11) encoding the light chain variable region of IP10.1 and the corresponding amino acid sequence (SEQ ID NO: 10) are shown in Figure 1B (wherein the CDR sequences are designated as SEQ ID NO, respectively) : 7, 8 and 9). The terms "interferon gamma-inducible protein 10", "IP-10" and "CXCL10" are used interchangeably and include human IP-10 variants, isoforms and species homologs. Therefore, the human antibody of the present invention can be cross-reactive with IP-10 from a species other than human in some cases. In other instances, the antibody may be fully specific to human IP-10 and may not exhibit species or other types of cross-reactivity. The complete amino acid sequence of human IP-10 has the gene bank accession number NP_001556 (SEQ ID NO: 157). The complete amino acid sequence of Rhesus macaque IP-10 has the gene bank accession number AAK95955 (SEQ ID NO: 159). The complete amino acid sequence of mouse IP-10 has the gene bank accession number NP_067249 (SEQ ID NO: 160). The term "CXCR3" refers to the receptor for IP-10 (CXCL10). The complete amino acid sequence of human CXCR3 has the gene bank accession number NP_001495 (SEQ ID NO: 158). The term "MIG" refers to a ligand other than IP-10 of CXCR3 (also known as a mononuclear factor induced by gamma interferon). The complete amino acid sequence of human MIG has the gene bank accession number NP_002407 (SEQ ID NO: 161). The term "ITAC" refers to a ligand other than IP-10 of CXCR3 (also known as interferon-inducible T cell alpha chemoattractant). The complete amino acid sequence of human ITAC has the gene bank accession number NP_005400 (SEQ ID NO: 162). The term "immune response" refers to the selective damage and destruction caused by lymphocytes, antigen presenting cells, phagocytic cells, granules and soluble macromolecules (including antibodies, interleukins and complements) produced by the above-mentioned cells or liver. Or from the human body to eliminate invasive pathogens, cells or tissues infected with pathogens, cancerous cells or (in the case of autoimmune or pathological inflammation) normal human cells or tissues. "Signal transduction pathway" refers to the biochemical relationship between a variety of signal transduction molecules that function in a portion of a cell that is passed from one part of a cell to another. As used herein, the phrase "cell surface receptor" encompasses, for example, molecular and molecular complexes that are capable of receiving a signal and transmitting this signal through the plasma membrane of the cell. An example of a "cell surface receptor" of the present invention is the CXCR3 receptor to which the IP-10 molecule binds. The term "antibody" as used herein, includes whole antibodies and any antigen-binding fragments thereof (ie, "antigen-binding portions") or single strands. "Antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds or an antigen binding portion thereof. Each heavy chain includes a heavy chain variable region (abbreviated herein as V)_H And the heavy chain constant region. The heavy chain constant region comprises three domains: C_H1 , C_H2 And C_H3 . Each light chain includes a light chain variable region (abbreviated herein as V)_L ) and the light chain constant region. The light chain constant region comprises a domain CL. V can be_H And V_L The region is further subdivided into hypervariable regions (referred to as complementarity determining regions (CDRs)) and more conserved regions (referred to as framework regions (FR)), which are inter-arranged. Every V_H And V_L It consists of three CDRs and four FRs, which are arranged from the amino-terminus to the carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant region of the antibody modulates the binding of the immunoglobulin to host tissues or factors comprising various cells of the immune system (eg, effector cells) and the first component of the classical complement system (Clq). As used herein, the term "antigen-binding portion" of an antibody (or simply "antibody portion") refers to one or more fragments of the antibody that retain the ability to specifically bind to an antigen (eg, IP-10). It has been shown that the antigen binding function of antibodies can be carried out by fragments of full length antibodies. An example of a binding fragment encompassed within the term "antigen-binding portion" of an antibody comprises (i) a Fab fragment, ie by V_L V_H , C_L And C_H1 a unitary fragment consisting of a domain; (ii) F(ab’)₂ a fragment, that is, a bivalent fragment comprising two Fab fragments joined by a disulfide bridge in the hinge region; (iii) by V_H And C_H1 a domain consisting of an Fd fragment; (iv) a single arm of the antibody_L And V_H Fv fragment consisting of a domain; (v) a dAb fragment (Ward et al. (1989)Nature 341 :544-546), which is made up of V_H Domain composition; and (vi) isolated complementarity determining regions (CDRs). In addition, despite the two domains of the Fv fragment (V_L And V_H ) is encoded by a separate gene, but it can be joined together by a synthetic linker using a recombinant method that enables it to become a V_L And V_H The regions are paired to form a single protein chain of a monovalent molecule (referred to as single-chain Fv (scFv)); see, for example, Bird et al. (1988)Science 242 :423-426; and Huston et al. (1988)Proc. Natl. Acad. Sci. USA 85 :5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. Such antibody fragments are obtained using conventional techniques known to those skilled in the art and screened for utility in the same manner as intact antibodies. The term "isolated antibody" as used herein is intended to mean an antibody that is substantially free of other antibodies having different antigenic specificities (for example, an isolated antibody that specifically binds to IP-10 is substantially free of specific binding except for IP). -10 antibodies to the antigen). However, an isolated antibody that specifically binds to IP-10 can be cross-reactive with other antigens, such as IP-10 molecules from other species. Furthermore, the isolated antibody may be substantially free of other cellular materials and/or chemicals. The term "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to a preparation of an antibody molecule having a single molecular composition. The monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. The term "human antibody" as used herein is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In addition, if the antibody contains a constant region, the constant region is also derived from a human germline immunoglobulin sequence. Human antibodies of the invention may comprise amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random mutagenesis or site-directed mutagenesis or by somatic mutation in vivo). However, the term "human antibody" as used herein is not intended to encompass an antibody that has been ligated into a human framework sequence from a CDR sequence derived from the germline of another mammalian species (eg, a mouse). The term "human monoclonal antibody" refers to an antibody displaying a single binding specificity having both a framework region and a CDR region derived from the variable region of a human germline immunoglobulin sequence. In one embodiment, the human monoclonal antibody system is produced by a hybridoma comprising B cells fused to immortal cells obtained from a transgenic non-human animal (eg, a transgenic mouse), the transgenic non-human animal having a human heavy chain transgene and Light chain transgenic genomics. The term "recombinant human antibody" as used herein, encompasses all human antibodies which are prepared, expressed, produced or isolated by recombinant means, for example (a) from a human immunoglobulin gene transgenic or transgenic animal (eg mouse) or self. The prepared hybridoma isolated antibody (further described below), (b) from a host cell transformed to express a human antibody, such as an antibody isolated from a transfectoma, (c) isolated from a recombinant, combinatorial human antibody library The antibody, and (d) an antibody produced, expressed, produced or isolated by any other means involving splicing of the human immunoglobulin gene sequence to other DNA sequences. The recombinant human antibodies have a framework region and a CDR region derived from a variable region of a human germline immunoglobulin sequence. However, in certain embodiments, the recombinant human antibodies can be subjected to in vitro mutagenesis (or, when in a transgenic animal using a human Ig sequence, undergo in vivo somatic mutagenesis), and thus the recombinant antibody V_H And V_L Amino acid sequence of the region, although derived from human germline V_H And V_L The sequence is associated with it, but it is a sequence that does not naturally occur within the antibody germline profile in humans in vivo. As used herein, "homotype" refers to an antibody species (eg, IgM or IgGl) encoded by a heavy chain constant region gene. The phrase "antibody recognizing an antigen" and "an antibody specific for an antigen" are used interchangeably herein with the term "antibody that specifically binds to an antigen". As used herein, an antibody that specifically binds to human IP-10 is intended to be 5 x 10^-9 M or smaller, better 1 × 10^-10 M or smaller and even better 1 × 10^-11 M or smaller K_D An antibody that binds to human IP-10. The antibody "cross-reacting with rhesus IP-10" is intended to be 1 × 10^-9 M or smaller, better 1 × 10^-10 M or smaller and even better 1 × 10^-11 M or smaller K_D An antibody that binds to rhesus monkey IP-10. Antibodies that do not cross-react with mouse IP-10 or "cross-react with human MIG" or "cross-react with human ITAC" are intended to be 1.5 × 10^-8 M or greater K_D More preferably 5-10 × 10^-8 M or greater K_D And even better 1 × 10^-7 M or greater K_D An antibody that binds to mouse IP-10, human MIG or human ITAC. In certain embodiments, such antibodies that do not cross-react with mouse IP-10, human MIG, and/or human ITAC exhibit a substantially undetectable binding to such proteins in a standard binding assay. As used herein, an antibody that "inhibits binding of IP-10 to CXCR3" is intended to mean 1 nM or less, more preferably 0.75 nM or less, even more preferably 0.5 nM or less and even more preferably. 0.25 nM or less_i An antibody that inhibits IP-10 binding to CXCR3. As used herein, an antibody that "inhibits IP-10-induced calcium flux" is intended to mean 10 nM or less, more preferably 7.5 nM or less, even more preferably 5 nM or less and even more preferably 2.5 nM or smaller IC₅₀ An antibody that inhibits IP-10 induced calcium flux. As used herein, an antibody that "inhibits IP-10-induced cell migration" is intended to mean 2 μg/ml or less, more preferably 1 μg/ml or less, or even more preferably 0.5 μg/ml or more. Small and even better ICs of 0.25 μg/ml or less₅₀ An antibody that inhibits human IP-10 induced cell migration. The term "K" as used herein_Association Or "K_a "Intended to refer to the association rate of a particular antibody-antigen interaction," and the term "K" as used herein._Dissociation Or "K_d It is intended to mean the rate of dissociation of a particular antibody-antigen interaction. The term "K" as used herein_D Desirable to refer to the dissociation constant, which is obtained from K_d For K_a Ratio (ie K_d /K_a And expressed in terms of molar concentration (M). K can be determined using established methods in the industry_D value. Determination of antibody K_D The preferred method is by using surface plasmon resonance, preferably using a biosensor system (such as the Biacore® system). As used herein, the term "high affinity" of an IgG antibody means that the antibody has 10 against the target antigen.^-8 M or smaller, better 10^-9 M or smaller and even better 10^-10 M or smaller K_D . However, for other antibody isotypes, the "high affinity" binding can vary. For example, a "high affinity" binding of IgM isotype means that the antibody has 10^-7 M or smaller, better 10^-8 M or smaller K_D . As used herein, the term "individual" encompasses any human or non-human animal. The term "non-human animal" encompasses all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, and the like. Various aspects of the invention are set forth in more detail in the following subsections.anti- IP-10 antibody An antibody of the invention specifically binds to human IP-10 and is characterized by a particular improved functional feature or property of the antibody as set forth above. Alternatively, the antibody can be cross-reactive with IP-10 from one or more non-human primates, such as rhesus monkeys. Preferably, the antibody does not cross-react with mouse IP-10. Furthermore, although MIG and ITAC are also ligands for the CXCR3 receptor, the antibodies of the invention preferably do not cross-react with human MIG or human ITAC. Preferably, the antibody of the invention has a high affinity (for example, 10^-8 M or less or 10^-9 M or less or even 10^-10 M or smaller K_D ) combined to IP-10. In addition, the antibodies of the invention are capable of inhibiting one or more of the functional activities of IP-10. For example, in one embodiment, the antibody inhibits binding of IP-10 to CXCR3. In another embodiment, the antibody inhibits IP-10 induced calcium flux. In yet another embodiment, the antibody inhibits IP-10 induced cell migration (chemotaxis). Standard assays for assessing the binding capacity of antibodies to IP-10 and/or MIG or ITAC of different species are known in the art, including, for example, ELISA, Western blot, and RIA. Suitable analyses are detailed in the examples. The binding kinetics (e.g., binding affinity) of the antibodies can also be assessed by standard assays known in the art (e.g., by Biacore analysis). Analysis of the effect of antibodies on the functional properties of IP-10 (e.g., receptor binding, calcium flux, chemotaxis) is further elaborated in the Examples. Thus, it is to be understood that "suppressing" one or more of the IP-10 functional properties (eg, biochemical, immunochemical, cellular, physiological, or other biological activity as determined by methods known in the art and as set forth herein). The antibody or the like is associated with a specific activity relative to a statistically significant decrease in activity observed in the absence of antibody (or in the presence of a control antibody of irrelevant specificity). Preferably, the antibody that inhibits IP-10 activity achieves a statistically significant reduction in the measured parameter of at least 10%, more preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80. % or 90%, and in certain preferred embodiments, the antibodies of the invention inhibit greater than 92%, 94%, 95%, 97%, 98% or 99% of IP-10 functional activity.Monoclonal antibody IP10.44 , IP10.52 , IP10.45 , IP10.46 , IP10.53 , IP10.43 , IP10.47 , IP10.48 , IP10.49 , IP10.50 , IP10.51 and IP10.54 The preferred anti-system human monoclonal antibody IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, IP10.51, IP10.52 , IP10.53 or IP10.54. IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, IP10.51, IP10.52, IP10.53 and IP10.54_H Amino acid sequences are shown in SEQ ID NOs: 16, 28, 40, 52, 64, 76, 88, 100, 112, 124, 136 and 148. IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, IP10.51, IP10.52, IP10.53 and IP10.54_L The amino acid sequence is shown in SEQ ID NOs: 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142 and 154. One of the specific anti-system human monoclonal antibodies IP10.44 (also referred to herein as BMS-986184), the structural and chemical characteristics of which are set forth below and in the examples below. IP10.44 V_H The amino acid sequence is shown in SEQ ID NO: 16 (Fig. 2A). IP10.44 V_L The amino acid sequence is shown in SEQ ID NO: 22 (Fig. 2B). V of an antibody that binds to human IP-10 as described herein_H And V_L The sequence (or CDR sequence) can be combined with other antibodies that bind to human IP-10._H And V_L The sequence (or CDR sequence) is "mixed and matched". Preferably, mixing and matching V_H And V_L Chains (or CDRs within such chains) from a specific V_H /V_L Paired V_H The sequence is structurally similar to V_H Sequence instead. Again, preferably, from a specific V_H /V_L Paired V_L The sequence is structurally similar to V_L Sequence instead. For example, the antibody of the present invention or antigen-binding portion thereof comprises: (a) including IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, Amino acid sequence of IP10.51, IP10.52, IP10.53 or IP10.54 (eg SEQ ID NO: 16, ie IP of 10.44)_H Heavy chain variable region; and (b) including IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, IP10.51, IP10 .52, IP10.53 or IP10.54 amino acid sequence (eg SEQ ID NO: 22, also known as IP10.44 V_L a light chain variable region or another anti-IP-10 antibody (ie, different from IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10) V of .50, IP10.51, IP10.52, IP10.53 or IP10.54)_L ; wherein the antibody specifically binds to human IP-10. In another embodiment, the antibody of the present invention or antigen-binding portion thereof comprises: (a) IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10. 50. The CDR1, CDR2 and CDR3 regions of the heavy chain variable region of IP10.51, IP10.52, IP10.53 or IP10.54, for example, the CDR1 comprising the heavy chain variable region of the amino acid sequence SEQ ID NO: , CDR2 and CDR3 regions (ie, CDR sequences of IP10.44, respectively, SEQ ID NOs: 13, 14 and 15); and (b) IP10.44, IP10.43, IP10.45, IP10.46, IP10. 47. CDR1, CDR2 and CDR3 regions of the light chain variable region of IP10.48, IP10.49, IP10.50, IP10.51, IP10.52, IP10.53 or IP10.54 (for example comprising an amino acid sequence SEQ ID NO: CDR1, CDR2 and CDR3 regions of the light chain variable region of 22 (ie, the CDR sequences of IP10.44, respectively, SEQ ID NOs: 19, 20 and 21) or another anti-IP-10 antibody (also That is, it is different from IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, IP10.51, IP10.52, IP10.53 or IP10. 54) CDR; wherein the antibody specifically binds to human IP-10. For example, an antibody or antigen binding portion thereof can comprise one of the heavy chain variable CDR1, CDR2 and CDR3 regions of IP10.44 and other light chain CDR1, CDR2 and/or CDR3 regions of an antibody that binds human IP-10 or More. In addition, it is well known in the art that, independently of the CDR1 and/or CDR2 domains, the CDR3 domain alone can determine the binding specificity of an antibody for a homologous antigen and can predictably produce a plurality of antibodies having the same binding specificity based on consensus CDR3 sequences. See, for example, Klimka et al.British J. of Cancer 83(2) :252-260 (2000); Beiboer et al.J. Mol. Biol. 296 :833-849 (2000); Rader et al.Proc. Natl. Acad. Sci. USA 95 :8910-8915 (1998); Barbas et al.J. Am. Chem. Soc. 116 :2161-2162 (1994); Barbas et al.Proc. Natl. Acad. Sci. USA 92 :2529-2533 (1995); Ditzel et al.J. Immunol. 157 :739-749 (1996); Berezov et al.BIAjournal 8 :Scientific Review 8 (2001); Igarashi et al.J. Biochem (Tokyo) 117 : 452-7 (1995); Bourgeois et al,J. Virol 72 :807-10 (1998); Levi et al.Proc. Natl. Acad. Sci. USA 90 :4374-8 (1993); Polymenis and Stoller,J. Immunol. 152 :5218-5329 (1994) and Xu and Davis,Immunity 13 :37-45 (2000). See also U.S. Patent Nos. 6,951,646, 6,914,128, 6,090,382, 6,818,216, 6,156,313, 6,827,925, 5,833,943, 5,762,905, and 5,760,185. The entire contents of each of these references are hereby incorporated by reference. Therefore, in another embodiment, the antibody of the present invention comprises at least IP 10.44, IP 10.43, IP 10.45, IP 10.46, IP 10.47, IP 10.48, IP 10.49, IP 10.50, IP 10.51, CDR3 area of heavy chain variable area of IP10.52, IP10.53 or IP10.54 and at least IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, CDR3 of the light chain variable region of IP10.50, IP10.51, IP10.52, IP10.53 or IP10.54 (eg SEQ ID NO: 15 and 21, ie the heavy and light chain of IP10.44 is variable District CDR3). Preferably, the antibodies (a) compete for binding to an antibody that derives a CDR3 sequence (eg, antibody IP10.44); (b) retain its functional properties; (c) bind to the same epitope; and/or (d) have Similar to binding affinity.Amino acid modification In another embodiment, the antibody of the invention comprises CDR1, CDR2 and CDR3 sequences and IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, The CDR sequences in IP10.51, IP10.52, IP10.53 or IP10.54 (e.g., IP 10.44) differ in one or more conservatively modified heavy and/or light chain variable region sequences. However, in a preferred embodiment, (a) V of IP 10.44_H The glutamic acid and tyrosine residues of CDR1 (such as the following sequenceEY GMH (SEQ ID NO: 13) underlined) unmodified, (b) IP10.44 V_H CDR2 glycine, alanine, leucine, isoleucine, glycine and alanine residues (eg sequence VI below)G FA GLI KG YA DSVKG (SEQ ID NO: 14) underlined) unmodified, and (c) IP10.44 V_H Alanine and aspartate residues of CDR3 (eg the following sequence EG)A GSN The underlined in IYYYYGMDV (SEQ ID NO: 15) was unmodified. It is understood in the art that certain conservative sequence modifications that do not remove antigen binding can be performed. See, for example, Brummell et al. (1993)Biochem 32 :1180-8; de Wildt et al. (1997)Prot. Eng. 10 :835-41; Komissarov et al. (1997)J. Biol. Chem. 272 :26864-26870; Hall et al. (1992)J. Immunol. 149 :1605-12; Kelley and O’Connell (1993)Biochem. 32 :6862-35;Adib-Conquy et al. (1998)Int. Immunol. 10 :341-6 and Beers et al. (2000)Clin. Can. Res. 6 : 2835-43. Thus, in one embodiment, the antibody comprises a heavy chain variable region comprising a CDR1, CDR2 and CDR3 sequence and/or a light chain variable region comprising a CDR1, CDR2 and CDR3 sequence, wherein: (a) a heavy chain variable region The CDR1 sequence includes SEQ ID NO: 13 and/or its conservative modifications, except for IP10.44._H The glutamic acid and tyrosine residues of CDR1 (such as the following sequenceEY The underlined GMH (SEQ ID NO: 13) is unmodified; and/or (b) the heavy chain variable region CDR2 sequence includes SEQ ID NO: 14 and/or its conservative modifications, except for IP10.44._H CDR2 glycine, alanine, leucine, isoleucine, glycine and alanine residues (eg sequence VI below)G FA GLI KG YA The underlined in DSVKG (SEQ ID NO: 14) is unmodified; and/or (c) the heavy chain variable region CDR3 sequence includes SEQ ID NO: 15 and its conservative modifications, except for IP10.44._H Alanine and aspartate residues of CDR3 (eg the following sequence EG)A GSN The underlined in IYYYYGMDV (SEQ ID NO: 15) is unmodified; and/or (d) the light chain variable region CDR1 and/or CDR2 and/or CDR3 sequences include SEQ ID NO: 19 and/or SEQ ID NO: 20 and/or SEQ ID NO: 21 and/or conservative modifications thereof; and (e) the antibody specifically binds to human IP-10. Additionally or alternatively, the antibody may possess one or more of the following functional properties, such as high affinity binding to human IP-10; capable of binding to monkeys (eg, cynomolgus monkey, rhesus monkey) IP-10 but not Substantially binds to mouse IP-10; is capable of not cross-reacting with human MIG or human ITAC; and is capable of inhibiting (a) binding of IP-10 to CXCR3, (b) IP-10 induced calcium flux and/or (c IP-10 induced cell migration (chemotaxis). In various embodiments, the antibody can be, for example, a human antibody, a humanized antibody, or a chimeric antibody. As used herein, the term "conservative sequence modification" is intended to mean an amino acid modification that does not significantly affect or alter the binding properties of an antibody containing an amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into the antibodies of the invention by standard techniques known in the art, such as site-directed mutagenesis and mutagenesis by PCR. The conservative amino acid-substituted amino acid residue is replaced by an amino acid residue having a similar side chain. A family of amino acid residues with similar side chains has been defined in the industry. Such families include amino acids with basic side chains (eg, lysine, arginine, histidine), amino acids with acidic side chains (eg, aspartic acid, glutamic acid), with Amino acid with an electrode side chain (eg, glycine, aspartame, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar Side chain amino acids (eg, alanine, valine, leucine, isoleucine, valine, phenylalanine, methionine), amino acids with beta-branched side chains (eg, sul Aminic acid, valine acid, isoleucine) and an amino acid having an aromatic side chain (for example, tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues in the CDR regions of an antibody of the invention can be replaced by other amino acid residues from the same side chain family, and the retention of the altered antibody can be tested using the functional assays set forth herein. Function (also known as the above function).Modified and modified antibody Can be used with IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, IP10.51, IP10.52, IP10.53 or IP10.54 V (eg antibody IP10.44)_H And / or V_L An antibody of one or more of the sequences is used as a starting material to engineer a modified antibody to prepare an antibody of the invention. Antibodies can be modified by modifying one or two variable regions (ie, V_H And / or V_L Remodeling within one or more residues, for example, within one or more CDR regions and/or one or more framework regions. Additionally or alternatively, the antibody can be engineered by modifying residues within the constant region, such as altering the effector function of the antibody. In certain embodiments, CDR grafting can be used to engineer the variable regions of an antibody. The antibody interacts with the target antigen primarily via amino acid residues located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequence within the CDRs between individual antibodies is more distinct than the sequences outside the CDRs. Since the CDR sequences are responsible for most of the antibody-antigen interactions, the expression of a specific natural antibody can be expressed by constructing a expression vector comprising CDR sequences derived from a specific natural antibody that has been grafted into a framework sequence of a different antibody. Recombinant antibodies (see, for example, Riechmann et al. (1998)Nature 332 :323-327; Jones et al. (1986)Nature 321 :522-525;Queen et al. (1989)Proc. Natl. Acad . SeeUSA 86 : 10029-10033; U.S. Pat. No. 5,225,539; 5,530,101; 5,585,089; 5,693,762 and 6,180,370). Accordingly, another embodiment of the present invention relates to an isolated monoclonal antibody or antigen-binding portion thereof comprising IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, Heavy chain variable regions of CDR1, CDR2 and CDR3 sequences of IP10.49, IP10.50, IP10.51, IP10.52, IP10.53 or IP10.54 (eg SEQ ID NOs: 13, 14 and 15 respectively) And / or contain IP10.44, IP10.43, IP10.45, IP10.46, IP10.47, IP10.48, IP10.49, IP10.50, IP10.51, IP10.52, IP10.53 or IP10. The light chain variable region of the CDR1, CDR2 and CDR3 sequences of 54 (e.g., SEQ ID NOS: 19, 20 and 21, respectively). Although these antibodies contain monoclonal antibody IP10.44 or other antibodies as described herein._H And V_L CDR sequences, but they may contain different framework sequences. Such framework sequences can be obtained from published DNA libraries containing published germline antibody gene sequences or published references. For example, the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrc-cpe.cam.ac.uk/vbase) Obtained) and Kabat et al. (1991), cited above; Tomlinson et al. (1992) "The Repertoire of Human Germline V_H Sequences Reveals about Fifty Groups of V_H Segments with Different Hypervariable Loops"J. Mol. Biol .227 :776-798; and Cox et al. (1994) "A Directory of Human Germ-line V_H Segments Reveals a Strong Bias in their Usage"Eur. J. Immunol .twenty four : 827-836; the contents of each are expressly incorporated herein by reference. As another example, germline DNA sequences of human heavy and light chain variable region genes can be found in a gene bank database. For example, the following heavy chain germline sequences found in HCo7 HuMAb mice can be obtained with the accession number: 1-69 (NG_0010109, NT_024637, and BC070333), 3-33 (NG_0010109 and NT_024637), and 3-7 (NG_0010109 and NT_024637). As another example, the following heavy chain germline sequences found in HCo12 HuMAb mice can be obtained with the accession number: 1-69 (NG_0010109, NT_024637, and BC070333), 5-51 (NG_0010109, and NT_024637), 4- 34 (NG_0010109 and NT_024637), 3-30.3 (CAJ556644) and 3-23 (AJ406678). The antibody protein sequence was compared to a compiled protein sequence library using a sequence similarity search method known as Gapped BLAST (Altschul et al. (1997) (published above), which is well known to those skilled in the art). Preferred framework sequences for use in the antibodies of the invention are structurally similar to those used by the selected antibodies of the invention, for example, similar to those used by IP 10.44._H 3-33 frame sequence and / or V_K A27 frame sequence. V can be_H CDR1, CDR2 and CDR3 sequences and V_K The CDR1, CDR2 and CDR3 sequences are grafted onto a framework region having the same sequence as found in the germline immunoglobulin gene of the derived framework sequence, or the CDR sequence can be grafted to contain one or more compared to the germline sequence On the frame of the mutation. For example, it has been found that, in certain instances, residues in the framework regions are beneficially mutated to maintain or enhance the antigen binding ability of the antibody (see, for example, U.S. Patent Nos. 5,530,101, 5,585,089, 5,693,762, and 6,180,370). number). Another type of variable region modification system mutation V_H And / or V_L Amino acid residues within the CDR1, CDR2 and/or CDR3 regions, thereby improving one or more binding properties (e.g., affinity) of the antibody of interest. Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce mutations, and the effects on antibody binding or other functional properties of interest can be assessed in in vitro or in vivo assays as set forth herein and provided in the Examples. . Conservative modifications are preferably introduced (as discussed above). The mutation may be an amino acid substitution, addition or deletion, but is preferably substituted. In addition, no more than one, two, three, four or five residues in the CDR regions are typically altered. Accordingly, in another embodiment, the invention provides an isolated anti-IP-10 monoclonal antibody or antigen binding portion thereof comprising the heavy chain and/or light chain variable region sequences set forth herein, wherein the sequences comprise a Or multiple amino acid substitutions, deletions or additions. For example, an isolated anti-IP-10 monoclonal antibody or antigen binding portion thereof comprises: a heavy chain variable region comprising: (a) V_H a CDR1 region comprising SEQ ID NO: 13 or an amino acid sequence having one, two or three amino acid substitutions, deletions or additions compared to SEQ ID NO: 13 (preferably, wherein IP10.44 V_H The glutamic acid and tyrosine residues of CDR1 (such as the following sequenceEY The underlined in GMH) is the same as in SEQ ID NO: 13; (b) V_H a CDR2 region comprising SEQ ID NO: 14 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NO: 14 (preferably , where IP10.44 is V_H CDR2 glycine, alanine, leucine, isoleucine, glycine and alanine residues (eg sequence VI below)G FA GLI KG YA The underlined in DSVKG) is the same as in SEQ ID NO: 14; (c)V_H a CDR3 region comprising SEQ ID NO: 15 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NO: 15 (preferably , where IP10.44 is V_H Alanine and aspartate residues of CDR3 (eg the following sequence EG)A GSN The underlined in IYYYYGMDV) is the same as in SEQ ID NO: 15; (d)V_L a CDR1 region comprising SEQ ID NO: 19 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NO: 19; V_L a CDR2 region comprising SEQ ID NO: 20 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NO: 20; ) V_L A CDR3 region comprising SEQ ID NO: 21 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NO:21. The engineered antibody of the invention comprises a pair of V_H And / or V_L The framework residues within are modified, for example, to improve antibody properties. Typically, such framework modifications are made to reduce the immunogenicity of the antibody. For example, one way is to "backmutate" one or more framework residues into the corresponding germline sequence. More specifically, an antibody that has been mutated by a receptor cell may contain a framework residue that is different from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibodies are derived. Another type of framework modification involves mutating the framework region or even one or more residues in one or more CDR regions to remove T cell epitopes, thereby reducing the potential immunogenicity of the antibody. This method is also referred to as "de-immunization" and is further described in detail in U.S. Patent Publication No. 20030153043. In addition to or in lieu of modifications made in the framework or CDR regions, the antibodies of the invention can be engineered to include modifications in the Fc region, typically altering one or more of the functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding And/or antigen-dependent cytotoxicity. Additionally, an antibody of the invention may be chemically modified (for example, one or more chemical moieties may be attached to the antibody) or modified to alter its glycosylation to also alter one or more of the functional properties of the antibody. Each of these embodiments is described in further detail below. The numbering of the residues in the Fc region is the EU index number of Kabat. In a preferred embodiment, the anti-system comprises an IgG4 isotype antibody of a serine to valerine mutation (S228P; EU index) at a position corresponding to position 228 in the hinge region of the heavy chain constant region. It has been reported that this mutation will eliminate the heterogeneity of the heavy chain disulfide bridge in the hinge region (Angal et al., supra; position 241 is based on the Kabat numbering system). In one embodiment, the hinge region of CH1 is modified to alter (eg, increase or decrease) the number of cysteine residues in the hinge region. This approach is further described in U.S. Patent No. 5,677,425. The number of cysteine residues in the CH1 hinge region is altered to, for example, facilitate light chain and heavy chain assembly or increase or decrease the stability of the antibody. In another embodiment, the Fc hinge region of the antibody is mutated to shorten the biological half life of the antibody. More specifically, one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has staphylococcal protein A that is impaired in binding to the native Fc-hinge domain SpA. (SpA) combination. This approach is further described in detail in U.S. Patent No. 6,165,745. In another embodiment, the antibody is modified to increase its biological half life. A variety of ways are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as set forth in U.S. Patent No. 6,277,375. Alternatively, to increase the biological half-life, the antibody can be altered in the CH1 or CL region to contain a salvage receptor binding epitope derived from two loops of the CH2 domain in the Fc region of IgG, such as U.S. Patent Nos. 5,869,046 and 6,121,022. As stated in the article. In other embodiments, the Fc region is altered to alter the effector function of the antibody by replacing the at least one amino acid residue with a different amino acid residue. For example, one or more amino acids selected from the group consisting of amino acid residues 234, 235, 236, 237, 297, 318, 320, and 322 can be replaced with different amino acid residues, such that the antibody is paired with an effector. The body has altered affinity but retains the antigen binding ability of the parent antibody. The effector ligand whose affinity is altered can be, for example, the Fc receptor or the C1 component of complement. This method is further described in detail in U.S. Patent Nos. 5,624,821 and 5,648,260. In another example, one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with different amino acid residues such that the antibody has altered C1q binding and/or reduces or eliminates Complement dependent cytotoxicity (CDC). This approach is further described in detail in U.S. Patent No. 6,194,551. In another example, one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to bind to complement. This approach is further described in PCT Publication WO 94/29351. In yet another example, the Fc region is modified by modification of one or more amino acids at the following positions to increase antibody-mediated antibody-dependent cellular cytotoxicity (ADCC) and/or increase antibody affinity for Fc gamma receptors :238,239,248,249,252,254,255,256,258,265,267,268,269,270,272,276,278,280,280,280 294,295,296,298,301,303,305,307,309,312,315,320,322,324,326,327,329,330,331,333,334,335,337 , 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439. This approach is further described in PCT Publication WO 00/42072. In addition, variants on human IgG1 for binding sites for FcγR1, FcγRII, FcγRIII and FcRn have been mapped and modified combinations have been described (see Shields et al. (2001)J. Biol. Chem .276 :6591-6604). Specific mutational display at positions 256, 290, 298, 333, 334 and 339 can be modified to the binding of FcyRIII. In addition, the following combinatorial mutants display improved FcyRIII binding: T256A/S298A, S298A/E333A, S298A/K224A, and S298A/E333A/K334A. In yet another embodiment, the glycosylation of the antibody is modified. For example, aglycosylated antibodies can be prepared (ie, the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of an antibody for an antigen. Such carbohydrate modifications can be achieved, for example, by altering one or more glycosylation sites within the antibody sequence. For example, one or more amino acid substitutions can be made to eliminate one or more variable region framework glycosylation sites, thereby eliminating glycosylation at that site. This aglycosylation increases the affinity of the antibody for the antigen. See, for example, U.S. Patent Nos. 5,714,350 and 6,350,861. Additionally or alternatively, an antibody having a modified type of glycosylation, such as a low fucosylated antibody having a reduced amount of fucosyl residues or an antibody having an increased halved GlcNac structure, can be prepared. These altered glycosylation patterns have been shown to increase the ADCC ability of antibodies. Such carbohydrate modifications can be achieved, for example, by expressing antibodies in host cells having altered glycosylation machinery. Cells having altered glycosylation machinery have been described in the art and can be used as host cells for the expression of recombinant antibodies of the invention to thereby produce antibodies with altered glycosylation. For example, the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene FUT8 (α(1,6)-fucosyltransferase), and thus the antibodies expressed in the Ms704, Ms705, and Ms709 cell lines are It lacks fucose on its carbohydrates. Ms704, Ms705 and Ms709 FUT8^-/- Cell lines are produced by targeting the destruction of the FUT8 gene in CHO/DG44 cells using two alternative vectors (see U.S. Patent Publication No. 20040110704 and Yamane-Ohnuki et al. (2004).Biotechnol Bioeng 87 :614-22). As a further example, EP 1,176,195 describes a cell line having a FUT8 gene encoding a functional disruption of a fucosyltransferase such that the antibody expressed in this cell line reduces or eliminates the alpha-1,6 bond-associated enzyme. Demonstrates low fucosylation. EP 1,176,195 also teaches cell lines which have low or no enzymatic activity for the addition of fucose to N-acetyl glucosamine bound to the Fc region of the antibody, such as the rat myeloma cell line YB2/0 ( ATCC CRL 1662). PCT Publication WO 03/035835 describes a variant CHO cell line Lec13 cell that has reduced ability to attach fucose to Asn (297) linked carbohydrates, which also produces low algae of antibodies expressed in the host cell Glycosylation (see also Shields et al. (2002)J. Biol. Chem .277 :26733-26740). Antibodies having modified glycosylation characteristics can also be produced in eggs, as set forth in PCT Publication WO 06/089231. Or, can be in plant cells (such as duckweed (Lemna An antibody having a modified glycosylation profile is produced in )). A method of producing antibodies in a plant system is disclosed in U.S. Patent Application Serial No. 040,989, filed to Aal. PCT Publication WO 99/54342 describes cell lines engineered to express glycosyltransferases of modified glycoproteins, such as β(1,4)-N-ethylglucosyltransferase III (GnTIII), thereby The antibodies expressed in the engineered cell lines exhibit an increased ectopic GlcNac structure that produces increased ADCC activity of the antibody (see also Umana et al. (1999)Nat. Biotech. 17 :176-180). Alternatively, the fucose residue of the antibody can be cleaved using a fucosidase; for example, the fucosidase α-L-fucosidase removes fucosyl residues from the antibody (Tarentino et al. (1975)Biochem .14 :5516-23). Another modification of the antibodies herein encompassed by the present invention is pegylation. The antibody can be PEGylated to, for example, extend the biological (e.g., serum) half-life of the antibody. A PEGylated antibody, typically one or more PEG groups attached to an antibody or antibody fragment, such that the antibody or fragment thereof is reacted with polyethylene glycol (PEG) (eg, a reactive ester or aldehyde derivative of PEG) )reaction. Preferably, pegylation is carried out by a deuteration reaction or an alkylation reaction with a reactive PEG molecule (or a similar reactive water-soluble polymer). As used herein, the term "polyethylene glycol" is intended to encompass any form of PEG that has been used to derive other proteins, such as mono(C1-C10) alkoxy- or aryloxy-polyethylene glycol or poly. Ethylene glycol-maleimide. In certain embodiments, the anti-glycosylated antibody is intended to be PEGylated. Methods for PEGylating proteins are known in the art and are applicable to the antibodies of the invention. See, for example, EP 0 154 316 and EP 0 401 384.Antibody physical properties The antibodies of the invention can be characterized by various physical properties to detect and/or distinguish between different species. For example, an antibody can contain one or more glycosylation sites in the light or heavy chain variable region. Such glycosylation sites may increase the immunogenicity of the antibody or alter the pK of the antibody (by altering antigen binding) (Marshall et al. (1972)Annu Rev Biochem 41 :673-702; Gala and Morrison (2004)J Immunol 172 :5489-94; Wallick et al. (1988)J Exp Med 168 :1099-109;Spiro (2002)Glycobiology 12 :43R-56R; Parekh et al. (1985)Nature 316 : 452-7; Mimura et al. (2000)Mol Immunol 37 :697-706). Glycosylation is known to occur at the motif containing the N-X-S/T sequence. In some cases, it is preferred to have an anti-IP-10 antibody that does not contain variable region glycosylation. This can be achieved by selecting an antibody that does not contain a glycosylation motif in the variable region or by mutating residues within the glycosylation region. In a preferred embodiment, the antibody does not contain an aspartic acid isomeric site. The deamidamine of aspartame can occur on the N-G or D-G sequence and causes the production of an isoaspartic acid residue that introduces a kink into the polypeptide chain and reduces its stability (isoaspartic acid effect). Each antibody will have a unique isoelectric point (pI), which is typically in the pH range between 6 and 9.5. The pi of the IgGl antibody is typically in the pH range of 7-9.5, and the pi of the IgG4 antibody is typically in the pH range of 6-8. It is speculated that antibodies with pI not in the normal range may have certain unfolding and instability under in vivo conditions. Therefore, it is preferred to have an anti-IP-10 antibody having a pI value within a normal range. This can be achieved by selecting antibodies with pI in the normal range or by mutating charged surface residues.Nucleic acid molecule encoding an antibody of the invention Another aspect of the invention pertains to nucleic acid molecules encoding the antibodies of the invention. The nucleic acids may be present in intact cells, in cell lysates, or in partially purified or substantially pure form. Nucleic acids are "isolated" or "substantially pure" when purified by standard techniques to remove other cellular components or other contaminants (eg, other cellular nucleic acids or proteins), which include alkali/SDS Treatment, CsCl banding, column chromatography, agarose gel electrophoresis, and other methods well known in the art. See F. Ausubel et al., eds. (1987) Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York. The nucleic acid of the invention may be, for example, DNA or RNA and may or may not contain intron sequences. In a preferred embodiment, the nucleic acid is a cDNA molecule. The nucleic acids of the invention can be obtained using standard molecular biology techniques. For antibodies expressed by hybridomas (eg, hybridomas prepared from transgenic mice carrying human immunoglobulin genes, as further described below), cDNA encoding the light and heavy chains of antibodies produced by hybridomas can be borrowed Obtained by standard PCR amplification or cDNA selection techniques. For antibodies obtained from a library of immunoglobulin genes (eg, using phage display technology), the nucleic acid encoding the antibody can be recovered from the library. Preferred nucleic acid molecules of the invention are those which encode the VH and VL sequences of the IP10.44 monoclonal antibody. The DNA sequences encoding the VH and VL sequences of IP10.44 are shown in SEQ ID NOs: 17 and 23, respectively. After obtaining the DNA fragments encoding the VH and VL segments, the DNA fragments can be further manipulated by standard recombinant DNA techniques to, for example, convert the variable region genes into full length antibody chain genes, Fab fragment genes or scFv genes. In such manipulations, a DNA fragment encoding VL or VH is operably linked to another DNA fragment encoding another protein, such as an antibody constant region or a flexible linker. As used in this context, the term "operatively linked" is intended to mean joining two DNA fragments such that the amino acid sequence encoded by the two DNA fragments remains in frame. The isolated DNA encoding the VH region can be converted to a full-length heavy chain gene by operatively linking the DNA encoding VH to another DNA molecule encoding the heavy chain constant regions (CH1, CH2, and CH3). The sequence of the human heavy chain constant region gene is known in the art (see, for example, Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242 And DNA fragments encompassing such regions can be obtained by standard PCR amplification. The heavy chain constant region can be an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but is preferably an IgGl or IgG4 constant region. For a Fab fragment heavy chain gene, the DNA encoding VH is operably linked to another DNA molecule encoding only the heavy chain CH1 constant region. The isolated DNA encoding the VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the DNA encoding VL to another DNA molecule encoding the light chain constant region CL. The sequence of the human light chain constant region gene is known in the art (see, for example, Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242 And DNA fragments encompassing such regions can be obtained by standard PCR amplification. The light chain constant region can be a kappa or lambda constant region, but is preferably a kappa constant region. To generate the scFv gene, a DNA fragment encoding VH and VL is operably linked to a coding flexible linker (eg, encoding an amino acid sequence (Gly)₄ -Ser)₃ Another fragment, such that the VH and VL sequences can be represented as contiguous single-chain proteins in which the VL and VH regions are joined by a flexible linker (see, for example, Bird et al. (1988)Science 242 :423-426; Huston et al. (1988)Proc. Natl. Acad. Sci. USA 85 :5879-5883; McCafferty et al. (1990)Nature 348 :552-554).Single antibody production of the present invention The monoclonal antibodies (mAbs) of the present invention can be produced by various techniques, including conventional monoclonal antibody methods, such as Kohler and Milstein (1975).Nature 256 : Standard somatic cell hybridization technique in 495. Although somatic cell hybridization procedures are preferred, other techniques for producing monoclonal antibodies, such as B lymphocyte viruses or carcinogenic transformations, can in principle be employed. A preferred animal system for preparing hybridomas is a murine system. Hybridoma production in mice is a well established procedure. Immune protocols and techniques for isolating immune spleen cells for fusion are known in the art. Fusion partners (such as murine myeloma cells) and fusion procedures are also known. Chimeric or humanized antibodies of the invention can be prepared based on the sequence of a murine monoclonal antibody prepared as set forth above. DNA encoding heavy and light chain immunoglobulins can be obtained from murine hybridomas of interest and engineered using standard molecular biology techniques to contain non-murine (eg, human) immunoglobulin sequences. For example, to generate a chimeric antibody, the murine variable region can be ligated to a human constant region using methods known in the art (see, for example, U.S. Patent No. 4,816,567 issued to Cabilly et al.). For the production of a humanized antibody, the murine CDR regions can be inserted into a human framework using methods known in the art (see, for example, U.S. Patent No. 5, 225, 539 to the U.S. Patent No. 5, 530, 001; Nos. 5,693,762 and 6,180,370). In a preferred embodiment, the invention is directed against a human monoclonal antibody. Transgenic or transchromosomic mice that carry part of the human immune system rather than the mouse system can be used to generate such human monoclonal antibodies against IP-10. Such transgenic and transchromosomic mice are comprised of mice referred to herein as HuMAb mice and KM mice, respectively, and are collectively referred to herein as "human Ig mice." HuMAb Mouse® (Medarex, Inc.) contains human immunoglobulin gene mini-locus encoding non-rearranged human heavy chain (μ and γ) and kappa light chain immunoglobulin sequences and enables endogenous μ and kappa chain genes Targeted mutations in passivation (see, for example, Lonberg et al. (1994) Nature 368 (6474): 856-859). Therefore, mice exhibit reduced expression of mouse IgM or κ, and in response to immunization, species switching and somatic mutation of human heavy and light chain transgenes are introduced to generate high-affinity human IgGκ monoclonal antibodies (Lonberg, N Et al. (1994) (literature above); reviewed in Lonberg, N. (1994)Handbook of Experimental Pharmacology 113 :49-101; Lonberg, N. and Huszar, D. (1995)Intern. Rev. Immunol .13 : 65-93 and Harding, F. and Lonberg, N. (1995)Ann. NY Acad. Sci .764 :536-546). The preparation and use of HuMab mice and the genomic modification carried by these mice are further described in Taylor, L. et al. (1992)Nucleic Acids Research 20 :6287-6295; Chen, J. et al. (1993)International Immunology 5 : 647-656; Tuaillon et al. (1993)Proc. Natl. Acad. Sci. USA 90 :3720-3724; Choi et al. (1993)Nature Genetics 4 :117-123; Chen, J. et al. (1993)EMBO J .12 : 821-830; Tuaillon et al. (1994)J. Immunol .152 :2912-2920;Taylor, L. et al. (1994)International Immunology 6 : 579-591; and Fishwild, D. et al. (1996)Nature Biotechnology 14 : 845-851, the entire contents of which are incorporated herein by reference. See also U.S. Patent Nos. 5,545,806, 5,569,825, 5,625,126, 5,633,425, 5,789,650, 5,877,397, 5,661,016, 5,814,318, 5,874,299, and 5,770,429 (both to Lonberg and Kay) U.S. Patent No. 5,545,807 issued to Surani et al.; PCT Publication No. WO 92/03918, WO 93/12227, WO 94/25585, WO 97/13852, WO 98/24884 No. WO 99/45962 (issued to Lonberg and Kay); and PCT Publication No. WO 01/14424 to Korman et al. In another embodiment, a human antibody of the invention can be produced using a mouse that carries a human immunoglobulin sequence on a transgene and a transchromosome (eg, a mouse carrying a human heavy chain transgene and a human light chain transchromosome). The mice referred to herein as "KM mice" are described in detail in PCT Publication WO 02/43478, issued to Ishida et al. In addition, alternative transgenic animal systems displaying human immunoglobulin genes are available in the art and can be used to produce the anti-IP-10 antibodies of the invention. For example, alternative transgenic systems known as Xeno mice (Abgenix, Inc.) can be used; such as those disclosed in U.S. Patent Nos. 5,939,598, 6,075,181, 6,114,598 issued to Kucherlapati et al. , Nos. 6,150,584 and 6,162,963. In addition, alternative transchromosomal animal systems that exhibit human immunoglobulin genes are available in the art and can be used to produce the anti-IP-10 antibodies of the invention. For example, mice carrying human heavy chain transchromosomes and human light chain transchromosomes can be used, which are referred to as "TC mice"; these mice are described in Tomizuka et al. (2000)Proc. Natl. Acad. Sci. USA 97 : 722-727. In addition, cattle carrying human heavy and light chain transchromosomes have been described in the industry (Kuroiwa et al. (2002)Nature Biotechnology 20 : 889-894) and can be used to produce the anti-IP-10 antibodies of the invention. The human monoclonal antibodies of the present invention can also be prepared by screening a human immunoglobulin gene library using a phage display method. Such phage display methods for isolating human antibodies have been established in the industry. U.S. Patent Nos. 5,427, 908 and 5, 571, 698 to Dower et al., and U.S. Patent No. 5,969,108, issued to McCafferty et al. And U.S. Patent Nos. 5,885,793, 6,521,404, 6,544,731, 6,555,313, 6,582,915 and 6,593,081 to Griffiths et al. The human monoclonal antibodies of the present invention can also be prepared using SCID mice in which human immune cells have been reconstituted such that a human antibody response can be produced following immunization. The mice are described in, for example, U.S. Patent Nos. 5,476,996 and 5,698,767, issued toW.Humanity Ig Immunization of mice When a human Ig mouse is used to produce a human antibody of the present invention, the mouse can be immunized with a purified or enriched preparation of IP-10 antigen and/or recombinant IP-10 or IP-10 fusion protein, such as As explained in the following literature: Lonberg, N. et al. (1994)Nature 368 (6474): 856‐859; Fishwild, D. et al. (1996)Nature Biotechnology 14 : 845-851; and PCT Publication WO 98/24884 and WO 01/14424. Preferably, the mouse is 6-16 weeks of age at the time of the first infusion. For example, human Ig mice can be immunized intraperitoneally using a purified or recombinant preparation of IP-10 antigen (5-50 μg). Detailed procedures for generating fully human monoclonal antibodies to IP-10 are set forth in Example 1 below. The cumulative experience of using various antigens has been demonstrated, i.e., immunization with an antigen initially in complete Freund's adjuvant via intraperitoneal (IP) followed by incomplete Freund's adjuvant (incomplete Freund's adjuvant) Transgenic mice responded by performing IP immunization every other week (up to a total of 6 times). However, adjuvants other than Freund's adjuvant have also been found to be effective. In addition, intact cells were found to be highly immunogenic in the absence of adjuvant. The immune response can be monitored within the course of the immunization protocol, wherein plasma samples are obtained by post-mortem blood sampling. Plasma can be screened by ELISA (as set forth below) and can be fused using mice with sufficient anti-IP-10 human immunoglobulin titers. Mice can be boosted intravenously with antigen 3 days prior to sacrifice and removal of the spleen. It is expected that 2-3 fusions may be required for each immunization. Normally 6 to 24 mice are immunized for each antigen. Usually, HCo7 and HCo12 strains are used. In addition, both HCo7 and HCo12 transgenes can be bred together into a single mouse with two different human heavy chain transgenes (HCo7/HCo12).Generation of hybridoma producing the human monoclonal antibody of the present invention To generate a hybridoma producing a human monoclonal antibody of the invention, spleen cells and/or lymph node cells can be isolated from the immunized mouse and fused to a suitable immortalized cell line, such as a mouse myeloma cell line. The resulting hybridomas can be screened for the production of antigen-specific antibodies. For example, a single cell suspension of spleen lymphocytes from immunized mice is fused to one-sixth of P3X63-Ag8.653 non-secreting mouse myeloma cells (ATCC, CRL 1580) using 50% PEG. Put the cells at about 2 × 10⁵ Tiled in flat-bottomed microtiter plates, followed by 20% fetal bovine serum, 18% "653" conditioned medium, 5% Origen (IGEN), 4 mM L-glutamic acid, 1 mM acetone Sodium, 5 mM HEPES, 0.055 mM 2-mercaptoethanol, 50 units/ml penicillin (penicillin), 50 mg/ml streptomycin, 50 mg/ml gentamycin and 1× HAT ( Sigma; HAT was incubated in selective medium supplemented 24 hours after fusion for two weeks. After about two weeks, the cells can be cultured in a medium in which HAT is replaced with HT. Individual wells for human IgM and IgG antibodies can then be screened by ELISA. After the emergence of hybridoma overgrowth, the medium can usually be observed immediately after 10-14 days. The antibody secreting the hybridoma can be re-plated and screened, and if it is still positive for human IgG, the monoclonal antibody can be subcloned at least twice by limiting dilution. Stable melons can then be cultured in vitro to produce small amounts of antibody in tissue culture medium for characterization. To purify human monoclonal antibodies, selected hybridomas can be grown in two liter spinner flasks for purification of monoclonal antibodies. The supernatant was filtered and concentrated, and then subjected to affinity chromatography using Protein A-sepharose (Pharmacia, Piscataway, N.J.). The eluted IgG can be checked by gel electrophoresis and high performance liquid chromatography to ensure purity. The buffer solution can be replaced with PBS and the extinction coefficient of 1.43 can be used by OD₂₈₀ To determine the concentration. Individual antibodies can be aliquoted and stored at -80 °C.Generation of transfectoma producing monoclonal antibodies of the present invention Antibodies of the invention can also be produced in host cell transfectomas using, for example, a combination of recombinant DNA techniques and gene transfection methods well known in the art (e.g., Morrison, S. (1985) Science 229: 1202). For example, to express an antibody or antibody fragment thereof, a coding portion or full length light chain and heavy chain can be obtained by standard molecular biology techniques (eg, PCR amplification or cDNA selection using hybridomas expressing antibodies of interest). DNA, and the DNA can be inserted into a expression vector such that the genes are operably linked to transcriptional and translational control sequences. As used herein, the term "operatively linked" is intended to mean the ligation of an antibody gene into a vector such that the transcriptional and translational control sequences within the vector function as desired to regulate transcription and translation of the antibody gene. The performance vector and expression control sequences are selected to be compatible with the expression host cell used. The antibody light chain gene and the antibody heavy chain gene can be inserted into separate vectors, or more typically the two genes are inserted into the same expression vector. The antibody gene is inserted into the expression vector by standard methods (e.g., binding the complementary restriction site on the antibody gene fragment to the vector, or blunt-end ligation if no restriction site is present). The light chain and heavy chain variable regions of the antibodies described herein can be inserted into a expression vector encoding a heavy chain constant region and a light chain constant region of a desired isoform to produce a full length antibody gene of any antibody isotype, such that V_H The segment is operatively connected to the C in the carrier_H Section, and V_L The segment is operatively connected to the C in the carrier_L Section. Additionally or alternatively, the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain by the host cell. The antibody chain gene can be ligated into a vector such that the signal peptide is ligated in-frame to the amino terminus of the antibody chain gene. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (ie, a signal peptide from a non-immunoglobulin). In addition to the antibody chain gene, the recombinant expression vector of the present invention carries a regulatory sequence that controls the expression of the antibody chain gene in a host cell. The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes. Such regulatory sequences are described, for example, in Goeddel (Gene Expression Technology. Methods in Enzymology 185, Academic Press, San Diego, CA (1990)). Those skilled in the art will appreciate that the design of the expression vector (including the choice of regulatory sequences) may depend on factors such as the choice of host cell to be transformed, the degree of expression of the desired protein, and the like. Preferred regulatory sequences for mammalian host cell expression include viral elements that direct a higher degree of protein expression in mammalian cells, such as promoters and/or enhancers derived from: cytomegalovirus (CMV), Simian virus 40 (SV40), adenovirus (eg adenovirus major late promoter (AdMLP)) and polyomavirus. Alternatively, non-viral regulatory sequences can be used, such as the ubiquitin promoter or the beta-globin promoter. In addition, the regulatory elements are composed of sequences from different sources (eg, the SRα promoter system) containing sequences from the SV40 early promoter and long terminal repeats of human T cell type 1 leukemia virus (Takebe, Y. Et al. (1988)Mol. Cell. Biol .8 :466-472). In addition to the antibody chain genes and regulatory sequences, the recombinant expression vectors of the invention may also carry additional sequences, such as sequences that regulate the replication of the vector in a host cell (e.g., an origin of replication) and a selectable marker gene. The selectable marker gene facilitates selection of a host cell into which the vector has been introduced (see, for example, U.S. Patent Nos. 4,399,216, 4,634,665, and 5,179,017, all from Axel et al.). For example, a selectable marker gene typically confers resistance to a drug (eg, G418, hygromycin, or methotrexate) to a host cell into which the vector has been introduced. Preferred selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr- host cells selected/amplified with amine formazan) and the neo gene (for G418 selection). To express light and heavy chains, expression vectors encoding heavy and light chains are transfected into host cells by standard techniques. The various forms of the term "transfection" are intended to encompass a variety of techniques commonly used to introduce foreign DNA into prokaryotic or eukaryotic host cells, such as electroporation, calcium phosphate precipitation, DEAE-dextran transfection, and the like. Although it is theoretically possible to express an antibody of the invention in a prokaryotic or eukaryotic host cell, the antibody is best expressed in eukaryotic cells (and optimally mammalian host cells) due to the eukaryotic cells and especially mammals Cells are more likely than prokaryotic cells to assemble and secrete appropriately folded and immunologically active antibodies. Prokaryotic expression of antibody genes has been reported to be ineffective in producing high yields of active antibodies (Boss, M. A. and Wood, C. R. (1985)Immunology Today 6 :12-13). Preferred mammalian host cells for use in representing recombinant antibodies of the invention comprise Chinese hamster ovary cells (CHO cells) comprising dhfr-CHO cells as described in Urlaub and Chasin (1980)Proc. Natl. Acad. Sci. USA 77:4216-4220, which is used with DHFR selectable markers, such as, for example, R.J. Kaufman and P.A. Sharp (1982)Mol. Biol. 159: 601-621), NSO myeloma cells, COS cells, and SP2 cells. In particular, for use with NSO myeloma cells, another preferred expression system is the GS gene expression system disclosed in WO 87/04462, WO 89/01036 and EP 338,841. When introducing an antibody gene encoding a recombinant expression vector into a mammalian host cell, the antibody is produced by culturing the host cell for a period of time sufficient to allow the antibody to behave in the host cell or to secrete the antibody to the host. The medium in which the cells are grown. Antibodies can be recovered from the culture medium using standard protein purification methods.Immunoconjugate In another aspect, the invention features an anti-IP-10 antibody or fragment thereof conjugated to a therapeutic moiety, such as a cytotoxin, a drug (eg, an immunosuppressive agent) or a radiotoxin. Such conjugates are referred to herein as "immunoconjugates." An immunoconjugate comprising one or more cytotoxins is referred to as an "immunotoxin." A cytotoxin or cytotoxic agent comprises any agent that is detrimental to (eg, kills) cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide ), tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxycarbonate Dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoid, procaine , tetracaine, lidocaine, propranolol, and puromycin, and analogs or homologs thereof. Therapeutic agents also include, for example, antimetabolites (eg, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), Alkylating agents (eg, mechlorethamine, thiotepa, chlorambucil, mephalan, carmustine (BSNU), and lomoviz) Lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichloro Diamine platinum (II) (DDP) (cisplatin), anthracycline antibiotics (eg daunorubicin (previously daunomycin) and doxorubicin), antibiotics (eg dactinomycin) (dactinomycin) (previously actinomycin), bleomycin, glocomycin, and anthramycin (AMC) and anti-mitotic agents (eg, vincristine and vinblastine). Other preferred examples of therapeutic cytotoxins linked to antibodies of the invention include duocarmycin, calicheamicin, maytans Ine) and auristatin and its derivatives. One example of a calicheamicin antibody conjugate is commercially available MylotargTM (Wyeth-Ayerst). Cytotoxin can be coupled using linker technology available in the industry. Examples of the type of linker used to couple a cytotoxin to an antibody include, but are not limited to, hydrazine, thioether, ester, disulfide, and peptide-containing linkers. Alternatively, for example, it is readily soluble. A cleavage of a low pH by an enzyme in a liposomal chamber or a cleavage of a protease, such as a protease that preferentially expresses in a tumor tissue, such as a cell autolysozyme (eg, cell autolysing enzymes B, C, D). For additional discussion of linkers and methods of coupling therapeutic agents to antibodies, see also Saito, G. et al. (2003)Adv. Drug Deliv. Rev .55 :199-215; Trail, P.A. et al. (2003)Cancer Immunol. Immunother .52 :328-337; Payne, G. (2003)Cancer Cell 3 :207-212;Allen, T.M. (2002)Nat. Rev. Cancer 2 :750-763; Pastan, I. and Kreitman, R. J. (2002)Curr. Opin. Investig. Drugs 3 :1089-1091; Senter, P.D. and Springer, C.J. (2001)Adv. Drug Deliv. Rev .53 :247-264. The antibodies of the invention may also be coupled to a radioisotope to produce a cytotoxic radiopharmaceutical, also known as a radioimmunoconjugate. Examples of radioisotopes that can be coupled to an antibody for diagnosis or treatment include, but are not limited to, iodine¹³¹ ,indium¹¹¹ ,yttrium⁹⁰ And¹⁷⁷ . Methods for preparing radioimmunoconjugates have been established in the art. Examples of radioactive immunoconjugates are commercially available (including ZevalinTM (IDEC Pharmaceuticals) and BexxarTM (Corixa Pharmaceuticals)), and similar methods can be used and antibodies of the invention can be used to prepare radioimmunoconjugates. Antibody conjugates of the invention can be used to modify a given biological response, and the drug moiety should not be construed as being limited to classical chemotherapeutic agents. For example, a drug moiety can be a protein or polypeptide that possesses a desired biological activity. Such proteins may comprise, for example, enzymatically active toxins or active fragments thereof, such as aconite, ricin A, pseudomonas exotoxin or diphtheria toxin; proteins such as tumor necrosis factor or interference - g; or biological response modifiers, such as lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6 ") granule ball macrophage community stimulating factor ("GM-CSF"), granule globule community stimulating factor ("G-CSF") or other growth factors. Techniques for coupling the therapeutic moiety to an antibody are well known, for example, see Arnon et al, "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243- 56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery", Controlled Drug Delivery (2nd Edition), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review", Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985) and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62:119-58 (1982).Bispecific molecule In another aspect, the invention features a bispecific molecule comprising an anti-IP-10 antibody or fragment thereof of the invention. An antibody or antigen binding portion thereof of the invention may be derivatized or linked to another functional molecule (eg, another peptide or protein, such as another antibody or ligand of a receptor) to generate binding to at least two different binding sites or target molecules Bispecific molecule. An antibody of the invention may in fact be derivatized or linked to more than one other functional molecule to generate a multispecific molecule that binds to two or more different binding sites and/or target molecules; such multispecific molecules are also intended to be encompassed herein. In the term "bispecific molecule". To generate a bispecific molecule of the invention, an antibody of the invention may be functionally linked (eg, by chemical coupling, gene fusion, non-covalent association, or other means) to one or more additional binding molecules (eg, another antibody) , antibody fragments, peptides or binding mimics) to produce bispecific molecules. Thus, the invention encompasses bispecific molecules comprising at least one first binding specificity for IP-10 and a second binding specificity for a second target epitope. In a particular embodiment of the invention, the second target epitope is an Fc receptor, such as human Fc[gamma]RI (CD64) or human Fc[alpha] receptor (CD89). Thus, the invention encompasses the ability of a bispecific molecule to bind to an effector cell (eg, a mononuclear sphere, a macrophage or a polymorphonuclear cell (PMN)) that expresses FcγR, FcαR, or FceR, and a target cell that exhibits IP-10. These bispecific molecules allow cells expressing IP-10 to target effector cells and trigger Fc receptor-mediated effector cell activity (eg, phagocytosis of cells exhibiting IP-10, antibody-dependent cell-mediated cytotoxicity) ADCC), interleukin release or formation of superoxide anion). In embodiments of the invention in which the bispecific molecule is multispecific, the molecule may further comprise a third binding specificity in addition to anti-Fc binding specificity and anti-IP-10 binding specificity. In one embodiment, the third binding-specific portion is an anti-enhancement factor (EF) moiety, eg, a molecule that binds to a surface protein involved in cytotoxic activity and thereby increases the immune response against the target cell. An "anti-enhancement factor moiety" can be an antibody, a functional antibody fragment or a ligand that binds to a given molecule (eg, an antigen or receptor) and thereby enhances the effect of the binding determinant on the Fc receptor or target cell antigen. The "anti-enhancement factor moiety" can bind to an Fc receptor or a target cell antigen. Alternatively, the anti-enhancement factor moiety can bind to an entity that is different from the entity to which the first and second binding specificities bind. For example, an anti-enhancement factor moiety can bind to a cytotoxic T cell (eg, via CD2, CD3, CD8, CD28, CD4, CD40, ICAM-1, or other immune cells that increase the immune response against the target cell). In one embodiment, the bispecific molecule of the invention comprises at least one antibody or antibody fragment thereof (eg, comprising Fab, Fab', F(ab')₂ , Fv or single-chain Fv) as a binding specific part. The antibody may also be a light chain or heavy chain dimer or any minimal fragment thereof, such as an Fv or a single-stranded construct, as set forth in Ladner et al., U.S. Patent No. 4,946,778, the disclosure of which is expressly incorporated herein . In one embodiment, the binding specificity for an Fc gamma receptor is provided by a monoclonal antibody that is not blocked by human immunoglobulin G (IgG). As used herein, the term "IgG receptor" refers to any of the 8 genes (sequence genes) located on chromosome 1. These genes encode a total of 12 transmembrane or soluble receptor isoforms, which are equivalent Divided into three Fc gamma receptor species: FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16). In a preferred embodiment, Fcγ is regulated by the system human high-affinity FcyRI. Human FcγRI is a monomeric IgG (10)⁸ - 10⁹ M^-1 ) show high affinity 72 kDa molecules. The production and characterization of certain preferred anti-Fcγ monoclonal antibodies are described in PCT Publication No. WO 88/00052, the disclosure of which is incorporated herein by reference. The antibodies bind to an epitope of FcyRI, FcyRII or FcyRIII at a site other than the Fcy binding site of the receptor, and thus the binding thereof is not substantially blocked by physiological concentrations of IgG. The specific anti-FcyRI anti-systems mAb 22, mAb 32, mAb 44, mAb 62 and mAb 197 are useful in the present invention. Hybridomas producing mAb 32 are available from the American Type Culture Collection under ATCC Accession No. HB9469. In other embodiments, the anti-Fcy receptor anti-system monoclonal antibody 22 is in a humanized form (H22). The production and characterization of H22 antibodies are described in Graziano, R.F. et al. (1995).J. Immunol 155 (10): 4996-5002 and PCT Publication WO 94/10332. The cell line producing the H22 antibody was deposited in the American Type Culture Collection under the name HA022CL1 and has accession number CRL 11177. In other preferred embodiments, the binding specificity for the Fc receptor is provided by an antibody that binds to a human IgA receptor (eg, an Fc-alpha receptor (Fc[alpha]RI (CD89))), preferably without Human immunoglobulin A (IgA) blockade. The term "IgA receptor" is intended to include a gene product of the gene (FcαRI) located on chromosome 19. This gene is known to encode several 55 to 110 kDa alternatively spliced transmembrane isoforms. The FcαRI (CD89) phenotype is expressed in Mononuclear/macrophage, eosinophilic, and neutrophil pellets, but not on non-effector cell populations. FcαRI has moderate affinity for IgA1 and IgA2 (≈ 5 ( 10⁷ M^-1 ) and increased affinity when exposed to interleukins such as G-CSF or GM-CSF (Morton, H. C. et al. (1996)Critical Reviews in Immunology 16 :423-440). Four FcaRI-specific monoclonal antibodies (identified as A3, A59, A62 and A77) that bind to FcaRI outside the IgA ligand binding domain have been described (Monteiro, R.C. et al. (1992)J. Immunol. 148 :1764). FcαRI and FcγRI are preferred trigger receptors for use in the bispecific molecule of the present invention because (1) are mainly expressed in immune effector cells (eg, mononuclear spheres, PMN, macrophages, and dendritic cells). (2) to a high degree (eg, 5,000-100,000 cells/cell); (3) to mediators of cytotoxic activity (eg, ADCC, phagocytosis); (4) to mediate antigens targeted to them (including Enhanced antigen presentation by the body antigen). Although human monoclonal antibodies are preferred, other anti-systemic murine chimeric and humanized monoclonal antibodies can be employed in the bispecific molecules of the invention. The bispecific molecules of the invention can be prepared by coupling binding specificity (e.g., anti-FcR and anti-IP-10 binding specificity) components using methods known in the art. For example, each of the binding-specific portions of the bispecific molecule can be separately produced and then coupled to each other. Covalent coupling can be carried out using a variety of coupling agents or crosslinkers when binding specific moiety proteins or peptides. Examples of the crosslinking agent include protein A, carbodiimide, N-succinimide-S-ethylidene-thioacetate (SATA), 5,5'-dithiobis(2-nitrate Benzoic acid) (DTNB), o-phenyl bis-maleimide (oPDM), N-succinimide-3-(2-pyridyldithio) propionate (SPDP) and 4- (N-maleimidomethyl)cyclohexane-1-carboxylic acid sulfoaluminum imino ester (sulfo-SMCC) (see, for example, Karpovsky et al., (1984)J. Exp. Med .160 :1686;Liu, MA et al. (1985)Proc. Natl. Acad. Sci. USA 82 :8648). Other methods are described in Paulus (1985) Behring Ins. Mitt. No. 78, 118-132; Brennan et al. (1985)Science 229 :81-83) and Glennie et al. (1987)J. Immunol. 139 :2367-2375). Preferred coupling agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, IL). Where a specific portion of the antibody is bound, it can be coupled via a thiol linkage of the C-terminal hinge region of the two heavy chains. In a particularly preferred embodiment, the hinge region is modified to contain an odd number of (preferably one) sulfhydryl residues prior to coupling. Alternatively, the two binding specific portions can be encoded in the same vector and expressed and assembled in the same host cell. This method is especially useful for the bispecific molecular system MAb x MAb, MAb x Fab, Fab x F(ab')₂ Or when the ligand x Fab fusion protein. The bispecific molecule of the invention may be a single chain molecule comprising a single chain antibody and a binding determinant or a single chain bispecific molecule comprising two binding determinants. A bispecific molecule can include at least two single chain molecules. Methods of preparing bispecific molecules are described, for example, in U.S. Patent No. 5, 260, 203; U.S. Patent No. 5, 455, 030; U.S. Patent No. 4, 881, 175; U.S. Patent No. 5,132, 405; U.S. Patent No. 5,091,513; U.S. Patent No. 5,476,786 No. 5, 013, 653; U.S. Patent No. 5,258,498; and U.S. Patent No. 5,482,858. Binding of a bispecific molecule to its specific target can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, biological analysis (eg, growth inhibition), or Western blot analysis. . Each of these assays typically detects the presence of a protein-antibody complex of particular interest by employing a labeled reagent (e.g., an antibody) that specifically targets the complex of interest. For example, an FcR-antibody complex can be detected using, for example, an enzyme-linked antibody or antibody fragment that recognizes and specifically binds to an antibody FcR complex. Alternatively, any of a variety of other immunoassays can be used to detect such complexes. For example, antibodies can be radiolabeled and used in radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March 1986, Incorporated herein by reference). The radioisotope can be detected by, for example, using a gamma counter or a scintillation counter or by autoradiography.Pharmaceutical composition In another aspect, the invention provides a composition, such as a pharmaceutical composition, comprising a monoclonal antibody of the invention, or a combination thereof, or an antigen binding portion thereof, in association with a pharmaceutically acceptable carrier. Such compositions may comprise one or a combination (e.g., two or more different ones) of the antibodies or immunoconjugates or bispecific molecules of the invention. For example, a pharmaceutical composition of the invention can include a combination of antibodies (or immunoconjugates or bispecific molecules) that bind to different epitopes on a target antigen or have complementary activities. The pharmaceutical compositions of the invention may also be administered in combination, i.e., in combination with other agents. For example, a combination therapy can comprise a combination of an anti-IP-10 antibody of the invention and at least one other anti-inflammatory or immunosuppressive agent. Examples of therapeutic agents useful in combination therapies are set forth in more detail below in the section on the use of the antibodies of the invention. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and physiologically compatible similar agents. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). The administration of the active compound (i.e., antibody, immunoconjugate or bispecific molecule) can be applied to the material to protect the compound from the acid and other natural conditions that can inactivate the compound. The pharmaceutical compounds of the invention may comprise one or more pharmaceutically acceptable salts. "Pharmaceutically acceptable salt" means a salt which retains the desired biological activity of the parent compound and does not impart any undesirable toxicological effects (see, for example, Berge, S.M. et al. (1977)J. Pharm. Sci .66 :1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts comprise derived from non-toxic inorganic acids (eg, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, and the like) and derived from non-toxic organic acids (eg, aliphatic mono- and dicarboxylic acids, Alkanoic acid substituted with phenyl, hydroxyalkanoic acid, aromatic acid, aliphatic and aromatic sulfonic acid, and the like. Base addition salts include those derived from alkaline earth metals (eg, sodium, potassium, magnesium, calcium, and the like) and from non-toxic organic amines (eg, N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprene) Those with chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. The pharmaceutical compositions of the present invention may also comprise a pharmaceutically acceptable antioxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antibiotics An oxidizing agent such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) Metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Examples of suitable aqueous and non-aqueous vehicles which may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and Injectable organic esters such as ethyl oleate. For example, proper fluidity can be maintained by using a coating material such as lecithin, maintaining the desired particle size (in the case of a dispersing agent), and using a surfactant. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the presence of microorganisms is ensured by the above sterilization procedure and by incorporating various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, and the like). It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in such compositions. In addition, long-acting absorption of injectable pharmaceutical forms can be brought about by incorporating absorption delaying agents (for example, aluminum monostearate and gelatin). The pharmaceutically acceptable carrier comprises a sterile aqueous solution or dispersion and a sterile powder for the preparation of a sterile injectable solution or dispersion. The use of such media and pharmaceutical agents for pharmaceutically active substances is known in the art. The present invention encompasses its use in pharmaceutical compositions in addition to any conventional media or agents that are incompatible with the active compound. Additional active compounds may also be included in such compositions. Generally, the therapeutic compositions must be sterile and stable under the conditions of manufacture and storage. The compositions can be formulated as solutions, microemulsions, liposomes or other ordered structures suitable for high drug concentrations. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferred to include isotonic agents (e.g., sugars, polyols (e.g., mannitol, sorbitol) or sodium chloride) into the compositions. Long-acting absorption of the injectable compositions can be brought about by the inclusion of delaying compositions (such as monostearate and gelatin) in the compositions. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in one or a combination of any of the ingredients listed above, as appropriate, followed by sterile microfiltration. In general, dispersions are prepared by incorporating the active compound into a sterile vehicle containing the base dispersion medium and the other ingredients required from the above. In the case of the use of sterile vehicles for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and lyophilization (lyophilized), which may be prepared from the previously sterile solution of the active ingredient plus any desired additional A vehicle composed of a medicament. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the individual being treated and the particular mode of administration. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form is usually the amount of the composition which produces a therapeutic effect. Typically, the amount will range from about 0.01% to about 99% of the active ingredient, preferably from about 0.1% to about 70%, of the active ingredient in combination with a pharmaceutically acceptable carrier, preferably at 100%. The ground is about 1% to about 30%. The dosage regimen is adjusted to provide the optimal desired response (eg, a therapeutic response). For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the urgency of the condition being treated. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to a physically discrete unit suitable for use as a unit dosage for the individual to be treated; each unit contains a predetermined amount of active compound, which is calculated to produce the desired therapeutic effect with the desired pharmaceutical carrier. The specification of the unit dosage form of the invention depends on and directly on the following factors: (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the inherent incorporation of the active compound in the art of treating individual sensitivities Restrictions. For administration of the antibody, the dosage is in the range of from about 0.0001 mg/kg to 100 mg/kg, and more typically from 0.01 mg/kg to 5 mg/kg of host body weight. For example, the dose can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or in the range of 1-10 mg/kg. An exemplary treatment regimen requires administration of the antibody once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every three months, or once every three to six months. For example, a dosage regimen for an antibody comprises administering 1 mg/kg body weight or 3 mg/kg body weight via intravenous administration, wherein the antibody is administered using one of the following dosing schedules: (i) once every four weeks, 6 doses, then every 3 months; (ii) every 3 weeks; (iii) 3 mg/kg body weight, followed by 1 mg/kg body weight every three weeks. A preferred dosage regimen for the antibody also comprises administering a single dose of between 30-450 mg of the anti-IP-10 antibody (or antigen binding portion thereof). For example, a single dose of antibody is 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 Mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 450 mg or doses of 35 mg, 45 mg, 55 mg, 65 mg, 75 mg, 85 mg, 95 mg, 105 mg , 115 mg, 125 mg, 135 mg, 145 mg, 155 mg, 165 mg, 175 mg, 185 mg, 195 mg, 205 mg, 215 mg, 225 mg, 235 mg, 245 mg, 255 mg, 265 mg, 275 Mg, 285 mg, 295 mg, 305 mg, 315 mg, 325 mg, 335 mg, 345 mg, 355 mg, 365 mg, 375 mg, 385 mg, 395 mg, 405 mg or 445 mg. In some methods, antibodies are administered weekly or biweekly. In yet another method, the antibody is administered for a period of about 12 weeks, such as on days 1, 15, 29, 43, 57, and 71. For example, the method can comprise a single dose of about 40 mg of the antibody or antigen binding portion thereof (every two weeks, a period of about 12 weeks). In some methods, two or more monoclonal antibodies having different binding specificities are administered simultaneously, in which case the dosage of each antibody administered is within the indicated range. Antibodies are usually administered in a number of situations. The interval between single doses can be, for example, weekly, monthly, every three months, or yearly. The interval can also be irregular as indicated by measuring the blood concentration of the antibody against the target antigen of the patient. In some methods, the dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 μg/ml and in some methods about 25-300 μg/ml. Alternatively, the antibody can be administered by sustained release of the formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, human antibodies display the longest half-life, followed by humanized antibodies, chimeric antibodies, and non-human antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses are administered over relatively long periods of time at relatively infrequent intervals. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, relatively high doses of relatively short intervals are sometimes required until the disease progression is alleviated or terminated, and preferably until the patient exhibits partial or complete improvement in disease symptoms. Thereafter, a prophylactic regimen can be administered to the patient. The actual dose values of the antibodies (and other active ingredients) in the pharmaceutical compositions of the invention can be varied to achieve an amount of antibody effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient. The selected dosage value will depend on a number of pharmacokinetic factors, including the activity of the particular composition of the invention or its ester, salt or guanamine, the route of administration, the time of administration, and the excretion rate of the particular compound employed. , duration of treatment, other drugs, compounds and/or materials used in combination with the particular compositions used, age, sex, weight, physical condition, general health and prior medical history of the patient being treated and are well known in the medical arts Similar factors. The "therapeutically effective amount" of the anti-IP-10 antibody preferably reduces the severity of the symptoms of the disease, increases the frequency and duration of the disease-free period, or prevents damage or disability due to susceptibility. In the case of rheumatoid arthritis (RA), a therapeutically effective dose preferably prevents further deterioration of physical symptoms associated with RA, such as pain, fatigue, morning stiffness (lasting more than an hour) Diffuse muscle pain, loss of appetite, weakness, joint pain with temperature, swelling, tenderness, and joint stiffness after inactivity. The therapeutically effective dose preferably also prevents or delays the onset of RA, for example, in the presence of early or preliminary signs of the disease. Again, it involves delaying the chronic progression associated with RA. Laboratory tests for the diagnosis of RA include chemical methods (including measurement of IP-10 concentration), hematology, serology, and radiology. Thus, any clinical or biochemical analysis monitoring any of the above symptoms can be used to determine if a particular treatment is a therapeutically effective dose for the treatment of RA. Those skilled in the art will be able to determine such amounts based on factors such as the individual's size, the severity of the individual's symptoms, and the particular composition or route of administration selected. The compositions used in the present invention can be administered by one or more administration routes using one or more of a variety of methods known in the art. Those skilled in the art will appreciate that the route and/or mode of administration will vary depending on the desired result. Preferred routes of administration for antibodies include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. As used herein, the phrase "parenteral administration" means a mode of administration other than enteral and topical administration (usually by injection) and includes, but is not limited to, intravenous, intramuscular, intraarterial, Intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions . Alternatively, the antibody can be administered via the enteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. The active compounds can be prepared using carriers that protect the compound from rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as vinyl vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many of the methods used to prepare such formulations are patented or generally known to those skilled in the art. See for exampleSustained and Controlled Release Drug Delivery Systems , edited by J.R. Robinson, Marcel Dekker, Inc., New York, 1978. Therapeutic compositions can be administered using medical devices known in the art. For example, in a preferred embodiment, a needleless hypodermic injection device can be used (for example, as disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824 or The device of the invention is administered by the device of No. 4,596,556. Examples of well-known implants and modules that can be used in the present invention include: U.S. Patent No. 4,487, 603, the disclosure of which is incorporated herein by reference in its entirety in its entirety the entire entire entire entire entire entire entire disclosure A therapeutic device for the administration of a drug via the skin; U.S. Patent No. 4,447,233, the disclosure of which is incorporated herein by reference in its entirety in its entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all An invasive drug delivery system is disclosed in U.S. Patent No. 4,439,196, the disclosure of which is incorporated herein by reference. These patents are incorporated herein by reference. Many other such implants, delivery systems and modules are known to those skilled in the art. In certain embodiments, the antibodies employed in the invention can be formulated to ensure a reasonable distribution in vivo. For example, the blood brain barrier (BBB) rejects many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, in liposome form. For a method of making liposomes, see, for example, U.S. Patent Nos. 4,522,811; 5,374,548; and 5,399,331. Liposomes can include one or more moieties that are selectively transported into a particular cell or organ, thereby enhancing targeted drug delivery (see, for example, V.V. Ranade (1989).J. Clin. Pharmacol 29:685). Exemplary targeting moieties comprise folate or biotin (see, e.g., U.S. Patent No. 5,416,016 to Low et al.); Mannose (Umezawa et al. (1988)Biochem. Biophys. Res. Commun .153 :1038); Antibodies (P.G. Bloeman et al. (1995)FEBS Lett .357 :140;M. Owais et al. (1995)Antimicrob. Agents Chemother .39 :180); Surfactant Protein A Receptor (Briscoe et al. (1995)Am. J. Physiol .1233 :134);p120 (Schreier et al. (1994)J. Biol. Chem. 269 :9090); see also K. Keinanen; M.L. Laukkanen (1994)FEBS Lett. 346 :123;J.J. Killion;I.J. Fidler (1994Immunomethods 4 :273.Use and method of the present invention The antibodies (and immunoconjugates and bispecific molecules) of the invention have diagnostic and therapeutic uses in vitro and in vivo. For example, the molecules can be administered to cells in culture (eg, ex vivo or ex vivo), or administered in an individual (eg, in vivo) to treat, prevent, or diagnose various conditions. The term "individual" as used herein is intended to encompass both human and non-human animals. Non-human animals include all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles. These methods are particularly suitable for treating human patients suffering from conditions associated with abnormal IP-10 performance. When administering an IP-10 antibody and another agent, the two can be administered in either order or simultaneously. In one embodiment, the antibodies (and immunoconjugates and bispecific molecules) of the invention can be used to detect IP-10 concentrations or concentrations of cells containing IP-10. This can be achieved, for example, by contacting a sample (e.g., an in vitro sample) and a control sample with an anti-IP-10 antibody under conditions that permit formation of a complex between the antibody and IP-10. Any complex formed between the antibody and IP-10 was detected and compared in the sample and control. For example, standard assays well known in the art (e.g., ELISA and flow cytometry) can be performed using the compositions of the invention. Thus, in one aspect, the invention further provides a method of detecting the presence of IP-10 (e.g., human IP-10 antigen) in a sample or measuring the amount of IP-10, which comprises subjecting the sample to a control sample An antibody of the invention or an antigen binding portion thereof that specifically binds to IP-10 is contacted under conditions that permit formation of a complex between the antibody or portion thereof and IP-10. The formation of the complex is then detected, wherein the difference in complex formation between the sample and the control sample indicates the presence of IP-10 in the sample. Also within the scope of the invention are kits comprising compositions of the invention (e.g., antibodies, human antibodies, immunoconjugates, and bispecific molecules) and instructions for use. The kit may further comprise at least one additional reagent or one or more additional antibodies of the invention (eg, an antibody having complementary activity and binding to an epitope on a target antigen different from the first antibody). The set typically contains a flag indicating the intended use of the contents of the set. The term mark includes any written or recorded material that is provided on or in conjunction with the set or otherwise. IP-10 is known to have a chemoattractive effect on activated T cells and NK cells and recruit these cells to sites of inflammation and autoimmune responses. Thus, the anti-IP-10 antibodies (and immunoconjugates and bispecific molecules) of the invention can be used to inhibit inflammatory or autoimmune mediated by activated T cells and/or NK cells in various clinical indications. reaction. The invention thus provides a method of inhibiting an inflammatory or autoimmune response mediated by activated T cells and/or NK cells, comprising administering a T cell or NK cell to an antibody or antigen binding portion thereof of the invention (or The immunoconjugate or bispecific molecule of the invention is contacted to inhibit an inflammatory response or an autoimmune response. Specific examples of inflammatory or autoimmune conditions in which an antibody of the present invention can be used include, but are not limited to, the following diseases: A.Multiple sclerosis and other demyelinating diseases It has been shown that the expression of IP-10 mRNA is increased in murine experimental allergic encephalomyelitis (EAE) (a mouse model of multiple sclerosis) (Godiska, R. et al. (1995)J. Neuroimmunol. 58 :167-176). In addition, increased IP-10 concentrations were found in cerebrospinal fluids of MS patients during acute demyelinating events (Sorensen, T.L. et al. (1999)J. Clin. Invest .103 :807-815; Franciotta et al. (2001)J. Neuroimmunol. 115 :192-198). It has also been shown that IP-10 is expressed by astrocytes in MS lesions but not in unaffected white matter (Balashov, K.E. et al. (1999)Proc. Natl. Acad. Sci. USA 96 :6873-6878) and the expression of reactive astrocytes in macrophages and surrounding parenchyma in MS plaques (Simpson, J.E. et al. (2000)Neuropathol. Appl. Neurobiol. 26 :133-142). PCT Patent Publication WO 02/15932 shows that administration of an anti-IP-10 antibody in a mouse hepatitis virus (MHV) model of MS reduces T lymphocyte and macrophage invasion, inhibits demyelination progression, and increases myelin Regeneration and improved neurological function (see also Liu, MT et al. (2001)J. Immunol. 167 :4091-4097). It has been shown that administration of murine anti-IP-10 antibodies reduces the incidence and severity of clinical and histological diseases in murine EAE (Fife, B.T. et al. (2001)J. Immunol. 166 :7617-7624). In view of the foregoing, MS and other demyelinating diseases can be treated using the anti-IP-10 antibodies of the invention by administering the antibodies to an individual in need of treatment. Antibodies can be used alone or in combination with other anti-MS agents (eg, interferon beta-1a (eg Avonex®, Rebif®, interferon beta-1b (eg Betaseron®, glatiramer acetate) (eg Copaxone® and/or Mitoxantrone (eg Novantrone®) is used in combination.Rheumatoid arthritis It has been shown that IP-10 concentrations are significantly elevated in synovial fluid, synovial tissue and serum in patients with rheumatoid arthritis (RA) (Patel, D.D. et al. (2001)Clin. Immunol .98 :39-45; Hanaoka, R. et al. (2003)Arthritis Res. and Therapy 5 :R74-R81). It has been shown that the IP-10 receptor CXCR3 is preferentially expressed in the synovial tissue of mast cells from RA patients (Ruschpler, P. et al. (2003)Arthritis Res. Ther .5 :R241-R252). In the rat model of adjuvant-induced arthritis (AA), a detectable autoantibody response against self-IP-10 has been reported (Salomon, I. et al. (2002)J. Immunol .169 :2685-2693). In addition, administration of a DNA vaccine encoding IP-10 increases the production of neutralizing anti-IP-10 antibodies in rats, and these IP-10 autoantibodies can accept AA resistance to naive rats (Salomon) , I. et al., above). In view of the foregoing, the anti-IP-10 antibody of the present invention can be used to treat rheumatoid arthritis by administering the antibody to an individual in need of treatment. The antibodies may be used alone or in combination with other anti-RA agents, such as non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids (eg, prednisone, hydrocortisone) (eg, prednisone) Hydrocortisone)), TNF inhibitor (including adalimumab (Humira®, etanercept) (Enbrel® and infliximab (Remicade®), disease-relieving anti-rheumatic drugs (including Aminoguanidine, cyclophosphamide, cyclosporine, auranofin, azathioprine, sodium thiomalate, hydroxychloroquine sulfate, leflunomide, minocycline (minocycline), penicillamine (penicillamine) and sulfasalazine, fibromyalgia medicine, osteoporosis medicine and gout medicine.Inflammatory bowel disease It has been shown that IP-10 expression is significantly enhanced in cells infiltrating the lamina propria of colonic biopsy from patients with ulcerative colitis (Uguccioni, M. et al. (1999)Am. J. Pathol .155 :331-336). In addition, it has been shown that neutralizing IP-10 protects mice from epithelial ulcers in acute colitis and enhances crypt cell survival (Sasaki, S. et al. (2002)Eur. J. Immunol .32 :3197-3205). Similarly, treatment with anti-IP-10 antibodies resulted in improved inflammatory scores in IL-10 −/− mice that developed colitis similar to Crohn's disease in humans (Singh, U.P. et al. (2003)J. Immunol. 171 :1401-1406). In view of the foregoing, the anti-IP-10 antibody of the present invention can be used to treat inflammatory bowel disease (IBD) (including ulcerative colitis and Crohn's disease) by administering the antibody to an individual in need of treatment. The antibodies may be used alone or in combination with other anti-IBD agents, for example, those containing mesalamine (including sulfamethamine and others containing 5-aminosalicylic acid (5- ASA) agents (eg olsalazine and balsalazide), non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids (eg, prednisone, hydrocortisone), TNF inhibition Agent (including adalimumab (Humira®, enalapril (Enbrel® and Remicade®), immunosuppressive agents (eg 6-mercaptopurine, azathioprine and cyclosporin A) and antibiotics D.Systemic lupus erythematosus It has been shown that serum IP-10 concentrations are significantly increased in patients with systemic lupus erythematosus (SLE) and have been shown to be associated with disease activity (see, for example, Narumi, S. et al. (2000).Cytokine 12 :1561-1565). Thus, in another embodiment, an anti-IP-10 antibody of the invention can be used to treat SLE by administering the antibody to an individual in need of treatment. Antibodies can be used alone or in combination with other anti-SLE agents, such as non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids (eg, prednisone, hydrocortisone), immunosuppression Inhibitors (eg, cyclophosphamide, azathioprine, and methotrexate), antimalarial drugs (eg, hydroxychloroquine), and biopharmaceuticals that inhibit the production of dsDNA antibodies (eg, LJP 394). E.I Type diabetes It has been shown that serum IP-10 levels are elevated in patients with type 1 diabetes, especially in newly attacked diseases, and that GAD-reactivity in these concentrations and GAD autoantibody-positive patients has been shown to produce gamma-interference. The number of T cells in the prime (Shimada, A. et al. (2001)Diabetes Care twenty four :510-515). In a separate study, serum IP-10 concentrations were found to increase in patients with newly diagnosed disease and at high risk of disease, and IP-10 concentrations were associated with IFN-γ concentrations (Nicoletti, F. et al. (2002)Diabetologia 45 :1107-1110). Furthermore, beta cells have been shown to secrete IP-10, causing chemical attraction of T cells, and it has been shown that mice lacking CXCR3 have delayed type I diabetes episodes (Frigerio, S. et al. (2002)Nature Medicine 8:1414-1420). Thus, in another embodiment, an anti-IP-10 antibody of the invention can be used to treat Type I diabetes by administering the antibody to an individual in need of treatment. The antibodies can be used alone or in combination with other anti-diabetic agents such as insulin. F.Inflammatory skin disorder It has been shown that IP-10 performance is associated with a variety of inflammatory skin conditions. For example, IP-10 has been detected in keratinocytes and skin infiltrates from active psoriasis plaques (Gottlieb, A. B. et al. (1988) J. Exp. Med. 168:941-948). Furthermore, CXCR3 is expressed by dermal CD3+ lymphocytes, indicating that CXCR3 is involved in the transport of T lymphocytes to psoriasis dermis (Rottman, J. B. et al. (2001) Lab. Invest. 81: 335-347). Thus, in another embodiment, the anti-IP-10 antibody of the invention can be used to treat psoriasis by administering the antibody to an individual in need of treatment. The antibodies may be used alone or in combination with other agents or treatments, for example, topical therapeutics (eg, steroids, coal tar, calcipotriene, tazarotene, guanidine) Phenol, salicylic acid), phototherapy, systemic medicine (eg, methotrexate, oral retinoids, cyclosporine, fumarate) and/or biopharmaceuticals (eg alfacept, alefacept) Eleizumab). Lichen planus (chronic inflammatory disease of the skin and oral mucosa) has been shown to be associated with infiltrating CD4+ and CD8+ T cells expressing CXCR3, and in addition, CD8+ infiltrating cytolytic T cells have been shown to have IP-10 in their cytolytic particles. And the lesion keratinocytes have been shown to overexpress IP-10 (Iijima, W. et al. (2003)Am. J. Pathol .163 :261-268). Thus, in another embodiment, the anti-IP-10 antibody of the invention can be used to treat lichen planus by administering the antibody to an individual in need of treatment. The antibodies can be used alone or in combination with other agents or treatments (eg, anti-inflammatory agents, antihistamines, corticosteroids, and phototherapy). It has been shown that IP-10 is elevated in other inflammatory skin conditions such as chronic discoid lupus erythematosus and Jessner's lymphocytic infiltration of the skin (Flier, J. et al. 2001)J. Pathol. 194 :398-405). Thus, the anti-IP-10 antibodies of the invention can be used to treat such inflammatory skin conditions by administering the antibodies to the individual in need of treatment. The antibodies can be used alone or in combination with other agents or therapies as set forth above. G.Autoimmune thyroid disease It has been shown that both IP-10 and CXCR3 are present in the thyroid gland of patients with Graves' disease (GD), but do not show (or worse) in normal thyroid tissue, and in new-onset GD patients The highest performance (Romagnani, P. et al. (Am. J. Pathol. 161: 195-206). It has also been shown that IP-10 is present in thyroid tissue in patients with Hashimoto's thyroiditis (Kemp, EH, etc.) (2003) Clin. Endocrinol. 59: 207-213). Thus, in another embodiment, an anti-IP-10 antibody of the invention can be used to treat autoimmune thyroid disease by administering the antibody to an individual in need of treatment. (Including Graves' disease and Hashimoto's thyroiditis. Antibodies may be used alone or in combination with other agents or treatments (eg antithyroid drugs, radioactive iodine and subtotal thyroidectomy).Scheler's syndrome It has been shown that the expression of IP-10 mRNA is significantly up-regulated in the salivary glands of patients with Sjogren's syndrome (SS), with the most prominent in the epithelium adjacent to the lymphoid infiltrate (see, for example, Ogawa, N. et al. (2002)Arthritis Rheum .46 :2730-2741). Thus, in another embodiment, the anti-IP-10 antibody of the invention can be used to treat Sjogren's syndrome by administering the antibody to an individual in need of treatment. The antibodies may be used alone or in combination with other anti-SS agents, such as artificial lubricants (eg, preservative-free artificial tears, artificial saliva, fragrance-free skin lotion, saline nasal spray, and vaginal lubricants). Lacriserts®, pilocarpine hydrochloride (Salagen®) for the treatment of dry eye, and ceyimeline (Eyoxac®), non-steroidal anti-inflammatory drugs (NSAID), steroids and immunological resistance for the treatment of dry mouth Antibiotics. I.Pulmonary inflammation IP-10 has been tested in a mouse model of allergic asthma, and the results show that IP-10 is up-regulated in the lungs after allergen challenge and IP-10 overexpression and increased airway hyperactivity, eosinophilia Balloon hyperplasia, increased IL-4 concentration, and CD8+ lymphocyte recruitment (Medoff, BD et al. (2002)J. Immunol. 168 :5278-5286). In addition, smokers with chronic obstructive pulmonary disease (COPD) have demonstrated IP-10 in their bronchial epithelium (Saetta, M. et al. (2002)Am. J. Respir. Crit. Care Med .165 :1404-1409). In addition, high IP-10 concentrations were shown in bronchoalveolar lavage fluid in patients with pulmonary sarcoma and lymphocytic alveolitis (Agostini, C. et al. (1998)J. Immunol. 161 :6413-6420). Thus, in another embodiment, an anti-IP-10 antibody of the invention can be used to treat a disease characterized by pulmonary inflammation (eg, asthma, COPD, pulmonary sarcoma, or lymphocytes by administering the antibody to an individual in need of treatment). Alveolar inflammation). The antibodies may be used alone or in combination with other agents for reducing lung inflammation, such as cromolyn sodium, nedocromil sodium, inhaled corticosteroids, systemic (eg oral) corticosteroids, short-acting beta antagonists, short-acting bronchodilators, long-acting beta antagonists or agonists (oral or inhalation), leukotriene modifiers, theophylline and oxygen therapy. J.Transplant rejection It has been shown that IP-10 plays a role in the exclusion of transplant organizations. For example, treatment of mice with neutralizing anti-IP-10 antibodies increases survival of intestinal allografts and reduces accumulation of host T cells and NK cells in the lamina propria (Zhang, Z. et al. (2002)J. Immunol. 168 :3205-3212). In addition, anti-IP-10 antibody treatment also increased the survival of allografts and reduced lymphocyte graft infiltration in mice receiving islet allografts (Baker, M.S. et al. (2003)Surgery 134 :126-133). In addition, cardiac allografts (rather than normal hearts) display IP-10 and CXCR3, and elevated IP-10 concentrations are associated with cardiac allograft vasculopathy (Zhao, D.X. et al. (2002)J. Immunol .169 :1556-1560). It has also been shown that CXCR3 and IP-10 are expressed by infiltrating lung allografts by inflammatory cells (Agostini, C. et al. (2001)Am J. Pathol. 158 :1703-1711). It has been shown that neutralizing CXCR3 or IP-10 in vivo attenuates obstructive bronchiolitis syndrome (BOS) in a murine lung transplant model, which is a major limitation on the survival of lung transplant recipients (Belperio, JA, etc.) People (2002)J. Immunol. 169 :1037-1049). In view of the foregoing, the present invention also provides a method of inhibiting transplant rejection by administering an anti-IP-10 antibody of the present invention to a transplant recipient in need of treatment. Examples of treatable tissue grafts include, but are not limited to, liver, lung (e.g., therapeutic BOS), kidney, heart, small intestine, and islet cells. The antibodies may be used alone or in combination with other agents for inhibiting transplant rejection, such as immunosuppressive agents (e.g., cyclosporine, azathioprine, methylprednisolone, pu Prednisolone, prednisone, mycophenolate mofetil, sirilimus, rapamycin, tacrolimus, anti-infectives (eg, acyclovir, clatumrimazole, ganciclovir, nystatin, trimethoprimsulfarnethoxazole), diuretics (eg cloth) Bumetanide, furosemide, metolazone, and ulcer medicines (eg, cimetidine, farnotidine, lansoprazole, Omeprazole, ranitidine, sucralfate. K.Bone marrow injury Invasive damage to the bone marrow can cause inflammatory cell infiltration. IP-10 has been shown to play a major role in secondary degeneration after bone marrow injury (Gonzalez et al. (2003)Exp. Neurol .184 : 456-463; see also PCT Patent Publication WO 03/06045). IP-10 has been shown to be in contused rat bone marrow 6 and 12 hours after injury (McTigue, D.M. et al. (1998)J. Neurosci. Res. 53 : 368-376) and in the bone marrow of injured mice 6 hours after injury (Gonzalez et al. (2003), supra). Thus, it has been shown that inhibition of IP-10 activity following bone marrow injury can be used to reduce infiltration of inflammatory cells and thereby reduce secondary tissue damage of inflammation. Inhibition also reduces infiltration of inflammatory cells, reduces secondary degeneration, and improves traumatic brain injury and recovery after stroke. Accordingly, the present invention also provides a method of treating bone marrow damage and brain damage (e.g., stroke) in an individual in need of treatment comprising administering to the subject an anti-IP-10 antibody of the invention. The antibodies can be used alone or in combination with other agents such as other anti-inflammatory agents. L.Neurodegenerative disease It has been found that IP-10 and CXCR3 in the central nervous system are up-regulated and associated with pathological changes associated with Alzheimer's disease (AD) (Xia, M.Q. and Hyman, D.T. (1999)J. Neurovirol .5 :32-41). In AD brain, CXCR3 displays constitutively expressed neurons and neurons in various cortical and subcortical regions, while IP-10 has been shown to be expressed in astrocytes and its concentration is significantly elevated compared to normal brain ( Xia, MQ et al. (2000)J. Neuroimmunol .108 :227-235). Thus, antibodies to the invention can be used to treat neurodegenerative diseases (eg, Alzheimer's disease and Parkinson's disease) by administering an anti-IP-10 antibody (alone or in combination with other therapeutic agents) to an individual in need of treatment. . Examples of anti-IP-10 antibodies that can be used in combination with Alzheimer's disease include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) (galantamine, tacrine) and vitamin E. An example of an agent against which an anti-IP-10 antibody can be used in the treatment of Parkinson's disease is levodopa. M.Gingivitis Peripheral periodontitis is associated with inflamed gingival tissue. Cells producing IP-10 and cells expressing CXCR3 receptor have been found in inflamed human gingival tissues (Kabashima, H. et al. (2002)Cytokine 20 :70-77). Thus, in another embodiment, the anti-IP-10 antibody of the invention can be used to treat gingivitis by administering the antibody to an individual in need of treatment. The antibodies can be used alone or in combination with other agents or treatments (eg, anti-mouth mouthwashes (eg, antibiotic mouthwashes), periodontal scaling, and root planing and periodontal surgery). N.Gene therapy related inflammation Replication-deficient adenovirus (used as an adenoviral vector used in gene therapy) can cause acute damage and inflammation in tissues infected with viral vectors. These adenoviral vectors have been shown to induce IP-10 expression via capsid-dependent activation of NFkB (Borgland, S. L. et al. (2000) J. Virol. 74:3941-3947). Thus, the anti-IP-10 antibodies of the invention can be used to inhibit IP-10 induced damage and/or inflammation during treatment with a gene therapy that stimulates an undesired viral vector (e.g., an adenoviral vector).O. Angiogenic disease It has been shown that IP-10 inhibits angiogenesis both in vitro and in vivo (Strieter et al. (1995)Biochem. Biophys. Res. Commun .210 : 51-57; Angiolillo et al. (1995J. Exp. Med .182 :155-162; Luster et al. (1995)J. Exp. Med .182 :219-231). Angiogenesis plays a key role in many disease processes, such as wound healing reactions. For example, the vascular system in the injured bone marrow remains active and remodeled until at least 28 days after injury (Popovich et al. (1997)J. Comp. Neurol .377 :443-464). It is believed that IP-10 exerts its vasopressor effect by inhibiting endothelial cell growth and chemotaxis. It achieves this function via its heparin binding motif as well as via receptor mediation mechanisms. Via the heparin binding motif, it prevents the binding of the angiogenic factors FGF-2 and VEFG165 to their receptors. It also exerts its effects via a receptor mediation process. The IP-10 receptor CXCR3 undergoes alternate splicing to produce two known variants, CXCR3A and CXCR3B. IP-10 binding to the CXCR3A receptor causes proliferation and chemotaxis of target cells, whereas IP-10 binding to the CXCR3B receptor has an opposite inhibitory effect on growth and chemotaxis. IP-10 is used as an angiogenesis inhibitor via the CXCR3B receptor (Lasagni et al. (2003)J. Exp. Med. 197 :1537-1549). In view of the foregoing, the anti-IP-10 antibodies of the present invention can be used to treat diseases requiring angiogenesis, for example, in the case where the vasopressor behavior of IP-10 is delayed or hinders healing and aggravates the disease process. Such diseases include: 1) abnormal physiological neovascularization, which may affect wound healing, female estrous cycle, pregnancy, exercise-induced hypertrophy, and the like; 2) indications that may require stimulation of new blood vessels, including inducing lateral accessory tubes Formation (including myocardial ischemia, peripheral ischemia, cerebral ischemia), coronary artery disease, peripheral vascular disease, stroke, wound healing, subsequent implantation of organ transplantation (eg islet cell transplantation), rupture and hernia repair, reconstruction surgery , tissue modification, restenosis, hair loss, hemorrhoids and stagnation ulcers, gastrointestinal ulcers, placental insufficiency, aseptic necrosis, pulmonary hypertension and systemic hypertension, vascular dementia, Alzheimer's disease, Autosomal dominant cerebral arterial disease (CADASIL) with cerebral infarction and leukoencephalopathy; thyroid pseudocyst and lymphedema; and 3) indications for vascular remodeling, including vascular malformations, psoriasis and pre-eclampsia. The antibodies of the invention may be used alone or in combination with other angiogenesis inducing agents. P.Inflammatory nephropathy It has been reported that CXCR3 receptors are expressed by mesangial cells in patients with IgA nephropathy, membrane proliferative glomerulonephritis, or rapidly progressive glomerulonephritis (Romagnani, P. et al. (1999)J. Am. Soc. Nephrol. 10 :2518-2526). In addition, in the mouse model of nephrotoxic nephritis, the IP-10 mRNA concentration in the cortex of the nephritis kidney increased 6-fold 7 days after the induction of nephritis (Schadde, E. Etc. (2000)Nephrol. Dial. Transplant .15 :1046-1053). In addition, high IP-10 performance was observed in kidney biopsy samples from human patients with glomerulonephritis compared to normal kidneys (Romagnani, P. et al. (2002)J. Am. Soc. Nephrol .13 :53-64). Thus, the anti-IP-10 antibodies of the invention can be used to treat inflammatory nephropathy, including IgA nephropathy, membrane proliferative glomerulonephritis, and rapidly progressive glomerulonephritis. The antibodies of the invention may be used alone or in combination with other agents or treatments (e.g., antibiotics, diuretics, hypertensive drugs, and dialysis) for the treatment of glomerulonephritis. Q.Atherosclerosis It has been shown that IP-10 is used for mitosis and chemokines in vascular smooth muscle, which is an important feature of smooth muscle cells due to its contribution to the pathogenesis of atherosclerosis (Wang, X. et al. (1996)J. Biol. Chem. 271 :24286-24293). It has also been shown that IP-10 is induced in smooth muscle cells after treatment with LPS or interferon gamma and is also induced in the rat carotid artery after balloon angioplasty (Wang, X. et al. (1996), supra literature). In addition, IP-10 has been shown to be expressed in atheroma-associated endothelial cells, smooth muscle cells, and macrophages, suggesting that IP-10 can be used to recruit and preserve the observations in vascular wall lesions during atherosclerotic formation. Activated T cells (Mach, F. et al. (1999)J. Clin. Invest .104 :1041-1050). Therefore, the anti-IP-10 antibody of the present invention can be used to treat or prevent atherosclerosis. The antibody can be used alone or in combination with other agents or treatments (eg, hypertension drugs and cholesterol lowering drugs) for the treatment of atherosclerosis. R.Viral infection IP-10 can be upregulated in a variety of viral infections and can play a beneficial role in recruiting activated T cells to combat viral infection. However, in some cases, the production of IP-10 during viral infection may cause deleterious effects and thus IP-10 activity may be undesirable, and it may be desirable to inhibit the viruses using the anti-IP-10 antibodies of the invention. IP-10 activity in infection. For example, IP-10 has been shown to stimulate replication of human immunodeficiency virus (HIV) in mononuclear bulbar macrophages and peripheral hemolymphs (Lane, B.R. et al. (2003)Virology 307 :122-134). In addition, IP-10 concentrations in the cerebrospinal fluid and brain of HIV-infected patients and in the central nervous system of HIV gp120-transgenic mice have increased (Asensio, V.C. et al. (2001)J. Virol. 75 :7067-7077). It has also been shown that IP-10 concentrations are elevated in patients with chronic persistent hepatitis C virus (HCV) and chronic active hepatitis (Narumi, S. et al. (1997)J. Immunol. 158 :5536-5544). In HCV-infected livers, it has been shown that IP-10 is expressed by hepatocytes, but not by other cell types in the liver, and a significantly higher proportion of CXCR3-positive T cells are found in the liver compared to blood (Harvey, CE). Et al. (2003)J. Leukoc. Biol .74 :360-369). It has been shown that increased IP-10 secretion is associated with an inflammatory response to acute ocular type I herpes simplex virus (HSV-1) infection in mice, and that the use of anti-IP-10 antibodies to treat HSV-1 infected mice is reduced. Monocyte infiltration in the corneal stroma reduces corneal conditions and inhibits the progression of the virus from the corneal stroma to the retina during acute infection (Carr, DJ et al. (2003)J. Virol. 77 :10037-10046). It has also been shown that IP-10 performance is manifested in viral meningitis. IP-10 is shown to be present in CSF in patients with viral meningitis and is responsible for chemotactic activity on neutrophils, peripheral blood mononuclear cells, and activated T cells (Lahrtz, F. et al. (1997)Eur. J. Immunol. 27 : 2484-2489; Lahrtz, F. et al. (1998)J. Neuroimmunol. 85 :33-43). In view of the foregoing, an anti-IP-10 antibody of the invention can be used to treat a viral infection involving undesired IP-10 activity by administering the antibody to an individual in need of treatment. Non-limiting examples of treatable viral infections include HIV (eg, HIV-induced encephalitis), HCV, HSV-1, viral meningitis, and severe acute respiratory syndrome (SARS). The antibodies may be used alone or in combination with other antiviral agents, for example, as follows: for HIV infection, nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and / or protease inhibitors (and combinations thereof); for HCV infection, interferon alpha 2a, pegylated interferon alpha 2a and / or ribavirin; and for HSV-1 infection, Acyclovir, valacyclovir and/or famciclovir.S. Bacterial infections . Bacterial infection induces IP-10 production in affected cells (see Gasper, N.A. et al. (2002)Infect Immun. 70 :4075-82. Bacterial meningitis is also known to specifically elicit IP-10 performance (Lapinet, J.A. et al. (2000)Infect Immun. 68 :6917-23). In the bacterial infection model, IP-10 is also produced in the somatic cells of the seminiferous tubules, which strongly indicates that these chemokines accumulate during the inflammation of the testicles, which are usually observed in the pathogenesis of bacterial infections. Possible roles in sexual and T lymphocytes (Aubry, F. et al. (2000)Eur Cytokine Netw. 11 :690-8). In view of the foregoing, an anti-IP-10 antibody of the invention can be used to treat bacterial infections involving undesired IP-10 activity by administering the antibody to an individual in need of treatment. Examples of bacterial infections include, but are not limited to, bacterial meningitis and bacterial pneumonia. The antibodies can be used alone or in combination with other antibacterial agents such as antibiotics. The invention is further illustrated by the following examples, which are not to be construed as limiting the invention. The disclosure of all of the figures and all of the references, patents and published patent applications in this application are hereby expressly incorporated by reference.Materials and methods :Instance 1 : Design of variants of antibody IP10.1 Idruzumab (also known as IP10.1) was previously evaluated in patients with RA, Crohn's disease and ulcerative colitis in several clinical trials. Clinical response signals were observed in these trials. However, further development of Iduzumab has encountered difficulties such as (1) high doses required for IV and SC delivery and suboptimal (units) nM affinity/efficacy for high drug delivery frequencies for SC delivery; (2) Significant IV infusion reactions from higher amounts of protein administration; and (3) up to 30% isomerization observed using a 2-year shelf life. In view of the above-described problem of idruzumab, a next generation antibody having improved affinity and no isomerization potential is produced. Antibody IP10.1 was first constructed into scFv molecules and activity was confirmed prior to optimization. A scFv optimized library was generated using a combination of randomization (NNS) and doped oligonucleotides (70% parental, 30% all others) in the HCDR region of IP10.1. This DNA library was acquired using a PROfusion® mRNA display system via several rounds of transcription and translation using rabbit reticulocyte lysates. The encoded mRNA is fused to its own scFv via a puromycin linkage. During selection, any of the biotin-labeled IP-10 scFvs were captured by streptavidin beads and amplified by PCR to proceed to the next round. The PROfusion mRNA display system was continued until a significant target binding signal was observed by quantitative polymerase chain reaction (qPCR®). The increased stringency is then selected by lowering the target concentration and by biasing the pure line with closer affinity during the dissociation rate selection. The binding population was selected and sequenced. A unique line of non-chemically dominant lines in the HCDR region was expressed via the High Through Mammalian Expression System (HMEP) and the affinity for IP-10 was tested using the SPR (Biacore) test. In summary, more than 50 variants were generated by targeting the CDR1, CDR2 and CDR3 residues in the variable region of the heavy chain and screened for binding to human IP-10. Variants showing a significant improvement in dissociation rate at 37 °C were reformatted to IgG (IgG1) and a further selection process was performed. A comparison of the CDR sequences of IP10.1 and its variants (reformatted to IgGl full length antibodies) is shown in Table 1. Table 2 shows the binding affinities of these variants at 37 °C compared to IP10.1. Further analysis of the cross-reactivity of these variants with cynomolgus IP10, mouse IP10 or MIG (data not shown) and cross-competition, physical stability, conformational stability, hydrophobic interactions and aggregation with IP10.1 ( The data is not shown). Both pure lines (IP10.44 and IP10.52) showed significantly higher affinity than IP10.1, competed with IP10.1 for binding to IP-10, and had improved biophysical characteristics compared to IP10.1. Therefore, IP10.44 and IP10.52 were selected for further research. Therefore, mandatory stability studies (oxidation and deamination) were performed on pure IP10.44 and IP10.52 to further distinguish their properties. Although both antibodies exhibited similar behavior under conditions of forced stability, IP 10.52 showed a slightly increased deamination and faster dissociation rate in the VH region compared to IP 10.44. Therefore, IP10.44 was chosen for further characterization.table 1 Selection of variants for IgG1f reformattingtable 2 Variant with improved binding affinity for IP10.1Instance 2 : Characterization of IP10.44A. IP10.44 Biophysical and biochemical characterization 1. Combine In a Biacore®-based binding study, IP10.1 has a KD of approximately 5 nM and IP10.44 exhibits a KD of 10 pM (Biacore has a detection limit of 90 pM), indicating at least a 50-fold improvement. Like IP10.1, IP10.44 has a similar KD in monkeys and humans and does not cross-react with mice. table 32. Epitope mapping a. hydrogen / Helium exchange mass spectrometry (HDX-MS) The HDX-MS method detects protein conformation and conformational kinetics in solution by monitoring the exchange rate and extent of the indole hydrogen atom in the main chain. The extent of HDX depends on the solvent accessibility of the main chain hydrogenamine atom and protein hydrogen bonds. The quality of the protein can be increased by accurately measuring the HDX by MS. When this technique is paired with enzymatic digestion, the structural features under the peptide level can be resolved, thereby enabling the distinction between surface exposed peptides and internal folders. Typically, sputum labeling and subsequent quenching experiments are performed followed by on-line pepsin digestion, peptide separation, and MS analysis. Epitope mapping was performed on IP-10 using anti-IP10 mAb IP10.44 and IP10.1. Prior to the epitope mapping experiment, a non-deuteration experiment was performed to generate a common pepsin peptide (20 μM) for recombinant human IP-10 and a protein complex of recombinant IP-10 and anti-IP-10 mAb (1: A list of 1 molar ratios to achieve 100% sequence coverage of IP10. In the HDX-MS experiment, 5 μL of each sample (IP-10 or IP-10 mAb) was diluted to 55 μL D₂ O buffer (10 mM phosphate buffer, D₂ In O, pD 7.0), the labeling reaction was started. The reaction was carried out as follows for different time periods: 20 seconds; 1 minute; 10 minutes; and 240 minutes. At the end of each labeled reaction period, the reaction was terminated by the addition of quench buffer (100 mM phosphate buffer containing 4 M GdnCl and 0.4 M TCEP, pH 2.5, 1:1, v/v) and 50 μL The quenched sample was injected into a Waters® HDX-MS system for analysis. The uptake of common pepsin peptides was monitored in the absence/presence of anti-IP10 mAb. HDX-MS measurement of IP10.44 in IP-10, which has an epitope including the same peptide region as IP10.1: Peptide region 1 (13-18): SISNQP (SEQ ID NO: 163) peptide Region 2 (19-27): VNPRSLEKL (SEQ ID NO: 164) Peptide Region 3 (29-43): IIPASQFCPRVEIIA (SEQ ID NO: 165) The uptake changes in these peptide regions can be graded into regions 3 > 1 ≈ 2 Where region 3 has the most significant uptake change, and regions 1 and 2 have the least significant uptake changes. Competition experiments confirmed that IP10.44 competes with IP10.1 for binding to IP-10, indicating that it binds to the same epitope as IP10.1 and (as IP10.1) does not interact with human MIG or human ITAC (as defined herein) Cross reaction.b. Crystallography method Crystals were grown from pre-formed composites of IP10 and IP10.44 Fab. The protein concentration in 50 mM pH 8 Tris-HCl, 150 mM NaCl is approximately 6 mg/ml. This fraction was mixed with a well solution consisting of 100 mM pH 5.0 Tris-maleic acid, 18% (w:v) PEG 3350 at a ratio of 1:2 and crystals were grown by suspension-descent vapor diffusion. The crystals were cryoprotected in a solution of 75% pore solution and 25% glycerol. Advanced Photon Source outside Chicago, IL uses the Pilatus 6M detector to collect data at beamline 17-ID (IMCA-CAT). The crystal temperature was maintained at 100 K. The data was collected into 900 images for a 180° data sweep with a 0.2° wedge. Data was processed using autoPROC (which was integrated using XDS (Kabsch, 2010a, b) and calibrated using AIMLESS (Evans & Murshudov, 2013)) and the following statistics were obtained:table 4 Space group: P2₁ Unit cell: a = 53.6 Å; b = 86.8 Å; c = 133.5 Å; β = 98.8°. Mosaic: 0.29-0.41. Molecular replacement uses the program PHASER and a model derived from the IP10/Fab structure, which consists of three parts: Fv (VL and VH domains) containing no CDRs and containing residues mutated to Gly or Ala, CL: CH1 domain dimers and IP10 dimers (as shown in Table 5), which meet the PHASER criteria at each step to successfully lay out the components, the criterion being for the first component in space Group P2₁ The medium TFZ score is at least 6, and the other components are at least 8.table 5 The resulting electron density map shows the electron density of the residues and side chains lost from the model. The structure was completed using a COOT molecular graphics program (Emsley et al., 2010) and BUSTER refinement (Blanc et al., 2004 and Global Phasing, Ltd.).result The structure of the IP10 / IP 10.44 Fab complex was determined at a resolution of 2.23 Å. The most obvious feature on the surface of IP10 is the protrusion of the side chains Ile 12, Ser 13 and Ile 14 (data not shown). This overhang is inserted between the pores produced by the long CDR-H3 and between it and CDR-H1 and H2. The IP10 up to residues 12-14 highlight where the opposite CDR-H3 of the opposite recess extends (data not shown). Residues involving epitopes of IP10.1 and IP10.44 as defined by exposure (S. Sheriff et al. 1987; Sheriff, 1993) on IP10: Val 7, Cys 9, Thr 10, Cys 11, Ile 12 Ser 13, Ile 14, Ser 15, Asn 16, Pro 37, Arg 38, Lys 47, Gly 49, Glu 50, Lys 51, Arg 52, Cys 53.3. stability IP 10.44 shows a high thermal stability and thermal reversibility of a first melting temperature of 70.2 ° C (TM1 of IP10.1 is 64 ° C) and a thermal reversibility of 73 ° C of 41.2 %. A stable CHO pool representing IP10.44 was used to generate 8 batches of IP 10.44 (approximately 20 L scale). The cell culture exhibited a degree of expression of approximately 50 mg/L at this stage and a purified yield of 60-70% using the one-step protein-A purification method. The antibodies were formulated in buffer (20 mM histidine and 10% pH 6 sucrose) and tested for consistency, purity, heterogeneity and glycosylation by various methods. The results confirmed that the antibody was consistent and the purity was >97% of the monomer fraction, as can be seen by particle size exclusion chromatography. Heterogeneity and glycosylation are typical scenarios expected for human IgG1 antibodies.table 6 B. Cell-based IP10.44 active The kinetic analysis based on Biacore® shows the excellent KD of IP10.44 relative to IP10.1, which is mainly due to the dissociation constant (k)._Dissociation ) The improvement is promoted. The estimated t1/2 of IP10.1 (the half-life of IP-10 association) is approximately 3 hours, while IP10.44 is >100 hr. Thus, existing assays (calcium flow, chemotaxis) with a duration of < two hours and requiring a concentration of exogenous IP-10 (≥ 10 nM) that is significantly higher than the KD of either antibody are not expected to distinguish between the two antibodies. To allow for this distinction, a new cell analysis was developed with a duration of ≥ 24 hours and with an IP-10 concentration that is comparable to or lower than the KD of any antibody and closer to IBD patients (approximately 2-digit pM) A robust signal-to-noise ratio induced at IP-10 concentration. These analyses were developed by a two-pronged approach: 1) Optimization of the following analysis: where anti-IP-10 Ab and IP-10 were pre-incubated for ≥ 24 hours, then added to the cells and added at low concentrations (< 100 pM) IP-10 (exogenous) provides a robust signal-to-noise ratio; 2) identifies new analysis of cellular function by inducing at least 24 hours of approximately 2-digit pM endogenous IP-10 induced by inflammatory stimuli . For the first approach, two assays were used: inhibition of the binding of I125-IP-10 (20 pM) to whole cells (B cell line expressing CXCR3 and intestinal epithelial cell line). For the second approach, two other assays were used: measuring IL-6 secretion by hPBMC treated with IFNγ/α or IFNγ/α/IL-1β/LPS for 24 hours, and the measurement was first performed by IL-12p40 secretion by hPBMC stimulated by IFNy for 24 hours and then stimulated by LPS for 24 hours. In these newly established cell-based assays, IP10.44 showed excellent activity against IP10.1. For example, in a whole cell binding assay, IP10.44 exhibits at least 5 fold greater than IP10.1 blocking exogenous IP-10 to its target cells (including CXCR3 expressing cells (CXCR3/300.19) and intestinal epithelial cells ( The combination of KM12SM)). In addition, IP10.44 exhibited approximately 6-fold greater inhibition of the efficacy of endogenous IP-10-mediated IL-6 secretion by hPBMC stimulated with IFNα/γ, approximately 6-fold greater than IP10.1. Similarly, IP10.44 inhibits endogenous IP-10-mediated IL-12p40 secretion achieved by IFNγ/LPS-stimulated hPBMC and its efficacy is 4 times greater than IP10.1, and exhibits significantly better maximal inhibition (using Approximately 100% of the IP 10.44 pairs use approximately 75% of IP 10.1, as shown in Table 7.table 7 Mechanical studies using hPBMC-based assays confirmed the primary cellular source of mononuclear spheroids IP-10, IL-6 and IL-12p40. Importantly, as a support for the excellent cellular activity observed in IP10.44 in these in vitro assays, a high affinity IP-10 mouse generation of IP10.44 in CD40-induced congenital immune colitis in SCID The display showed that the inhibition of IL-6 and IL-12p40 in the blood was superior to that of the low affinity mouse substitute (lack of T/B cells) of IP10.1 (see below).C. In vivo activity 1. Target occlusion (TE) Test IP10.44 provides the ability to block the long-term repression of IP-10 in cynomolgus monkeys. Two LC-MS-based sensitive assays were established to specifically measure free IP-10 concentrations in cynomolgus monkey serum and additionally quantified using IP10.44 and IP10.1 stimulated samples. Using these analyses, time-dependent changes in the free IP-10 concentration of the cynomolgus monkeys administered with the antibodies at 10 mg/kg relative to the vehicle were measured. IP10.1 transiently reduced free IP-10 6 hours after administration and then increased by up to 6-fold over the 10-day duration, in contrast to IP10.44, which completely blocked free IP-10 for up to 10 days ( Figure 14). These data show that IP10.44 is superior to IP10.1 in target occlusion in the cycle.2. PK/PD ( Pharmacokinetics and pharmacodynamic parameters ) Studies based on the use of CXCR3 KO mice have reported that the absence of CXCR3 signaling on NK cells in the natural environment reduces their frequency in circulating and lymphoid organs. Internal studies have shown that high-affinity anti-IP-10 mouse substitutes (rather than low-affinity) significantly reduce the frequency of CXCR3+ NK cells in blood and spleen in naive mice, thereby identifying NK cell subsets as inhibition A potential PD biomarker at CXCR3 that is signaled by IP-10. Using this finding and considering that neither IP10.44 nor IP10.1 cross-reacted with mouse IP-10, the effects of the two antibodies on the frequency of human CXCR3+ NK in the blood and spleen of NSG/HSC mice were tested (naturally absent Mouse T/B/NK cells can be supplemented with human hematopoietic stem cells (HSCs) to complement human T/B/NK cells to produce mouse strains of mice with a "humanized" immune system). IP10.44 (rather than IP10.1) significantly reduced these doses at 50 mg/kg (based on the selection of two human antibodies in NSG mice, the suboptimal PK was selected to maximize target coverage) Human CXCR3+ NK cell frequency in the spleen of mice (Figure 15). It was observed in this study that either antibody had no significant effect on CXCR3+ NK cells in the blood, which may be due to the low frequency of this cell population due to aging in the circulation (> 6 months after reconstitution).3. IBD model Test the performance in the IBD model. Neither IP10.44 nor IP10.1 cross-reacted with mouse IP-10, rendering mice unsuitable for direct testing of these molecules in an experimental colitis model. Therefore, two anti-mouse IP-10 surrogate antibodies, namely antibodies 18G2 and 6A1, were identified, and their affinities were comparable to IP10.44 and IP10.1, respectively. In cell-based assays, 18G2 demonstrated approximately 8-fold better efficacy in inhibiting IP-10-induced calcium flux in mice in the CXCR3/300.19 cell line than 6A1. In vivo PD studies showed that 18G2 was superior to 6A1 in reducing the frequency and quantity of CXCR3+ NK cells in the blood of naive mice. Two surrogates were tested in two different colitis models, one for colitis induced by TNBS in wild-type mice whose pathogenesis involves congenital and adaptive immunity, and the other colitis system was SCID ( CD40 induction in mice lacking T/B) whose pathogenesis involves only innate immunity. In both models, anti-p40 antibodies have been shown to be effective in reducing disease and thus serve as positive controls. Importantly, the high-affinity surrogate 18G2 demonstrated significantly better performance than the IP10.1 substitute 6A1 (Figures 16A and 16B). This superiority is not due to the difference in PK/exposure, where 6A1 is more than 2 times higher than 18G at the end trough. Thus, this data suggests that the increased affinity observed with IP10.44 relative to IP10.1 can translate into greater potency in the context of intestinal inflammation promoted by innate and adaptive immunity. Since CD40-induced mouse colitis is a more robust model involving significant systemic inflammation, the effect of high affinity 18G2 and low affinity 6A1 on the concentration of circulating proinflammatory cytokines was also assessed. Consistent with the superior efficacy relative to 6A1, 18G2 more robustly reduced circulating concentrations of several interleukins (including IFNγ, IL-12p40, IL-6, TNFα, MCP-1, and RANTES) (Fig. 17A-D). A separate study using high affinity surrogate 18G2 in this model demonstrated a reduced association of interleukin subgroups (including IFNy, IL-12p40, IL-6 and TNFa) between blood and inflamed intestine. To determine whether targeting IP-10 and targeting TNFα (representing standard IBD care) can be distinguished in terms of mechanism of action, a SCID mouse model of CD40-induced colitis was used. This model was selected due to the presence of a large amount of IP-10 and TNFα in the circulation and in the intestine and the efficacy against IP-10 and anti-TNFα antibodies. In a comparative study of high affinity anti-IP-10 mouse substitute (18G2) and anti-TNFa substitutes in this model, both antibodies exhibited significant potency (Figure 22). Importantly, multi-intercellular analysis revealed significant differences between the two interventions in reducing inflammatory mediators in serum and inflamed intestines, suggesting that the mechanisms for achieving their efficacy may vary. Compared with anti-TNFα substitutes, 18G2 significantly reduced the serum concentrations of IFNγ, IL-12p40, IL-6, RANTES and MIP1β and the colon concentrations of INFγ, IL-12p40, IL-6, IL-17 and IL-22, such as Measured by multi-intercellular assay based on luminex (Fig. 18A-F). Taken together, these data indicate that the targeted IP-10 and targeted TNFα can be differentially engineered in a systemic and localized inflammatory environment in experimental colitis. In addition, 18G2 robustly reduces TNFα in circulating and inflamed intestines, while anti-TNFα has a small effect on IP-10 concentrations in either chamber, thereby providing another set of two interventions for distinguishing experimental colitis. evidence.D. Immunogenicity The immunogenicity of IP10.44 was evaluated using an in vitro T cell proliferation assay and compared to the immunogenicity of IP10.1 in the same assay. IP10.44 exhibits 20-25% immunogenicity, compared to IP10.1 showing 7-10% immunogenicity.E. Pharmacokinetics and pharmacodynamics in cynomolgus monkeys IP10.44 exhibited a non-linear PK in cynomolgus monkeys (data not shown). Free drug analysis was performed for IP10.44 and IP10.1. As the dose was increased from 0.5 mg/kg to 10 mg/kg, the total body serum clearance (CLT) of IP10.44 was reduced by a factor of about 4, but the volume of distribution (Vss) remained similar at steady state. Therefore, T-1/2 is increased by about 5 times. This is consistent with the PK of IP10.1 in monkeys and humans. At 0.5 mg/kg, the CLT of IP10.44 is 2 times higher than IP10.1. It can be assumed that the non-linear PK is caused by target-mediated drug treatment (TMDD) and that the higher binding affinity of IP10.44 causes higher clearance at lower doses when the target is not saturated. However, the PK comparison of IP10.44 and IP10.1 at higher doses showed conflicting results: the CLT values of the two antibodies were similar at 10 mg/kg, but the CLT of IP10.44 was higher than IP10 at 20 mg/kg. .1 2.7 times. IP10.44 showed better than IP10.1 in suppressing free serum IP-10 concentration (Figures 19A and 19B). After intravenous bolus dose, IP10.44 demonstrated dose-dependent repression of free serum IP-10 and was completely repressed (by suppressing free IP-10 from baseline concentration (approximately 40 pM) to below LLOQ The duration of (1 pM) is approximately 3 days (for 0.5 mg/kg) and approximately 10 days (at 10 mg/kg). The rapid rebound of free serum IP-10 (returning to baseline on day 17) may be caused by accelerated drug decline from ADA. On the other hand, at doses up to 20 mg/kg, IP10.1 does not block free serum IP-10, but free serum IP-10 is raised above baseline (up to a 7-fold increase) and this Consistent observations in the clinic. A simple regression of free serum IP-10 repression with the free drug concentration of IP10.44 revealed an IC50 of 223 ± 88 pM (Figure 20). In addition, the PK/PD model for free drug PK, free and total serum IP in monkeys can be estimated to have an in vivo Kd of 43 ± 6 pM for IP10.44, which is stronger than the value of IP10.1 in monkeys. It is about 150 times (Kd is 6.5 ± 1.1 nM in vivo) (Figs. 21A to 21F). In addition, after an intravenous dose of IP 10.44 or IP 10.1, a rapid increase in total serum IP-10 was observed with a Tmax of 4 to 30 hours. The increase in total IP-10 was dose-dependent and the maximum increase was up to 5 nM (for IP 10.44) and up to 12 nM (for IP10.1), which represents a 100-fold increase over the baseline concentration (approximately 40 pM) . In conclusion, IP10.44 showed an in vivo KD superior (about 150-fold) IP10.1 (in vivo KD of 43 ± 6 pM vs. 6.5 ± 1.1 nM) in suppressing free serum IP-10 in cynomolgus monkeys. IP10.1 increased (>5-fold) free serum IP-10 levels in monkeys and humans above baseline, while IP10.44 (after intravenous administration to monkeys) showed sustained and complete (<1 pM LLOQ) Free serum IP-10 was suppressed for approximately 3 days (at 0.5 mg/kg) and approximately 10 days (at 10 mg/kg). Free drug analysis was used to characterize the PK of IP10.44 in monkeys. IP10.44 exhibits a non-linear PK in monkeys, which is most likely due to drug delivery from target mediation. This is similar to the non-linear PK of IP10.1 observed in monkeys and humans. The higher affinity of IP10.44 relative to IP-10 resulted in a relatively shorter half-life (T-1/2) in monkeys compared to IP10.1. It is predicted that the human T-1/2 of IP10.44 at 1 mg/kg and 10 mg/kg is about 2 and about 6 days, respectively. At the same dose, the corresponding human T-1/2 of IP10.1 was approximately 4 and approximately 8 days, respectively. The subcutaneous bioavailability (70%) of IP10.44 in humans can be assumed to be the same as IP10.1. Based on preclinical PK/PD information, the human dose of IP10.44 (subcutaneously administered every two weeks) is expected to be 120 mg/70 kg. At this dose, the 90% percent free serum IP-10 concentration corresponding to the UC patient population was reduced by 80% to the 10th percentile of healthy individuals. No adverse effects were observed in a single intravenous bolus dose of up to 20 mg/kg in the cynomolgus PK/PD study. In summary, IP10.44 shows acceptable PK/PD properties and security characteristics.Instance 3 : (A) Single incremental dose study (SAD) and multi-dose studies (MAD) and (B) moderate to the safety, tolerability, pharmacokinetics and target occlusion of BMS-986184 (IP 10.44) in healthy individuals Evaluation of safety, efficacy, pharmacokinetics, target occlusion and pharmacodynamics of BMS-986184 in patients with severe ulcerative colitis (UC)introduction Part A was used to evaluate the safety, tolerability, pharmacokinetics (PK), and target occlusion (TE) randomization, placebo-controlled, double-blind, single BMS-986184 in healthy male and female participants. Progressive (SAD) and multiple dose (MAD) studies. In Part A1 (SAD), there are up to 5 sequential intravenous (IV) dose groups and designated as groups S1, S2, S3, S4 and S5. Additionally, there may be up to 2 subcutaneous dose groups and designated as groups S6 and S7. The expected dose selected for the SC dose group (S6 and S7) did not exceed the average exposure dose observed during the intravenous dose group S1-S4. Other dose groups may be added as needed, at doses lower or higher than the previous groups. In Part A2 (MAD), there may be up to 2 intravenous (IV) or subcutaneous (SC) groups and designated as groups M1 and M2. Part B was used to assess the safety, efficacy, pharmacokinetics, targeted occlusion, and pharmacodynamics of BMS-986184 in male and female UC patients, placebo-controlled, double-blind, and mechanism-verified (POM) the study. Part B will begin after Part A's safety, tolerability, PK and TE evaluation. A schematic of the study design is presented in Table 8.table 8 : Research design schematic

Abbreviations: IV = intravenous; MAD = multiple incremental doses; POM = mechanism validation; SAD = single incremental dose; SC = subcutaneous; Q2W = every other week * Self-dose group S3 and above, all dose values are from the previous A set of real-time PK and PD (serum-free IP-10) assays were obtained. There is an AUC and Cmax cap for each dose group that does not exceed the predetermined safety factor from the AUC under NOAEL. ** The MAD dose for group M1 is selected after group S3 is completed and analyzed and may include dose S3 or lower. The MAD dose for group M2 is selected after completion of group S4 and analysis and may include dose S4 or lower (except for the dose used in Ml). *** If the TE data supports the possibility of SC administration in the MAD, the SC group is implemented.section A For healthy participants SAD/MAD Research design ( section A) In Part A, healthy participants were subjected to screening assessments to determine eligibility. Participants must complete the screening process within 21 days of the first day. The schedule of units and participants can be adjusted using a ±2 day window visit. Participants were allowed to enter the clinical facility on the morning of Day-1.Among healthy participants SAD Research design ( section A1) There were 8 healthy male or female participants in each sequential SAD dose group (S1-S7). Make each group double-blind and randomized. For the first dose group (S1), the outpost group was administered. One healthy male or female participant received a single dose of BMS-986184 and one healthy male or female participant received a matching placebo. The available safety data from the two participants (including any reported adverse events, findings from the physical examination, etc.) were evaluated by the inquirer and the sponsor within 24 hours prior to treatment of the remaining participants in the first dose group (S1). A clinical laboratory result, vital signs and ECG). On day 1, the remaining 6 healthy male or female participants in the first dose group (S1) were randomized to receive a single dose of BMS-986184 or matched placebo at a ratio of 5:1. For each sequential dose group (S2-S7), on day 1, 8 healthy male or female participants were randomized to receive a single dose of BMS-986184 or matched comfort on day 1 at a 3:1 ratio. Agent. The dose selection criteria are set forth below.Among healthy participants SAD/MAD Research design ( section A) In Part A, healthy participants were subjected to screening assessments to determine eligibility. Participants must complete the screening process within 21 days of the first day. The schedule of units and participants can be adjusted using a ±2 day window visit. Participants were allowed to enter the clinical facility on the morning of Day-1.Among healthy participants SAD Research design ( section A1) There were 8 healthy male or female participants in each sequential SAD dose group (S1-S7). Make each group double-blind and randomized. For the first dose group (S1), the outpost group was administered. One healthy male or female participant received a single dose of BMS-986184 and one healthy male or female participant received a matching placebo. The available safety data from the two participants (including any reported adverse events, findings from the physical examination, etc.) were evaluated by the inquirer and the sponsor within 24 hours prior to treatment of the remaining participants in the first dose group (S1). A clinical laboratory result, vital signs and ECG). On day 1, the remaining 6 healthy male or female participants in the first dose group (S1) were randomized to receive a single dose of BMS-986184 or matched placebo at a ratio of 5:1. For each sequential dose group (S2-S7), on day 1, 8 healthy male or female participants were randomized to receive a single dose of BMS-986184 or matched comfort on day 1 at a 3:1 ratio. Agent. The dose selection criteria are set forth in Table 9.table 9 : Schematic of a study visit to a SAD study in a health participant (Part A1)

Abbreviations: CPU = clinical pharmacology unit; D = day; SAD = single incremental dose * Participants with any ongoing AE/SAE at D15 should remain indoors until resolved or not clinically considered significant.

= research drug investment

= Visiting days MAD study design in healthy participants (Part A2) There are 8 healthy male or female participants in each sequential MAD dose group (M1-M2). On day 1, the same 8 healthy male or female participants were randomized to receive BMS-986184 or matched placebo on day 1 at a 3:1 ratio. Make each group double-blind and randomized. The dose selection criteria are set forth below. Participants in the MAD group (M1 and M2) were kept confined to the clinical facility until the 50th day of vacation. Participants with any ongoing AE or SAE on day 50 should remain at the study site until the explorer determines that the event has been resolved or is deemed clinically insignificant. Participants are expected to return to the clinical unit for follow-up evaluation on days 57, 64, 71, 85 and 99. The schedule of units and participants can be adjusted using a ±2 day window visit. The approximate study duration of some A2 MAD participants was up to 120 days. Participants who quit early in the study need to complete a study discharge assessment that is expected to begin on day 99. Participants who are interrupted for reasons other than AE can be replaced. Up to 16 participants plan to complete Part A2 of the SAD study. Physical examination, vital sign measurement, eye assessment, 12-lead ECG, and clinical laboratory evaluation were performed at selected times throughout the dosing interval. Participants' AEs were closely monitored throughout the study. Blood samples were collected at selected time points for safety and PK analysis. Approximately 495 mL of blood was drawn from each participant during Part A2 of the study. A schematic view of the study visit of Part A2 is presented in Table 10.table 10 : Visit to the MAD study in healthy participants is schematic (Part A2)

Abbreviations: CPU = clinical pharmacology unit; D = day; MAD = multiple incremental doses

= research drug investment

= Visiting days The study design of POM in UC patients (Part B) There are up to 36 participants with moderate to severe UC in Part B. Part B contains 3 time periods: screening period, treatment period, and safety follow-up period. If the interim analysis shows an inadequate target occlusion at the expected therapeutic dose or if an intolerance safety event occurs, an additional higher dose group of 36 participants (24 active agents: 12 placebo) may be added, if predicted PK exposure is much lower than the exposure range associated with safety findings, and a lower dose group of 36 participants (24 active: 12 placebo) can be added. The final determination was made on the dose volume and administration of the individuals with UC during the PoM study (Part B) immediately after the PK and PD data became available from the SAD/MAD study in healthy individuals. The protocol was modified at this time to include the final dose selection for the PoM study in the UC participants. Participants were subjected to screening assessments to determine eligibility. Participants in Part B must complete the screening process (randomization) within 28 days of Day 1. During the screening period, participants were subjected to receptor testing and medical history, smoking history, screening test procedures, screening endoscopy, and laboratory evaluation to confirm active intestinal mucosal inflammation caused by UC and not caused by other causes. .Treatment period : On Day 1, a maximum of 36 participants with UC were randomized to receive a single dose at a ratio of 2:1 every other week (on Days 1, 15, 29, 43, 57 and 71) over a 12-week period. BMS-986184 or match the placebo. Part B is double-blind and randomized. On day 85, participants were subjected to endoscopic examination. For participants who experience UC episodes during the treatment period, they should be as close as possible to the study protocol. If the participant accepts a therapy that is not permissible according to the study protocol and/or requires hospitalization based on the investigator's recommendations, the participant should be treated according to the interrogator's judgment and discontinue the study. Investigator access is strongly encouraged to implement medical monitoring to discuss any participant who experiences a UC episode during the study period.Safety follow-up period: Follow-up visits were performed every other week (on days 99, 113, and 127) within 57 days. The approximate study duration of Part B participants was a maximum of 177 days. Can be replaced by participants who are interrupted for reasons other than AE. Plan to use up to 72 participants. Physical examination, vital sign measurements, 12-lead ECG, and clinical laboratory evaluation were performed at selected times throughout the dosing interval. Participants' AEs were closely monitored throughout the study. Blood samples were collected at selected time points for safety and PK analysis. Approximately 300 mL of blood was drawn from each participant during Part B of the study. A schematic of the study visit of Part B is presented in Table 11.table 11 : Visit to the POM study in UC patients (Part B)

Abbreviations: D = days; POM = mechanism verification * D8 ± 1 day

= study drug administration (±3 days)

= number of days of visit (± 2 days, except for D8 ± 1 day)

= endoscopyNumber of participants A maximum of 72 participants were randomized into 9 groups (7 SAD groups and 2 MAD groups) in Part A. In Part A1 (SAD), each group consisted of 8 participants (6 active: 2 placebo). A total of 56 participants were treated in Part A1 (SAD). If MAD was initiated, the other 16 participants (6 actives per group: 2 placebos) were treated in Part A2 (MAD). Although the number of participants was not based on statistical verification, the application of BMS-986184 to 6 participants in each group resulted in an 80% chance of observing at least one occurrence of any AE, which would be taking samples. The incidence occurred in the group at 24%. If the incidence of AE was 32%, the sample size of the participants treated with 6 BMS-986184 observed that the probability of any AE occurring at least once was 90%. In Part B (POM) of the study, a total of 36 participants were randomized (24 active: 12 placebo) to receive a targeted therapeutic dose from a portion of A2. If the interim analysis shows an inadequate target occlusion at the expected therapeutic dose or if an intolerance safety event occurs, an additional higher dose group of 36 participants (24 active agents: 12 placebo) may be added, if predicted PK exposure is much lower than the exposure range associated with safety findings, and a lower dose group of 36 participants (24 active: 12 placebo) can be added. If the interim analysis shows an inadequate target occlusion at the expected therapeutic dose or if an intolerance safety event occurs, an additional higher dose group of 36 participants (24 active agents: 12 placebo) may be added, if predicted PK exposure is much lower than the exposure range associated with safety findings, and a lower dose group of 36 participants (24 active: 12 placebo) can be added. Study endpoint definition The date on which the first participant signed the study-specific informed consent was defined as the starting point for the study. Participants may be considered for recruitment when signing a study-specific informed consent form (ICF). The date on which the last participant completed the discharge procedure or the last follow-up visit was defined as the study endpoint.Scientific principles of research design There are several reasons to begin the development of BMS-986184 in the NHV via FIH research. It is a safer development path for incremental and gradual dose escalation before being used for participants with UC. It will accurately establish a therapeutic window and evaluate a wide range of doses (30 mg up to about 450 mg, intravenously and possibly subcutaneously) to better inform the therapeutic index. Immune repression and infection were assessed in healthy participants in the absence of disease effects and without affecting the activated immune system after a single dose. Repeated dosing with participants with UC after completion of SAD and MAD in healthy participants.Dose demonstration No prior clinical experience was available, and the doses selected for FIH studies were based on predicted PK exposure, PK/TE (ie, free IP-10 in serum) relationships established from non-clinical studies, and established in animal toxicology studies. The margin of safety. In short, the PK model is used to estimate human PK parameters, thereby solving the nonlinear PK in monkeys and then extending to humans. The predicted human PK parameters were used to estimate Cmax and AUC to calculate the safety margin in the dose range tested in the FIH study. The corresponding PD response was estimated using the PK/PD model to investigate the relationship between the concentration of BMS-986184 in the dose range tested in FIH and free IP-10 in serum. The predicted PD response is used to provide the expected target occlusion at the respective dose values, thereby determining the appropriate dose range to fully explore the relationship between PK and target occlusion. To address the uncertainty of the transition from non-linear data to humans, the dose values and quantities of each group can be continuously adjusted based on safety, tolerability, and real-time PK/PD analysis. The first two dose values (30 mg and 75 mg) in the SAD were fixed. The remaining dose values in Part A and the entire dose range in Part B can be adjusted based on PK/PD analysis to achieve the expected PK exposure and free IP-10 for each dose group. In addition, the expected PK exposure in the selected SAD dose group will not exceed the predetermined safety factor estimated from Cmax and AUC under NOAEL to ensure the safety of the study participants. Dose selection argument for SAD in healthy participants (Part A1) In Section A1, dose escalation decisions were made using safety, PK and TE data. The available safety data from the current dose group (including any reported adverse events, findings from a physical examination, eye examination, any clinical laboratory results, etc.) are evaluated by the inquirer and the sponsor prior to determining the dose escalation of the subsequent dose group. Vital signs and ECG). Participants were not randomized to subsequent dose groups until safety data from the current dose values up to day 15 in all participants were reviewed by the investigator and sponsor and measured for safety and tolerability. The first and second dose groups (S1 and S2) (30 mg and 75 mg) in Part A1 were separately fixed. For the remaining dose group (S3-S5) except for SAD group 2, the PK/PD relationship established using cumulative data (except for safety evaluation) based on real-time PK/PD analysis in the previous dose group is used to guide Dose selection. The expected reserve dose in some A1 SAD ranges from 30 mg up to approximately 450 mg. In Section A1 (SAD section of the study), consider the potential non-linear PK derived from drug delivery from the target, and choose to cover a wide range of exposures to describe PK and target occlusion (ie, free IP from baseline in serum). -10 reduces the quantitative relationship between and establishes a sufficient margin of safety in humans to enable patient research. Since TMDD was observed in the monkey model, the intravenous administration route was chosen to study under the single dose condition of FIH in an attempt to better describe the PK at the lower end of the dose range (where the nonlinearity is most pronounced). Because subcutaneous administration is expected due to optimal compliance and convenience in the target patient population, BMS-986184 was also administered subcutaneously in the SAD section of the study to determine the feasibility of subcutaneous administration and the study was intended to be studied. The appropriate dosing regimen tested in the subsequent sections. The size of the starting dose to be administered by the intravenous route is selected taking into account the toxicological findings from preclinical studies. The maximum recommended starting dose (MRSD) was calculated using the NOAEL dose in monkeys. The NOAEL in monkeys, which can be considered as the most sensitive species, was 30 mg/kg/week. The MRSD based on the body surface area method and taking into account the 10-fold safety margin of the NOAEL dose is approximately 58 mg. Since the predicted value from the PK/PD model indicates greater than the minimum pharmacological activity at this dose, the MRSD is not suitable for testing as the starting dose in humans. Therefore, the initial dose in SAD was reduced to 30 mg, and the predicted free IP-10 reduction from baseline in serum was estimated to be 37% (Table 12). The expected safety margins for the estimated Cmax from NOAEL exposure and AUC at 30 mg were 59 and 322, respectively. The proposed dose escalation protocol is expected to include exposure around the predicted effective dose. Assuming a neutralization (eg, as defined by ≥90% reduction) of free IP-10 under steady-state troughs to promote expected performance in patients, it is desirable to achieve 90% and 95% reduction in free IP-10 under steady-state troughs. The dosing regimen is expected to be 180 mg and 300 mg, respectively, and is administered every 2 weeks (Q2W). Therefore, a single dose escalation of up to 300 mg of the study drug should be sufficient to describe the steep portion of the PK/PD signature and capture the predicted effective dose range. At 300 mg, the expected safety margins for estimated Cmax and AUC from NOAEL exposure were 6.4 and 13 times, respectively (Table 13). Considering that UC patients can exhibit greater PK and PD variability (due to differences in target load compared to healthy individuals), it may be necessary to test doses greater than 300 in SAD to provide adequate safety information, thereby enabling this Compounds perform long-term clinical studies in patients with UC. To this end, the highest proposed dose for the SAD portion of the study was approximately 450 mg. It should be noted that the 450 mg administration is optional and depends on the safety, PK and TE data obtained from the previous SAD group. If the observed PK and TE data indicate that the maximum inhibition of free IP-10 under the trough can be achieved at lower dose values, the highest dose proposed is not explored in the SAD study. The expected safety margins for Cmax and AUC for this dose value estimated from NOAEL exposure were 4 and 8 times, respectively (Table 12). A proposed dose of 30 mg to 450 mg ensures adequate description of PK/PD while inducing a broad exposure range to provide adequate safety information to inform dose selection for subsequent patient studies. Table 13 summarizes the expected exposures in humans and the subsequent safety margins based on exposures under NOAEL and LOAEL. Table 12 summarizes the expected target occlusions in humans on day 14 after single dose administration.table 12 : Average reduction in free IP-10 in SAD on day 14 (intravenous administration) (partial A1) * After the first dose group, all remaining dose values are reserved and can be modified based on real-time PK/PD analysis.table 13 : Dose range and safety margin in SAD (intravenous administration) (Part A1) * After the first 2 dose groups, all remaining dose values are reserved and can be modified based on real-time PK/PD analysis using available PK and PD data. The expected average AUC in the selected dose group will not exceed the predetermined AUC value. After 30 mg and 75 mg were administered to the first two groups, the choice of the remaining dose group will depend on the observed PK/PD characteristics in healthy individuals. To ensure that the expected exposure range is increased to ensure an appropriate margin of safety, consider the following factors before making a decision on subsequent dose escalation. The predicted average Cmax and AUC for the predicted dose values will not exceed the predetermined values in Table 13. Increasing the predicted dose value between consecutive SAD groups will not exceed approximately 3 fold increments. The predicted mean PK exposure (AUC(INF)) in the subsequent dose group will increase by no more than about 4 fold from the mean AUC (INF) in the previous dose group. The minimum safe exposure margins for Cmax and AUC (INF) from NOAEL exposure will be maintained at 4 and 8 times, respectively. Dose selection argument in SC After a minimum of 2 dose groups were administered intravenously in the SAD, a feasibility assessment was performed to determine whether BMS-986184 was administered subcutaneously. Subcutaneous administration of the formulation can be carried out at a concentration of 40 mg/mL. BMS-986184 was further tested after subcutaneous administration if the expected TE was achieved after intravenous administration (Table 13) and could be considered to be achieved without the administration of excessive subcutaneous injection. Due to the expected nonlinear PK of BMS-986184 and subsequent dose-dependent bioavailability, the absolute bioavailability of matched dose values needs to be properly assessed. If implemented, the dose value via the subcutaneous route will be matched to the corresponding intravenous dose. The subcutaneous dose value of group S6 can be similar to the intravenous dose group S2 or S3, and the subcutaneous dose value of group S7 can be similar to the intravenous dose group S3 or S4. The dose is selected based on the available PK, TE, safety data in the SAD and considering the potential dose values tested in Part B. The predicted mean Cmax and AUC of the subcutaneous group will not exceed the mean Cmax and AUC at the corresponding dose values after intravenous administration. Dose selection demonstration of MAD in healthy participants (Part A2) In Part A2 (MAD part of the study), two dose values can be studied to describe the safety, tolerability and persistence after administration of multiple BMS-986184 TE. In Part A2, based on PK/PD modeling, the available safety, PK and TE data obtained from the partial A1 SAD of the study and the potential therapeutic dose values tested in Part B are used to determine the MAD group (M1 and M2). The dose values tested and the route of administration (intravenous and/or subcutaneous). The goal of the MAD portion of the study was to select a dose value that was achieved at the dosing interval and maintained a free IP-10 reduction of approximately 50% or greater, while ensuring that the safety exposure margins for Cmax and AUC (INF) from NOAEL exposure were at least 5 times and 10 times. The choice of dosing interval will depend on the observed PK (ie T-HALF) and PD (IP-10 inhibition over time). Currently, a 2-week dosing interval can be considered desirable, however, one week can be considered based on the observed PK/PD and safety characteristics. For the first dose group (M1), the dose was selected after reviewing the PK, TE and safety data from the first 3 SAD groups (S1-S3) and the data was considered safe to proceed. Considering the observed PK, TE, safety, and expected steady state PK and TE after multiple administrations, the dose values can be similar to group S2 or S3. For the second dose group (M2), the dose values were selected after reviewing the PK, TE and safety data from the first 4 SAD groups (S1-S4) and the data was considered safe to proceed. Table 14 - Table 5.5.1-3 illustrates the potential dose values that can be tested in the MAD and the corresponding PK exposure with a margin of safety.table 14 : Potential dose value and safety margin in MAD (Part A2) * The dosing regimen and the route of administration are intended to be interpreted to provide an exposure range and a corresponding margin of safety. The actual dosing regimen and route of administration are determined based on PK/PD modeling from the cumulative data in the SAD. Dose selection demonstration of POM in UC patients (Part B) Immediately after the PK and PD data were obtained from SAD/MAD studies in healthy participants, the dose volume during the POM study (Part B) in UC patients and The final measurement was carried out. The protocol was modified at this time to include the final dose selection for the POM study in UC patients. A single dosing regimen was chosen to be tested in Part B. However, if an unexpected safety finding is obtained if the observed PD is insufficient or the dose is low, another dose group can be added to include the higher dose. The decision is made using the same considerations of the route of administration (intravenous or subcutaneous), the ability to achieve and maintain a 90% or greater reduction in free IP-10, the duration of the dosing interval, and the maintenance of the margin of safety exposure. treatment Study treatment is defined as any inquiry treatment, marketed product, placebo, or medical device that is intended to be administered to a research participant based on the study randomization or treatment assignment. Research treatments include product of exploration (IP) and non-exploratory products (Non-IP). Exploratory products (also referred to as inquiry medical products in some areas) are defined as pharmaceutical forms of active substances or placebos tested or used as reference in clinical studies, including those that have been approved for marketing but are different from the licensed form for use or assembly. (mixed or packaged) or used as an unlicensed indication or as a product for obtaining additional information about the form of the license. Other medicines that are used as support for prevention, diagnosis, or treatment, or that are exempt from medicine (such as a standard care component for a given diagnosis) can be considered a non-exploratory product. For this protocol, the study drug contained the invasive product BMS-986184-01 injection (150 mg/vial (40 mg/mL), 3.75 mL vial) and a similar placebo. BMS-986184-01 or a similar placebo is administered as a solution subcutaneously or intravenously (depending on the dose group).table 15 : Research treatment for IMI012004table 16 : dose selection and time Research evaluation and procedures Performance evaluation Performance evaluations were performed only for Part B, as measured by endoscopic and histopathological scores in participants with moderate to severe UC. Main performance evaluation Correction Baron score The corrected Baron was used to assess the severity of mucosal disease assessed by endoscopy. The modified Baron scoring system has an endoscopic index score with a scale of 0 to 4, with a higher score indicating a greater severity. The corrected Baron score is as follows: a score of 0 indicates a normal smooth, glaring mucosa with a visible vascular pattern and is not easily broken; a score of 1 indicates a granular mucosa, a vascular pattern is invisible, is not easily broken, and is congested; a score of 2 indicates the same mucosa as 1 but Easy to break the mucosa. Endoscopic examination and endoscopic evaluation In order to ensure quality data and standardization, endoscopic examinations were performed as much as possible by the same endoscopic physician at the clinical site throughout the trial according to the investigator's judgment. Flexible sigmoidoscopy or colonoscopy should be performed prior to administration of the study drug at baseline (Day 1) and Week 12 (Day 85) study visits. Baseline endoscopy (colonoscopy or sigmoidoscopy) must be performed within 28 days of randomization, must be documented, and should be implemented as close as possible to randomization. The 85th day of the optometry (colonoscopy or sigmoidoscopy) should be performed no more than 3 days before or after the 85th visit. Colonoscopy or sigmoidoscopy can be performed at baseline (Day 1) and Day 85. The procedure performed (colonoscopy or sigmoidoscopy) does not need to be the same at all points in time. Colon cancer should be screened as indicated by the local guidelines and should be performed at the discretion of the investigator. Any biopsies that were implemented to assess colon cancer were evaluated at the instigator's discretion by a local reader. In addition, any biopsy performed to obtain a histologically confirmed UC diagnosis is evaluated by the local reader at the instigator's discretion. A colonoscopy procedure performed at screening can be used to determine the endoscopic subscore component of the Mayo Score and replace the sigmoidoscopy (if performed within 28 days of randomization). The biopsy should be obtained from the most severely affected area of the colorectum (except when specifically targeting unaffected areas in the baseline endoscopic assessment). If all parts of the colon and colon are equally affected, a rectal biopsy should be obtained. For histopathological analysis, large biopsy should be used to obtain two biopsies. If there is an ulcer, the biopsy should point to the edge of the ulcer. Endoscopic images were acquired during each endoscopic examination (days 1 and 85) and sent for independent endoscopic mucosal scoring by a central endoscopy reader and Meonet was measured The spectroscopy score and the correction of the Baron score. A detailed image review charter from the Central Reading Lab provides an overview of endoscopic procedures, video recording, and equipment for video capture and transmission of endoscope records. For each participant, the video recording of the entire endoscopic procedure is performed using an acceptable storage medium. The endoscope record is read blindly by a qualified gastroenterologist based on an image review charter. For the purpose of determining the eligibility of participants for recruitment, as described in Section 9.1.2, the baseline Mayo score is determined locally by the inquirer and by the central endoscopy reader (3rd party supplier). Endoscopic mirror score. All other endoscopic scores were performed by a central endoscopic reader (3rd party supplier) (Baron score corrected under the baseline and Mayo's mirror score, corrected Baron score on the 85th day). The Mayo score used for the clinical endpoint in the trial was scored using the Mayo endoscopy method derived from the central endoscopy reader. The corrected Baron score for the clinical endpoint in the trial was also derived from the central endoscopy reader. Colon tissue was collected on days 1 and 85 prior to administration during the endoscopic procedure. To ensure quality data and standardization, colonic histopathology scores (Geboes, Modified Riley, and Robarts Histopathology Index, were read primarily on Days 1 and 85 by a single blind pathologist contracted by a central reading laboratory. See section 9.1.2). A detailed image review charter from the Central Reading Laboratory will outline the histopathology procedures for fixed sample transfer, processing, slide preparation, and slide digitization for histopathological scoring. The endoscopic record is read blindly by a qualified pathologist based on the image review charter. Secondary performance evaluation Endoscopy evaluation - Fixed Baron score Histopathological evaluation Correction Riley index The revised Riley index considers six characteristics [acute inflammatory cell infiltrates (neutrophils in the lamina propria), crypt abscesses, mucin consumption, surface epithelial integrity, chronic inflammatory cell infiltrates (circular in the lamina propria) Histopathology scoring system for cells) and crypt structure irregularities, each characteristic rating is scale 0-3, with higher scores indicating more severe tissue conditions.Geboes score The Geboes scoring system uses a 6-rated system (0-5) based on structural changes, chronic inflammatory infiltrates, lamina propria and eosinophils, neutrophils in the epithelium, crypt destruction, and erosion or ulceration. A histopathological scoring system for measuring disease activity. Higher levels indicate more serious disease activity. Robarts Histopathology Index The Robarts Histopathology Index (RHI) total score ranged from 0 (no disease activity) to 33 (severe disease activity). RHI can be calculated as: RHI = 1 × chronic inflammatory infiltrate grade (4 grades) + 2 × lamina propria neutrophil (4 grades) + 3 × neutrophils in the epithelium (4 grades) + 5 × erosion or ulceration (4 grades, after combination Geboes 5.1 and 5.2); where chronic inflammatory infiltrates 0 = no increase 1 = mild but clear increase 2 = moderate increase 3 = significantly increase lamina propria neutrophil = no 1 = mild but clear increase 2 = moderate increase 3 = significantly increase neutrophil in the epithelium 0 = no 1 = crypt involving < 5% 2 = crypt involving < 50% 3 = involved > 50% of crypt erosion or ulceration 0 = no erosion, ulcer or granulation tissue 1 = recovery of epithelium + fatigue inflammation 1 = possible erosion - lesion zone 2 = clear erosion 3 = ulcer or granulation tissue Clinical evaluation Mayo score Meo scores were used to assess disease activity. The Mayo scoring system is a composite index consisting of the following four disease variables (each score is scale 0 to 3, with higher scores indicating greater frequency or severity): fecal frequency, rectal bleeding, endoscopy Discovery and physician general evaluation (PGA). Use these three items to calculate some Mayo scores. The endoscopic Mayo sub-component is included to calculate the complete Mayo score. The partial and total Mayo scores are automatically calculated by the IVRS and are available to the inquirer and the sponsor. The Mayo score is between 0 and 12 points and utilizes all four disease variables, with higher scores indicating more severe disease. The endoscopic mirror score only includes the 0-3 endoscope scale. In addition to the endoscopic mirror score, some Mayo scores included all components (rectal bleeding, fecal frequency, overall physician evaluation). Review the Mayo scoring system and discuss with the inquiry staff at the Inquirer Meeting or other forums the method of standardizing the rating between employees. For fecal frequency components, score 0 = participants have a normal amount of feces, 1 = one or two feces are not normal, 2 = three or four feces are not normal, and 3 = five or more feces are not normal. For rectal bleeding, 0 = no blood was seen in the feces, 1 = less than half of the day, the feces of the defecation had bloodshot, 2 = most of the feces in the daily defecation had significant blood, and 3 = only the blood was discharged during defecation. PGA scores are 0 = normal, 1 = mild disease, 2 = moderate disease, 3 = serious diseaseTwo-type patient related results (PRO) The two-form PRO uses the component of rectal bleeding and fecal frequency from the diary as a composite score for additional efficacy evaluation.Diary moment for Mayo score The diary moment depends on the time when the endoscopic examination is performed. For visits that do not perform endoscopic procedures (Days 8, 15, -29, 43, 57, and 71 days of treatment), participants will complete the diary at least 5 days prior to each study visit. For visits during the endoscopy of the baseline (days 1 and 85 of the treatment period), participants will complete the diary for at least 5 consecutive days prior to the date of preparation of the endoscopic examination. Endoscopic examination must be performed prior to clinical evaluation and within 3 days prior to administration (excluding intestinal preparation and endoscopy procedures). Exploratory effectiveness evaluation Endoscopy and clinical evaluation Endoscopic, clinical, and histological remissions were assessed using modified Baron scores, clinical and histological evaluations.Colonic mucosal biopsy For all participants in Part B, a biopsy is required during endoscopic examination (as part of the study) or early before the 85th day. A biopsy was performed on each of the 5 to 6 samples (the most severely affected colon site away from 30 cm during retraction of the endoscope). If the most affected area is ulcerated, the specimen should be obtained from the edge of the ulcer. In the absence of any visible lesion characteristics of UC, 2 samples should be collected from the 10 cm area when the endoscope is retracted. In addition, at baseline visits, 2 biopsies from each of the participants in the unaffected area should be obtained (if within 30 cm during retraction of the endoscope), as explained below. One to two biopsy samples should be placed in each container provided for study. A formalin-fixed vial was pre-filled with 10% neutral buffered formalin and RNA later flasks were pre-filled with RNA later solution. Pharmacokinetics The pharmacokinetics of BMS-986184 was derived from serum concentration versus time data. The following pharmacokinetic parameters were evaluated for SAD and MAD in healthy participants: The following pharmacokinetic parameters were evaluated for partial A1 SAD in healthy participants. The following pharmacokinetic parameters were evaluated for partial A2 MAD in healthy participants. The following pharmacokinetic parameters were evaluated for partial B POMT in UC patients. The pharmacokinetic parameter values of individual participants were derived by a non-compartmental method and by a validation pharmacokinetic analysis program. The actual time is used for analysis.table 17 : Pharmacokinetic Sampling Schedule for BMS-986184 - SAD (Part A1)^a EOI = End of infusion, this sample should be taken just before the infusion is stopped (preferably within 2 minutes before the end of the infusion). If the end of the infusion is delayed beyond the nominal infusion duration, the collection of this sample should be delayed accordingly.table 18 : Pharmacokinetic Sampling Schedule for BMS-986184 - MAD (Part A2)^a EOI = end of infusion, for participants who follow intravenous administration, this sample should be taken just before the infusion is stopped (preferably within 2 minutes prior to the end of the infusion). If the end of the infusion is delayed beyond the nominal infusion duration, the collection of this sample should be delayed accordingly.table 19 : Pharmacokinetic Sampling Schedule for BMS-986184 - POM (Part B)^a EOI = end of infusion, for participants who follow intravenous administration, this sample should be taken just before the infusion is stopped (preferably within 2 minutes prior to the end of the infusion). If the end of the infusion is delayed beyond the nominal infusion duration, the collection of this sample should be delayed accordingly.^b These samples were collected during the follow-up period.^c Samples of participants who were interrupted due to adverse events should be collected. Serum samples were analyzed by BMS-986184 by validated ligand binding immunoassays. Pharmacokinetic samples collected from participants receiving placebo were not analyzed unless a placebo status was warranted. Immunogenicity evaluation The appearance of the specific ADA of BMS-986184 was determined from the measurements obtained at the time of the planned time. Validated immunoassays were used to analyze the samples. The study endpoint was the incidence of persistent positive ADA produced by the start of the drug treatment at the most (and including) the final dose. The following definitions apply: Participant's ADA status: • Baseline ADA-positive participant: Participant with baseline ADA-positive sample • ADA-positive participant: Any time during the defined observation period after starting treatment relative to baseline Participants with at least one ADA positive sample. ● ADA negative participants: participants who did not have ADA positive samples after starting treatment Pharmacodynamics Fecal calprotectin Fecal calprotectin is a surrogate marker for intestinal inflammation in IBD because it is associated with excretion of intestinal granules. Fecal calprotectin can be traced longitudinally as a marker of therapeutic response.High sensitivity CRP (hsCRP) hsCRP is an inflamed non-specific acute phase reactant marker. hsCRP is used as a safety marker and can be longitudinally tracked as a marker for therapeutic response. Biomarker Target occlusion biomarker Serum for target occlusion IP-10 concentration ( Total and free ) section A and B) In Part A, blood was drawn for measurement of serum free and total IP-10 concentrations to evaluate TE.table 20 : Sampling schedule for serum TE biomarkers for BMS-986184 - SAD (Part A1)table twenty one :BMS-986184 -MAD TE biomarker sampling schedule (Part A2) In Part B, blood was drawn at the time indicated in Table 9.8.1.1-3 for measurement of serum free and total IP-10 concentrations to evaluate TE. Additional details of blood collection and processing are provided to the location in the laboratory procedure manual.table twenty two : BMS-986184 TE Biomarker Sampling Schedule - Part B (POM)Tissue target occlusion biomarker ( section B) Colonic biopsy was used to measure free and total IP-10 concentrations to assess tissue TE.Pharmacokinetic biomarker ( section B) Blood was drawn for a certain period of time only in Part B prior to administration for evaluation of hsCRP. Fecal calprotectin was also measured.Exploratory serum / Plasma biomarker ( section B) Blood is drawn only in Part B prior to administration for evaluation of exploratory serum biomarkers that may be associated with IP-10 neutralization or related pathways. Exploratory serum biomarkers may include, but are not limited to, other CXCR3-related chemokines (CXCL9/MIG, CXCL11/ITAC), IL-1 (α, β), IL-6, IL-10, IL-12 , G-CSF, MIP-3β, IFN-γ and novel markers that can be associated with UC disease activity and/or mucosal healing. Proteomic descriptions can also be performed to support understanding of the activity of BMS-986184 in ulcerative colitis. Immune cell phenotyping ( section B) Blood is drawn only in Part B prior to administration for immunocyte phenotyping, which may include, but is not limited to, the following markers: CXCR3, CD3, CD4, CD56, CD16, CD45RA, CCR7. These results are used to evaluate baseline predictors of pharmacokinetic changes that may occur due to anti-IP-10 therapy and/or potentially identify responses. immunochemistry ( section B) Immunohistochemistry of formalin-fixed samples can include the following antigens according to standard procedures: CD3, CD68, IP-10, Foxp3, cytokeratin 18, EpCAM, IL17, and CXCR3. Gene expression description Whole blood RNA which performed ( section B) Blood was taken only in Part B before administration. These samples provide broad RNA description (microarray or RNA sequencing) to identify novel pharmacokinetic and potency biomarkers associated with inflammatory and/or UC disease pathways, mechanisms of action, and BMS-986184 therapeutic response. In addition, these samples were used to explore the genetic performance of baseline predictive efficacy against BMS-986184 treated participants.organization RNA which performed ( section B) Colon biopsy stored in RNA later is processed to isolate RNA. These samples provide broad RNA description (microarray or RNA sequencing) to identify novel pharmacokinetic and potency biomarkers associated with inflammatory and/or UC disease pathways, mechanisms of action, and BMS-986184 therapeutic response. In addition, these samples were used to explore the genetic performance of baseline predictive efficacy against BMS-986184 treated participants.Overview of the sequence listing Equivalents Many equivalents of the specific embodiments of the invention described herein may be identified or determined by routine experiment. These equivalents are intended to be included within the scope of the claims below.

Figure 1A shows the nucleotide sequence (SEQ ID NO: 5) and the amino acid sequence (SEQ ID NO: 4) of the heavy chain variable region of the IP10.1 (6A5) human monoclonal antibody. The CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2) and CDR3 (SEQ ID NO: 3) regions are depicted and indicate V, D, and J germline sources. Figure 1B shows the nucleotide sequence (SEQ ID NO: 11) and the amino acid sequence (SEQ ID NO: 10) of the light chain variable region of the IP10.1 human monoclonal antibody. The CDR1 (SEQ ID NO: 7), CDR2 (SEQ ID NO: 8) and CDR3 (SEQ ID NO: 9) regions are depicted and indicate V and J germline sources. Figure 2A shows the nucleotide sequence (SEQ ID NO: 17) and the amino acid sequence (SEQ ID NO: 16) of the heavy chain variable region of the IP10.44 human monoclonal antibody. The CDR1 (SEQ ID NO: 13), CDR2 (SEQ ID NO: 14) and CDR3 (SEQ ID NO: 15) regions are depicted and indicate V, D, and J germline sources. Figure 2B shows the nucleotide sequence (SEQ ID NO: 23) and the amino acid sequence (SEQ ID NO: 22) of the light chain variable region of the IP10.44 human monoclonal antibody. The CDR1 (SEQ ID NO: 19), CDR2 (SEQ ID NO: 20) and CDR3 (SEQ ID NO: 21) regions are depicted and indicate V and J germline sources. Figure 3A shows the nucleotide sequence (SEQ ID NO: 29) and the amino acid sequence (SEQ ID NO: 28) of the heavy chain variable region of the IP10.45 human monoclonal antibody. The CDR1 (SEQ ID NO: 25), CDR2 (SEQ ID NO: 26) and CDR3 (SEQ ID NO: 27) regions are depicted and indicate V, D, and J germline sources. Figure 3B shows the nucleotide sequence (SEQ ID NO: 35) and the amino acid sequence (SEQ ID NO: 34) of the light chain variable region of the IP10.45 human monoclonal antibody. The CDR1 (SEQ ID NO: 31), CDR2 (SEQ ID NO: 32) and CDR3 (SEQ ID NO: 33) regions are depicted and indicate V and J germline sources. Figure 4A shows the nucleotide sequence (SEQ ID NO: 41) and the amino acid sequence (SEQ ID NO: 40) of the heavy chain variable region of the IP10.46 human monoclonal antibody. The CDR1 (SEQ ID NO: 37), CDR2 (SEQ ID NO: 38) and CDR3 (SEQ ID NO: 39) regions are depicted and indicate V, D, and J germline sources. Figure 4B shows the nucleotide sequence (SEQ ID NO: 47) and the amino acid sequence (SEQ ID NO: 46) of the light chain variable region of the IP10.46 human monoclonal antibody. The CDR1 (SEQ ID NO: 43), CDR2 (SEQ ID NO: 44) and CDR3 (SEQ ID NO: 45) regions are depicted and indicate V and J germline sources. Figure 5A shows the nucleotide sequence (SEQ ID NO: 53) and the amino acid sequence (SEQ ID NO: 52) of the heavy chain variable region of the IP 10.52 human monoclonal antibody. The CDR1 (SEQ ID NO: 49), CDR2 (SEQ ID NO: 50) and CDR3 (SEQ ID NO: 51) regions are depicted and indicate V, D, and J germline sources. Figure 5B shows the nucleotide sequence (SEQ ID NO: 59) and the amino acid sequence (SEQ ID NO: 58) of the light chain variable region of the IP 10.52 human monoclonal antibody. The CDR1 (SEQ ID NO: 55), CDR2 (SEQ ID NO: 56) and CDR3 (SEQ ID NO: 57) regions are depicted and indicate V and J germline sources. Figure 6A shows the nucleotide sequence (SEQ ID NO: 65) and the amino acid sequence (SEQ ID NO: 64) of the heavy chain variable region of the IP10.53 human monoclonal antibody. The CDR1 (SEQ ID NO: 61), CDR2 (SEQ ID NO: 62) and CDR3 (SEQ ID NO: 63) regions are depicted and indicate V, D and J germline sources. Figure 6B shows the nucleotide sequence (SEQ ID NO: 71) and the amino acid sequence (SEQ ID NO: 70) of the light chain variable region of the IP10.53 human monoclonal antibody. The CDR1 (SEQ ID NO: 67), CDR2 (SEQ ID NO: 68) and CDR3 (SEQ ID NO: 69) regions are depicted and indicate V and J germline sources. Figure 7A shows the nucleotide sequence (SEQ ID NO: 77) and the amino acid sequence (SEQ ID NO: 76) of the heavy chain variable region of the IP 10.43 human monoclonal antibody. The CDR1 (SEQ ID NO: 73), CDR2 (SEQ ID NO: 74) and CDR3 (SEQ ID NO: 75) regions are depicted and indicate V, D and J germline sources. Figure 7B shows the nucleotide sequence (SEQ ID NO: 83) and the amino acid sequence (SEQ ID NO: 82) of the light chain variable region of the IP10.43 human monoclonal antibody. The CDR1 (SEQ ID NO: 79), CDR2 (SEQ ID NO: 80) and CDR3 (SEQ ID NO: 81) regions are depicted and indicate V and J germline sources. Figure 8A shows the nucleotide sequence (SEQ ID NO: 89) and the amino acid sequence (SEQ ID NO: 88) of the heavy chain variable region of the IP10.47 human monoclonal antibody. The CDR1 (SEQ ID NO: 85), CDR2 (SEQ ID NO: 86) and CDR3 (SEQ ID NO: 87) regions are depicted and indicate V, D, and J germline sources. Figure 8B shows the nucleotide sequence (SEQ ID NO: 95) and the amino acid sequence (SEQ ID NO: 94) of the light chain variable region of the IP10.47 human monoclonal antibody. The CDR1 (SEQ ID NO: 91), CDR2 (SEQ ID NO: 92) and CDR3 (SEQ ID NO: 93) regions are depicted and indicate V and J germline sources. Figure 9A shows the nucleotide sequence (SEQ ID NO: 101) and the amino acid sequence (SEQ ID NO: 100) of the heavy chain variable region of the IP10.48 human monoclonal antibody. The CDR1 (SEQ ID NO: 97), CDR2 (SEQ ID NO: 98) and CDR3 (SEQ ID NO: 99) regions are depicted and indicate V, D, and J germline sources. Figure 9B shows the nucleotide sequence (SEQ ID NO: 107) and the amino acid sequence (SEQ ID NO: 106) of the light chain variable region of the IP10.48 human monoclonal antibody. The CDR1 (SEQ ID NO: 103), CDR2 (SEQ ID NO: 104) and CDR3 (SEQ ID NO: 105) regions are depicted and indicate V and J germline sources. Figure 10A shows the nucleotide sequence (SEQ ID NO: 113) and the amino acid sequence (SEQ ID NO: 112) of the heavy chain variable region of the IP10.49 human monoclonal antibody. The CDR1 (SEQ ID NO: 109), CDR2 (SEQ ID NO: 110) and CDR3 (SEQ ID NO: 111) regions are depicted and indicate V, D, and J germline sources. Figure 10B shows the nucleotide sequence (SEQ ID NO: 119) and the amino acid sequence (SEQ ID NO: 118) of the light chain variable region of the IP10.49 human monoclonal antibody. The CDR1 (SEQ ID NO: 115), CDR2 (SEQ ID NO: 116) and CDR3 (SEQ ID NO: 117) regions are depicted and indicate V and J germline sources. Figure 11A shows the nucleotide sequence (SEQ ID NO: 125) and the amino acid sequence (SEQ ID NO: 124) of the heavy chain variable region of the IP10.50 human monoclonal antibody. The CDR1 (SEQ ID NO: 121), CDR2 (SEQ ID NO: 122) and CDR3 (SEQ ID NO: 123) regions are depicted and indicate V, D, and J germline sources. Figure 11B shows the nucleotide sequence (SEQ ID NO: 131) and the amino acid sequence (SEQ ID NO: 130) of the light chain variable region of the IP10.50 human monoclonal antibody. The CDR1 (SEQ ID NO: 127), CDR2 (SEQ ID NO: 128) and CDR3 (SEQ ID NO: 129) regions are depicted and indicate V and J germline sources. Figure 12A shows the nucleotide sequence (SEQ ID NO: 137) and the amino acid sequence (SEQ ID NO: 136) of the heavy chain variable region of the IP 10.51 human monoclonal antibody. The CDR1 (SEQ ID NO: 133), CDR2 (SEQ ID NO: 134) and CDR3 (SEQ ID NO: 135) regions are depicted and indicate V, D, and J germline sources. Figure 12B shows the nucleotide sequence (SEQ ID NO: 143) and the amino acid sequence (SEQ ID NO: 142) of the light chain variable region of the IP 10.51 human monoclonal antibody. The CDR1 (SEQ ID NO: 139), CDR2 (SEQ ID NO: 140) and CDR3 (SEQ ID NO: 141) regions are depicted and indicate V and J germline sources. Figure 13A shows the nucleotide sequence (SEQ ID NO: 149) and the amino acid sequence (SEQ ID NO: 148) of the heavy chain variable region of the IP 10.54 human monoclonal antibody. The CDR1 (SEQ ID NO: 145), CDR2 (SEQ ID NO: 146) and CDR3 (SEQ ID NO: 147) regions are depicted and indicate V, D, and J germline sources. Figure 13B shows the nucleotide sequence (SEQ ID NO: 155) and the amino acid sequence (SEQ ID NO: 154) of the light chain variable region of the IP 10.54 human monoclonal antibody. The CDR1 (SEQ ID NO: 151), CDR2 (SEQ ID NO: 152) and CDR3 (SEQ ID NO: 153) regions are depicted and indicate V and J germline sources. Figure 14 is a graph showing the activity of antibodies IP10.1 and IP10.44 to suppress free serum IP-10. Figure 15 is a graph showing the activity of antibodies IP10.1 and IP10.44 to reduce NK cell frequency. Figure 16A (TNBS colitis) and 16B (CD40-induced colitis) are graphs showing the efficacy of antibody surrogates for IP10.1 (6A1) and IP10.44 (18G2) in two different colitis models. Figure 17A (IFNγ), 17B (TNFα), 17C (IL-12p40) and 17D (IL-6) show antibody replacements for IP10.1 (6A1) and IP10.44 (18G2) to reduce CD40-induced colitis A graph of the activity of circulating concentrations of interleukins in the model. Figures 18A and 18B (IL-6), 18C and 18D (IFNγ) and 18E and 18F (IL-12p40) show reduction of antibody substitutes using the CD40-induced colitis model IP10.44 (18G2) and anti-TNFα antibodies A graph of the activity of circulating concentrations of interleukins in serum and inflamed intestines. Figures 19A (IP 10.44) and 19B (IP 10.1) are graphs showing the temporal characteristics of free serum IP-10 after an intravenous dose of IP 10.44 and IP 10.1. Figure 20 is a graph showing free serum IP-10 repression (% of baseline) compared to serum IP10.44 in cynomolgus monkeys. 21A to 21F are graphs showing the observed and predicted free and total serum IP-10 by PK/PD modeling (LLOQ of free serum IP-10 is 1 pM; if the value is lower than LLOQ, LLOQ is used for mapping) . Figure 22 is a graph comparing the high affinity of anti-IP-10 mouse substitute (18G2) with anti-TNFa substitute.

Claims (58)

An isolated monoclonal antibody or antigen binding portion thereof that binds to human IP-10 and includes heavy and light chain variable regions, wherein the heavy chain variable region comprises from SEQ ID NOs: 16, 28, 40, 52 CDR1, CDR2 and CDR3 regions of the heavy chain variable region of 64, 76, 88, 100, 112, 124, 136 or 148. An isolated monoclonal antibody or antigen binding portion thereof that binds to human IP-10 and includes a heavy chain and a light chain variable region, wherein the heavy chain variable region comprises a heavy chain variable region from SEQ ID NO: CDR1, CDR2 and CDR3 regions. The antibody or antigen-binding portion thereof of claim 1, wherein the heavy chain CDR1, CDR2 and CDR3 regions comprise the following amino acid sequences, respectively: (a) SEQ ID NOs: 13, 14 and 15; (b) SEQ ID NO : 25, 26 and 27; (c) SEQ ID NOs: 37, 38 and 39; (d) SEQ ID NOs: 49, 50 and 51; (e) SEQ ID NOs: 61, 62 and 63; (f) SEQ ID NO: 73, 74 and 75; (g) SEQ ID NOs: 85, 86 and 87; (h) SEQ ID NOs: 97, 98 and 99; (i) SEQ ID NOs: 109, 110 and 111; SEQ ID NOs: 121, 122 and 123; (k) SEQ ID NOs: 133, 134 and 135; or (l) SEQ ID NOs: 145, 146 and 147. The antibody of claim 1, or an antigen binding portion thereof, wherein the heavy chain CDR1, CDR2 and CDR3 regions comprise the amino acid sequences of SEQ ID NOS: 13, 14, and 15, respectively. The antibody or antigen-binding portion thereof of claim 1 or 3, wherein the light chain variable region comprises SEQ ID NO: 22, 34, 46, 58, 70, 82, 94, 106, 118, 130, 142 or 154 The CDR1, CDR2 and CDR3 regions of the light chain variable region. The antibody or antigen binding portion thereof of claim 1 or 3, wherein the light chain variable region comprises the CDR1, CDR2 and CDR3 regions from the light chain variable region of SEQ ID NO: 22. The antibody or antigen-binding portion thereof according to any of the preceding claims, wherein the light chain CDR1, CDR2 and CDR3 regions comprise the following amino acid sequences, respectively: (a) SEQ ID NOs: 19, 20 and 21; SEQ ID NOs: 31, 32 and 33; (c) SEQ ID NOs: 43, 44 and 45; (d) SEQ ID NOs: 55, 56 and 57; (e) SEQ ID NOs: 67, 68 and 69; (f) SEQ ID NOs: 79, 80 and 81; (g) SEQ ID NOs: 91, 92 and 93; (h) SEQ ID NOs: 103, 104 and 105; (i) SEQ ID NOs: 115, 116 and 171; (j) SEQ ID NO: 127, 128 and 129; (k) SEQ ID NO: 139, 140 and 141; or (l) SEQ ID NO: 151, 152 and 153. The antibody or antigen-binding portion thereof according to any of the preceding claims, wherein the light chain CDR1, CDR2 and CDR3 regions comprise the amino acid sequences of SEQ ID NOs: 19, 20 and 21, respectively. The antibody or antigen-binding portion thereof according to any of the preceding claims, wherein the heavy chain variable region comprises SEQ ID NO: 18, 30, 42, 54, 66, 78, 90, 102, 114, 126, 138 or 150 amino acid sequence. The antibody or antigen-binding portion thereof according to any of the preceding claims, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 18. The antibody or antigen-binding portion thereof according to any of the preceding claims, wherein the light chain variable region comprises SEQ ID NO: 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 or Amino acid sequence of 156. The antibody or antigen-binding portion thereof according to any of the preceding claims, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 24. An isolated monoclonal antibody or antigen binding portion thereof that binds to human IP-10 and comprises the heavy and light chain CDR1, CDR2 and CDR3 regions comprising the following amino acid sequences: (a) SEQ ID NO: 13 , 14 and 15 and SEQ ID NOs: 19, 20 and 21; (b) SEQ ID NOS: 25, 26 and 27 and SEQ ID NOS: 31, 32 and 33, respectively; (c) SEQ ID NO: 37, respectively , 38 and 39 and SEQ ID NO: 43, 44 and 45; (d) SEQ ID NO: 49, 50 and 51 and SEQ ID NO: 55, 56 and 57, respectively; (e) SEQ ID NO: 61, respectively , 62 and 63 and SEQ ID NO: 67, 68 and 69; (f) SEQ ID NO: 73, 74 and 75 and SEQ ID NO: 79, 80 and 81, respectively; (g) SEQ ID NO: 85, respectively , 86 and 87 and SEQ ID NO: 91, 92 and 93; (h) SEQ ID NO: 97, 98 and 99 and SEQ ID NO: 103, 104 and 105, respectively; (i) SEQ ID NO: 109, respectively , 110 and 111 and SEQ ID NO: 115, 116 and 117; (j) are SEQ ID NO: 121, 122 and 123 and SEQ ID NO: 127, 128 and 129, respectively; (k) are SEQ ID NO: 133, respectively , 134 and 135 and SEQ ID NO: 139, 140 and 141; or (l) are SEQ ID NOs: 145, 146 and 147 and SEQ ID NOs: 151, 152 and 153, respectively. An isolated monoclonal antibody or antigen binding portion thereof which binds to human IP-10 and comprises a heavy chain comprising the amino acid sequences of SEQ ID NOS: 13, 14 and 15 and SEQ ID NOS: 19, 20 and 21, respectively. And light chain CDR1, CDR2 and CDR3 regions. An isolated monoclonal antibody or antigen binding portion thereof that binds to human IP-10 and comprises heavy and light chain variable region sequences having at least 95% amino acid identity to SEQ ID NOS: 16 and 22, respectively. An isolated monoclonal antibody or antigen binding portion thereof that binds to human IP-10 and comprises a heavy chain and a light chain variable region comprising the following amino acid sequences, respectively: (a) SEQ ID NOs: 16 and 22; b) SEQ ID NOs: 28 and 34; (c) SEQ ID NOs: 40 and 46; (d) SEQ ID NOs: 52 and 58; (e) SEQ ID NOs: 64 and 70; (f) SEQ ID NO: 76 and 82; (g) SEQ ID NOS: 88 and 94; (h) SEQ ID NOS: 100 and 106; (i) SEQ ID NO: 112 and 118; (j) SEQ ID NO: 124 and 130; SEQ ID NOs: 136 and 142; or (l) SEQ ID NOs: 148 and 154. An isolated monoclonal antibody or antigen binding portion thereof that binds to human IP-10 and includes heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOS: 16 and 22, respectively. An isolated monoclonal antibody or antigen binding portion thereof that binds to human IP-10 and comprises a heavy chain and a light chain variable region comprising the following amino acid sequences, respectively: (a) SEQ ID NOs: 18 and 24; b) SEQ ID NOs: 30 and 36; (c) SEQ ID NOS: 42 and 48; (d) SEQ ID NOS: 54 and 60; (e) SEQ ID NO: 66 and 72; (f) SEQ ID NO: 78 and 84; (g) SEQ ID NOs: 90 and 96; (h) SEQ ID NOs: 102 and 108; (i) SEQ ID NOs: 114 and 120; (j) SEQ ID NOs: 126 and 132; SEQ ID NOs: 138 and 144; or (l) SEQ ID NOS: 150 and 156. An isolated monoclonal antibody or antigen binding portion thereof that binds to human IP-10 and comprises a full length heavy chain and a light chain comprising the amino acid sequences of SEQ ID NOS: 18 and 24, respectively. The antibody or antigen-binding portion thereof according to any of the preceding claims, which exhibits one or a combination of the following properties: (a) inhibiting IP-10 binding to CXCR3; (b) inhibiting IP-10 induced calcium flux (c) inhibiting IP-10-induced cell migration; (d) cross-reacting with rhesus IP-10; (e) not cross-reacting with mouse IP-10; (f) not cross-reacting with human MIG; / or (g) does not cross-react with human ITAC. Preceding the requested item in any one antibody or antigen binding portion thereof binds to human IP-10 to 1 × 10 ^-9 M or K _D of less. Preceding the requested item in any one antibody or antigen binding portion thereof binds to human IP-10 to 1 × 10 ^-10 M or K _D of less. Preceding the requested item in any one antibody or antigen binding portion thereof binds to human IP-10 to 1 × 10 ^-11 M or K _D of less. The antibody or antigen-binding portion thereof according to any of the preceding claims, which binds to an amine in SISNQP (SEQ ID NO: 163), VNPRSLEKL (SEQ ID NO: 164) and/or IIPASQFCPRVEIIA (SEQ ID NO: 165) Base acid residue. The antibody or antigen-binding portion thereof according to any of the preceding claims, which is a human, humanized or chimeric antibody. The antibody or antigen-binding portion thereof according to any of the preceding claims, which is an isotype of IgGl, IgG2 or IgG4. The antibody or antigen-binding portion thereof according to any of the preceding claims, which is an antibody fragment or a single chain antibody. A bispecific molecule comprising the antibody or antigen binding portion thereof and a second antibody or antigen binding portion thereof according to any of the preceding claims. An immunoconjugate comprising the antibody or antigen-binding portion thereof according to any one of claims 1 to 27 linked to a therapeutic agent. The immunoconjugate of claim 29, wherein the therapeutic agent is a cytotoxin or a radioisotope. A composition comprising an antibody or antigen-binding portion thereof according to any one of claims 1 to 27, a bispecific molecule according to claim 28 or an immunoconjugate as claimed in claim 29 or 30, and pharmaceutically acceptable Carrier. An isolated nucleic acid encoding a heavy chain and/or a light chain variable region of an antibody or antigen binding portion thereof according to any one of claims 1 to 27. A performance vector comprising the nucleic acid of claim 32. A host cell comprising the expression vector of claim 33. A method of making an anti-IP-10 antibody comprising expressing the antibody in a host cell as claimed in claim 34 and isolating the antibody from the host cell. A method of inhibiting an inflammatory or autoimmune response mediated by an activated T cell or NK cell, which comprises binding the T cell or NK cell to an antibody or antigen thereof according to any one of claims 1 to 27 Partial contact, thereby inhibiting the inflammatory response or autoimmune response. A method of treating an inflammatory disease or an autoimmune disease in an individual in need of treatment, comprising administering to the individual an antibody or antigen-binding portion thereof according to any one of claims 1 to 27, thereby treating the inflammatory disease of the individual Or autoimmune disease. The method of claim 37, wherein the disease is inflammatory bowel disease (IBD). The method of claim 38, wherein the IBD is ulcerative colitis or Crohn's disease. The method of claim 37, wherein the disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, inflammatory skin conditions (eg, psoriasis, lichen planus), autoimmune thyroid disease ( For example, Graves' disease, Hashimoto's thyroiditis, Sjogren's syndrome, lung inflammation (eg, asthma, chronic obstructive pulmonary disease, pulmonary sarcoma, lymphocytosis) Alveolitis), transplant rejection, bone marrow damage, brain damage (eg stroke), neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease), gingivitis, gene therapy induction Inflammation, angiogenic diseases, inflammatory nephropathy (eg, IgA nephropathy, membrane proliferative glomerulonephritis, rapidly progressive glomerulonephritis), multiple sclerosis, and atherosclerosis. The method of any one of claims 37 to 40, wherein the method comprises administering a single dose of the antibody or antigen-binding portion thereof at a dose between 30 mg and 450 mg. The method of claim 41, wherein the dosage is selected from the group consisting of 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 Mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg or 450 mg. The method of claim 41, wherein the dosage is selected from the group consisting of 35 mg, 45 mg, 55 mg, 65 mg, 75 mg, 85 mg, 95 mg, 105 mg, 115 mg, 125 mg, 135 mg, 145 mg, 155 Mg, 165 mg, 175 mg, 185 mg, 195 mg, 205 mg, 215 mg, 225 mg, 235 mg, 245 mg, 255 mg, 265 mg, 275 mg, 285 mg, 295 mg, 305 mg, 315 mg, 325 mg, 335 mg, 345 mg, 355 mg, 365 mg, 375 mg, 385 mg, 395 mg, 405 mg or 445 mg. The method of claim 41, wherein the dosage is 40 mg. The method of claim 41, wherein the dosage is 100 mg. The method of claim 41, wherein the dosage is 150 mg. The method of claim 41, wherein the dosage is 250 mg. The method of any one of claims 41 to 47, wherein the antibody or antigen-binding portion thereof is administered weekly or biweekly. The method of any one of claims 41 to 48, wherein the antibody or antigen-binding portion thereof is administered for a period of about 12 weeks. The method of any one of claims 41 to 49, wherein the antibody or antigen-binding portion thereof is administered on days 1, 15, 29, 43, 57 and 71. The method of any one of claims 41 to 50, wherein the antibody or antigen-binding portion thereof is formulated for intravenous administration. The method of any one of claims 41 to 50, wherein the antibody or antigen-binding portion thereof is formulated for subcutaneous administration. The method of any one of claims 41 to 52, wherein the condition is ulcerative colitis. A method of treating ulcerative colitis in a subject in need thereof, comprising administering to the individual the antibody or antigen-binding portion thereof according to any one of claims 1 to 27, thereby treating the ulcerative colitis of the individual, wherein The method comprises intravenously administering a single dose of about 40 mg of the antibody or antigen binding portion thereof for a period of about 12 weeks every two weeks. A method of treating a viral or bacterial infection involving an undesired IP-10 activity in a subject in need thereof, comprising administering to the individual an antibody or antigen-binding portion thereof according to any one of claims 1 to 27, thereby treating the individual The virus or bacterial infection. The method of claim 55, wherein the viral infection is mediated by human immunodeficiency virus (HIV), hepatitis C virus (HCV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome (SARS) virus. . An antibody, or an antigen-binding portion thereof, according to any one of claims 1 to 27, wherein the bispecific molecule of claim 28 or the immunoconjugate of claim 29 or 30 is used for inhibiting an inflammatory response or Autoimmune response. Use of an antibody or antigen-binding portion thereof according to any one of claims 1 to 27, such as the bispecific molecule of claim 28 or the immunoconjugate of claim 29 or 30, for use in the manufacture of An agent for an inflammatory response or an autoimmune response.