Anti-il-33 antibodies, compositions, methods and uses thereof

Abstract

The invention provides antibodies, and antigen-binding fragments thereof, that specifically bind to IL-33, as well as uses, and associated methods thereof.

1 . An isolated nucleic acid molecule, comprising one or more nucleotide sequences encoding an antibody, or antigen-binding fragment thereof, that specifically binds to human IL-33, comprising one from each of the following:
 (a) a light chain complementarity determining region 1 (CDR-L1) selected from the group consisting of SEQ ID NO:20, 37, 190, 193, 257, 258, 259, and 260;   (b) a CDR-L2 selected from the group consisting of SEQ ID NO:21, 196, 199, 261, 262, 263, and 264;   (c) a CDR-L3 selected from the group consisting of SEQ ID NO:22, 38, 208, 265, 26, 267, and 268;   (d) a heavy chain complementarity determining region 1 (CDR-H1) selected from the group consisting of SEQ ID NO:16, 33, 269, 270, and 271;   (e) a CDR-H2 selected from the group consisting of SEQ ID NO:17, 34, 168, 171, 174, 180, 202, 205, 211, 214, 217, 220, 223, 226, 229, 232, 235, 272, 273, 274, and 275; and   (f) a CDR-H3 selected from the group consisting of SEQ ID NO:18, 35, 114, 119, 122, 127, 130, 133, 136, 139, 142, 145, 148, 153, 156, 159, 177, 187, 276, 277, 278, and 279.   
     
     
         2 . An isolated nucleic acid molecule, comprising one or more nucleotide sequences encoding an antibody, or antigen-binding fragment thereof, comprising the CDR-H1, CDR-H2, and CDR-H3 sequences as set forth in SEQ ID NO:225, and the CDR-L1, CDR-L2, and CDR-L3 sequences as set forth in SEQ ID NO:207. 
     
     
         3 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment comprises:
 (i) a CDR-L1 comprising SEQ ID NO:20;   (ii) a CDR-L2 comprising SEQ ID NO:21;   (iii) a CDR-L3 comprising SEQ ID NO:208;   (iv) a CDR-H1 comprising SEQ ID NO:16;   (v) a CDR-H2 comprising SEQ ID NO:226; and   (vi) a CDR-H3 comprising SEQ ID NO: 18.   
     
     
         4 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment comprises a VL framework sequence and a VH framework sequence, and wherein one or both of the VL framework sequence or VH framework sequence is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the human germline sequence from which it was derived, and wherein the human germline VL sequence from which the VL framework sequence is derived is selected from the group consisting of DPK9, DPK12, DPK18, DPK24, HK102_V1, DPK1, DPK8, DPK3, DPK21, Vg_38K, DPK22, DPK15, DPL16, DPL8, V1-22, VA consensus, Vλ1 consensus, Vλ3 consensus, Vκ1 consensus, Vκ1 consensus, Vκ2 consensus, and Vκ3, and wherein the human germline VH sequence from which the VH framework sequence is derived is selected from the group consisting of DP54, DP47, DP50, DP31, DP46, DP71, DP75, DP10, DP7, DP49, DP51, DP38, DP79, DP78, DP73, VH3, VH5, VH1, and VH4. 
     
     
         5 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% identical to SEQ ID NO:225, and a VL comprising an amino acid sequence at least 90% identical to SEQ ID NO:207. 
     
     
         6 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment comprises an Fc domain, and wherein the Fc domain is the Fc domain of an IgA1 IgA2, IgD, IgE, IgM, IgG1, IgG2, IgG3, or IgG4. 
     
     
         7 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment comprises a heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO:244, and a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO:209. 
     
     
         8 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:244, and a light chain comprising the amino acid sequence of SEQ ID NO:209. 
     
     
         9 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment binds human IL-33 with a KD about or less than a value selected from the group consisting of 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 10 pM, 5 pM, and 1 pM, and optionally, wherein the antibody, or antigen binding fragment thereof, binds cynomolgus monkey IL-33 with a KD about or less than a value selected from the group consisting of 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, 13 pM, 10 pM, 5 pM, and 1 pM. 
     
     
         10 . The isolated nucleic acid molecule as claimed in  claim 2 , wherein the binding KD of the antibody, or antigen binding fragment, to cynomolgus IL-33 is within 10-fold of the binding KD to human IL-33. 
     
     
         11 . The isolated nucleic acid molecule of  claim 2 , wherein the terminal half-life in a human of the antibody or antigen binding fragment is at least about 31 days. 
     
     
         12 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment comprises a VH framework sequence derived from a human germline DP54 sequence. 
     
     
         13 . The isolated nucleic acid molecule of  claim 2 , wherein the antibody or antigen binding fragment comprises a VL framework sequence derived from a human germline DPK9 sequence. 
     
     
         14 . The isolated nucleic acid molecule of  claim 2 , wherein the ratio of binding KD of the antibody or antigen binding fragment to human IL-33 compared with the binding to cynomolgus IL-33 is between 5:1 and 1:5. 
     
     
         15 . The isolated nucleic acid molecule of  claim 2 , wherein the KD of the antibody, or antigen binding fragment thereof, binding to active IL-33 is at least 10, 100, 1×10 3 , 1×10 4 , 1×10 5 , 1×10 6 , 1×10 7  times less than the KD of the antibody, or antigen binding fragment thereof, binding to an inactive form of IL-33. 
     
     
         16 . The isolated nucleic acid molecule of  claim 2 , wherein the terminal half life of the antibody or binding fragment thereof in cynomolgus monkeys is at least about 15 days. 
     
     
         17 . An isolated nucleic acid molecule comprising a nucleic acid sequence as set forth in one or more of SEQ ID NOs: 398, 399, 400, and 401. 
     
     
         18 . An isolated nucleic acid molecule comprising the nucleic acid sequence of the nucleic acid insert in the plasmid deposited with the ATCC and having Accession No. PTA-122724, the nucleic acid insert in the plasmid deposited with the ATCC and having Accession No. PTA-122725, or both. 
     
     
         19 . A vector comprising the nucleic acid molecule of  claim 17 . 
     
     
         20 . A host cell comprising the nucleic acid molecule of  claim 17 . 
     
     
         21 . The host cell as claimed in  claim 20 , wherein said cell is a mammalian cell. 
     
     
         22 . A vector comprising the nucleic acid molecule of  claim 1 . 
     
     
         23 . A host cell comprising the nucleic acid molecule of  claim 1 . 
     
     
         24 . A host cell comprising the vector of  claim 22 . 
     
     
         25 . A method of producing the antibody of  claim 1 , the method comprising growing the host cell of  claim 24  under conditions where the antibody is produced, and, optionally, isolating the antibody produced. 
     
     
         26 . A vector comprising the nucleic acid molecule of  claim 3 . 
     
     
         27 . A host cell comprising the nucleic acid molecule as claimed in  claim 3 . 
     
     
         28 . A host cell comprising the vector of  claim 26 . 
     
     
         29 . A method of producing the antibody of  claim 3 , the method comprising growing the host cell of  claim 28  under conditions where the antibody is produced, and, optionally, isolating the antibody produced.