US2016168238A1PendingUtilityA1

Humanized, anti-n2 antibodies and methods of treating ischemia-reperfusion injury

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Assignee: DECLMMUNE THERAPEUTICS INCPriority: Mar 12, 2013Filed: Dec 14, 2015Published: Jun 16, 2016
Est. expiryMar 12, 2033(~6.6 yrs left)· nominal 20-yr term from priority
Inventors:Robyn Puro
A61P 37/06A61P 9/10C07K 2317/71C07K 2317/76C07K 2317/41A61P 29/00C07K 2317/40C07K 2317/14C07K 2317/33C07K 2317/524A61K 2039/505A61K 39/39583C07K 2317/24C07K 16/18C07K 2317/34C07K 2317/52C07K 2317/92
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Claims

Abstract

The present invention encompasses humanized antibodies that specifically bind N2 peptide, methods for the preparation thereof and methods for the use thereof.

Claims

exact text as granted — not AI-modified
1 . A humanized, anti-N2 antibody or antigen-binding fragment thereof comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:
 i. the VH region comprises three complementarity determining regions (CDRs) VH CDR1, VH CDR2 and VH CDR3 wherein the VH CDR1 comprises SEQ ID NO: 3, VH CDR2 comprises SEQ ID NO: 4 and VH CDR3 comprises SEQ ID NO: 5;   ii. the VH region comprises four framework regions (FWR) VH FWR1, VH FWR2, VH FWR3 and VH FWR4 wherein:
 a. the VH FWR1 comprises SEQ ID NO: 15, SEQ ID NO: 19 or SEQ ID NO: 23; 
 b. the VH FWR2 comprises SEQ ID NO: 16, SEQ ID NO: 20 or SEQ ID NO:24; 
 c. VH FWR3 comprises SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 43, SEQ ID NO: 44 or SEQ ID NO: 45; and 
 d. VH FWR4 comprises SEQ ID NO: 18, SEQ ID NO: 22, or SEQ ID NO: 26; 
   iii. the VL region comprises three complementarity determining regions (CDRs) VL CDR1, VL CDR2 and VL CDR3 wherein the VL CDR1 comprises SEQ ID NO: 6, VH CDR2 comprises SEQ ID NO: 7 and VH CDR3 comprises SEQ ID NO: 8;   iv. the VL region comprises four framework regions (FWR) VL FWR1, VL FWR2, VL FWR3 and VL FWR4 wherein:
 a. the VL FWR1 comprises SEQ ID NO: 27, SEQ ID NO: 31, or SEQ ID NO: 35; 
 b. VL FWR2 comprises SEQ ID NO: 28, SEQ ID NO: 32, or SEQ ID NO: 36; 
 c. VL FWR3 comprises SEQ ID NO: 29, SEQ ID NO: 33, or SEQ ID NO: 37; and 
 d. VL FWR4 comprises SEQ ID NO: 30, SEQ ID NO: 34, or SEQ ID NO: 38. 
   
     
     
         2 . The antibody or antigen-binding fragment of  claim 1 , wherein:
 i. the VH region comprises three complementarity determining regions (CDRs) VH CDR1, VH CDR2 and VH CDR3 wherein the VH CDR1 consists of SEQ ID NO:3, VH CDR2 consists of SEQ ID NO: 4 and VH CDR3 consists of SEQ ID NO: 5;   ii. the VH region comprises four framework regions (FWR) VH FWR1, VH FWR2, VH FWR3 and VH FWR4 wherein:
 a. the VH FWR1 consists of SEQ ID NO: 15, SEQ ID NO: 19 or SEQ ID NO: 23; 
 b. The VH FWR2 consists of SEQ ID NO: 16, SEQ ID NO: 20 or SEQ ID NO:24; 
 c. VH FWR3 comprises SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 43, SEQ ID NO: 44 or SEQ ID NO: 45; and 
 d. VH FWR4 consists of SEQ ID NO: 18, SEQ ID NO: 22, or SEQ ID NO: 26; 
   iii. the VL region comprises three complementarity determining regions (CDRs) VL CDR1, VL CDR2 and VL CDR3 wherein the VL CDR1 consists of SEQ ID NO: 6, VH CDR2 comprises SEQ ID NO: 7 and VH CDR3 consists of SEQ ID NO: 8;   iv. the VL region comprises four framework regions (FWR) VL FWR1, VL FWR2, VL FWR3 and VL FWR4 wherein:
 a. the VL FWR1 consists of SEQ ID NO: 27, SEQ ID NO: 31, or SEQ ID NO: 35; 
 b. VL FWR2 consists of SEQ ID NO: 28, SEQ ID NO: 32, or SEQ ID NO: 36; 
 c. VL FWR3 consists of SEQ ID NO: 29, SEQ ID NO: 33, or SEQ ID NO: 37; and 
 d. VL FWR4 consists of SEQ ID NO: 30, SEQ ID NO: 34, or SEQ ID NO: 38. 
   
     
     
         3 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region comprises a sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11. 
     
     
         4 . The antibody or antigen-binding fragment of  claim 1 , wherein the VL region comprises a sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14. 
     
     
         5 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of a sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11. 
     
     
         6 . The antibody or antigen-binding fragment of  claim 1 , wherein the VL region consists of a sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO:13 and SEQ ID NO: 14. 
     
     
         7 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 9 and the VL region consists of the amino acid sequence of SEQ ID NO: 12. 
     
     
         8 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 9 and the VL region consists of the amino acid sequence of SEQ ID NO: 13. 
     
     
         9 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 9 and the VL region consists of the amino acid sequence of SEQ ID NO: 14. 
     
     
         10 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 10 and the VL region consists of the amino acid sequence of SEQ ID NO: 12. 
     
     
         11 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 10 and the VL region consists of the amino acid sequence of SEQ ID NO: 13. 
     
     
         12 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 10 and the VL regions consists of the amino acid sequence of SEQ ID NO: 14. 
     
     
         13 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 11 and the VL region consists of the amino acid sequence of SEQ ID NO: 12. 
     
     
         14 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 11 and the VL region consists of the amino acid sequence of SEQ ID NO: 13. 
     
     
         15 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 11 and the VL region consists of the amino acid sequence of SEQ ID NO: 14. 
     
     
         16 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 43 and VL region consists of a sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14. 
     
     
         17 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 44 and VL region consists of a sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14. 
     
     
         18 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 45 and VL region consists of a sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14. 
     
     
         19 . The antibody or antigen-binding fragment of  claim 1 , wherein the VH region consists of the amino acid sequence of SEQ ID NO: 42 and VL region consists of a sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . The antibody or antigen-binding fragment of  claim 1 , wherein the isotype of the constant region is IgG1, IgG2, IgG3, or IgG4. 
     
     
         23 . The antibody or antigen-binding fragment of  claim 22 , wherein the isotype of the IgG constant region is IgG1. 
     
     
         24 . (canceled) 
     
     
         25 . The antibody or antigen-binding fragment of  claim 1 , having a heavy chain immunoglobulin constant domain selected from the group consisting of a human IgG1 constant domain and a human IgG4 constant domain. 
     
     
         26 . The antibody or antigen-binding fragment of  claim 1 , having a human Ig kappa constant domain. 
     
     
         27 . The antibody or antigen-binding fragment of  claim 1 , wherein the antibody is aglycosylated. 
     
     
         28 . The antibody or antigen-binding fragment of  claim 1 , having a human IgG1 constant domain that is aglycosylated by replacing the amino acid corresponding to asparagine (Asn) 297 of the constant region heavy chain with an alternative amino acid residue. 
     
     
         29 - 30 . (canceled) 
     
     
         31 . The antibody or antigen-binding fragment of  claim 1 , wherein the heavy chain immunoglobulin constant domain is a human IgG4 constant domain wherein serine 228 is replaced with proline. 
     
     
         32 . The antibody or antigen-binding fragment of  claim 1 , which is a scFv, diabody, Fab, minibody or scFv-Fc. 
     
     
         33 . A nucleotide sequence encoding the antibody or antigen-binding fragment of any one  claim 1 . 
     
     
         34 . A vector comprising the nucleotide sequence of  claim 33 . 
     
     
         35 . An isolated cell comprising the vector of  claim 34 . 
     
     
         36 . A method for producing a humanized antibody, or antigen-binding fragment thereof, comprising culturing the cell of  claim 35  and recovering the antibody, or fragment thereof, from the culture medium or from said cultured cells. 
     
     
         37 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an antibody or antigen-binding fragment of  claim 1 . 
     
     
         38 . A method of treating an inflammatory disease or disorder comprising administering to a subject an effective amount of the antibody or antigen-binding fragment of  claim 1 . 
     
     
         39 . The method of  claim 38 , wherein the inflammatory disease or disorder is ischemia-reperfusion injury. 
     
     
         40 - 42 . (canceled)

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