Anti-human nicotinamide phosphoribosyltransferase (nampt) antibodies

Abstract

Anti-nicotinamide phosphoribosyltransferase (NAMPT) antibodies, or antigen binding fragments thereof, are described, as well as methods for treating a subject having a (NAMPT)-associated local and/or systemic inflammatory disorder.

1 . A method of treating a subject having Coronavirus disease 2019 (COVID-19), the method comprising administering to the subject an effective amount of an isolated antibody, or an antigen-binding fragment thereof, that binds to human nicotinamide phosphoribosyltransferase (NAMPT). 
     
     
         2 - 27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof comprises:
 (i) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3; a CDR2 domain having an amino acid sequence as set forth in SEQ ID NOs: 4 or 29; and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and   (ii) a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 6 or 11; a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 7, 12, 14, 33, 35 or 37; and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8.   
     
     
         29 . The method of  claim 1 , wherein a heavy chain variable region of the isolated antibody comprises:
 (a) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 4, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; or   (b) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 29, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5.   
     
     
         30 . The method of  claim 1 , wherein a light chain variable region of the isolated antibody comprises:
 (a) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 7, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (b) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 12, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (c) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 14, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (d) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 33, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (e) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 35, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (f) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 37, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (g) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 7, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (h) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 12, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (i) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11; a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 14; and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (j) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11; a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 33; and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (k) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11; a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 35; and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8; or   (l) a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11; a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 37; and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8.   
     
     
         31 . The method of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 4, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 6, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 7, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (b) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 4, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 12, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (c) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 4, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 14, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (d) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 29, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 14, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (e) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 29, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 33, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (f) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 29, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 35, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (g) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 29, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 37, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (h) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 4, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 33, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8;   (i) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 4, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11; a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 35; and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8; or   (j) a heavy chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 3, a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 4, and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 5; and a light chain variable region comprising a CDR1 domain having an amino acid sequence as set forth in SEQ ID NO: 11; a CDR2 domain having an amino acid sequence as set forth in SEQ ID NO: 37; and a CDR3 domain having an amino acid sequence as set forth in SEQ ID NO: 8.   
     
     
         32 . The method of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof is humanized. 
     
     
         33 . The method of  claim 1 , wherein the isolated antibody contains a light chain variable region with an amino acid sequence as set forth in SEQ ID NO: 2, 10, 13, 30, 31, 32, 34 or 36. 
     
     
         34 . The method of  claim 1 , wherein the isolated antibody contains a heavy chain variable region with an amino acid sequence as set forth in SEQ ID NO: 1, 9, 15, 16 or 28. 
     
     
         35 . The method of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain comprising a variable region comprising the amino acid sequence as set forth in SEQ ID NO: 15, and a light chain comprising a variable region comprising the amino acid sequence as set forth in SEQ ID NO: 13. 
     
     
         36 . The method of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain comprising a variable region comprising the amino acid sequence as set forth in SEQ ID NO: 26, and a light chain comprising a variable region comprising the amino acid sequence as set forth in SEQ ID NO: 18. 
     
     
         37 . The method of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof comprises a humanized heavy chain variable region derived from murine antibody AL-303 or AL-310, and a humanized light chain variable region derived from murine antibody AL-303 or AL-310. 
     
     
         38 . The method of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof binds to human NAMPT in a homodimeric conformation, wherein the antibody binds an epitope on human NAMPT comprising either
 a) an epitope on human NAMPT comprising at least one amino acid in amino acid residues 17-44 of SEQ ID NO: 60; at least one amino acid in amino acid residues 117-127 of SEQ ID NO: 60; at least one amino acid in amino acid residues 162-170 of SEQ ID NO: 60; at least one amino acid in amino acid residues 242-261 of SEQ ID NO: 60; at least one amino acid in amino acid residues 262-273 of SEQ ID NO: 60; at least one amino acid in amino acid residues 289-305 of SEQ ID NO: 60; at least one amino acid in amino acid residues 332-342 of SEQ ID NO: 60; at least one amino acid in amino acid residues 374-389 of SEQ ID NO: 60; at least one amino acid in amino acid residues 418-425 of SEQ ID NO: 60; at least one amino acid in amino acid residues 453-466 of SEQ ID NO: 60; and at least one amino acid in amino acid residues 408-416 of SEQ ID NO: 60; or   b) an epitope on human NAMPT comprising at least one amino acid in amino acid residues 29-51 of SEQ ID NO: 60; at least one amino acid in amino acid residues 61-72 of SEQ ID NO: 60; at least one amino acid in amino acid residues 156-170 of SEQ ID NO: 60; at least one amino acid in amino acid residues 216-234 of SEQ ID NO: 60; at least one amino acid in amino acid residues 316-331 of SEQ ID NO: 60; at least one amino acid in amino acid residues 332-342 of SEQ ID NO: 60; at least one amino acid in amino acid residues 373-389 of SEQ ID NO: 60; at least one amino acid in amino acid residues 417-431 of SEQ ID NO: 60; at least one amino acid in amino acid residues 454-469 of SEQ ID NO: 60; and at least one amino acid in amino acid residues 470-478 of SEQ ID NO: 60.   
     
     
         39 . The method of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof comprises an Fc domain. 
     
     
         40 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody. 
     
     
         41 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof is an IgG antibody. 
     
     
         42 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof is an IgG1 or an IgG4 antibody.