US2017037137A1PendingUtilityA1
Synergistic combinations of ox40l antibodies for the treatment of gvhd

Assignee: KYMAB LTDPriority: Mar 3, 2015Filed: Oct 25, 2016Published: Feb 9, 2017
Est. expiryMar 3, 2035(~8.6 yrs left)· nominal 20-yr term from priority
Inventors:Philip Bland-Ward Miha Kosmac Steve Holmes Ian Kirby Jamie Campbell
C07K 2317/76C07K 2317/21C07K 2317/622A61K 31/436C07K 2317/31C07K 2317/624C07K 2317/22C07K 16/2875C07K 2317/565C07K 2317/55C07K 2317/24A61K 2039/505A61K 39/3955C07K 2317/33G01N 33/4833A61K 45/06C07K 2317/90A61K 2039/507C07K 2317/54
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References
Claims
Abstract

The present invention relates to anti-human OX40L antibodies, new medical uses and methods.
Claims

exact text as granted — not AI-modified
What is claimed herein is: 
     
         1 . A method of treating an hOX40L-mediated disease or condition in a human subject in need thereof, comprising:
 administering to the subject   a) a therapeutically effective, or prophylactically effective, amount of anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L; and   b) a therapeutically effective, or prophylactically effective, amount of second agent that is capable of inhibiting IL-2, selected from the group consisting of rapamycin; tacrolimus; cyclosporine; a corticosteroid; methylprednisolone; and   anti-IL2R antibodies.   
     
     
         2 . The method of  claim 1 , wherein the hOX40L-mediated disease or condition is an autoimmune disease or condition or a systemic inflammatory disease or condition. 
     
     
         3 . The method of  claim 1 , wherein the hOX40L mediated disease is characterized by a ratio of CD45RA+CCR7+CD95+OX40+ T stem cell memory (Tscm) cells to CD45RA+CCR7+CD95− T-naive (Tn) cells greater than 50:50 
     
     
         4 . The method of  claim 1 , wherein the administering of anti-OX40L antibody of fragment thereof that antagonizes specific binding of OX40 to OX40L and the second agent results in a synergistic effect. 
     
     
         5 . The method of  claim 2 , wherein the second agent that is capable of inhibiting IL-2 is rapamycin. 
     
     
         6 . The method of  claim 1 , wherein the second agent that is capable of inhibiting IL-2 is administered at least one time sequentially or simultaneously with the anti-hOX40L antibody or fragment. 
     
     
         7 . The method of  claim 1 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time followed by once a week, bi-weekly or once a month administration of the same after the first administration; and
 the second agent that is capable of inhibiting IL-2 is administered at least one time before, simultaneously with or after the administration of the anti-OX40L antibody.   
     
     
         8 . The method of  claim 1 , wherein the antibody or antibody fragment is humanized or human antibody or antibody fragment. 
     
     
         9 . The method of  claim 1 , wherein the antibody or antibody fragment is selected from the group consisting of multispecific antibodies, bi-specific antibodies, single-chain Fv antibodies (scFv), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments thereof. 
     
     
         10 . The method of  claim 1 , wherein the antibody or antibody fragment competes for binding of OX40L with an antibody comprising the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 48. 
     
     
         11 . The method of  claim 1 , wherein the antibody or antibody fragment thereof comprises a HCDR3 of from 16 to 27 amino acids and derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the human JH gene segment is IGHJ6 or IGHJ6*02. 
     
     
         12 . The method of  claim 1 , wherein the antibody or antibody fragment thereof comprises a CDR selected from:
 a. the HCDR3 of antibody comprising variable region Seq ID No:40 or Seq ID No:46;   b. the HCDR3 of antibody comprising variable region Seq ID No:8 or SEQ ID No:14;   c. the HCDR3 of antibody comprising variable region Seq ID No:72 or Seq ID No:78;   d. the HCDR3 of antibody comprising variable region Seq ID No:100 or Seq ID No:106;   e. an HCDR3 of any of the antibodies having the variable region amino acid sequence of Seq ID Nos: 215, 217, 219, 221, 223, 225, 227, 229 or 230; and   f. an HCDR3 of any of the antibodies having the variable region amino acid sequence of Seq ID Nos: 232 or 234.   
     
     
         13 . The method of  claim 1 , wherein the antibody or antibody fragment thereof comprises:
 a. the CDRs of Seq ID No:40 or Seq ID No:46 for CDRH3, SEQ ID No:38 or SEQ ID No:44 for CDRH2, SEQ ID No:36 or SEQ ID No:42 for CDRH1, SEQ ID No:50 or SEQ ID No:56 for CDRL1, SEQ ID No:52 or SEQ ID No:58 for CDRL2 and SEQ ID No:54 or SEQ ID No:60 for CDRL3;   b. the CDRs of Seq ID No:8 or SEQ ID No:14 for CDRH3, SEQ ID No:6 or SEQ ID No:12 for CDRH2, SEQ ID No:4 or SEQ ID No:10 for CDRH1, SEQ ID No:18 or SEQ ID No:24 for CDRL1, SEQ ID No:20 or SEQ ID No:26 for CDRL2 and SEQ ID No:22 or SEQ ID No:28 for CDRL3;   c. the CDRs of Seq ID No:72 or Seq ID No:78 for CDRH3, SEQ ID No:70 or SEQ ID No:76 for CDRH2, SEQ ID No:68 or SEQ ID No:74 for CDRH1, SEQ ID No:82 or SEQ ID No:88 for CDRL1, SEQ ID No:84 or SEQ ID No:90 for CDRL2 and SEQ ID No:86 or SEQ ID No:92 for CDRL3;   d. the CDRs of Seq ID No:100 or Seq ID No:106 for CDRH3, SEQ ID No:98 or SEQ ID No:104 for CDRH2, SEQ ID No:96 or SEQ ID No:102 for CDRH1, SEQ ID No:110 or SEQ ID No:116 for CDRL1, SEQ ID No:112 or SEQ ID No:118 for CDRL2 and SEQ ID No:114 or SEQ ID No:120 for CDRL3;   e. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences
 SEQ ID NO: 215 and SEQ ID NO: 214; 
 SEQ ID NO: 217 and SEQ ID NO: 216; 
 SEQ ID NO: 219 and SEQ ID NO: 218; 
 SEQ ID NO: 221 and SEQ ID NO: 220; 
 SEQ ID NO: 223 and SEQ ID NO: 222; 
 SEQ ID NO: 225 and SEQ ID NO: 224; 
 SEQ ID NO: 225 and SEQ ID NO: 226; 
 SEQ ID NO: 227 and SEQ ID NO: 214; 
 SEQ ID NO: 229 and SEQ ID NO: 228; or 
 SEQ ID NO: 230 and SEQ ID NO: 214; 
   f. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences
 SEQ ID NO: 232 and SEQ ID NO: 231; or 
 SEQ ID NO: 234 and SEQ ID NO: 233; 
   g. the VH and/or VL domains of Seq ID No:34 for VH and/or Seq ID No:48 for VL;   h. the VH and/or VL domains of Seq ID No:2 for VH and/or Seq ID No:16 for VL;   i. the VH and/or VL domains of Seq ID No:66 for VH and/or Seq ID No:80 for VL;   j. the VH and/or VL domains of Seq ID No:94 for VH and/or Seq ID No:108 for VL;   k. the VH domain and the VL domain of amino acid sequences
 SEQ ID NO: 215 and SEQ ID NO: 214; 
 SEQ ID NO: 217 and SEQ ID NO: 216; 
 SEQ ID NO: 219 and SEQ ID NO: 218; 
 SEQ ID NO: 221 and SEQ ID NO: 220; 
 SEQ ID NO: 223 and SEQ ID NO: 222; 
 SEQ ID NO: 225 and SEQ ID NO: 224; 
 SEQ ID NO: 225 and SEQ ID NO: 226; 
 SEQ ID NO: 227 and SEQ ID NO: 214; 
 SEQ ID NO: 229 and SEQ ID NO: 228; or 
 SEQ ID NO: 230 and SEQ ID NO: 214; 
 or 
   l. the VH domain and the VL domain of amino acid sequences
 SEQ ID NO: 232 and SEQ ID NO: 231; or 
 SEQ ID NO: 234 and SEQ ID NO: 233. 
   
     
     
         14 . The method of  claim 1 , wherein the antibody comprises the VH sequence of SEQ ID No:215 and the VL sequence of SEQ ID No:214. 
     
     
         15 . A method of treating or preventing an hOX40L-mediated disease or condition in a human subject in need thereof, comprising:
 administering to the subject a therapeutically or prophylactically effective amount of a combination of:   a) an anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L; and   b) a second agent that is capable of inhibiting IL-2.   
     
     
         16 . The method of  claim 15 , wherein the hOX40L-mediated disease or condition is an autoimmune disease or condition or a systemic inflammatory disease or condition. 
     
     
         17 . The method of  claim 15 , wherein the hOX40L mediated disease is characterized by a ratio of CD45RA+CCR7+CD95+OX40+ T stem cell memory (Tscm) cells to CD45RA+CCR7+CD95− T-naive (Tn) cells greater than 50:50 
     
     
         18 . The method of  claim 15 , wherein the second agent is selected from the group consisting of:
 rapamycin; tacrolimus; cyclosporine; a corticosteroid; methylprednisolone; and anti-IL2R antibodies wherein the administering of anti-OX40L antibody of fragment thereof that antagonizes specific binding of OX40 to OX40L and the second agent results in a synergistic effect.   
     
     
         19 . The method of  claim 15 , wherein the second agent is rapamycin. 
     
     
         20 . The method of  claim 15 , wherein the antibody or antibody fragment is humanized or human antibody or antibody fragment. 
     
     
         21 . The method of  claim 15 , wherein the antibody or antibody fragment thereof comprises:
 a. the CDRs of Seq ID No:40 or Seq ID No:46 for CDRH3, SEQ ID No:38 or SEQ ID No:44 for CDRH2, SEQ ID No:36 or SEQ ID No:42 for CDRH1, SEQ ID No:50 or SEQ ID No:56 for CDRL1, SEQ ID No:52 or SEQ ID No:58 for CDRL2 and SEQ ID No:54 or SEQ ID No:60 for CDRL3;   b. the CDRs of Seq ID No:8 or SEQ ID No:14 for CDRH3, SEQ ID No:6 or SEQ ID No:12 for CDRH2, SEQ ID No:4 or SEQ ID No:10 for CDRH1, SEQ ID No:18 or SEQ ID No:24 for CDRL1, SEQ ID No:20 or SEQ ID No:26 for CDRL2 and SEQ ID No:22 or SEQ ID No:28 for CDRL3;   c. the CDRs of Seq ID No:72 or Seq ID No:78 for CDRH3, SEQ ID No:70 or SEQ ID No:76 for CDRH2, SEQ ID No:68 or SEQ ID No:74 for CDRH1, SEQ ID No:82 or SEQ ID No:88 for CDRL1, SEQ ID No:84 or SEQ ID No:90 for CDRL2 and SEQ ID No:86 or SEQ ID No:92 for CDRL3;   d. the CDRs of Seq ID No:100 or Seq ID No:106 for CDRH3, SEQ ID No:98 or SEQ ID No:104 for CDRH2, SEQ ID No:96 or SEQ ID No:102 for CDRH1, SEQ ID No:110 or SEQ ID No:116 for CDRL1, SEQ ID No:112 or SEQ ID No:118 for CDRL2 and SEQ ID No:114 or SEQ ID No:120 for CDRL3;   e. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences
 SEQ ID NO: 215 and SEQ ID NO: 214; 
 SEQ ID NO: 217 and SEQ ID NO: 216; 
 SEQ ID NO: 219 and SEQ ID NO: 218; 
 SEQ ID NO: 221 and SEQ ID NO: 220; 
 SEQ ID NO: 223 and SEQ ID NO: 222; 
 SEQ ID NO: 225 and SEQ ID NO: 224; 
 SEQ ID NO: 225 and SEQ ID NO: 226; 
 SEQ ID NO: 227 and SEQ ID NO: 214; 
 SEQ ID NO: 229 and SEQ ID NO: 228; or 
 SEQ ID NO: 230 and SEQ ID NO: 214; 
   f. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences
 SEQ ID NO: 232 and SEQ ID NO: 231; or 
 SEQ ID NO: 234 and SEQ ID NO: 233; 
   g. the VH and/or VL domains of Seq ID No:34 for VH and/or Seq ID No:48 for VL;   h. the VH and/or VL domains of Seq ID No:2 for VH and/or Seq ID No:16 for VL;   i. the VH and/or VL domains of Seq ID No:66 for VH and/or Seq ID No:80 for VL;   j. the VH and/or VL domains of Seq ID No:94 for VH and/or Seq ID No:108 for VL;   k. the VH domain and the VL domain of amino acid sequences
 SEQ ID NO: 215 and SEQ ID NO: 214; 
 SEQ ID NO: 217 and SEQ ID NO: 216; 
 SEQ ID NO: 219 and SEQ ID NO: 218; 
 SEQ ID NO: 221 and SEQ ID NO: 220; 
 SEQ ID NO: 223 and SEQ ID NO: 222; 
 SEQ ID NO: 225 and SEQ ID NO: 224; 
 SEQ ID NO: 225 and SEQ ID NO: 226; 
 SEQ ID NO: 227 and SEQ ID NO: 214; 
 SEQ ID NO: 229 and SEQ ID NO: 228; or 
 SEQ ID NO: 230 and SEQ ID NO: 214; 
 or 
   l. the VH domain and the VL domain of amino acid sequences
 SEQ ID NO: 232 and SEQ ID NO: 231; or 
 SEQ ID NO: 234 and SEQ ID NO: 233. 
   
     
     
         22 . The method of  claim 15 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time followed by once a week, bi-weekly or once a month administration of the same after the first administration; and
 the second agent is administered at least one time before, simultaneously with or after the administration of the anti-OX40L antibody.   
     
     
         23 . The method of  claim 15 , wherein the antibody or antibody fragment is humanized or human antibody or antibody fragment. 
     
     
         24 . The method of  claim 15 , wherein the antibody or antibody fragment is selected from the group consisting of multispecific antibodies, bi-specific antibodies, single-chain Fv antibodies (scFv), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments thereof. 
     
     
         25 . The method of  claim 15 , wherein the antibody or antibody fragment competes for binding of OX40L with an antibody comprising the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 48. 
     
     
         26 . The method of  claim 15 , wherein the antibody or antibody fragment thereof comprises a HCDR3 of from 16 to 27 amino acids and derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the human JH gene segment is IGHJ6 or IGHJ6*02. 
     
     
         27 . The method of  claim 15 , wherein the antibody or antibody fragment thereof comprises a CDR selected from:
 g. the HCDR3 of antibody comprising variable region Seq ID No:40 or Seq ID No:46;   h. the HCDR3 of antibody comprising variable region Seq ID No:8 or SEQ ID No:14;   i. the HCDR3 of antibody comprising variable region Seq ID No:72 or Seq ID No:78;   j. the HCDR3 of antibody comprising variable region Seq ID No:100 or Seq ID No:106;   k. an HCDR3 of any of the antibodies having the variable region amino acid sequence of Seq ID Nos: 215, 217, 219, 221, 223, 225, 227, 229 or 230; and   l. an HCDR3 of any of the antibodies having the variable region amino acid sequence of Seq ID Nos: 232 or 234.
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