Claims for Patent: 9,434,785

Summary for Patent: 9,434,785

Title:	Anti-human OX40L antibodies and methods of treating graft versus host disease with the same
Abstract:	The present invention relates to anti-human OX40L antibodies, new medical uses and methods.
Inventor(s):	Bland-Ward; Philip (Cambridge, GB), Campbell; Jamie (Cambridge, GB), Holmes; Steve (Cambridge, GB), Kirby; Ian (Cambridge, GB), Kosmac; Miha (Cambridge, GB), Kean; Leslie Susan (Seattle, WA), Tkachev; Victor (Seattle, WA)
Assignee:	Kymab Limited (Cambridge, GB)
Application Number:	14/935,937
Patent Claims:	1. A method of treating or preventing graft versus host disease (GvHD) in a human subject in need thereof, comprising: administering an anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L to a subject determined to have 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 wherein the antibody or fragment thereof is administered in an amount effective to reduce the ratio of said Tscm cells in said human, wherein a blood sample obtained from the human subject has been subjected to an assay to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95- Tn cells in the sample. 2. The method of claim 1, further comprising a step of assaying the blood sample obtained from the human subject to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95- Tn cells in the blood sample. 3. The method of claim 2, wherein the assay comprises flow cytometry. 4. The method of claim 1, wherein the ratio is greater than 60:40, or greater than 70:30, or greater than 75:25, or greater than 80:20, or greater than 85:15, or greater than 90:10, or greater than 95:5. 5. The method of claim 1, wherein the antibody or antibody fragment is humanized, human antibody or antibody fragment. 6. 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. 7. A method of treating or preventing graft versus host disease (GvHD) in a human subject in need thereof, comprising: administering an anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L to a subject determined to have a ratio of CD45RA+CCR7+CD95+OX40+ T stem cell memory (Tscm):CD45RA+CCR7+CD95- T-naive (Tn) cells greater than 50:50 wherein the antibody of fragment thereof is administered in an amount effective to reduce the ratio of said Tscm cells in said human, 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. 8. 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. 9. The method of claim 1, wherein the antibody or antibody fragment thereof comprises a CDR selected from: a. the HCDR3 of antibody comprising variable regions Seq ID No:40 or Seq ID No: 46; b. the HCDR3 of antibody comprising variable regions Seq ID No:8 or SEQ ID No: 14; c. the HCDR3 of antibody comprising variable regions Seq ID No:72 or Seq ID No: 78; d. the HCDR3 of antibody comprising variable regions 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. 10. 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. 11. A method of treating or preventing graft versus host disease (GvHD) in a human subject in need thereof, comprising: administering an anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L to a subject determined to have a ratio of CD45RA+CCR7+CD95+OX40+ T stem cell memory (Tscm): CD45RA+CCR7+CD95- T-naive (Tn) cells greater than 50:50 wherein the antibody or fragment thereof is administered in an amount effective to reduce the ratio of said Tscm cells in said human, wherein the antibody comprises the VH sequence of SEQ ID No:215 and the VL sequence of SEQ ID No:214. 12. The method of claim 1, further comprising administering to the human a further therapeutic agent, wherein the further therapeutic agent is independently selected from the group consisting of rapamycin, sirolimus, tacrolimus, ciclosporin, corticosteroids, methylprednisolone, methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12/IL-23 antibodies, ustekinumab, anti-CD20 antibodies, rituximab, anti-CD30 antibodies, brentuximab, CTLA4-Fc molecules, abatacept, CCR5 receptor antagonists maraviroc, anti-CD40L antibodies, anti-VLA4 antibodies, natalizumab, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, alemtuzumab, anti-CD45 antibodies, cyclophosphamide, anti-thymocyte globulins, anti-complement C5 antibodies, -eculizumab, anti-a4b7 integrin antibodies, vedolizumab, anti-IL6 antibodies, -tocilizumab, anti-IL2R antibodies, basilixumab, anti-CD25 antibodies, daclizumab, anti-TNFa/TNFa-Fc molecules, etanercept, adalimumab, infliximab, golimumab, certolizumab pegol, and Vorinostat. 13. The method of claim 12, wherein the further therapeutic agent is rapamycin or tacrolimus. 14. A method of preventing or treating graft versus host disease, comprising: a. obtaining at least two T-cell samples derived from a subject who has or is at risk of graft versus host disease, wherein said at least two T-cell samples comprise a first sample taken at a first time point and a second sample taken at a second time point after the time first sample has been taken, b. determining levels of CD45RA+CCR7+CD95+OX40+ Tscm cells in said first and second samples; c. treating said subject to reduce the proportion of CD45RA+CCR7+CD95+OX40+ Tscm cells compared to said second sample by administering an anti-OX40L antibody or antibody fragment thereof in an amount effective to reduce the levels of Tscm cells, when the level of Tscm cells in said second sample are elevated as compared to said first sample, in order to treat or prevent said graft versus host disease. 15. The method of claim 14, wherein said first sample is collected: i. before the onset of said graft versus host disease; or ii. after the onset of said graft versus host disease; and wherein said second sample is collected no longer than one month after the first sample. 16. The method of claim 15, wherein the second sample is collected no longer than 1 week after the first sample. 17. The method of claim 15, wherein the treatment is administered in step (c) when the levels of Tscm cells in said second sample are greater than double the levels as compared to said first sample. 18. The method of claim 15, wherein a first administration of the antibody or antibody fragment is performed after the first sample is taken and before the second sample is taken. 19. The method of claim 15, further comprising the steps of d. obtaining a third T-cell sample derived from said subject after the second sample has been taken; e. determining the level of CD45RA+CCR7+CD95+OX40+ Tscm cells in said third sample; f. treating said subject to reduce the proportion of CD45RA+CCR7+CD95+OX40+ Tscm cells by administering an anti-OX40L antibody or antibody fragment thereof that specifically binds OX40L, when the levels of Tscm cells in said third sample are elevated as compared to said second or said first sample. 20. The method of claim 7, wherein a blood sample obtained from the human subject has been subjected to an assay to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95- Tn cells in the sample. 21. The method of claim 7, further comprising a step of assaying a blood sample obtained from the human subject to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95- Tn cells in the blood sample. 22. The method of claim 21, wherein the assay comprises flow cytometry. 23. The method of claim 11, wherein a blood sample obtained from the human subject has been subjected to an assay to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95- Tn cells in the sample. 24. The method of claim 23, wherein the assay comprises flow cytometry. 25. The method of claim 11, further comprising a step of assaying a blood sample obtained from the human subject to measure the ratio of CD45RA+CCR7+CD95+OX40+ Tscm:CD45RA+CCR7+CD95- Tn cells in the blood sample. 26. The method of claim 7, wherein the further therapeutic agent is rapamycin or tacrolimus. 27. The method of claim 11, wherein the further therapeutic agent is rapamycin or tacrolimus. 28. The method of claim 7, wherein the ratio is greater than 60:40, or greater than 70:30, or greater than 75:25, or greater than 80:20, or greater than 85:15, or greater than 90:10, or greater than 95:5. 29. The method of claim 11, wherein the ratio is greater than 60:40, or greater than 70:30, or greater than 75:25, or greater than 80:20, or greater than 85:15, or greater than 90:10, or greater than 95:5. 30. 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.

Details for Patent 9,434,785

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2035-09-09
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2035-09-09
Hoffmann-la Roche Inc.	ZENAPAX	daclizumab	Injection	103749	12/10/1997		2035-09-09
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2035-09-09
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2035-09-09
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2035-09-09