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US-RE50880-E1 - Anti-human OX40L antibodies and methods of treatment

Abstract

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

Inventors

  • Jamie Campbell
  • Steve Holmes
  • Ian Kirby
  • Miha Kosmac

Assignees

  • KYMAB LIMITED

Dates

Publication Date
20260505
Application Date
20220801

Claims (20)

  1. 1 . An antibody or a fragment thereof that specifically binds to hOX40L and competes for binding to said hOX40L with the antibody 02D10 which comprises a heavy chain amino acid sequence of SEQ ID No:62 and a light chain amino acid sequence of SEQ ID No:64, the antibody or fragment thereof comprising a VH domain which comprises the HCDR3 sequence of SEQ ID NO:40 or 46.
  2. 2 . The antibody or fragment thereof according to claim 1 , wherein the VH domain comprises the HCDR1 sequence of SEQ ID NO:36 or 42.
  3. 3 . The antibody or fragment thereof according to claim 1 , wherein the VH domain comprises the HCDR1 sequence of SEQ ID NO:36 or 42, and the VH domain comprises the HCDR2 sequence of SEQ ID NO:38 or 44.
  4. 4 . The antibody or fragment thereof according to claim 1 , wherein the VH domain comprises the HCDR1 sequence of SEQ ID NO:36 or 42, and the VH domain comprises the HCDR2 sequence of SEQ ID NO:38 or 44, and wherein the antibody or fragment thereof further comprises a VL domain which comprises the LCDR1 sequence of SEQ ID NO:54 or 60.
  5. 5 . The antibody or fragment thereof according to claim 1 , wherein the VH domain comprises the HCDR1 sequence of SEQ ID NO:36 or 42, and the VH domain comprises the HCDR2 sequence of SEQ ID NO:38 or 44, and wherein the antibody or fragment thereof further comprises a VL domain comprising the LCDR1 sequence of SEQ ID NO:54 or 60, and the VL domain comprising the LCDR2 sequence of SEQ ID NO:52 or 58.
  6. 6 . The antibody or fragment thereof according to claim 1 , wherein the VH domain comprises the HCDR1 sequence of SEQ ID NO:36 or 42, and the VH domain comprises the HCDR2 sequence of SEQ ID NO:38 or 44, and wherein the antibody or fragment thereof further comprises a VL domain comprising the LCDR1 sequence of SEQ ID NO:54 or 60, the VL domain comprising the LCDR2 sequence of SEQ ID NO:52 or 58, and the VL domain comprising the LCDR3 sequence of SEQ ID NO:54 or 60.
  7. 7 . The antibody or fragment thereof according to claim 6 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO:34.
  8. 8 . The antibody or fragment thereof according to claim 6 comprising a first and a second copy of the VH domain.
  9. 9 . The antibody or fragment thereof according to claim 6 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO:48.
  10. 10 . The antibody or fragment thereof according to claim 6 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO:48 and the VH domain comprises the amino acid sequence of SEQ ID NO:34.
  11. 11 . The antibody or fragment thereof according to claim 6 comprising a first and a second copy of the VL domain.
  12. 12 . The antibody or fragment thereof according to claim 6 comprising a kappa light chain.
  13. 13 . The antibody or fragment thereof according to claim 6 comprising a constant region.
  14. 14 . The antibody or fragment thereof according to claim 10 comprising a IgG4-PE constant region of SEQ ID NO:128.
  15. 15 . A composition comprising an antibody or a fragment thereof that specifically binds to hOX40L and competes for binding to said hOX40L with the antibody 02D10 which comprises a heavy chain amino acid sequence of SEQ ID No:62 and a light chain amino acid sequence of SEQ ID No:64, and a pharmaceutically acceptable excipient, diluent, or carrier; wherein the antibody or fragment thereof comprises a VH domain comprising the HCDR3 sequence of SEQ ID NO:40 or 46.
  16. 16 . The composition according to claim 15 , wherein the VL domain comprises the amino acid sequence of SEQ ID NO:48 and the VH domain comprises the amino acid sequence of SEQ ID NO:34.
  17. 17 . The composition according to claim 15 , further comprising another agent that is a therapeutic or prophylactic agent for graft versus host disease (GvHD) or transplant rejection.
  18. 18 . The composition according to claim 15 contained in a kit with a label or instructions for use to treat and/or prevent graft versus host disease (GvHD) or transplant rejection.
  19. 19 . The composition according to claim 18 , wherein the kit comprises a marketing authorisation number.
  20. 20 . The composition according to claim 18 , wherein the kit further comprises an IV or injection device that comprises the antibody or fragment thereof.

Description

CROSS REFERENCE TO RELATED APPLICATION The present application is a reissue application of U.S. Pat. No. 9,139,653, which issued on Sep. 22, 2015, from U.S. application Ser. No. 14/700,896, filed Apr. 30, 2015. The present invention relates to anti-human OX40L antibodies, new medical uses and methods. SEQUENCE LISTING The sequence listing of the present application has been submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file name K00018-1-US-SequenceListing.txt, creation date of Apr. 30, 2015 and a size of 114,805 as an XML file with a file name 37488-0792RE1.xml, a creation date of Jul. 8, 2022, and a size of 178,728 bytes. The sequence listing is part of the specification and is herein incorporated by reference in its entirety. BACKGROUND OX40 ligand (OX40L) is a TNF family member; a 34 kDa type II transmembrane protein. The crystallized complex of human OX40 and OX40L is a trimeric configuration of one OX40L (trimer) and three OX40 monomers. The human extracellular domain is 42% homologous to mouse OX40L. OX40L is not constitutively expressed but can be induced on professional APCs such as B-cells, dendritic cells (DCs) and macrophages. Other cell types such as Langerhans cells, endothelial cells, smooth muscle cells, mast cells and natural killer (NK) cells can be induced to express OX40L. T-cells can also express OX40L. The OX40L receptor, OX40, is expressed on activated T cells (CD4 and CD8 T cells, Th2, Th1 and Th17 cells) and CD4+Foxp3+ cells, even in the absence of activation. The interaction between OX40 and OX40L occurs during the T-cell-DC interaction 2 or 3 days after antigen recognition. After leaving DCs, the OX40-expressing T-cell may interact with an OX40L-expressing cell other than a DC and receive an OX40 signal from this cell, which may provide essential signals for the generation of memory T-cells, the enhancement of Th2 response and the prolongation of the inflammatory responses. OX40 signals into responder T-cells render them resistant to Treg mediated suppression. Graft versus host disease is a major cause of mortality following allogenic bone marrow treatment. In the acute version of the disease, mature T-cells present in the bone marrow graft recognise the donor tissue as foreign in an environment of damaged tissue, which, via host APC's cause the activation and proliferation of the donor T-cells, with subsequent T-cell migration into the liver, spleen, gut, skin and lungs, causing tissue damage by the CTL effector response and inflammatory cytokine/chemokine release. Onset for acute disease is usually within the first 100 days post transplantation (Hill-Ferrara, Blood May 1, 2000 vol. 95 no. 9 2754-275, Reddy-Ferrara Blood, Volume 17, Issue 4, December 2003). Chronic GvHD usually appears 100 days post transplantation and several factors are thought to be involved, including thymic damage caused by prior acute GvHD which results in a reduced clearance of pathogenic T-cells (Zhang et al, Sep. 1, 2007 vol. 179 no. 5 3305-3314), up-regulation of TGF-β, which causes fibrosis (McCormick et al J Immuno, Nov. 15, 1999 vol. 163 no. 10 5693-5699), and a B-cell component driven by elevated B-Cell activating factor (BAFF) (Sarantopoulos et al, Clin Cancer Res Oct. 15, 2007 13; 6107) as well as auto-antibodies against platelet derived growth factor receptor (Svegliati et al, Blood Jul. 1, 2007 vol. 110 no. 1 237-241). Clinical studies have shown that OX40 is up-regulated in both acute (Morante et al, Clinical and Experimental Immunology, 145:36-43) and chronic (Kotani et al, Blood Nov. 15, 2001 vol. 98 no. 10 3162-3164) GvHD. Administration of an antagonistic anti-OX40L enhanced survival in a lethal acute mouse model of GvHD, with a 70% survival in the treated group compared to the untreated who all died by day 43 (Tsukada et al, Blood, 1 Apr. 2000, Volume 95, Number 7) whereas treatment with an agonistic anti-OX40 Ab accelerated the disease and mortality (Blazar et al Blood May 1, 2003 vol. 101 no. 9 3741-3748). Blockade of the OX40-OX40L interaction has been shown to be efficacious in several other inflammatory disease, with anti-OX40L Ab being used to treat a mouse model of colitis (Totsuka et al., AJP-GI Apr. 1, 2003 vol. 284 no. 4 G595-G603), and that an anti-OX40L Ab could block the development of diabetes in NOD mice (Pakala et al European Journal of Immunology Volume 34, Issue 11, pages 3039-3046, November 2004). REFERENCES Lamb, L. S., Abhyankar, S. A., Hazlett, L., O'Neal, W., Folk, R. S., Vogt, S., Parrish, R. S., Bridges, K., Henslee-Downey, P. J. and Gee, A. P. (1999), Expression of CD134 (OX-40) on T-cells during the first 100 days following allogeneic bone marrow transplantation as a marker for lymphocyte activation and therapy-resistant graft-versus-host disease. Cytometry, 38: 238-243.Xupeng Ge, Julia Brown, Megan Sykes, Vassiliki A. Boussiotis, CD134-Allodepletion Allows Selective Elimination of Alloreactive Human T-cells without Loss of Vi