Resumen
[0001] The present invention provides a novel use and methods comprising antibodies, or antigen-binding fragments thereof, which bind to a CCR7 receptor for use as a novel therapeutic agent in prevention and/or treatment of graft versus host disease (GVHD), preferably in hematopoietic stem cell transplantation (HSCT), more preferably allogeneic hematopoietic stem cell transplantation. GVHD of the invention can be acute (aGVHD) and/or chronic (cGVHD), preferably acute. The antibodies and antigen-binding fragments are capable of selectively depleting ex vivo or in vitro immune cells expressing CCR7 and are capable in vivo of selectively killing immune cells expressing a CCR7 receptor and of impairing/blocking migration and of activation of said immune cells, which are involved in the development and evolution of GVHD. The use of said antibodies for depleting, killing and impairing/blocking migration and activation of immune cells expressing CCR7 cells is disclosed, thus providing an alternative therapy for preventing and treating GVHD in both acute and chronic types. [0002] La présente invention concerne une nouvelle utilisation et des procédés comprenant des anticorps, ou des fragments de liaison à l'antigène de ceux-ci, qui se lient à un récepteur CCR7 pour une utilisation en tant que nouvel agent thérapeutique dans la prévention et/ou le traitement d'une maladie du greffon contre l'hôte (GVHD), de préférence dans une transplantation de cellules souches hématopoïétiques (HSCT), de préférence encore une transplantation de cellules souches hématopoïétiques allogéniques. La GVHD selon l'invention peut être aiguë (aGVHD) et/ou chronique (cGVHD), de préférence aiguë. Les anticorps et les fragments de liaison à l'antigène sont capables de réduire de manière sélective des cellules immunitaires ex vivo ou in vitro exprimant CCR7 et sont capables de détruire de manière sélective in vivo des cellules immunitaires exprimant un récepteur CCR7 et d'altérer/bloquer la migration et l'activation desdites cellules immunitaires, qui sont impliquées dans le développement et l'évolution de la GVHD. L'invention concerne également l'utilisation desdits anticorps pour l'appauvrissement, la destruction et l'altération/blocage de la migration et l'activation de cellules immunitaires exprimant les cellules CCR7, ce qui permet d'obtenir ainsi une thérapie alternative pour prévenir et traiter la GVHD à la fois dans des types aigus et chroniques.
Reivindicaciones
1. An anti-CCR7 antibody or antigen-binding fragment thereof, for use in preventing or treating Graft Versus Host Disease (GVHD) in a recipient of a transplant comprising a donor cell. 2. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to claim 1, wherein the anti-CCR7 antibody has an IC50 of no more than 100 nM for inhibiting at least one of CCR7-dependent intracellular signalling and CCR7 receptor internalization, by at least one CCR7-ligand selected from CCL19 and CCL21. 3. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to claim 2, wherein the anti-CCR7 antibody inhibits CCR7-dependent intracellular signalling without substantial agonistic effects. 4. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to any one of the claims 1 - 3, wherein the anti-CCR7 antibody has a Kd for the N-terminal extracellular domain of human CCR7 that is not more than a factor 20 higher than the Kd of a reference anti-CCR7 antibody, whereby the reference anti-CCR7 antibody is a mouse anti- CCR7 antibody of which the amino acid sequence of the heavy chain variable domain is SEQ ID NO: 1 and of which the amino acid sequence of the light chain variable domain is SEQ ID NO: 2. 5. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to any one of the preceding claims, wherein the anti-CCR7 antibody is a chimeric, humanized or human antibody. 6. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to claim 5, wherein the anti-CCR7 antibody is an antibody having the HVRs of the anti- human CCR7 antibody of which the amino acid sequence of the heavy chain variable domain is SEQ ID NO: 1 and of which the amino acid sequence of the light chain variable domain is SEQ ID NO: 2. 7. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to any one of the preceding claims, wherein the anti-CCR7 antibody effects at least one of killing, inducing apoptosis, blocking migration, blocking activation, blocking proliferation and blocking dissemination of CCR7 expressing cells in the recipient. 8. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to any one of the preceding claims, wherein the transplant comprising the donor cell is a transplant comprising one or more of an organ, tissue, a progenitor cell, a stem cell and a hematopoietic cell. CA 03123512 2021-06-15 WO 2020/127509 PCT/EP2019/085991 44 9. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to claim 8, wherein the transplant comprising the donor cell is a transplant comprising a hematopoietic stem or progenitor cell. 10. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to claim 9, wherein the recipient suffers from a malignant disorder and wherein preferably, the prevention or treatment of GHVD maintains or promotes the graft versus tumor effect or the graft versus leukemia effect. 11. An anti-CCR7 antibody or antigen-binding fragment thereof, for use according to any one of the preceding claims, wherein the prevention or treatment of GHVD comprises at least one of: a) administration of the anti-CCR7 antibody to the recipient prior to that the recipient receives the transplant comprising the donor cell; b) administration of the anti-CCR7 antibody to the recipient after that the recipient has received the transplant comprising the donor cell, and preferably before that the recipient shows symptoms of GHVD or before that the recipient has been diagnosed with GHVD; c) administration of the anti-CCR7 antibody to the recipient after that the recipient has received the transplant comprising the donor cell, and preferably after that the recipient shows symptoms of GHVD or after that the recipient has been diagnosed with GHVD; d) administration of the anti-CCR7 antibody to the recipient of a transplant comprising the donor cell, which transplant has been prepared prior to transplantation by an ex vivo incubation with the anti-CCR7 antibody or antigen-binding fragment thereof; and, e) administration of the anti-CCR7 antibody to the recipient after recurrence of GHVD. 12. An ex vivo method for preparing an organ, tissue or cell preparation from a donor for transplantation into a recipient, the method comprising the steps of: a) incubating the organ, tissue or cell preparation with an anti-CCR7 antibody or antigen- binding fragment thereof as defined in claims 2 - 7, whereby the anti-CCR7 antibody effects at least one of: i) a reduction of the number of, and ii) an inhibition of the activity of, CCR7 expressing donor cells in the organ, tissue or cell preparation; and, b) optionally, removal of at least one of the anti-CCR7 antibody and the CCR7 expressing donor cells from the organ, tissue or cell preparation. 13. A method according to claim 12, wherein the anti-CCR7 antibody is comprised in a preservation solution used to preserve the organ, tissue or cell preparation prior to transplantation. 14. A method according to claim 13, wherein the organ or tissue is perfused or washed with the preservation solution comprising the anti-CCR7 antibody. CA 03123512 2021-06-15 WO 2020/127509 PCT/EP2019/085991 15. A method according to daim 12 or 13, wherein the anti-CCR7 antibody and the CCR7 expressing donor cells are removed from the cell preparation by affinity purification of the anti-CCR7 antibody and the CCR7 expressing donor cells bound thereto. 5
