Transient antibody targeting of CD45RC to prevent the development of acute graft versus host diseases
Laetitia Boucault1, Maria - Dolores Lopez Robles1, Allan Thiolat2,3, Séverine Bézie1, Michael Schmück - Henneresse5, Cécile Braudeau1,7, Nadège Vimond1, Antoine Freuchet1, Elodie Austrusseau1, Sébastien Maury2, Eliane Piaggio6, Regis Josien1,7, Hans - Dieter Volk5, José Cohen2,3,4, Ignacio Anegon1, Carole Guillonneau1.
1Nantes Université, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France; 2Université Paris - Est, UMR_S955, UPEC, Paris, France; 3U955, Equipe Immunorégulation et biothérapie, Inserm, Paris, France; 4Groupe Hospitalo - Universitaire Chenevier Mondor, Centre d’Investigation Clinique Biothérapie, Assistance Publique - Hôpitaux de Paris (AP - HP), Créteil, France; 5Berlin - Brandenburg Center for Regenerative Therapies, Charité – Universitäts Medizin Berlin, Berlin, Germany; 6Institut Curie Research Center, INSERM U932, PSL Research University, Paris, France; 7Laboratoire d’Immunologie, CIMNA, CHU Nantes, Nantes, France
Allogeneic bone marrow transplantation (BMT) is the main treatment of many diseases but its most important side effect is the development of acute graft-versus-host disease (aGVHD). Despite the development of new therapies, GVHD occurs in 30 to 50% of the patients treated with BMT. aGVHD is characterized by generation of effector T cells with production of inflammatory cytokines and the reduction of regulatory T cells number. Thus, a treatment modifying the balance between effector and regulatory cells seems to be a promising approach against aGVHD. We have demonstrated that targeting the CD45RC molecule with a short term anti-CD45RC mAb treatment transiently decrease CD45RChigh effector cells and improve regulatory function of CD45RClow/- Tregs cells in a heart allograft rat model (Picarda E et al., JCI insight, 2017).
We demonstrate here, in rat and mouse allogeneic BMT, and in xenogeneic GVHD in hPBMCs-humanized NSG mice, that ex vivo depletion of CD45RChigh T cells or in vivo short course treatment with anti-CD45RC mAbs inhibit aGVHD. In the semi allogeneic rat model of GVHD, we showed that 55% of animals (n=8) treated with anti-CD45RC mAbs (1.5 mg/kg/2.5 days during 30 days) associated with sub optimal dose of rapamycin (0.4 or 0.8 mg/kg each day during 10 days) survived at long term. We show that the rats were fully engrafted with donor cells and developed a donor specific tolerance. In the NSG mice xenogeneic model, we tested an anti-human CD45RC mAb every 2.5 days during 30 days in association with sub optimal dose of rapamycin. This treatment efficiently delayed the weight loss of the mice following human PBMCs infusion in NSG mice and prolonged their survival for 70% of treated animals (n=10). Furthermore, we tested the injection of PBMC depleted of CD45RChigh cells by cell sorting and demonstrated that the depletion of the PBMCs before the injection induced long term survival in 87% of the mice (n=6). Finally, we validated the possibility to reject a human tumor despite an anti-CD45RC mAb treatment in NSG mice infused with human PBMCs. We also showed a favorable safety profile of an anti-human CD45RC mAb since it did not abolish human memory anti-viral immune responses, nor trigger cytokine release in in vitro assays.
Our results highlighted the potential of a short term anti-CD45RC mAb as a new innovative therapy against GVHD.
Labex IGO project «Investissements d’Avenir» ANR-11-LABX-0016-01. IHU-Cesti project funded by the «Investissements d’Avenir», ANR-10-IBHU-005. ANR COLT-45RC 18-CE18-0024-02. Agence de la Biomedecine. Fondation Centaure.
