Comparative Evaluation of CD40 (2C10R4) and CD154 (5C8H1 and IDEC-131) in a Nonhuman Primate Cardiac Allotransplant Model

作者：O'Neill Natalie A; Zhang Tianshu; Braileanu Gheorghe; Sun Wenji; Cheng Xiangfei; Hershfeld Alena; Laird Christopher T; Kronfli Anthony; Hock Lindsay A; Dahi Siamak; Kubicki Natalia; Sievert Evelyn; Hassanein Wessam; Cimeno Arielle; Pierson Richard N; Azimzadeh Agnes M^*

来源：Transplantation, 2017, 101(9): 2038-2047.

DOI：10.1097/TP.0000000000001836

Background Specific blockade of T cell costimulation pathway is a promising immunomodulatory approach being developed to replace our current clinical immunosuppression therapies. The goal of this study is to compare results associated with 3 monoclonal antibodies directed against the CD40/CD154 T cell costimulation pathway.
Methods Cynomolgus monkey heterotopic cardiac allograft recipients were treated with either IDEC-131 (humanized CD154, n = 9), 5C8H1 (mouse-human chimeric CD154, n = 5), or 2C10R4 (mouse-rhesus chimeric CD40, n = 6) monotherapy using a consistent, comparable dosing regimen for 3 months after transplant.
Results Relative to the previously reported IDEC-131-treated allografts, median survival time (35 31 days) was significantly prolonged in both 5C8H1-treated (142 +/- 26, P < 0.002) and 2C10R4-treated (124 +/- 37, P < 0.020) allografts. IDEC-131-treated grafts had higher cardiac allograft vasculopathy severity scores during treatment relative to either 5C8H1 (P = 0.008) or 2C10R4 (P = 0.0002). Both 5C8H1 (5 of 5 animals, P = 0.02) and 2C10R4 (6/6, P = 0.007), but not IDEC-131 (2/9), completely attenuated IgM antidonor alloantibody (alloAb) production during treatment; 5C8H1 (5/5) more consistently attenuated IgG alloAb production compared to 2C10R4 (4/6) and IDEC-131 (0/9). All evaluable explanted grafts experienced antibody-mediated rejection. Only 2C10R4-treated animals exhibited a modest, transient drop in CD20(+) lymphocytes from baseline at day 14 after transplant (-457 +/- 152 cells/L) compared with 5C8H1-treated animals (16 +/- 25, P = 0.037), and the resurgent B cells were primarily of a naive phenotype.
Conclusions In this model, CD154/CD40 axis blockade using IDEC-131 is an inferior immunomodulatory treatment than 5C8H1 or 2C10R4, which have similar efficacy to prolong graft survival and to delay cardiac allograft vasculopathy development and antidonor alloAb production during treatment.

• 出版日期2017-9