The Effect of ASP2409, a Novel CD86-Selective Variant of CTLA4-Ig, on Renal Allograft Rejection in Nonhuman Primates

Abstract

These results support the potential of ASP2409 as an improved CTLA4-Ig for maintenance immunosuppression in organ transplantation.

Selective CD28 Inhibition Modulates Alloimmunity and Cardiac Allograft Vasculopathy in Anti–CD154-Treated Monkeys

“…After genomic DNA digestion (RNase-Free DNase I, Qiagen), purified RNA was assessed (Agilent Bioanalyzer; Nanodrop), and 200ng of RNA per sample processed through the Nanostring nCounter System (NanoString Technologies Inc., Seattle, WA) (26) by the Deep Sequencing Core at Johns Hopkins University (Baltimore, MD). Normalization and data analysis was carried out with the NanoString nSolver® Analysis Software v3.0 based on the geometric mean of the positive controls and the 4 reference genes that were most stable across all samples (HPRT1, RPL32, TBP, and YWHAZ). Values lower than the mean + 3 standard deviations of the 8 negative control counts were excluded from statistical analysis.…”

“…The CD28:B7 (CD80/CD86) costimulatory pathway is critically involved in primary T cell activation and differentiation, and as such represents an attractive therapeutic target for modulating pathogenic and protective T cell-mediated immune responses. Blockade of the B7 pathway with cytotoxic T lymphocyte antigen 4 Ig (CTLA4-Ig) reagents inhibits transplant rejection and autoimmune diseases in rodents and nonhuman primates (NHPs) (1–4), and belatacept (a high affinity variant of CTLA4-Ig) has translated clinically as an effective alternative to conventional small-molecule-based immunosuppressive regimens in renal transplantation (5). Targeting B7 is further effective in preclinical models when combined with antagonists of the CD40:CD154 pathway (anti-CD40 or anti-CD154 mAbs) (6–10).…”

Les futures générations d’anticorps modulateurs des points de contrôle de la réponse immunitaire

“…Parmi les premières paires de récepteurs/ 1 IRCM, Inserm, Université de Montpellier, ICM, Montpellier, F-34298 France. 2 Centre de recherche en cancérologie de Marseille (CRCM), Inserm U1068, CNRS UMR 7258, Aix-Marseille Université et Institut Paoli-Calmettes, Marseille, France. 3 Centre de recherche en transplantation et immunologie (CRTI) UMR1064, Inserm, Université de Nantes, Nantes, 44093, France.…”

“…Son utilisation vise à bloquer l'interaction de CD28 avec les molécules CD80 et CD86 par compétition pour la fixation à ces dernières, CTLA-4 possédant une affinité pour celles-là plus forte que CD28. D'autres versions de CTLA4-Ig ont été développées ultérieurement, notamment le MAXY-4 qui présente une affinité encore plus élevée pour ses ligands, ainsi que l'ASP2409 [2] qui possède un tropisme pour CD86, ligand préférentiel de CD28. Cependant, les molécules CTLA4-Ig, si elles bloquent le signal CD28, entrent également en compétition avec les interactions CTLA-4/CD80, privant ainsi le système du bras « co-inhibition » et compromettant l'activité suppressive des lymphocytes Treg.…”