TY - JOUR
T1 - A novel monoclonal antibody to CD40 prolongs islet allograft survival
AU - Lowe, M.
AU - Badell, I. R.
AU - Thompson, P.
AU - Martin, B.
AU - Leopardi, F.
AU - Strobert, E.
AU - Price, A. A.
AU - Abdulkerim, H. S.
AU - Wang, R.
AU - Iwakoshi, N. N.
AU - Adams, A. B.
AU - Kirk, A. D.
AU - Larsen, C. P.
AU - Reimann, K. A.
PY - 2012/8
Y1 - 2012/8
N2 - The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well-documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile. 2C10, a novel antagonistic monoclonal antibody to CD40, inhibits antigen-specific T cell-dependent antibody responses and significantly prolongs islet allograft survival in nonhuman primates.
AB - The importance of CD40/CD154 costimulatory pathway blockade in immunosuppression strategies is well-documented. Efforts are currently focused on monoclonal antibodies specific for CD40 because of thromboembolic complications associated with monoclonal antibodies directed towards CD154. Here we present the rational development and characterization of a novel antagonistic monoclonal antibody to CD40. Rhesus macaques were treated with the recombinant anti-CD40 mAb, 2C10, or vehicle before immunization with keyhole limpet hemocyanin (KLH). Treatment with 2C10 successfully inhibited T cell-dependent antibody responses to KLH without significant peripheral B cell depletion. Subsequently, MHC-mismatched macaques underwent intraportal allogeneic islet transplantation and received basiliximab and sirolimus with or without 2C10. Islet graft survival was significantly prolonged in recipients receiving 2C10 (graft survival time 304, 296, 265, 163 days) compared to recipients receiving basiliximab and sirolimus alone (graft survival time 8, 8, 10 days). The survival advantage conferred by treatment with 2C10 provides further evidence for the importance of blockade of the CD40/CD154 pathway in preventing alloimmune responses. 2C10 is a particularly attractive candidate for translation given its favorable clinical profile. 2C10, a novel antagonistic monoclonal antibody to CD40, inhibits antigen-specific T cell-dependent antibody responses and significantly prolongs islet allograft survival in nonhuman primates.
KW - Co-stimulation blockade
KW - immunosuppressive therapy
KW - islet transplantation
KW - type 1 diabetes mellitus
UR - http://www.scopus.com/inward/record.url?scp=84864478677&partnerID=8YFLogxK
U2 - 10.1111/j.1600-6143.2012.04054.x
DO - 10.1111/j.1600-6143.2012.04054.x
M3 - Article
C2 - 22845909
AN - SCOPUS:84864478677
SN - 1600-6135
VL - 12
SP - 2079
EP - 2087
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 8
ER -