Premium
Fc‐Silent Anti‐ CD 154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection
Author(s) -
Kim S. C.,
Wakwe W.,
Higginbotham L. B.,
Mathews D. V.,
Breeden C. P.,
Stephenson A. C.,
Jenkins J.,
Strobert E.,
Price K.,
Price L.,
Kuhn R.,
Wang H.,
Yamniuk A.,
Suchard S.,
Farris A. B.,
Pearson T. C.,
Larsen C. P.,
Ford M. L.,
Suri A.,
Nadler S.,
Adams A. B.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14197
Subject(s) - cd154 , medicine , immunosuppression , cd40 , immunology , foxp3 , pharmacology , immune system , biology , cytotoxic t cell , in vitro , biochemistry
The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD 40/ CD 154 pathway. Unfortunately, successful clinical translation of anti‐ CD 154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD 154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti‐human CD 154 domain antibody ( dA b, BMS ‐986004). The anti‐ CD 154 dA b effectively blocked CD 40‐ CD 154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti‐ CD 154 dA b was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti‐ CD 154 dA b and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti‐ CD 154 dA b treatment increased the frequency of CD 4 + CD 25 + Foxp3 + regulatory T cells. This study demonstrates that the use of a novel anti‐ CD 154 dA b that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti‐ CD 154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.