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Updated: Mar 8, 2026
Murine Heterotopic Heart Transplant Technique
Published on: July 8, 2014
Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection
S C Kim1, W Wakwe1, L B Higginbotham1
1Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
Abstract:
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 CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.
Insights
A novel domain antibody targeting the CD40/CD154 pathway shows promise for transplant therapy. This costimulation blockade effectively prolongs allograft survival in primates without causing dangerous side effects like thromboembolism.
Area of Science:
- Immunology
- Transplantation Biology
- Drug Development
Background:
- Costimulation blockade, particularly targeting the CD40/CD154 pathway, offers potential for improving transplant outcomes.
- Previous anti-CD154 therapies have faced challenges in clinical translation due to safety concerns, including thromboembolism.
- Developing safer and equally effective agents is crucial for advancing targeted transplant therapies.
Purpose of the Study:
- To evaluate the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004).
- To assess the potential of this dAb to provide effective costimulation blockade without inducing thromboembolism.
- To determine its impact on allograft survival and regulatory T cell populations in a preclinical model.
Main Methods:
- Utilized a novel anti-human CD154 domain antibody (dAb) lacking Fc binding activity.
- Tested the dAb in a nonhuman primate kidney transplant model.
- Assessed allograft survival, thromboembolism, and changes in regulatory T cell populations (CD4+CD25+Foxp3+).
Main Results:
- The anti-CD154 dAb effectively blocked CD40-CD154 interactions without causing platelet activation.
- In primate kidney transplants, the dAb significantly prolonged allograft survival (Median survival time 103 days) without thromboembolism.
- Combination therapy with the dAb and conventional immunosuppression led to sustained allograft survival (Median survival time 397 days) and increased regulatory T cells.
Conclusions:
- The novel anti-CD154 dAb is a safe and effective agent for prolonging renal allograft survival in a preclinical primate model.
- This dAb offers a promising alternative to previous anti-CD154 therapies by mitigating the risk of thromboembolism.
- The findings support the potential clinical utility of this Fc-null domain antibody in transplantation.
