Mechanistic Rationale for Dual Costimulation Blockade, Belatacept, Dazodalibep in Kidney Transplantation

Dual costimulation may represent a new paradigm in kidney transplantation immunosuppression, according to study investigators.1

Recently, the first clinical trial of dual costimulation blockade in humans combined dazodalibep and belatacept as the sole maintenance antirejection therapy in adults undergoing kidney transplantation. The regimen prevented transplant rejection in over 50% of patients, with most rejections occurring by week 12, allowing for early recognition and intervention.1

“Even though we knew this would work back in the 1990s, this is the first time we were able to do it in humans,” said Allan Kirk, MD, PhD, a transplant surgeon at Duke Kidney/Transplant Clinic in an interview with HCPLive.

Since the 1990s, calcineurin inhibitors and corticosteroids have been the standard of care in kidney transplantation, successfully reducing acute rejection, but not improving long-term graft survival. Due to the therapeutic regimens’ nephrotoxicity and association with diabetes and hypertension, many patients report reduced quality of life.1,2

Belatacept, a selective CD28–CD80/86 costimulation blocker, was first evaluated in kidney transplantation in the phase 3 BENEFIT trial. In BENEFIT recipients demonstrated improved renal function, fewer cardiovascular and metabolic adverse effects, and a survival advantage at 7 years compared with cyclosporine-treated patients, led to approval by the US Food and Drug Administration (FDA) in 2011.1,2

However, CD28–CD80/86, which is critical for early T cell priming, does not inhibit other costimulatory pathways that sustain effector T cell responses or promote T cell–B cell interactions. This incomplete suppression allows some T cells to become activated, which demonstrated increased rates of early acute rejection in belatacept-treated patients, highlighting the limitations of targeting a single costimulatory pathway.1,2

Mechanistically, full T cell activation requires costimulatory signals from multiple, nonredundant pathways. Key pathways include the immunoglobulin-related superfamily, such as CD28–CD80/86 and inducible costimulator–inducible costimulator ligand (ICOS–ICOSL), as well as tumor necrosis factor–related interactions including CD40–CD40 ligand. While CD28 signaling is critical for early T cell priming, ICOS signaling sustains effector T cell responses and promotes T cell–B cell collaboration and antibody production.1,2

Dazodalibep is a nonantibody fusion protein that selectively inhibits CD154 (CD40 ligand), a critical mediator of T cell–B cell interactions and effector T cell survival. CD154 signaling promotes T cell help to B cells, antibody production, and expansion of effector T cells, pathways that are not fully suppressed by CD28 blockade alone. By disrupting these complementary costimulatory signals, dazodalibep prevents both cellular and humoral alloimmune responses, supporting long-term graft tolerance.1,2

Importantly, unlike earlier anti-CD154 antibodies, dazodalibep lacks an Fc domain, minimizing the risk of thromboembolic complications observed in preclinical and early clinical studies. Combined with belatacept, dual blockade therefore addresses both early T cell priming and downstream effector pathways, providing a mechanistic rationale for more durable, CNI-free maintenance immunosuppression.1,2

Investigators evaluated the dual costimulatory blockade in a phase 2a, open-label, single-arm, pilot trial evaluating the efficacy, safety, and tolerability of dual costimulation blockade combining dazodalibep and belatacept in adult recipients of a first, human leukocyte antigen (HLA)–nonidentical kidney allograft from a deceased, living unrelated, or living related donor.1

To follow along with the findings, watch the rest of our interview with Dr. Kirk here.

Editor’s Note: Kirk reports relevant disclosures with Ededon Pharmaceuticals.

References

1. Vincenti F, Shoji J, Wojciechowski D, et al. Dual costimulation blockade with the CD154-specific fusion protein dazodalibep and belatacept for prophylaxis of kidney allograft rejection. American Journal of Transplantation. 2025;0(0). doi:https://doi.org/10.1016/j.ajt.2025.12.290

2. Schroder PM, Fitch ZW, Schmitz R, Choi AY, Kwun J, Knechtle SJ. The past, present, and future of costimulation blockade in organ transplantation. Current Opinion in Organ Transplantation. 2019;24(4):391-401. doi:https://doi.org/10.1097/mot.0000000000000656