Allan Kirk, MD, PhD

Dual Costimulation Blockade May Eliminate Daily Oral Immunosuppression in Kidney Transplant

A pilot trial evaluating dual costimulatory blockade, dazodalibep + belatecept, may promote immunosuppression adherence and present a non-calcineurin treatment option for kidney transplant recipients.

The phase 2a pilot trial is the first clinical trial to evaluate dual costimulation blockade in humans, with study investigators reporting that a significant number of patients did not require any daily oral medications for 1 year.

“That's never been done,” said Allan Kirk, MD, PhD, a transplant surgeon at Duke Kidney/Transplant Clinic, in an interview with 

 “All immunosuppressive regimens have involved at least some oral medication every single day. And this just showed proof of concept that you could do episodic therapy instead of daily therapy. And I think for patients that's a big plus.”

In a previous interview, we broke down the 

mechanistic rationale and history of targeting the costimulatory pathway with Kirk

Kirk and fellow study investigator concluded the phase 2a, open-label, single-arm, pilot trial to evaluate the efficacy, safety, and tolerability of dual costimulation blockade, 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.

The mean cumulative amount of dazodalibep and belatacept each patient received during the course of the trial was 18,673.9 mg and 6,975.8 mg, respectively.

After administration of dazodalibep and belatacept, patients returned to the transplant center for safety monitoring and costimulation-blockade therapy administration on day 7 and week 2, then every 2 weeks for 5 visits, and then monthly for 9 visits until week 48. All patients were monitored for acute rejection, graft survival, and patient survival through week 48. Patients were followed for a 12-week safety follow-up period after discontinuation of the investigational regimen and conversion to standard-of-care management at the investigator’s discretion.

Investigators deemed the primary endpoint as the incidence of efficacy failure, defined as treated biopsy-proven acute rejection (tBPAR) ≥ grade 1A, graft loss, or death at week 24 after transplantation. The secondary endpoints were the incidence of tBPAR, graft loss, death, or loss to follow-up; incidence of antibody-mediated rejection; incidence of biopsy-proven acute rejection; incidence of treated acute rejections; the proportion of patients with de novo DSAs; as well as the safety and tolerability of dual costimulation. These were evaluated at weeks 12, 24, and 48.

Additional exploratory endpoints included the proportion of patients with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 at weeks 12, 24, and 48. The safety endpoints were treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs).

The trial population included 23 patients, 18 to 70 years of age. Of the 23 enrolled patients who received dazodalibep and belatacept, 13 completed and 10 discontinued the trial. All patients discontinuing either dazodalibep and/or belatacept entered the safety follow-up.

Upon analysis, investigators reported the incidence of composite efficacy failure was 25% (5/20) at weeks 12, 24, and 48. Additionally, there were reversible rejections in patients who received transplants from living related donors (n = 3), a living unrelated donor (n = 1), and a deceased heart-beating donor (n = 1). Overall, they observed 100% graft and patient survival, with 1 patient experiencing delayed graft function.

Investigators did not observe any patients with antibody-mediated rejections, sharing that 30% had treated acute rejections by week 48 (n = 6). Of these, 5 were diagnosed within 12 weeks of transplantation.

The mean (SD) eGFR for all efficacy-evaluable patients at week 48 was 71.3 (12.7) mL/min/1.73 m2 and was similar for patients who did or did not experience an episode of rejection. The percentage of evaluable patients with an eGFR ≥60 mL/min/1.73 m2 was 59%, 74%, and 92% at weeks 12, 24, and 48, respectively.

“This means that people on this approach need to be monitored carefully and early if you catch a rejection, it's easy to reverse,” explained Kirk.

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

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. 

https://doi.org/10.1016/j.ajt.2025.12.290

Kirk A, Hillenbrand A. Mechanistic Rationale for Dual Costimulation Blockade, Belatacept, Dazodalibep in Kidney Transplantation. HCPLive. Published February 18, 2026. Accessed February 19, 2026. 

https://www.hcplive.com/view/mechanistic-rationale-for-dual-costimulation-blockade-belatacept-dazodalibep-in-kidney-transplantation

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Targeting CD28 and CD154 pathways, dual blockade with belatacept and dazodalibep offers potential to improve adherence in kidney transplant recipients.



Belatacept + Dazodalibep: Mechanistic Breakthrough in Transplant Immunosuppression

Dual costimulation may represent a new paradigm in

immunosuppression, according to study investigators.

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.

“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 

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.

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 

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.

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.

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.

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.

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.

To follow along with the findings, watch the 

Schroder PM, Fitch ZW, Schmitz R, Choi AY, Kwun J, Knechtle SJ. The past, present, and future of costimulation blockade in organ transplantation. 

https://doi.org/10.1097/mot.0000000000000656

Targeting CD28 and CD154 pathways, dual blockade with belatacept and dazodalibep offers a new mechanistic approach in kidney transplant care.

Allan Kirk, MD, PhD

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