Eliezer Katz, MD, is the chief medical officer at Eledon Pharmaceuticals. 

Eliezer Katz, MD

Targeting Costimulatory Pathways With Eliezer Katz, MD

After kidney transplantation, clinicians often have to navigate long-term patient outcomes, including preventing early acute rejection, preserving graft function, and ensuring overall safety.

Over the years, calcineurin inhibitors have been effective at preventing early acute rejection, but their broad mechanism of action can contribute to nephrotoxicity, metabolic disturbances, and cardiovascular complications over time.

As a result, long-term graft survival has not improved proportionally, despite reductions in acute rejection rates since the 1990s. Overall, chronic allograft dysfunction remains a major clinical challenge, often driven by a combination of calcineurin inhibitor nephrotoxicity, subclinical immune activation, medication nonadherence, and metabolic or cardiovascular complications.

Costimulatory pathways have emerged as a focal point in efforts to refine immunosuppression following kidney transplantation. These pathways act upstream in T- and B-cell activation, offering potential to reduce chronic, low-grade immune activation without broadly suppressing the immune system.

“The immune system can be activated through multiple pathways. One of these is the calcineurin pathway, while another is the costimulation pathway,” explained Eliezer Katz, MD, Chief Medical Officer at Eledon Pharmaceuticals. “CD40 ligand sits at the center of this costimulation pathway. By blocking CD40 ligand, tegoprubart prevents the immune system from mounting a full attack on the graft.”

Costimulatory blockade occurs earlier in the immune activation process than CNIs, which act downstream after T cells are engaged. Early intervention at this level may reduce memory T-cell formation, preserve regulatory T-cell signaling, and potentially mitigate chronic immune-mediated injury that contributes to long-term graft dysfunction.

Mechanistic Rationale for CD40 Ligand Blockade

The CD40–CD40 ligand (CD40L) pathway sits at the intersection of T-cell activation, B-cell maturation and class switching, germinal center formation, and antibody-mediated rejection biology. This makes it particularly relevant to humoral rejection, chronic antibody-mediated injury, and long-term graft fibrosis.

Early anti-CD40L antibodies were limited by thromboembolic events, likely due to CD40L expression on activated platelets and Fc-mediated crosslinking that triggered platelet aggregation. Tegoprubart, a humanized monoclonal antibody targeting CD40L, is engineered to minimize Fc-mediated platelet activation while selectively disrupting cellular and humoral costimulatory signaling.

Early Clinical Evaluation: Phase 1b and Phase 2 BESTOW Trial

In the phase 1b trial, over 24 months, tegoprubart had an acceptable safety profile. All patients experienced ≥1 TEAE, while SAEs were reported for 3 patients, and AESIs were reported for 7 patients. No cases of biopsy-proven acute rejection, de novo DSA, delayed graft function, or graft loss were reported.

Investigators observed functional eGFR levels were restored within 1 month after transplantation and generally maintained over 24 months. At 12 and 24 months, mean (SD) eGFRs were 67.0 (19.85) mL/min/1.73 m² and 74.2 (24.91) mL/min/1.73 m², respectively.

In the 12-month, randomized, head-to-head phase 2 BESTOW trial, investigators evaluated tegoprubart, compared with a standard tacrolimus treatment regimen in kidney transplant recipients, with a target enrollment of > 120 participants across multiple global sites.

All participants received standard induction and maintenance therapy, including rATG, mycophenolate, and steroids. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) at 12 months. Secondary endpoints included biopsy-proven acute rejection, graft survival, composite efficacy failure, delayed graft function, donor-specific antibodies, and new-onset diabetes after transplant (NODAT).

Preliminary 12‑month data indicate mean eGFR values of 69 mL/min/1.73 m² in the tegoprubart group versus 66 mL/min/1.73 m² in the tacrolimus group.

Upon subgroup analyses, investigators observed increased eGFR in some donor subgroups, including living-related donors and higher Kidney Donor Profile Index cases.

In terms of safety, biopsy-proven acute rejection occurred in 20.6% compared to 14.1% of participants, and composite efficacy failure was 22% compared to 17%, respectively, indicating tegoprubart maintained immunosuppressive efficacy within the study’s predefined margin.

“Most transplant rejection occurs in the first year, making early control critical. Maintaining kidney function during this period, and beyond, is essential for long-term graft survival,” Katz said. “By targeting CD40 ligand and preserving kidney function, tegoprubart has the potential to improve long-term outcomes and allow patients to enjoy their grafts for many years.”

While the data are early and further evaluation is ongoing, mechanistic and clinical rationale suggest targeted CD40L blockade may offer a more precise approach to immunosuppression, explains Katz. By modulating immune activation without broadly suppressing T-cell function, clinicians may be able to maintain graft protection while mitigating systemic toxicities associated with calcineurin inhibitors.

Editor’s Note: Katz reports relevant disclosures with Eledon Pharmaceuticals. 

Pellegrino B. Immunosuppression: Practice Essentials, History, Drugs. Medscape.com. Published October 28, 2024. 

https://emedicine.medscape.com/article/432316-overview?form=fpf#a1

Wojciechowski D, Wiseman A. Long-Term Immunosuppression Management. 

Clinical Journal of the American Society of Nephrology

Eledon Presents Phase 2 BESTOW Trial Results for Tegoprubart for the Prevention of Rejection in Kidney Transplantation at the American Society of Nephrology’s Kidney Week 2025 Annual Meeting | Eledon Pharmaceuticals, Inc. Eledon Pharmaceuticals, Inc. Published 2025. ​

https://ir.eledon.com/news-releases/news-release-details/eledon-presents-phase-2-bestow-trial-results-tegoprubart

Articles

Long-term kidney allograft survival remains constrained by calcineurin inhibitor–associated nephrotoxicity and chronic immune-mediated injury, despite marked reductions in early acute rejection. Costimulatory pathway modulation, particularly CD40–CD40L blockade, offers an upstream strategy to attenuate T- and B-cell activation, potentially limiting memory T-cell development and humoral injury. Tegoprubart is engineered to avoid Fc-mediated platelet activation that hampered earlier anti-CD40L agents. Early trials suggest preserved renal function with acceptable safety, with ongoing randomized comparisons versus tacrolimus.

Tegoprubart, a CD40L-targeted therapy, may improve long-term kidney transplant outcomes by reducing immune-mediated injury.

Targeting Costimulatory Pathways in Kidney Transplant With Eliezer Katz, MD

2-Year Phase 1b Tegoprubart Preserves Kidney Function in Transplant Recipients, With Eliezer Katz, MD

2-year phase 1b results from the first adult de novo kidney transplant recipients treated with tegoprubart as the core immunosuppressive agent showed preserved 

, no episodes of acute rejection, and an acceptable safety profile.

The findings were presented at the American Society of Transplant Surgeons (ASTS) Winter Symposium, January 22–25, 2026, in Phoenix, AZ, and highlight the potential for non-calcineurin inhibitor-based immunosuppression.

Currently, the standard of care for kidney transplant immunosuppression in the United States is a calcineurin inhibitor–based regimen with tacrolimus and mycophenolate. Overall, > 90% of patients are maintained on these 2 agents, with or without corticosteroids.

Tacrolimus is a potent immunosuppressive drug used primarily to prevent organ rejection in transplant recipients. It acts as a calcineurin inhibitor, binding to FKBP12 to block T-cell activation and IL-2 production. While highly effective, neurotoxic effects are common, including hand tremors, insomnia, and headaches. Long-term tacrolimus use is associated with nephrotoxicity, supporting continued evaluation of noncalcineurin inhibitor–based regimens.

“Calcineurin inhibitors are very effective at preventing rejection, but they come at a significant cost,” said Eliezer Katz, MD, Chief Medical Officer of Eledon Pharmaceuticals, in an interview with 

. “Beyond nephrotoxicity, calcineurin inhibitors can damage pancreatic islet cells, leading to diabetes, and cause neurologic side effects such as tremor, brain fog, insomnia, and headaches. They are also associated with hypertension and cardiovascular effects. Patients are grateful that their graft is functioning, but many are still suffering from these side effects.”

Tegoprubart, a humanized monoclonal antibody, selectively inhibits CD40 ligand (CD154), a co-stimulatory molecule in T-cell activation. The investigational drug has the potential to enter the treatment landscape as a non–calcineurin inhibitor immunosuppressive option, with sustained preservation of kidney function observed through 24 months.¹

To investigate tegoprubart, Katz and colleagues conducted a multicenter, phase 1b, single-arm trial, enrolling adults who were Epstein–Barr virus (EBV)–seropositive, had low levels of panel-reactive antibodies, and had no donor-specific antibodies (DSAs) at screening before receipt of their first kidney transplant from a living or deceased donor.

On the day of transplantation, all patients received induction with rATG ≤6 mg/kg and maintenance therapy with intravenous tegoprubart (20 mg/kg, administered on days 1, 7, 14, 21, and 28 post-transplantation). After this, every 21 days, patients received mycophenolate and corticosteroids.

The primary safety endpoints included the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). If a patient experienced > 1 adverse event with the same preferred term, they were counted once for that term.

At 12 and 24 months, exploratory endpoints included the incidence of biopsy-proven acute rejection, graft failure, de novo DSA formation, and mean estimated glomerular filtration rate (eGFR). Patients who completed 12 months of treatment were offered enrollment in an open-label extension study.

Overall, 8 patients completed 12 months of treatment and continued into the extension study. The mean (standard deviation [SD]) treatment duration with tegoprubart was 29.50 (5.42) months, with 7 of the 8 patients completing at least 24 months of treatment.

“Tegoprubart has a different mechanism of action. It offers the possibility of achieving effective immunosuppression without many of these side effects, as we demonstrated in a phase 2 study that we recently presented at Kidney Week in Houston in early November,” explained Katz. “The fundamental difference is specificity. Tacrolimus is a small molecule taken orally, and its effects are distributed throughout the body. Because calcineurin plays a role in many cellular processes, inhibiting it affects virtually every organ system, which explains the wide range of side effects.”

Over 24 months, tegoprubart had an acceptable safety profile. All patients experienced ≥1 TEAE, while SAEs were reported for 3 patients, and AESIs were reported for 7 patients. No cases of biopsy-proven acute rejection, de novo DSA, delayed graft function, or graft loss were reported.

Investigators observed that functional eGFR levels were restored within 1 month after transplantation and generally maintained over 24 months. At 12 and 24 months, mean (SD) eGFRs were 67.0 (19.85) mL/min/1.73 m² and 74.2 (24.91) mL/min/1.73 m², respectively.

Tegoprubart is also advancing through additional clinical programs, including the Phase 2 BESTOW trial in kidney transplantation and early investigator‑initiated studies in islet cell transplant rejection, with further data and regulatory guidance expected as development continues.

E. Katz, T. Coates, J. Gill2, et al. Long-Term Outcomes of a Phase 1, Single-Arm Cohort of De Novo Kidney Transplant Recipients Treated with Tegoprubart, an Anti-CD40L Antibody, as the Core Immunosuppression Regimen. Poster presented at: American Society of Transplant Surgeons (ASTS) Winter Symposium. January 22-25, 2026; Phoenix, AZ.

Araya AA, Tasnif Y. Tacrolimus. PubMed. Published May 29, 2023. 

https://www.ncbi.nlm.nih.gov/books/NBK544318/

Laskow DA, Neylan JF, Shapiro RS, Pirsch JD, Vergne-Marini PJ, Tomlanovich SJ. The role of tacrolimus in adult kidney transplantation: a review. 

Videos

Eliezer Katz, MD, says investigational anti-CD40L therapy tegoprubart shows promise as a non-calcineurin inhibitor option for adult de novo kidney transplant patients