Targeting Costimulatory Pathways in Kidney Transplant With Eliezer Katz, MD

Published on: February 5, 2026

After kidney transplantation, clinicians often have to navigate long-term patient outcomes, including preventing early acute rejection, preserving graft function, and ensuring overall safety.1

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.1

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.1

Targeting Costimulatory Pathways

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.1,2

“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.1,2

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.1

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.1,2

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.3

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.3

In the ongoing 12-month, randomized, head-to-head phase 2 BESTOW trial, investigators are evaluating tegoprubart, compared with a standard tacrolimus treatment regimen in kidney transplant recipients, with a target enrollment of > 120 participants across multiple global sites.3

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).3

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.3

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.3

Clinical Implications

“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.2,3

References

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. 2021;16(8):1264-1271. doi:https://doi.org/10.2215/cjn.15040920
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

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