Tegoprubart (AT-1501) calcineurin-free donor islet transplant

Overview

Tegoprubart (AT-1501) is a humanized IgG1 monoclonal antibody developed by Eledon Pharmaceuticals that binds CD40 Ligand (CD40L / CD154) on activated T cells, blocking costimulatory interaction with CD40 on antigen-presenting cells, B cells, and endothelial cells.

For a quarter-century since the 2000 Edmonton Protocol, clinical islet transplantation (including FDA-approved Lantidra and Vertex's Phase 3 zimislecel / VX-880 trial) has relied on tacrolimus, a calcineurin inhibitor (CNI), to prevent graft rejection. However, tacrolimus has two severe drawbacks in Type 1 Diabetes:

1. Direct Beta-Cell Toxicity (Diabetogenicity): Calcineurin signaling is required for beta-cell insulin gene transcription, granule exocytosis, and survival; tacrolimus directly impairs insulin secretion from the newly transplanted islets.
2. Nephrotoxicity & Neurotoxicity: Chronic tacrolimus causes progressive renal arteriolar vasoconstriction and interstitial fibrosis (declining eGFR), hand tremors, hypertension, and post-transplant diabetes.

First-generation anti-CD40L antibodies (ruplizumab / hu5c8) showed dramatic transplant tolerance in primates two decades ago but were halted in human trials because their wild-type IgG1 Fc region cross-linked FcγRIIa receptors on human platelets, causing thromboembolism. Tegoprubart (AT-1501) was specifically engineered with Fc point mutations that silence FcγR and complement binding while preserving high-affinity CD40L blockade (PMID: 37647390).

Key Clinical Evidence

University of Chicago Phase 1/2 Trial (NCT06305286, Dr. Piotr Witkowski)

Funded by Breakthrough T1D (formerly JDRF) and The Cure Alliance, NCT06305286 is an investigator-initiated Phase 1/2 trial led by Dr. Piotr Witkowski at the University of Chicago evaluating intraportal allogeneic human donor islet transplantation under a calcineurin-inhibitor-free regimen:

• Regimen: Peri-transplant induction with anti-thymocyte globulin (ATG) (or basiliximab for second infusions) plus etanercept (anti-TNF-$\alpha$), followed by chronic maintenance with intravenous tegoprubart (20 mg/kg every 3 weeks) plus oral mycophenolate mofetil / mycophenolic acid (MMF/MPA) — with zero tacrolimus.
• June 2026 ADA Scientific Sessions Readout (n = 12 Initial Cohort):
  • 100% Insulin Independence (12/12): All 12 consecutive patients in the initial cohort achieved complete insulin independence (several after a single islet infusion, others after a second infusion depending on baseline body weight and insulin demand).
  • Normoglycemic HbA1c & Time in Range: 12 of 12 (100%) achieved HbA1c below 6.5%, with a mean most recent HbA1c of ~5.4% (an average reduction of ~2.6 percentage points from baseline), >94% continuous glucose monitoring time in the target range (70–180 mg/dL [3.9–10.0 mmol/L]), and zero severe hypoglycemic episodes post-transplant.
  • Durability to Date: Median follow-up across the 12 patients was 8 months, with the earliest-treated recipients maintaining complete insulin independence out to 22 months.
  • Superior Engraftment Efficiency (BETA-2 Score): Composite BETA-2 beta-cell function scores were roughly double those observed in historical tacrolimus-treated islet recipients at equivalent islet equivalents per kilogram (IEQ/kg), reflecting the absence of tacrolimus-induced beta-cell suppression.
  • Safety & Rejection Profile: Zero acute rejection episodes, zero de novo donor-specific HLA antibodies (DSA), zero thromboembolic events, and preserved kidney function (eGFR) without CNI tremor or new-onset hypertension. Typical systemic immunosuppression adverse events (such as mycophenolate-related gastrointestinal or white-blood-cell effects) were managed with standard mycophenolate dose reductions.

Combination Partnerships (Sernova & NewcelX)

• Sernova Cell Pouch Cohort C (NCT03513939): Sernova and Eledon expanded their clinical collaboration in July 2025 to evaluate a tacrolimus-free tegoprubart regimen in Cohort C of Sernova's subcutaneous Cell Pouch islet transplant trial (sernova-bio-hybrid-organ).
• NewcelX (NCEL-101 / IsletRx): NewcelX is evaluating tegoprubart alongside its hESC-derived islet clusters (newcelx-ncel101-isletrx) in preclinical translational studies.

Limitations & Watch Items

1. Systemic Immunosuppression Is Still Required: Tegoprubart is a less toxic immunosuppressive backbone, not an immunosuppression-free cure. Recipients still undergo ATG lymphocyte depletion at induction, take daily mycophenolate, and receive intravenous tegoprubart infusions every 3 weeks, remaining subject to systemic infection and malignancy surveillance precautions.
2. Multi-Year Durability & Stem-Cell Pairing: While 22-month durability in the earliest patients and 12/12 insulin independence are major milestones, 3- to 5-year follow-up and pairing tegoprubart with scalable stem-cell-derived islets (such as VX-880/zimislecel-class cells) will determine its ultimate reach.

Summary of Strengths & Limitations

Strengths

• In the June 2026 ADA readout of NCT06305286 (Dr. Piotr Witkowski, University of Chicago), 12 of 12 (100%) patients in the initial cohort achieved complete insulin independence (longest follow-up 22 months; median 8 months) with mean HbA1c ~5.4% and zero severe hypoglycemic events
• Eliminates calcineurin inhibitors (tacrolimus), avoiding both direct calcineurin-inhibitor beta-cell toxicity (yielding markedly higher BETA-2 engraftment scores per infused islet mass) and calcineurin-driven kidney toxicity, tremor, and hypertension
• Fc-modified IgG1 architecture abrogates platelet Fc-gamma-RIIa binding, with zero thromboembolic events, zero acute rejection episodes, and zero de novo donor-specific HLA antibodies reported across the cohort

Limitations

• {'Still requires chronic systemic immunosuppression': 'induction with anti-thymocyte globulin (ATG) and etanercept followed by lifelong intravenous infusions of tegoprubart (20 mg/kg every 3 weeks) plus daily oral mycophenolate (MMF/MPA)'}
• Carries systemic immunosuppression risks (infection susceptibility and mycophenolate gastrointestinal/hematologic side effects requiring dose adjustments)
• Currently paired in NCT06305286 with scarce deceased-donor human islets, though collaborations are underway to pair tegoprubart with Sernova's Cell Pouch and NewcelX's stem-cell islets