# A Phase 1 Clinical Trial of Siltuximab for the Treatment of Antibody-Mediated Rejection after Lung Transplantation

> **NIH NIH R61** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $283,671

## Abstract

PROJECT SUMMARY/ABSTRACT
Long-term outcomes after lung transplantation remain disappointing, and the median survival is 6.7 years.
Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung
transplantation. Antibody-mediated rejection (AMR), which is increasingly recognized after lung transplantation,
is caused by donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) and frequently
results in CLAD and death. Recent multicenter studies using intensive monitoring for AMR report an incidence
over 25%. Treatment for AMR has generally focused on antibody-depletion and prevention of additional antibody
development. Various combinations have been used including high-dose corticosteroids, intravenous immune
globulin (IVIG), Rituximab, Carfilzomib, anti-thymocyte globulin (ATG), and plasma exchange (PLEX). However,
there have been no randomized controlled trials to guide management, and outcomes after AMR are dismal.
One-year allograft survival after AMR is approximately 50%, and 2-year survival is only 20%. IL-6, initially
identified as B-cell stimulating factor 2 (BSF-2), is a pleiotropic cytokine that drives deleterious inflammatory,
alloimmune, and fibrogenic responses. In conjunction with other cytokines, IL-6 is responsible for normal
antibody production and is critical for the induction of follicular helper T-cells as well as the production of IL-21
which regulates immunoglobulin synthesis. IL-6 is also crucial for B-cell differentiation into plasmablasts and for
enhancing plasmablast survival. These characteristics make IL-6 an especially attractive cytokine to target in
the management of AMR. Human studies examining the role of IL-6 signaling blockade in the management of
AMR after kidney transplantation have shown promising results, even in refractory cases. We have used IL-6
signaling blockade in a very small number of lung transplant recipients with AMR at our center with encouraging
results. Our principal hypothesis is that IL-6 signaling blockade added to routine immunosuppressive treatment
for AMR would improve clinical outcomes. However, evaluating the safety of this approach is necessary before
examining efficacy in larger clinical trials because infections are the most common serious adverse events
associated with IL-6 signaling blockade and a common cause of death at all timepoints after lung transplantation.
Thus, we propose a Phase 1 clinical trial using Siltuximab, a monoclonal antibody to IL-6, in addition to routine
immunosuppressive therapy for AMR to examine safety and define the optimal dose for the treatment of AMR.
The primary endpoint is safety and tolerability, and secondary endpoints include pharmacodynamics and
functional biological measures relevant to AMR (e.g., DSA, cell-free DNA). Data from this trial will inform the
design of a future Phase 2 clinical trial that assesses efficacy. Carefully designed and implemented clinical trials
are necessary to im...

## Key facts

- **NIH application ID:** 10925203
- **Project number:** 7R61HL169189-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Derek E Byers
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $283,671
- **Award type:** 7
- **Project period:** 2023-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10925203

## Citation

> US National Institutes of Health, RePORTER application 10925203, A Phase 1 Clinical Trial of Siltuximab for the Treatment of Antibody-Mediated Rejection after Lung Transplantation (7R61HL169189-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10925203. Licensed CC0.

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