# Belatacept in De Novo Heart Transplant

> **NIH NIH R34** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $269,861

## Abstract

ABSTRACT
While the last decade has seen improvements in survival following heart transplant, long-term
outcomes remain suboptimal with an unacceptably high burden of comorbidities contributing to
morbidity and mortality. Amongst these, renal dysfunction remains at the forefront with underlying
pre-transplant renal impairment perpetuated by chronic calcineurin inhibitor (CNI) exposure
leading to severe chronic kidney disease (creatinine > 2.5mg/dL, dialysis, or transplant) in almost
one-quarter of heart transplant recipients within 10-years. Simultaneously, cardiac allograft
survival is limited by the relentless immunological processes, both innate and adaptive that drive
the development of cardiac allograft vasculopathy (CAV), fibrosis, and graft failure. The
appearance of de novo donor specific antibodies (dnDSA) in particular portend a worse outcome5-
7. Clinically, hypertension, hypercholesterolemia and diabetes further contribute to renal
dysfunction and adverse allograft outcomes. Thus, there is an urgent need for therapies that more
favorably modulate the immune response while simultaneously reduce the comorbidity profile.
Belatacept (CTLA4-Ig; NULOJIX®) is a fusion protein comprised of the extracellular domain of
human CTLA4 and the Fc domain of a human immunoglobulin (Ig) G1. By binding to CD80 and
CD86 on antigen presenting cells (APCs), belatacept prevents CD28 mediated signaling critical
for i) T cell activation and proliferation, ii) T follicular helper cell (Tfh) differentiation, iii) cognate
T/B cell interactions and iv) both effector and regulatory mechanisms responsible for the balance
between acceptance and rejection. Belatacept is FDA approved for use in kidney transplant
recipients on the basis of two randomized controlled trials, which demonstrated impressive renal
sparing benefits, a striking reduction in de novo donor specific antibodies (DSA), and improved
long-term outcomes. The core hypothesis underlying this proposal is that belatacept, combined
with an entry period of concomitant tacrolimus, will preserve or protect renal function in de novo
heart transplant recipients and provide sustained long-term benefit. Specifically, we hypothesize
that, in addition to the renoprotective benefits of a CNI-free regimen, belatacept will improve
outcomes by i) impairing de-novo humoral responses and their downstream consequences, ii)
mitigating alloimmune memory, and iii) reducing the burden of comorbidities. The goal of the
current R34 application is to develop a clinical trial protocol that will test our hypothesis by 1)
determining the efficacy of a belatacept-based CNI sparing regimen on improving renal function
and cardiac allograft outcomes in heart transplant recipients, and 2) investigating the effects of
belatacept on T-cell alloimmunity, humoral responses, and fibrosis.

## Key facts

- **NIH application ID:** 10018320
- **Project number:** 1R34AI152962-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Marlena Habal
- **Activity code:** R34 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $269,861
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018320

## Citation

> US National Institutes of Health, RePORTER application 10018320, Belatacept in De Novo Heart Transplant (1R34AI152962-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10018320. Licensed CC0.

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