The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates

  • Sci Transl Med. 2023 Aug 30;15(711):eadf6376. doi: 10.1126/scitranslmed.adf6376.
Imran J Anwar  1 ,  Dora M Berman  2  3 ,  Isabel DeLaura  1 ,  Qimeng Gao  1 ,  Melissa A Willman  2 ,  Allison Miller  1 ,  Alan Gill  4 ,  Cindy Gill  4 ,  Steve Perrin  5 ,  Camillo Ricordi  2  3  6  7  8 ,  Philip Ruiz  3 ,  Mingqing Song  1 ,  Joseph M Ladowski  1 ,  Allan D Kirk  1 ,  Norma S Kenyon  2  3  6  7
Affiliations
  • 1. Duke Transplant Center, Department of Surgery, Duke University School of Medicine; Durham, NC 27710, USA.
  • 2. Diabetes Research Institute, University of Miami, Miami, FL 33136, USA.
  • 3. Department of Surgery, University of Miami, Miami, FL 33136, USA.
  • 4. ALS Therapy Development Institute, Cambridge, MA 02472, USA.
  • 5. Eledon Pharmaceuticals, Irving, CA 92612, USA.
  • 6. Department of Microbiology and Immunology, University of Miami, Miami, FL 33136, USA.
  • 7. Department of Biomedical Engineering, University of Miami, Miami, FL 33136, USA.
  • 8. Department of Medicine, University of Miami, Miami, FL 33136, USA.
PMID: 37647390 DOI: 10.1126/scitranslmed.adf6376
Abstract

Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.

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