Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant.

Autor:	Vincenti F; Departments of Medicine and Surgery, University of California San Francisco, San Francisco, California., Bestard O; Department of Nephrology and Kidney Transplantation, University Hospital Vall d'Hebron, Barcelona, Spain.; Nephrology and Kidney Transplantation Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain., Brar A; Department of Medicine, University of California San Francisco, San Francisco, California., Cruzado JM; Department of Nephrology, Hospital Universitari de Bellvitge, University of Barcelona, Barcelona, Spain.; Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Seron D; Department of Nephrology and Kidney Transplantation, University Hospital Vall d'Hebron, Barcelona, Spain., Gaber AO; Department of Surgery, Houston Methodist Hospital, Houston, Texas., Ali N; Department of Surgery, Transplant Institute, New York University Langone Health, New York, New York., Tambur AR; Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Lee H; Sanofi, Cambridge, Massachusetts., Abbadessa G; Sanofi, Cambridge, Massachusetts., Paul JA; Sanofi, Bridgewater, New Jersey., Dudek M; Sanofi R&D, Frankfurt, Germany., Siegel RJ; Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Torija A; Nephrology and Kidney Transplantation Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain., Semiond D; Sanofi, Cambridge, Massachusetts., Lépine L; Sanofi R&D, Chilly-Mazarin, France., Ternes N; Sanofi R&D, Chilly-Mazarin, France., Montgomery RA; Department of Surgery, Transplant Institute, New York University Langone Health, New York, New York., Stegall M; Department of Surgery, Mayo Clinic Rochester, Rochester, Minnesota.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2024 Mar 01; Vol. 35 (3), pp. 347-360. Date of Electronic Publication: 2023 Dec 26.
DOI:	10.1681/ASN.0000000000000287
Abstrakt:	Significance Statement: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. Background: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. Methods: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. Results: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. Conclusions: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. Clinical Trial Registration Number: NCT04294459 . (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)
Databáze:	MEDLINE
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