Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection.
BACKGROUND
Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy.


METHODS
Eight episodes of mixed antibody-mediated rejection (AMR) and acute cellular rejection (ACR) in six transplant recipients were treated with bortezomib at labeled dosing. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels and repeated allograft biopsies.


RESULTS
Six kidney transplant patients received bortezomib for AMR and concomitant ACR. In each case, bortezomib therapy provided (1) prompt rejection reversal, (2) marked and prolonged reductions in DSA levels, (3) improved renal allograft function, and (4) suppression of recurrent rejection for at least 5 months. Moreover, immunodominant DSA (iDSA) (i.e., the antidonor human leukocyte antigen antibody with the highest levels) levels were decreased by more than 50% within 14 days and remained substantially suppressed for up to 5 months. One or more additional DSA were present at lower concentrations (non-iDSA) in each patient and were also reduced to nondetectable levels. Bortezomib-related toxicities (gastrointestinal toxicity, thrombocytopenia, and paresthesias) were all transient.


CONCLUSIONS
Bortezomib therapy: (1) provides effective treatment of AMR and ACR with minimal toxicity and (2) provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.
Everly
Matthew J
MJ
Department of Surgery, Division of Transplantation, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0558, USA.
Everly
Jason J
JJ
Susskind
Brian
B
Brailey
Paul
P
Arend
Lois J
LJ
Alloway
Rita R
RR
Roy-Chaudhury
Prabir
P
Govil
Amit
A
Mogilishetty
Gautham
G
Rike
Adele H
AH
Cardi
Michael
M
Wadih
George
G
Tevar
Amit
A
Woodle
E Steve
ES
D000208:Acute Disease; D001706:Biopsy; D001897:Boronic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D003404:Creatinine / Q000097:blood; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D010292:Paresthesia / Q000139:chemically induced; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D014481:United States; D014486:United States Food and Drug Administration
D001897:Boronic Acids; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003404:Creatinine