Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejectionresults from a first-in-patient phase 1 trial

作者：Eskandary F.; Jilma B.; Muehlbacher J.; Wahrmann M.; Regele H.; Kozakowski N.; Firbas C.; Panicker S.; Parry G. C.; Gilbert J. C.; Halloran P. F.; Boehmig G. A.

来源：American Journal of Transplantation, 2018, 18(4): 916-926.

DOI：10.1111/ajt.14528

• clinical research
• practice
• clinical trial
• complement biology
• immunosuppressant - fusion proteins and monoclonal antibodies
• immunosuppression
• immune modulation
• kidney transplantation
• nephrology
• pathology
• histopathology
• protocol biopsy
• rejection: antibody-mediated (ABMR)

The classical pathway (CP) of complement may contribute to the pathogenesis of antibody-mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first-in-patient phase 1b trial was to evaluate the safety/tolerability and CP-blocking potential of 4 weekly doses (60mg/kg) of the anti-C1s antibody BIVV009 in complement-mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3years posttransplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement-fixing donor-specific antibodies (DSA). During 7 weeks follow-up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA-triggered CP activation in serum. Five of 8 C4d-positive recipients turned C4d-negative in 5-week follow-up biopsies, while another 2 recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody-triggered CP activation, even though short-course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials.gov NCT#02502903.
This first-in-patient phase 1 trial demonstrates safety, tolerability, and profound complement inhibition efficacy of a novel humanized anti-C1s monoclonal antibody in a cohort of 10 kidney allograft recipients with late antibody- mediated rejection.

• 出版日期2018-4