Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant
In a phase 1/2 study, isatuximab monotherapy was well tolerated in highly sensitized kidney transplant candidates and produced durable reductions in anti-HLA antibodies, but had only partial desensitization activity with limited impact on calculated panel reactive antibody.
Background
There is no standardized desensitization regimen for kidney transplant candidates, and highly sensitized patients with calculated panel reactive antibody (cPRA) of 80% or higher, particularly those at 99.90% or higher, are underserved by the Kidney Allocation System. Because CD38 is highly expressed on plasma cells, it is a potential target for depleting cells that produce alloantibodies and donor-specific antibodies.
Study design
This open-label, single-arm phase 1/2 study evaluated the safety, pharmacokinetics, and preliminary efficacy of isatuximab, a CD38-targeting therapy, in patients awaiting kidney transplantation. Twenty-three patients were enrolled in two cohorts (12 with cPRA at least 99.90% and 11 with cPRA 80.00% to under 99.90%) and received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks, with a predefined composite desensitization endpoint.
Key findings
Isatuximab was well tolerated and reduced CD38-positive plasmablasts, plasma cells, and NK cells, with significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate by the composite endpoint was 83.3% in the cPRA 99.90%+ cohort and 81.8% in the lower-cPRA cohort, with most responders maintaining decreased anti-HLA antibodies for 26 weeks after the last dose. However, cPRA values were minimally affected, with only 9 of 23 patients (39%) reaching target cPRA levels; six patients received transplant offers and four were accepted.
Clinical implications
Isatuximab produced a durable decrease in anti-HLA antibodies with partial desensitization activity, suggesting it could be investigated further as an adjunct to existing desensitization strategies for patients on the kidney transplant waitlist. The short treatment period with long follow-up helped clarify the mechanism and timing of any antibody rebound.
Category
Transplant
Source
Journal of the American Society of Nephrology
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