Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Abstract

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 .

Graphical abstract

Figure 1

Patient disposition.

Figure 2

Examples of patients who were responders per protocol but did not meet target cPRA in criterion 1. Class I and class II anti-HLA antibody heat maps illustrate the MFI values of the top 60 HLA alleles (from the top, in descending order on the basis of their BL titer) at neat, 1:16, and 1:256 dilutions. Each dilution includes BL, W9 (approximately 9 weeks after the last dose), W25 (approximately 25 weeks after the last dose). Spaghetti plots illustrate the absolute change in MFIs in neat serum of anti-HLA antibodies with BL MFI ≥10,000. BL, baseline; C, cycle; cPRA, calculated panel reactive antibody; D, day; FUP, follow-up; MFI, mean fluorescence intensity; N, neat; WK, week.

Figure 3

Sustained decrease in total IgG and IgM levels up to last analyzed timepoint. Evolution of (A) total IgG levels and (B) total IgM levels.

Figure 4

No notable changes were observed in the total mBC or total Treg population, although decreases in plasmablasts and plasma cells were observed at C3D1 that returned to baseline by week 17 after last dose. (A) Plasmablasts, (B) plasma cells, (C) CD38⁺ mBCs, (D) CD38⁻ mBCs, (E) overall Treg cells, (F) CD38⁺ Treg cells, and (G) CD38⁻ Treg cells over isatuximab treatment from BL to follow-up at week 17* *Plotted with logarithmic scale for ease of visualization. “0” values were replaced with “0.01.” mBC, memory B cell.

Figure 5

Boxplots of mBC function. Median IgG-secreting HLA-sp mBCs against all HLA antigens at distinct time points were 8.5 (4–19.75) at BL, 7 (0–15.7) at C3D1 and 5 (0.5–14.5) at FUP week 1, against class I HLA antigens were 12.5 (3.5–24) at BL, 9 (2.25–24.5) at C3D1, and 5.5 (0–16.3) at FUP week 1 and against class II HLA antigens were 8 (3.8–15.2) at BL, 5 (0–12.3) at C3D1, and 5 (1–12) at FUP week 1. ns, nonsignificant.

Figure 6

Boxplots of HLA-specific IgG-producing bone marrow–residing plasma cells. (A) Median IgG-secreting plasma cell frequencies at two distinct time points against all HLA antigens in the three tested patients were 1.6 (1.1–2.4) at BL and 0 (0–0.25) at FUP week 1, against HLA-I antigens were 1.3 (1.1–2.1) at BL and 0 (0–1) at FUP week 1, and against HLA-II antigens were 2 (1.1–3) at BL and 0 (0–0) at FUP week 1. (B) The median IgG-secreting plasma cell frequencies at BL and FUP week 1 in patient 0712 was 1.1 (1.1–1.3) versus 0 (0–0), in patient 0714 was 2 (1–3) versus 0 (0–3), and in patient 0724 was 1.28 versus 0.