Torque Teno Virus Control by the Classical Pathway of Complement Activation-A Retrospective Analysis From a First-in-Human Trial Utilizing Sutimlimab

Abstract

Torque Teno virus (TTV) load is linked with the functionality of its host's immune system and has been proposed as a potential monitoring tool for immune-modulating therapy. However, the immunological mechanisms of TTV control are incompletely understood. To assess the effect of the classical complement pathway on TTV, 64 healthy volunteers and 10 kidney transplant recipients treated with the anti-C1s antibody sutimlimab were analyzed for serum TTV copy numbers (c/mL) by qPCR. Overall, a correlation was observed between the decrease in complement activity caused by sutimlimab and the TTV load increase (ρ = -0.367, p < 0.001). Subgroup analysis indicated a trend toward TTV load increase in healthy volunteers following the highest sutimlimab dose compared to baseline (100 mg/kg body weight; median 3.5 log₁₀ c/mL, interquartile range [IQR] 2.8-4.4 vs. 2.9 log₁₀ c/mL, 0.8-3.5; p = 0.063). Administering multiple lower doses (30 mg/kg) also showed a trend toward TTV load increase in healthy volunteers (1.8 log₁₀ c/mL, 0-2.3 vs. 1.9, 1.3-2.8; p = 0.054) and a significant increase in transplant recipients (3.5 log₁₀ c/mL, 3.0-6.1 vs. 4.1, 3.5-6.4; p = 0.004). This report suggests a role for the classical complement pathway in controlling TTV load.

Keywords: Torque Teno virus; classical pathway; complement; immunosuppression; sutimlimab.

Figure 1

Correlation of complement activity and TTV load. The relation of the logarithmic values of C3d deposition as a surrogate of complement activity to the logarithmic copy number of TTV is shown in scatter plots. (A) In data set 1, all study participants and all time points were included in the analysis (184 data points). (B) In data set 2, the transplant recipients were excluded (144 data points). The contributions of the cohorts are visualized by color‐coding. Pearson's correlation coefficient (ρ) was calculated. C3d, complement component 3d; MFI, mean fluorescence intensity; TTV, Torque Teno virus.

Figure 2

TTV load in cohorts receiving single doses of the anti‐C1s antibody sutimlimab. Logarithmic TTV loads at baseline and after 14 days are shown as line plots and boxplots demonstrating the median, interquartile range, and range. Outliers are indicated by small concentric circles. The results of each cohort (cohort 1 and 2: n = 3; cohort 3–7: n = 6) are presented in panels distinguished by the sutimlimab dosage; placebo subjects (n = 12) were removed from each cohort and are summarized in the top left panel. Individual subjects are distinguished by color‐coding. TTV load negative data points in cohorts 4 (n = 2), 6 (n = 2), and the placebo group (n = 4) are overlapping and appear as single subjects. The TTV loads were compared between the two time points using the Wilcoxon signed‐rank test for nonparametric paired data. c/mL, copies per milliliter; d, days; TTV, Torque Teno virus.

Figure 3

TTV load in cohorts receiving multiple doses of the anti‐C1s antibody sutimlimab. Subjects received four weekly doses of sutimlimab between Days 0 and 21. Logarithmic TTV loads at baseline and after 14 and 35 days are shown as line plots and boxplots demonstrating the median, interquartile range, and range. Outliers are indicated by small concentric circles. The results of each cohort (cohort size: n = 6) are presented in panels distinguished by sutimlimab dosage; placebo subjects (n = 4) were removed from each cohort and are summarized in the top panel. Individual subjects are distinguished by color coding. The TTV loads were compared between the three time points using the Friedman test, an extension of the Wilcoxon signed‐rank test for more than two comparisons. c/mL, copies per milliliter; d, days; TTV, Torque Teno virus.

Figure 4

TTV load in kidney transplant patients receiving multiple doses of the anti‐C1s antibody sutimlimab. Ten patients with antibody‐mediated rejection received four weekly administrations of 60 mg/kg sutimlimab between Days 1 and 22 following an initial safety test dose of 10 mg/kg on Day 0. Logarithmic TTV loads at baseline and after 14, 36, and 50 days are shown as line plots and boxplots demonstrating the median, interquartile range, and range. Outliers are indicated by small concentric circles. Individual subjects are distinguished by color coding. TTV load was compared between the four time points using the Friedman test (p = 0.004). c/mL, copies per milliliter; d, days; TTV, Torque Teno virus.