Figure 4.
Therapeutic application of ATX-F8-117 reduces the formation of new FVIII inhibitor antibodies in a primed FVIII antibody model. (A) Groups of 20 HLA-DR2tg mice (FVIII+/+) were primed with 10 weekly immunizations of rhFVIII, followed by dose-escalation treatment with ATX-F8-117 or PAP 133-152 via subcutaneous flank injections. Three days after the dose-escalating peptide treatment, mice were primed 4 times, at weekly intervals, via subcutaneous (s.c.) flank injections with 1 µg of rhFVIII. Treatment with ATX-F8-117 or PAP 133-152 control was continued twice weekly starting 2 days after FVIII priming. Plasma samples were collected from both treatment groups as indicated (B = bleed). (B) Plasma was collected at the indicated time points, and total anti-FVIII IgG levels were determined by ELISA. Data are mean ± standard error of the mean (SEM). (C) FVIII inhibitors from plasma collected at the indicated time points were analyzed using a modified Bethesda assay. Data are mean ± SEM. (D) Plasma was collected at day 105-106, and anti-FVIII IgG subclass distribution was determined by ELISA. Each circle represents 1 mouse; data are mean ± SEM. Open blue circles, ATX-F8-117; filled red circles, PAP 133-152.*P < .05, **P < .01, robust regression model using M estimation, Huber weighting, and the default parameter c = 1.345 with treatment as a factor and day 56 data as a covariate (B-C). (E) Correlation between anti-FVIII IgG1 subclass antibodies and FVIII inhibitors in plasma samples collected at day 105-106 from animal treated with PAP 133-152 (left panel) or ATX-F8-117 (right panel) using 2-tailed nonparametric Spearman correlation analysis (r); 95% confidence intervals are also shown. ***P < .001. ns, not significant.

Therapeutic application of ATX-F8-117 reduces the formation of new FVIII inhibitor antibodies in a primed FVIII antibody model. (A) Groups of 20 HLA-DR2tg mice (FVIII+/+) were primed with 10 weekly immunizations of rhFVIII, followed by dose-escalation treatment with ATX-F8-117 or PAP 133-152 via subcutaneous flank injections. Three days after the dose-escalating peptide treatment, mice were primed 4 times, at weekly intervals, via subcutaneous (s.c.) flank injections with 1 µg of rhFVIII. Treatment with ATX-F8-117 or PAP 133-152 control was continued twice weekly starting 2 days after FVIII priming. Plasma samples were collected from both treatment groups as indicated (B = bleed). (B) Plasma was collected at the indicated time points, and total anti-FVIII IgG levels were determined by ELISA. Data are mean ± standard error of the mean (SEM). (C) FVIII inhibitors from plasma collected at the indicated time points were analyzed using a modified Bethesda assay. Data are mean ± SEM. (D) Plasma was collected at day 105-106, and anti-FVIII IgG subclass distribution was determined by ELISA. Each circle represents 1 mouse; data are mean ± SEM. Open blue circles, ATX-F8-117; filled red circles, PAP 133-152.*P < .05, **P < .01, robust regression model using M estimation, Huber weighting, and the default parameter c = 1.345 with treatment as a factor and day 56 data as a covariate (B-C). (E) Correlation between anti-FVIII IgG1 subclass antibodies and FVIII inhibitors in plasma samples collected at day 105-106 from animal treated with PAP 133-152 (left panel) or ATX-F8-117 (right panel) using 2-tailed nonparametric Spearman correlation analysis (r); 95% confidence intervals are also shown. ***P < .001. ns, not significant.

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