Background:
Ublituximab, a novel monoclonal antibody (mAb) targeting a unique epitope on the CD20 antigen, is glycoengineered for enhanced B-cell targeting through antibody-dependent cellular ...cytotoxicity (ADCC). Greater ADCC may allow lower doses and shorter infusion times versus other anti-CD20 mAbs.
Objective:
The objective was to determine optimal dose, infusion time, and activity of ublituximab in relapsing multiple sclerosis.
Methods:
This is a phase 2, placebo-controlled study. Patients received three ublituximab infusions (150 mg over 1–4 hours on day 1 and 450–600 mg over 1–3 hours on day 15 and week 24) in six dosing cohorts. The primary endpoint was B-cell depletion.
Results:
In all cohorts (N = 48), median B-cell depletion was >99% by week 4, maintained at weeks 24 and 48. Most common adverse events (AEs) were infusion-related reactions (all grade 1–2), with no apparent increased incidence at shorter infusion times. There were no AE-related discontinuations. At weeks 24 and 48, no T1 gadolinium-enhancing lesions (p = 0.003) and a 10.6% decrease in T2 lesion volume (p = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA).
Conclusion:
Ublituximab was safely infused as rapid as 1 hour, producing robust B-cell depletion and profound reductions in magnetic resonance imaging (MRI) activity and relapses.
Renal injury is greater in male compared with female rats after renal wrap (RW) hypertension. We investigated the role of gonadal steroids in the sex differences in RW disease severity in male (M) ...and female (F), castrated (Cast), and ovariectomized (OVX) rats and after dihydrotestosterone (DHT) and 17beta-estradiol (E2) treatment. Male castration attenuated the severity of RW-induced glomerulosclerosis (GS) GS index (GSI): RW-M, 2.1 +/- 0.2; RW-Cast, 1.3 +/- 0.2; RW-Cast+DHT, 2.4 +/- 0.4, mean glomerular volume (MGV; microm3 x 10(6): RW-M, 1.9 +/- 0.1; RW-Cast, 1.45 +/- 0.15; RW-Cast+DHT, 1.91 +/- 0.15), tubular damage, and proteinuria (mg/day: RW-M, 130 +/- 8; RW-Cast, 105 +/- 5; RW-Cast+DHT, 142 +/- 9), whereas DHT treatment abrogated these effects. Ovariectomy increased the GSI (RW-F, 0.69 +/- 0.05; RW-OVX, 1.2 +/- 0.1; RW-OVX+E2, 0.65 +/- 0.05), tubular damage, and MGV (microm3 x 10(6): RW-F, 1.0 +/- 0.06; RW-OVX, 1.5 +/- 0.05; RW-OVX+E2, 0.96 +/- 0.06), whereas E2 treatment prevented these effects. Furthermore, DHT treatment of RW-OVX animals exacerbated the GSI (1.9 +/- 0.19), MGV (1.7 +/- 0.2 x 10(6) microm3), and proteinuria (171 +/- 21 mg/day) even further. Our data show that the lack of E2 and presence of androgens contribute to progressive renal disease induced by RW hypertension, suggesting that gonadal steroid status is an independent factor in the greater susceptibility men exhibit toward hypertension-associated renal disease compared with women.
In two parallel randomized trials in patients with MS, ublituximab resulted in lower relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not affect ...disability.
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