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ABSTRACT E7777 is a therapeutic recombinant fusion protein comprised of diphtheria toxin fragments and human interleukin‐2 (IL‐2). Treatment with E7777 generates anti‐drug antibodies (ADA). E7777‐G000‐302 assessed the efficacy and safety of E7777 in patients with relapsed or refractory cutaneous T‐cell lymphoma (CTCL). Here, we describe the association between E7777 (at 9 μg/kg) and ADAs, and its effect on pharmacokinetics (PK), efficacy, and safety. Of 91 patients with immunogenicity results at baseline, 78.0% and 5.5% had preexisting anti‐E7777 (E‐ADAs) and anti‐IL‐2 antibodies (I‐ADAs), respectively. The prevalence of E‐ADAs and I‐ADAs peaked at C3D1 (median titer 650,175) and C8D1 (median titer 32,805), respectively. However, I‐ADA fold increases (1312‐fold) were higher than E‐ADA increases (181‐fold). ADAs' effect on PK was assessed after treatment. E7777 reached Cmax at 60 min after infusion, with clearance of 44.6 mL/min at C1D1 and 133 mL/min at C5D1. Cmax and AUC(0–t) decreased by 60% and 84%, respectively, at C5D1 compared with C1D1. Of patients in the safety analysis set (n = 84) evaluated for treatment‐emergent (TE) ADAs, 92.9% were considered TE E‐ADA positive and 82.1% were TE I‐ADA positive. The objective response rate was 39.0% in TE E‐ADA‐positive patients and 42.6% in TE I‐ADA‐positive patients. Serious TE adverse events were reported by 32.1% of TE E‐ADA‐positive patients, 29.0% of TE I‐ADA‐positive patients, 100% of E‐ADA‐negative patients, and 73.3% of I‐ADA‐negative patients. These results indicate that the presence of ADAs decreased E7777 exposure over time but did not adversely impact efficacy and safety in patients with CTCL.