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 C