Background: IMGN529 is a CD37-targeting ADC comprising a CD37-binding antibody conjugated to the maytansinoid anti-mitotic, DM1. CD37 is present on the surface of normal and malignant B lymphocytes. In preclinical studies, IMGN529 exhibits potent antitumor activity against NHL cells via direct inhibition, effector function and delivery of the maytansinoid payload. Methods: Study objectives are: determine the maximum tolerated dose/recommended phase 2 dose of IMGN529 in adult patients (pts) with relapsed or refractory NHL, and evaluate safety, pharmacokinetics, pharmacodynamics, and evidence of preliminary efficacy. IMGN529 is given intravenously on Day (d) 1 of each 21d cycle (C). Results: To date, 22 pts have been enrolled across four dose levels ranging from 0.1 to 0.8 mg/kg. NHL subtypes enrolled: 10 Follicular lymphoma (FL), 7 Diffuse large B-cell (DLBCL), 5 other. A reduction in lymphocyte count seen early after dosing (d 2) in the majority of pts suggests a CD37-mediated reduction in lymphocytes. One pt with DLBCL treated at 0.4 mg/kg, and 1 pt with FL treated at 0.2 mg/kg achieved partial remission in C 3 and C 5 respectively. Dose limiting toxicities (DLTs) consisted of grade (G) 4 neutropenia > 7 days (1pt) and G2 peripheral neuropathy (1pt) at 0.8 mg/kg and G3 febrile neutropenia (2 pts) at 0.4 mg/kg. Adverse events (AEs) of G3 or higher occurred in 8 pts; those reported in more than 1 pt were: neutropenia (5 pts) and febrile neutropenia (2pts). Four of these pts experienced transient, early onset (C1d2-4) G3 neutropenia which may be a manifestation of cytokine release. The protocol was amended to provide peri-infusional steroids as a prophylactic regimen and dose re-escalation is ongoing; 3 patients treated at 0.4 mg/kg have completed C 1 with no DLTs. Clinical trial enrollment is ongoing with additional data expected. Preclinical studies to investigate the mechanism of the transient neutropenia are underway. Conclusions: IMGN529, a CD37-targeting ADC, has demonstrated early evidence of clinical activity and has the potential to be a novel therapeutic for B-cell lymphoproliferative malignancies. Clinical trial information: 01534715.