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Background Tetraspanin CD37, highly expressed in mature B-cells, represents an opportunity for therapeutic targeting in B-cell malignancies. GEN3009 (DuoHexaBody-CD37), a humanized biparatopic IgG 1 antibody with an E430G hexamerization-enhancing mutation targeting two non-overlapping CD37 epitopes, was shown to induce potent tumor cell killing through enhanced complement-dependent cytotoxicity (CDC) and other fragment crystallizable-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), in vitro and in vivo. GEN3009 was assessed in non-clinical studies and a phase 1 dose-escalation study of B-cell non-Hodgkin’s lymphoma (B-NHL).Methods After a non-clinical toxicity study was conducted in cynomolgus monkeys, a phase 1, first-in-human, open-label, multicenter dose-escalation trial of GEN3009 monotherapy enrolled adults with relapsed/refractory (R/R) B-NHL ( NCT04358458). A modified Bayesian optimal interval design informed dose escalation and de-escalation with dose levels ranging from 6 mg to 2000 mg. Primary endpoints were the rate of dose-limiting toxicities (DLTs) to determine the recommended phase 2 dose (RP2D) and safety and tolerability.Results In the toxicity study, 10 mg/kg GEN3009 weekly was identified as the highest non-severely toxic dose. In the phase 1 study, from March 13, 2020, to July 28, 2023, 46 patients with R/R B-NHL received intravenous GEN3009 infusions. Median duration of treatment was 1.2 months (range, 0.0–14.5). No DLTs were observed up to 1600 mg. The most common treatment-emergent adverse events were neutropenia (n=41 (89.1%)), infusion-related reactions (n=39 (84.8%)), and thrombocytopenia (n=18 (39.1%)). Plasma GEN3009 concentrations increased over time with increasing GEN3009 doses, with no apparent accumulation of GEN3009 observed over the course of treatment. Antitumor activity was observed at dose levels of ≥180 mg in both aggressive and indolent NHL. GEN3009 treatment reduced total hemolytic complement activity (CH50) levels in serum, and peak changes in CH50 levels were significantly correlated with clinical response (p=0.008 by Wilcoxon rank-sum test).Conclusions Based on safety, efficacy, and pharmacokinetics, the RP2D of GEN3009 was determined to be 1200 mg. Preliminary data suggest that GEN3009 monotherapy demonstrated an acceptable safety profile at the RP2D of 1200 mg, with modest clinical activity. These findings provide the first clinical proof-of-concept for hexamerization-potentiated molecules that induce antitumor activity through enhanced CDC.