Erzotabart (GEN3014): A Comprehensive Scientific Review

Executive Summary

Erzotabart (GEN3014) is an investigational hexamerization-enhanced human immunoglobulin G1 (IgG1) kappa monoclonal antibody developed by Genmab, targeting the cell surface glycoprotein CD38. Utilizing Genmab's proprietary HexaBody® technology, Erzotabart incorporates an E430G mutation in its Fc region, designed to promote antibody hexamer formation upon antigen binding, thereby significantly augmenting Fc-mediated effector functions, particularly Complement-Dependent Cytotoxicity (CDC). The therapeutic rationale was to create a more potent anti-CD38 therapy for hematologic malignancies, notably multiple myeloma.

Preclinical studies indicated that Erzotabart binds CD38 with high affinity and exhibits potent in vitro effector functions, including CDC, Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP), alongside inhibition of CD38 cyclase activity and in vivo antitumor effects. The clinical development program was centered around the GEN3014-01 (NCT04824794) trial, a Phase 1/2 study evaluating Erzotabart in patients with relapsed or refractory hematologic malignancies. A key component of this trial was a head-to-head comparison of intravenous Erzotabart with subcutaneous daratumumab.

Preliminary results from this comparison showed Erzotabart achieved a numerically higher overall response rate (55% vs. 52%) and notably deeper responses (Very Good Partial Response or better: 29% vs. 17%; Complete Response or better: 7% vs. 2%) compared to daratumumab. However, concerns regarding the safety profile, including a higher incidence of Grade 3 or higher adverse events and treatment discontinuations with Erzotabart, coupled with the less convenient intravenous administration, complicated its differentiation.