The novel CD19-targeting antibody-drug conjugate huB4-DGN462 shows improved anti-tumor activity compared to SAR3419 in CD19-positive lymphoma and leukemia models

Abstract

Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked <i>via</i> sulfo-SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved <i>in vitro</i> anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines. <i>In vivo</i> experiments using lymphoma xenografts models confirmed the <i>in vitro</i> data. The response of B-cell lymphoma lines to huB4-DGN462 was not correlated with CD19 expression, the presence of <i>BCL2</i> or <i>MYC</i> translocations, <i>TP53</i> inactivation or lymphoma histology. In conclusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.