Abstract Purpose Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. Experimental Design We assessed the activity of loncastuximab tesirine in in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels and identified combination partners providing synergy with loncastuximab tesirine. Results Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine has strong cytotoxic activity in B-cell lymphoma cell lines and the in vitro activity is correlated with CD19 expression level and with intrinsic sensitivity of cell lines to the ADC’s warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Conclusions Our data support the further development of loncastuximab tesirine as single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression, and the existence of lymphoma populations characterized by resistance to multiple therapies.

Targeting CD19-positive lymphomas with the antibody-drug conjugate (ADC) loncastuximab tesirine: preclinical evidence as single agent and as combinatorial approach