AACR 2017 | Poster 2651/10 – huB4-DGN462, a novel CD19 targeting antibody drug conjugate, shows promising activity in CD19+ Lymphoma models

On Monday 3^rd April at this year’s American Association for Cancer Research (AACR) annual meeting, a poster (2651 / 10) by Eugenio Gaudio, from the Institute of Oncology Research, Bellinzona, Switzerland, et al. titled “A novel CD19 targeting antibody-drug conjugate, huB4-DGN462, shows promising in vitro and in vivo activity in CD19-positive lymphoma models” was presented.

The group investigated the preclinical activity of a novel CD19-specifc ADC, consisting of the humanized anti-CD19 antibody huB4 and DGN462 via a cleavable disulfide linker, sulfo-SPDB. Activity of the huB4-DGN462 ADC or the unconjugated DGN462 toxin was measured in vitro using a total of 54 Lymphoma cell lines (n = 27 DLBCL; n = 10 MCL; n = 6 MZL; n = 5 ALCL; n = 6 others). Efficacy of huB4-DGN462 was also analyzed in vivo in CD19-expressing xenograft tumor models.

Key Highlights:

• huB4-DGN462 was cytotoxic in 48 B-cell Lymphoma lines (median IC₅₀ 100pM; 95%CI, 38–214)
• Cytotoxic activity was not associated with DLBCL cell of origin, or limited by P53, BCL2, MYC, or CDKN2A status
• huB4-DGN462 was significantly (P = 0.007) less active in 8 TCL lines (median IC₅₀ 75nM; 95% CI, 0.5–5.75) than in B-cell Lymphoma; in accordance with the lower CD19 expression in TCLs
• huB4-DGN462 induced caspase 3/7 activation in 89% (48/54) cell lines
• In two DLBCL xenograft models (DoHH2 SC model and Farage disseminated model), huB4-DGN462 showed strong anti-tumor activity after a single IV dose
• In DoHH2 model, at 1.7mg Ab/kg, huB4-DGN462 lead to a significant, dose-dependent delay in tumor growth and survival benefit versus a non-targeted control DGN462 ADC
• In Farage model, a significant, dose-dependent increase in survival was reported in mice treated with as little as 0.17mg Ab/kg of huB4-DGN462; At 1.7mg Ab/kg, life span increased by >400% versus untreated mice

The poster concluding by stating that this data indicates that the novel ADC huB4-DGN462 has potent activity in preclinical models, providing cause for further study.