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A novel anti-CD19 antibody drug conjugate
Results
huB4-DGN462 is a novel anti-CD19 antibody-drug conjugate
The humanized anti-CD19 antibody huB428 was conju- gated with DGN462, a novel member of the DNA-alkylat- ing indolinobenzodiazepine pseudodimers (IGNs) class22 via the cleavable disulfide linker, sulfo-SPDB, at a drug-to- antibody ratio (DAR) of 2.8 (Figure 1A). This novel CD19- targeting ADC, huB4-sulfo-SPDB-DGN462 or huB4-
DGN462, combines the anti-CD19 antibody used in SAR3419 (Figure 1B)9 and the potent linker/payload exploited in the anti-CD33 IMGN779.24 To evaluate the consequence of conjugation on antigen binding, the rela- tive binding affinity of huB4-DGN462 and the unconju- gated huB4 antibody to CD19 was determined by FACS analysis on the Burkitt's lymphoma Ramos cell line, which endogenously express human CD19 (Figure 1C). The huB4-DGN462 bound with similar high affinity (KD ~0.15 nM) as the unconjugated antibody, suggesting that
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Figure 1. huB4-DGN462 is a novel anti-CD19 antibody-drug conjugate (ADC). (A) Chemical structure of huB4-DGN462. (B) Chemical structure of SAR3419. (C) Relative binding affinities of huB4 and huB4-DGN462 on Ramous cells. Cells were cultured with the indicated concentrations of either the unconjugated antibody or intact ADC, and binding was detected by flow cytometry using a fluorescently labeled anti-human antibody. (D) In vitro potency of huB4-DGN462 and SAR3419 in diffuse large B-cell lymphoma (DLBCL) (top) or B-cell acute lymphoblastic leukemia (B-ALL) (bottom) cell lines with or without blocking antibody. ABC: antibodies bound per cell.
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