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A novel anti-CD19 antibody drug conjugate
SAR3419, an ADC that demonstrated clinical activity as single agent10,29 and in combination with the anti-CD20 monoclonal antibody rituximab.13 SAR3419 comprises the maytansinoid microtubule disruptor, DM4, conjugated to the huB4 anti-CD19 antibody via the hydrophobic linker SPDB.6,9 Utilizing the same anti-CD19 antibody in SAR3419, we created huB4-DGN462, which incorporates
the ultra-potent DNA-alkylating payload, DGN462 linked by the more hydrophilic sulfo-SPDB linker. This sulfo- SPDB-DGN462 linker/payload combination has previous- ly been shown to have significantly greater potency (up to 3 logs) than the SPDB-DM4.22 As predicted, huB4- DGN462 was more potent than SAR3419 in in vitro anti- proliferative and apoptotic assays as well as in in vivo
A
B
Figure 2. huB4-DGN462 exhibits more potent in situ antitumor efficacy than SAR3419 in both disseminated (A) and subcutaneous (B) germinal center B-cell type diffuse large B-cell lymphoma (GCB DLBCL) xenograft models. (A) Nude mice bearing Farage xenografts were treated with vehicle, a single dose of huB4-DGN462 (0.17, 0.56 or 1.7 mg antibody /kg), or a single dose of non-targeting IgG1-DGN462 (1.7 mg antibody /kg), as indicated. (Right) Nude mice bearing Farage xenografts were treated with vehicle or a single dose of SAR3419 (2.5 or 5 mg antibody /kg) as indicated. The table summarizes the data for the experiments. (B) Nude mice with subcutaneous DOHH2 xenografts were treated with vehicle, a single dose of huB4-DGN462 (0.56 or 1.7 mg antibody /kg), or a single dose of non-targeting IgG1-DGN462 (1.7 mg antibody /kg), as indicated. (Right) Nude mice bearing DOHH2 xenografts were treated with vehicle or a single dose of SAR3419 (2.5 or 5 mg antibody /kg) as indicated. The table summarizes the data for the experiments. Ab: antibody. T/C: treated versus control. PR: partial response (defined when the tumor volume at any given measurement point was <50% of the initial pretreatment tumor volume).27 CR: complete response (defined when no palpable tumor could be detected).27 TGD: tumor growth delay.
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