Abstract

It is estimated that 63,000 cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed in the United States alone in 2007, of which 19,000 will die of their disease. The selectively over-expressed, tumor-associated, lineage specific CD19 antigen is one of the hallmarks of B-cell NHL. Therefore, the design of high affinity-CD19-based modality epitomize an important step towards improving treatment outcome. In this report, we tested the efficacy of SAR3419, a novel humanized anti-CD19 antibody, i.e., huB4, conjugated to the cytotoxic maytansine derivative, DM4. The in vivo anti-tumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using our established CD19-positive human lymphoma xenograft models, the diffuse large cell lymphoma (WSU-DLCL2) and the transformed follicular small cleaved cell lymphoma (WSU-FSCCL), both EBV-negative. In all, we followed 112 tumor-engrafted SCID mice, 56 bearing bilateral WSU-DLCL2 tumors (subcutaneous) and 56 bearing the WSU-FSCCL (systemic disease). Starting 7 days after xenograft establishment (100 – 200 mg tumor size), SAR3419 (7.5, 15 and 30mg/kg), free DM4 (0.6mg/kg), naked huB4 (30mg/kg), CHOP (at maximum tolerated dose in SCID mice as previously defined) or rituximab (40mg/kg) were administered iv on Days 1 and 4 (except CHOP given on day 1 only). Animals were monitored 3 times weekly for tumor measurements and toxicity and were euthanized when tumor burden reached 10% of body weight (WSU-DLCL2) or became moribund (WSU-FSCCL). Our results showed that WSU-DLCL2-bearing animals treated with SAR3419 dosage of 15 mg/kg had no measurable tumor up to Day 155 (end of experiment) and considered cured (7/7 tumor-free survivors, TFS). In the higher dose of SAR3419 (30mg/kg), all animals (7/7) were tumor-free at time of death. However, 4/7 animals died of unrelated causes before the end of the experiment. At the dosage of 7.5 mg/kg, SAR3419 induced a T-C of 64 days and Log10 kill of 4.6 (2/7 TFS). Treatment with rituximab resulted in high anti-tumor activity (T-C of 72 days; Log10 kill of 5.19 and 4/7 TFS). Animals treated with huB4 or CHOP had T-C of 5 and 13 days, and Log10 kill 0.15 and 0.82, respectively. In the WSU-FSCCL model, by the end of the experiment (Day 150), SAR3419 induced 100%, 4/7 and 2/7 survivors, at 30, 15 and 7.5 mg/kg, respectively. The number of survivors in the other arms of the study was 2/7 for rituximab, 3/7 for CHOP and 2/7 for huB4. All animals in the no treatment (control arm) had died by Day 75. Necropsy and H&E analysis revealed that all deaths featured leptomeningeal lymphoma in the control and treated groups. Overall, SAR3419 is a very active immunoconjugate that produced 100% cures in the two models tested. SAR3419 was found better than either rituximab or CHOP at optimal dosages. We conclude that SAR3419 holds promise as novel and well tolerated immunoconjugate therapy in B-cell NHL.

Author notes

Disclosure: Employment: co-authors from institution #2 are employed by aventis-sanofi which provided research funding for this work. Research Funding: aventis-sanofi provided research grant funding for the project.