Abstract C107: The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse post induction therapy in preclinical models of pediatric acute lymphoblastic leukemia.
Authors: Lock Richard B. , Carol Hernan , Szymanska Barbara , Boehm Ingrid , Evans Kathryn , Houghton Peter J. , Smith Malcolm A. 
Published: June 2012

Abstract
Introduction: SAR3419 is an antibody-drug conjugate (ADC) of a humanized anti-CD19 antibody and the maytansinoid DM4 currently in clinical trials for relapsed or refractory B cell non-Hodgkin's lymphoma. SAR3419 was previously shown by the Pediatric Preclinical Testing Program (PPTP) to be highly effective in delaying the progression of CD19+ B cell precursor acute lymphoblastic leukemia (BCP-ALL) xenografts in NOD/SCID mice, while being ineffective against CD19-T-lineage ALL. In the current study we evaluated the efficacy of SAR3419 against additional BCP-ALL and infant mixed lineage leukemia (MLL) xenografts, assessed its therapeutic range, and studied its efficacy in combination with an induction-type regimen of vincristine/dexamethasone/L-asparaginase (VXL).
Methods: Engraftment and responses of xenografts to drug treatments were assessed by enumeration of the proportion of human versus mouse CD45+ cells in the peripheral blood (PB) of NOD/SCID mice. Mice with established systemic disease received vehicle, SAR3419 (2.5–10 mg/kg, weekly × 3, i.p.), or VXL (0.15 mg/kg V weekly; 5 mg/kg × daily × 5; 1,000 IU/kg L daily × 5; i.p. × 2 weeks) followed by SAR3419 (10 mg/kg) either for 3 weeks or continuous treatment in an attempt to eradicate residual disease. Three measures of anti-leukemic activity were used: 1) an objective response measure (ORM) modeled after the clinical setting; 2) time to event based on the median event-free survival (EFS) of treated or control groups; 3) a treated to control (T/C) EFS measure.
Results: SAR3419 significantly delayed the progression of three MLL xenografts by 22.1 to 36.5 days and induced objective responses in all three. SAR3419 was also highly effective against a chemoresistant BCR-ABL1+ xenograft (ALL-4), inducing complete responses (CRs) over a wide range of doses (2.5–10 mg/kg), while the unconjugated antibody (huB4) had negligible efficacy, indicating that DM4 is critical for the high efficacy of this ADC. Relative surface CD19 expression across the BCP-ALL xenograft panel significantly correlated with both leukemia progression delay and ORM scores, indicating that CD19 density is an important determinant of SAR3419 efficacy. SAR3419 extended the progression delay induced by VXL treatment of ALL-4 and another chemoresistant BCP-ALL xenograft (ALL-19) by an additional 38.1 and 82.3 days, respectively, which improved the ORM from CRs to maintained CRs for both xenografts. Mice receiving VXL followed by 3 weeks of SAR3419 eventually relapsed with dissemination of leukemia into hematolymphoid organs. However, mice that received continuous weekly SAR3419 treatment post VXL eventually relapsed with extensive leukemia infiltration of the central nervous system (brain and spinal fluid), with no evidence of infiltration of major organs (bone marrow, spleen, liver, kidney, lung, PB).
Conclusions: SAR3419 was highly effective against aggressive and chemoresistant CD19+ pediatric ALL xenografts over a wide range of doses. When used as maintenance therapy following VXL, SAR3419 prevented hematolymphoid relapse. These findings suggest that SAR3419 may be effective for high-risk CD19+ ALL in both the remission induction and the post-remission settings.
Supported by NOI-CM-42216 and NOI-CM-91001-03 from the National Cancer Institute.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C107.