The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse postinduction therapy in preclinical models of pediatric acute lymphoblastic leukemia

Abstract

Purpose: Relapsed or refractory pediatric acute lymphoblastic leukemia (ALL) remains a major cause of death from cancer in children. In this study, we evaluated the efficacy of SAR3419, an antibody-drug conjugate of the maytansinoid DM4 and a humanized anti-CD19 antibody, against B-cell precursor (BCP)-ALL and infant mixed lineage leukemia (MLL) xenografts.

Experimental design: ALL xenografts were established as systemic disease in immunodeficient (NOD/SCID) mice from direct patient explants. SAR3419 was administered as a single agent and in combination with an induction-type regimen of vincristine/dexamethasone/l-asparaginase (VXL). Leukemia progression and response to treatment were assessed in real-time, and responses were evaluated using strict criteria modeled after the clinical setting.

Results: SAR3419 significantly delayed the progression of 4 of 4 CD19(+) BCP-ALL and 3 of 3 MLL-ALL xenografts, induced objective responses in all but one xenograft but was ineffective against T-lineage ALL xenografts. Relative surface CD19 expression across the xenograft panel significantly correlated with leukemia progression delay and objective response measure scores. SAR3419 also exerted significant efficacy against chemoresistant BCP-ALL xenografts over a large (10-fold) dose range and significantly enhanced VXL-induced leukemia progression delay in two highly chemoresistant xenografts by up to 82 days. When administered as protracted therapy following remission induction with VXL, SAR3419 prevented disease recurrence into hematolymphoid and other major organs with the notable exception of central nervous system involvement.

Conclusion: These results suggest that incorporation of SAR3419 into remission induction protocols may improve the outcome for high-risk pediatric and adult CD19(+) ALL.

Trial registration: ClinicalTrials.gov NCT01440179.

©2013 AACR.

Figures

Figure 1. SAR3419 exerts significant in vivo single-agent efficacy against B-lineage pediatric ALL xenografts

NOD/SCID mice were inoculated with cells from BCP-ALL xenografts ALL-2 (A) and ALL-3 (B), infant MLL-ALL MLL-3 (C) and MLL-8 (D) or T-ALL ALL-8 (E). Following establishment of disease, mice were randomized and treated with vehicle (dashed lines) or 10 mg/kg SAR3419 (solid lines) once a week for 3 weeks. Response to treatment was monitored by weekly enumeration of the %huCD45+ cells in the PB of individual mice (left panels); corresponding Kaplan-Meier curves (based on EFS) are shown on the right. Gray arrows indicate treatment times.

Figure 2. Summary of SAR3419 single-agent efficacy, dose response and VXL combination efficacy studies against pediatric ALL xenografts

(A) Distribution of ORMs of individual mice engrafted with BCP-ALL or infant MLL-ALL xenografts and treated with 10 mg/kg SAR3419 as described in the legend to Figure 1. (B) “COMPARE-like” plot of the midpoint difference representing the median ORM of xenografts shown in A. (C) Distribution of median ORMs of individual mice engrafted with ALL-4 or ALL-19 and treated with SAR3419 at different doses, MAb huB4, VXL or VXL followed by SAR3419. (D) “COMPARE-like” plot of the midpoint difference representing the median ORM of xenografts of xenografts shown in C. For the “COMPARE-like” plots in B and D a score of -5 to 0 indicates that an Objective Response was not achieved for a particular xenograft, whereas a score of >0 to 5 indicates an Objective Response. Red bars indicate that the EFS was significantly different between control and treated mice. Blue bars indicate no significant difference.

Figure 3. CD19 expression correlates with in vivo response to SAR3419

(A) CD19 gene expression expressed in heat map format (normalized to the mean, with relative expression depicted in logarithmic scale). (B) Representation of CD19 surface expression on three different xenografts (gray, isotype control; green, ALL-16; blue, ALL-3; red, ALL-19) as detected by flow cytometry. (C) Regression curves and 95% confidence intervals of CD19 mRNA in spleen-derived cells (top panels), and protein expression on cells derived from spleen (middle panels) or BM (bottom panels) correlated with the median ORMs (left panels) and LGDs (right panels) of the corresponding xenografts.

Figure 4. Efficacy of SAR3419 against BCP-ALL xenografts following remission induction with VXL therapy

Mice engrafted with ALL-4 (A, B, E), or ALL-19 (C, D, F), were treated with vehicle (black dotted lines); VXL (gray solid lines); VXL followed by 3 weekly doses of SAR3419 (black solid lines) or VXL followed by up to 13 weekly doses of SAR3419 (gray dashed lines). For additional details see Materials and Methods. The VXL treatment period is indicated by the gray shading, and SAR3419 treatment time points are marked by black (x 3) and gray arrows (x 10). Left panels represent the %huCD45+ cells in PB of individual mice, and the right panels depict Kaplan-Meier plots of EFS. Infiltration of %huCD45+ cells (E and F) in various organs or tissues at necropsy: VXL/SAR3419 times 3 weeks (black bars), VXL/SAR3419 extended treatment (white bars). PB, peripheral blood; Spl, spleen; BM, bone marrow; LN, lymph node; Liv, liver; Lu, lung; Kid, kidney; Br, brain; SF, spinal fluid.