TY - JOUR
T1 - The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse postinduction therapy in preclinical models of pediatric acute lymphoblastic leukemia
AU - Carol, Hernan
AU - Szymanska, Barbara
AU - Evans, Kathryn
AU - Boehm, Ingrid
AU - Houghton, Peter J
AU - Smith, Malcolm A
AU - Lock, Richard B
PY - 2013/4/1
Y1 - 2013/4/1
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies, Monoclonal, Humanized/administration & dosage
KW - Antigens, CD19/genetics
KW - Antineoplastic Agents/administration & dosage
KW - Dose-Response Relationship, Drug
KW - Drug Evaluation, Preclinical
KW - Humans
KW - Induction Chemotherapy
KW - Maytansine/administration & dosage
KW - Mice
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - RNA, Messenger/genetics
KW - Recurrence
KW - Treatment Outcome
KW - Xenograft Model Antitumor Assays
U2 - 10.1158/1078-0432.CCR-12-3613
DO - 10.1158/1078-0432.CCR-12-3613
M3 - Article
C2 - 23426279
VL - 19
SP - 1795
EP - 1805
JO - Clinical Cancer Reserach
JF - Clinical Cancer Reserach
SN - 1078-0432
IS - 7
ER -