title: The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse postinduction therapy in preclinical models of pediatric acute lymphoblastic leukemia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  These results suggest that incorporation of SAR3419 into remission induction protocols may improve the outcome for high-risk pediatric and adult CD19(+) ALL.
authors: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors: Hernan
authors: H
authors: Carol
authors: Barbara
authors: B
authors: Szymanska
authors: Kathryn
authors: K
authors: Evans
authors: Ingrid
authors: I
authors: Boehm
authors: Peter J
authors: PJ
authors: Houghton
authors: Malcolm A
authors: MA
authors: Smith
authors: Richard B
authors: RB
authors: Lock
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D060828:Induction Chemotherapy; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D008453:Maytansine; C569646:coltuximab ravtansine