BACKGROUND: Denintuzumab mafodotin (SGN-CD19A) is a CD19-targeting antibody-drug conjugate, comprising a monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin F. Since denintuzumab mafodotin has previously shown activity against B-cell malignancies in early-stage clinical trials, it was of interest to test it against the Pediatric Preclinical Testing Program preclinical models of CD19+ pediatric acute lymphoblastic leukemia (ALL). PROCEDURES: Denintuzumab mafodotin was evaluated against eight B-cell lineage ALL patient-derived xenografts (PDXs), representing B-cell precursor ALL, Ph-like ALL, and mixed-lineage leukemia rearranged infant ALL. Denintuzumab mafodotin was administered weekly for 3 weeks at 3 mg/kg. It was also tested in combination with an induction-type chemotherapy regimen of vincristine, dexamethasone, and l-asparaginase (VXL) against three PDXs. The relationship between cell surface and gene expression of CD19 and drug activity was also assessed. RESULTS: Denintuzumab mafodotin significantly delayed the progression of seven of eight PDXs tested and achieved objective responses in five of eight. There was no apparent subtype specificity of denintuzumab mafodotin activity. No correlations were observed between CD19 mRNA or cell surface expression and denintuzumab mafodotin activity, perhaps due to small sample size, and denintuzumab mafodotin treatment did not select for reduced CD19 expression. Combining denintuzumab mafodotin with VXL achieved therapeutic enhancement compared to either treatment alone. CONCLUSIONS: Denintuzumab mafodotin showed single-agent activity against selected B-lineage ALL PDXs, although leukemia growth was evident in most models at 28 days from treatment initiation. This level of activity for denintuzumab mafodotin is consistent with that observed in adults with ALL.
BACKGROUND:Denintuzumab mafodotin (SGN-CD19A) is a CD19-targeting antibody-drug conjugate, comprising a monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin F. Since denintuzumab mafodotin has previously shown activity against B-cell malignancies in early-stage clinical trials, it was of interest to test it against the Pediatric Preclinical Testing Program preclinical models of CD19+ pediatric acute lymphoblastic leukemia (ALL). PROCEDURES: Denintuzumab mafodotin was evaluated against eight B-cell lineage ALL patient-derived xenografts (PDXs), representing B-cell precursor ALL, Ph-like ALL, and mixed-lineage leukemia rearranged infant ALL. Denintuzumab mafodotin was administered weekly for 3 weeks at 3 mg/kg. It was also tested in combination with an induction-type chemotherapy regimen of vincristine, dexamethasone, and l-asparaginase (VXL) against three PDXs. The relationship between cell surface and gene expression of CD19 and drug activity was also assessed. RESULTS:Denintuzumab mafodotin significantly delayed the progression of seven of eight PDXs tested and achieved objective responses in five of eight. There was no apparent subtype specificity of denintuzumab mafodotin activity. No correlations were observed between CD19 mRNA or cell surface expression and denintuzumab mafodotin activity, perhaps due to small sample size, and denintuzumab mafodotin treatment did not select for reduced CD19 expression. Combining denintuzumab mafodotin with VXL achieved therapeutic enhancement compared to either treatment alone. CONCLUSIONS:Denintuzumab mafodotin showed single-agent activity against selected B-lineage ALL PDXs, although leukemia growth was evident in most models at 28 days from treatment initiation. This level of activity for denintuzumab mafodotin is consistent with that observed in adults with ALL.
Authors: Peter J Houghton; Christopher L Morton; Richard Gorlick; Richard B Lock; Hernan Carol; C Patrick Reynolds; Min H Kang; John M Maris; Stephen T Keir; E Anders Kolb; Jianrong Wu; Amy W Wozniak; Catherine A Billups; Larry Rubinstein; Malcolm A Smith Journal: Mol Cancer Ther Date: 2010-01-06 Impact factor: 6.261
Authors: Natalia L M Liem; Rachael A Papa; Christopher G Milross; Michael A Schmid; Mayamin Tajbakhsh; Seoyeon Choi; Carole D Ramirez; Alison M Rice; Michelle Haber; Murray D Norris; Karen L MacKenzie; Richard B Lock Journal: Blood Date: 2004-02-05 Impact factor: 22.113
Authors: E Anders Kolb; Richard Gorlick; C Patrick Reynolds; Min H Kang; Hernan Carol; Richard Lock; Stephen T Keir; John M Maris; Catherine A Billups; Christopher Desjardins; Raushan T Kurmasheva; Peter J Houghton; Malcolm A Smith Journal: Pediatr Blood Cancer Date: 2013-03-28 Impact factor: 3.167
Authors: Hagop M Kantarjian; Daniel J DeAngelo; Matthias Stelljes; Giovanni Martinelli; Michaela Liedtke; Wendy Stock; Nicola Gökbuget; Susan O'Brien; Kongming Wang; Tao Wang; M Luisa Paccagnella; Barbara Sleight; Erik Vandendries; Anjali S Advani Journal: N Engl J Med Date: 2016-06-12 Impact factor: 91.245