Preclinical activity of the antibody‐drug conjugate denintuzumab mafodotin (SGN‐CD19A) against pediatric acute lymphoblastic leukemia xenografts

Abstract

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.

Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia

“…This PDF file includes: Materials and Methods Figs. S1 to S30 Tables S1 to S10 References (75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86) Other Supplementary Material for this manuscript includes the following: Data…”

Insights into Modern Therapeutic Approaches in Pediatric Acute Leukemias

“…Jones et al proved that SGN-CD19A is an active therapy against pediatric ALL-patient-derived xenografts. However, the denintuzumab mafodotin preclinical activity levels did not outperform those achieved with vincristine as a single agent [ 196 ].…”

Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies

“…In a preclinical study, denintuzumab mafodotin showed single-agent efficacy against eight pediatric precursor B-cell lineage ALL patient-derived xenografts, and results from the corresponding clinical trials are anticipated [ 36 ]. Another anti-CD19 mAb named B43 conjugated with the tyrosine kinase inhibitor (TKI) genistein has entered clinical trials in children with r/r ALL and non-Hodgkin’s lymphoma (NHL), but no results were found in the literature search.…”