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ABBV-085, Antibody-Drug Conjugate Targeting LRRC15, Is Effective in Osteosarcoma: A Report by the Pediatric Preclinical Testing Consortium.

ABSTRACT: Membrane protein leucine-rich repeat containing 15 (LRRC15) is known to be expressed in several solid tumors including osteosarcoma. ABBV-085, an antibody-drug conjugate against LRRC15, conjugated to monomethyl auristatin E (MMAE), was studied in osteosarcoma patient-derived xenografts (PDXs) by the Pediatric Preclinical Testing Consortium (PPTC). LRRC15 expression data were obtained from PPTC RNA-sequencing data for the PDX models. The TARGET database was mined for LRRC15 expression in human osteosarcoma. Protein expression was confirmed via IHC in three PDX models. Seven osteosarcoma PDX models (OS1, OS9, OS33, OS34, OS42, OS55, and OS60) with varying LRRC15 gene expression were studied. ABBV-085 was administered at 3 mg/kg (OS33), 6 mg/kg (all seven PDXs), and 12 mg/kg (OS60) weekly for 4 consecutive weeks via intraperitoneal injection. Control cohorts included vehicle and an isotype MMAE-linked antibody. Tumor volumes and responses were reported using PPTC statistical analysis. OS1, OS33, OS42, OS55, and OS60 had high LRRC15 expression while OS9 and OS34 had low LRRC15 expression. ABBV-085 inhibited tumor growth in six of seven PDX models as compared with vehicle control and significantly improved event-free survival in five of seven models as compared with isotype controls. Two models showed maintained complete responses while all others showed progressive disease. Response correlated with LRRC15 expression. ABBV-085's antitumor activity against osteosarcoma PDX suggests LRRC15 may be a rational target for pursuing clinical trials in patients with this disease.

SUBMITTER: Hingorani P

PROVIDER: S-EPMC8715742 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Dose-response effect of eribulin in preclinical models of osteosarcoma by the pediatric preclinical testing consortium.

Project description:The pediatric preclinical testing program previously demonstrated activity of eribulin in osteosarcoma patient-derived xenograft (PDX) models. The phase 2 trial in patients with relapsed osteosarcoma failed to meet response endpoints. Eribulin was evaluated in the original and an expanded set of PDX models and tested at multiple dose levels and schedules to evaluate dose-response. Maximal response was observed at the highest dose, consistent with prior results. The alternative schedule generated similar responses. We demonstrate steep dose-response for eribulin in osteosarcoma PDX models, implying that any deviation from achievement of effective concentrations may have a significant impact on activity.

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Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program.

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

Project description:BackgroundDenintuzumab 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).ProceduresDenintuzumab 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.ResultsDenintuzumab 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.ConclusionsDenintuzumab 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.

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Initial testing of lenalidomide by the pediatric preclinical testing program.

Project description:BACKGROUND:Lenalidomide, a novel immunomodulatory agent, is reported to modulate stem cell differentiation, and have direct antiproliferative activity as well as inhibit inflammation and hyperalgesia. On the basis of this varied pharmacological profile, lenalidomide is under investigation as a treatment for a range of oncologic indications. PROCEDURES:Lenalidomide was evaluated against the PPTP in vitro panel using 96-hr exposure at concentrations ranging from 1 nM to 10 µM. It was tested against the PPTP in vivo panels at a dose of 30 mg/kg administered orally (PO) once daily for a planned for 6 weeks. RESULTS:In vitro activity was not observed at concentrations up to 10 µM. Lenalidomide was well tolerated, and induced significant differences in EFS distribution compared to control in 7 of 37 (18.9%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The best response in the solid tumor panel was PD2 [progressive disease with growth delay (EFS T/C > 1.5)], observed in 4 of 37 (10.8%) solid tumor xenografts. A single ALL xenograft showed a PD2 response. CONCLUSIONS:Direct antiproliferative effects of lenalidomide were not observed in vitro. In vivo lenalidomide demonstrated low activity against tumors in immune-deficient mice. Our results suggest that lenalidomide's utility in the pediatric clinical setting may depend upon its ability to induce antitumor activity through effects on host immune and stromal cells rather than through direct effects on tumor cells.

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