Dataset Information

LRRC15 antibody-drug conjugates show promise as osteosarcoma therapeutics in preclinical studies.

ABSTRACT:

Background

Osteosarcoma (OS), the most common bone tumor in children and adolescents, has high rates of metastasis leading to poor survival. Leucine-rich repeat containing 15 (LRRC15), a transmembrane protein whose expression is modulated by TGFβ, was recently shown to be highly expressed on the surface of OS tumor cells. Here, we evaluate a novel antibody-drug conjugate (ADC) targeting LRRC15 in OS human cell lines and murine xenografts. We compare this new ADC, which is conjugated to the anthracycline derivative PNU-159682 (PNU), to a previously studied LRRC15 ADC that is conjugated to the tubulin inhibitor monomethyl auristatin E (MMAE), since anthracyclines are standard of care in OS.

Procedure

We evaluated LRRC15 expression in OS cells using Western blots and flow cytometry, and analyzed the epigenetic landscape of the LRRC15 locus using chromatin immunoprecipitation. Efficacy of ADCs on cell growth was analyzed by IncuCyte live cell imaging. Intramuscular xenograft tumor growth was assessed by bioluminescence imaging and hematoxylin and eosin staining.

Results

LRRC15-PNU is more effective at inhibiting growth in vitro and in vivo than an isotype antibody control or the LRRC15-MMAE ADC in two high LRRC15 expressing OS cell lines. Low expressing cell lines are not sensitive to either ADC. Importantly, cells with low LRRC15 expression are amenable to re-expression after TGFβ treatment, suggesting a potential to sensitize insensitive OS cells to LRRC15 ADC treatment. In vivo, LRRC15-PNU had cure rates of 40-100% in OS xenograft models.

Conclusions

Overall, LRRC15-directed ADCs are a promising new avenue for OS treatment.

SUBMITTER: Slemmons KK

PROVIDER: S-EPMC9137401 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

LRRC15 antibody-drug conjugates show promise as osteosarcoma therapeutics in preclinical studies.

Slemmons Katherine K KK Mukherjee Sanjit S Meltzer Paul P Purcell James W JW Helman Lee J LJ

Pediatric blood & cancer 20201016 2

<h4>Background</h4>Osteosarcoma (OS), the most common bone tumor in children and adolescents, has high rates of metastasis leading to poor survival. Leucine-rich repeat containing 15 (LRRC15), a transmembrane protein whose expression is modulated by TGFβ, was recently shown to be highly expressed on the surface of OS tumor cells. Here, we evaluate a novel antibody-drug conjugate (ADC) targeting LRRC15 in OS human cell lines and murine xenografts. We compare this new ADC, which is conjugated to t ...[more]

PMID: 33063919

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Dataset Information

LRRC15 antibody-drug conjugates show promise as osteosarcoma therapeutics in preclinical studies.

Background

Procedure

Results

Conclusions

Publications

LRRC15 antibody-drug conjugates show promise as osteosarcoma therapeutics in preclinical studies.

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