Researchers have demonstrated the potential of antibody-drug conjugates (ADCs) targeting leucine-rich repeat containing 15 (LRRC15) as a promising therapeutic strategy for osteosarcoma (OS). The study, published in PMC, evaluated the efficacy of LRRC15-directed ADCs with different payloads in OS cell lines and murine xenograft models, revealing that an ADC conjugated to the anthracycline derivative PNU-159682 (PNU) was more effective than an ADC with the tubulin inhibitor monomethyl auristatin E (MMAE).
LRRC15 as a Therapeutic Target in Osteosarcoma
Osteosarcoma is the most common bone malignancy affecting children and adolescents. While patients with non-metastatic disease have a 5-year survival rate of approximately 70%, the rate drops to as low as 19% for those with metastatic disease. Current treatment involves multiagent chemotherapy, surgery, and adjuvant chemotherapy. However, there is a significant need for targeted agents to prevent and treat metastatic disease. LRRC15, a transmembrane protein, has emerged as an attractive target due to its high expression in various cancers, including OS, and limited expression in normal tissues.
Enhanced Efficacy of LRRC15-PNU ADC
The study compared ABBV-085, an LRRC15-specific ADC with an MMAE payload, to a novel LRRC15 ADC containing PNU-159682, an active metabolite of the anthracycline nemorubicin. In vitro experiments showed that LRRC15-PNU significantly inhibited cell growth in high LRRC15-expressing OS cell lines, while low-expressing cell lines remained insensitive. Notably, LRRC15 expression could be induced in low-expressing cells with TGFβ treatment, suggesting a potential sensitization strategy for ADC therapy.
In Vivo Xenograft Studies
In vivo, intramuscular xenograft models using SaOS2 and G292 cell lines demonstrated that LRRC15-PNU treatment significantly inhibited tumor growth, with cure rates ranging from 40% to 100%. In contrast, while LRRC15-MMAE showed some efficacy, it was less pronounced than that of LRRC15-PNU. The superior efficacy of LRRC15-PNU aligns with the fact that anthracyclines are a standard component of OS chemotherapy.
Implications and Future Directions
These findings suggest that LRRC15-directed ADCs, particularly those utilizing an anthracycline payload like PNU, represent a promising therapeutic avenue for OS. While the study observed toxicity associated with PNU treatment, potentially due to the known dose-limiting toxicities of anthracyclines, further research is warranted to optimize payload selection and minimize off-target effects. The ability to induce LRRC15 expression in tumors with low expression could also enhance the applicability of this targeted therapy.
"LRRC15 is an attractive target because it is highly expressed on many OS tumors," the authors noted. "Our data suggest that cell lines with low expression of LRRC15 are poised for LRRC15 re-expression. Furthermore, LRRC15 expression is induced by TGFβ, and perhaps low-expressing tumors could be sensitized to LRRC15 ADC treatment."
The study provides a foundation for developing clinically relevant LRRC15 ADCs for OS treatment, addressing the unmet medical need for therapies targeting metastatic disease.
