Antitumor activity of a B7-H3 antibody-drug conjugate in osteosarcoma patient-derived and metastatic models

Background: Osteosarcoma outcomes have not improved in over three decades, and prognosis remains poor for patients with pulmonary metastases. B7-H3 is highly expressed on osteosarcoma with limited normal-tissue expression, making it an attractive therapeutic target. This study evaluated the antitumor activity of a B7-H3-targeting antibody-drug conjugate (B7H3 ADC) in osteosarcoma PDX and metastatic models. Methods: The B7-H3 antibody (developed by ORBIT, MD Anderson) was conjugated to the tesirine payload SG3249. In vitro, cell viability was assessed in six PDX-derived osteosarcoma cell lines treated with B7H3 ADC (10-point dilution, 1000 nM start) over 120 h using Incucyte imaging. IC₅₀ values were calculated by nonlinear regression, and dose-response effects were analyzed by one-way ANOVA with η² and Cohen's f. In vivo, six PDX models were treated with a single 1 mg/kg IP dose of B7H3 ADC, isotype-ADC, or PBS. Tumor growth inhibition and EFS were evaluated. Metastatic efficacy was assessed in IV and tibial injection models using luciferase-labeled SJSA LM7 cells, with treatment initiated at ~3 × 10⁶ photons/sec. Results: B7H3 ADC produced strong, dose-dependent cytotoxicity across all six cell lines (IC₅₀ = 0.0795-0.6703 nM), with large effect sizes (η² = 0.80-0.93; Cohen's f = 2.01-3.65; p < 0.001). In vivo, three of six PDX models achieved maintained complete response (MCR), two showed partial response (PR), and one exhibited progressive disease (PD). In the IV metastasis model, control mice required euthanasia beginning on day 20, whereas all treated mice remained metastasis-free through day 93. In the tibial model, control mice were euthanized by day 25 with lung metastases detected by day 22. Treated mice showed complete tibial tumor regression by day 17 and remained metastasis-free through day 64. Conclusions: B7H3 ADC demonstrated potent and reproducible antitumor activity in osteosarcoma PDX and metastatic models, inducing durable tumor regression and preventing metastatic progression. These findings support B7-H3 as a promising therapeutic target and justify further development of B7H3 ADC for primary and metastatic osteosarcoma.