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The investigational anti-B7-H3 antibody-drug conjugate vobramitamab duocarmazine exerts anti-tumor activity in vitro and in vivo in pediatric sarcoma preclinical models
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  • Published: 08 January 2026

The investigational anti-B7-H3 antibody-drug conjugate vobramitamab duocarmazine exerts anti-tumor activity in vitro and in vivo in pediatric sarcoma preclinical models

  • Giovanna Bianchi1,
  • Fabio Pastorino1,
  • Gaia Rolandi1,
  • Eleonora Ciampi1,
  • Daniela Segalerba1,
  • Barbara De Giovanni2,
  • Barbara Cafferata2,
  • Matilde Balbi3,
  • Silvia Ravera3,4,
  • Valerio Gaetano Vellone2,5,
  • Mirco Ponzoni  ORCID: orcid.org/0000-0002-6164-42861 &
  • …
  • Chiara Brignole1 

Cell Death & Disease , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Paediatric cancer
  • Preclinical research

Abstract

Prognosis for pediatric sarcoma (pSC)-affected patients, especially those with relapsed/refractory disease, is dismal. The available treatment options are unsatisfactory, challenging researchers to address this unmet need. The investigational B7-H3 targeted ADC vobramitamab duocarmazine (vobra duo) showed clinical effectiveness towards several B7-H3-positive adult tumors and pre-clinical efficacy in pediatric neuroblastoma models. Cytotoxicity of vobra duo was evaluated in 2D and 3D models toward pSC cell lines expressing B7-H3, showing a dose-dependent cell viability reduction. Proliferation was assessed by time-lapse single-cell segmentation. Compared to controls, vobra duo resulted in a significant increase in the cell doubling time. AKT/mTOR master effectors of cell proliferation were investigated by phospho-specific western blot assays. A down-modulation of phospho-AKT/ -P70 S6K and -4E-BP1 protein expression was detected in both A204 (rhabdomyosarcoma) and U-2-OS (osteosarcoma) cells, the most treatment-sensitive and resistant cell lines, respectively, suggesting their involvement in vobra duo-mediated anti-proliferative effect. In response to treatment, all cell lines underwent apoptotic cell death. A significant increase in the executioner cleaved caspase-3 was detected, and a partial but significant reversion of apoptotic cell death was noted following pre-treatment with the pan-caspase inhibitor, Q-VD-OP-h. Vobra duo also triggered caspase-independent apoptotic events: i) increased AIF nuclear translocation, ii) increased mitochondrial superoxide production, and iii) the depolarization of mitochondrial membrane potential. In vivo, the effectiveness of vobra duo was assayed by single and repeated intravenous administration in the mouse rhabdomyosarcoma model. The single injection of 3 mg/Kg of vobra duo induced a significant tumor growth delay. Repeated vobra duo doses ameliorated this outcome, reverting rhabdomyosarcorma to rhabdomyoma tumor, by increasing Desmin and Myogenin/Myf-4 differentiation markers expression, and reducing both Ki-67 and CD133. In conclusion, the in vitro and in vivo anti-tumor effects towards pSC highlight the need to extend the investigation to patient-derived preclinical models, to pave the way for clinical translation.

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Data availability

Data are available upon kind request.

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Acknowledgements

The Authors thanks Macrogenics Inc. (Rockville, MD, USA) for providing vobra duo.

Funding

This work was supported by Italian Ministry of Health (“Ricerca Corrente” to P.M. and to Scientific Direction, IRCCS Istituto Giannina Gaslini) and by Fondazione Italiana per la Lotta al Neuroblastoma. E.C. is a recipient of AIRC ID.24397 contract. G.R. is a recipient of a Fondazione Italiana per la Lotta al Neuroblastoma fellowship.

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Authors and Affiliations

  1. Laboratory of Experimental Therapies in Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    Giovanna Bianchi, Fabio Pastorino, Gaia Rolandi, Eleonora Ciampi, Daniela Segalerba, Mirco Ponzoni & Chiara Brignole

  2. Pathology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy

    Barbara De Giovanni, Barbara Cafferata & Valerio Gaetano Vellone

  3. Department of Experimental Medicine, University of Genoa, Genoa, Italy

    Matilde Balbi & Silvia Ravera

  4. IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Silvia Ravera

  5. Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa, Genoa, Italy

    Valerio Gaetano Vellone

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Contributions

G.B., C.B. study conceptualization, experimental design, experimental work, and data analysis. G.R., E.C., D.S., S.R., M.B., experimental work and data analyses. F.P. experimental work, experimental design, and data analyses. B. DG. histological and immunehistochemical staining. B.C., V.G.V. histological and immunehistochemical analyses. G.B., C.B., S.R., V.G.V., manuscript preparation and revision. M.P. supervision of the project, data analyses. All authors read and approved the manuscript.

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Correspondence to Mirco Ponzoni.

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All methods were performed in accordance with the relevant institutional and national guidelines and regulations. Animal experiments were approved by the Animal Welfare Body (OPBA) of IRCCS Ospedale Policlinico San Martino and by the Italian Ministry of Health (approval number: 539/2024-PR). No human participant were involved in this research.

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Bianchi, G., Pastorino, F., Rolandi, G. et al. The investigational anti-B7-H3 antibody-drug conjugate vobramitamab duocarmazine exerts anti-tumor activity in vitro and in vivo in pediatric sarcoma preclinical models. Cell Death Dis (2026). https://doi.org/10.1038/s41419-025-08397-z

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  • Received: 23 June 2025

  • Revised: 27 November 2025

  • Accepted: 15 December 2025

  • Published: 08 January 2026

  • DOI: https://doi.org/10.1038/s41419-025-08397-z

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