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A recombinant fragment antigen-binding (Fab) of trastuzumab displays low cytotoxic profile in adult human cardiomyocytes: first evidence and the key implication of FcγRIIA receptor

Acta Pharmacologica Sinica volume 46, pages 618–631 (2025)Cite this article

Abstract

Fragment crystallizable gamma receptors (FcγRs) mediate various cellular responses with significant cardiovascular implications. They contribute to the anticancer activity of trastuzumab (TRZ), a recombinant humanized monoclonal antibody that interferes with human epidermal growth factor receptor 2 (HER2), thereby blocking its physiological function in cardiac cells. This is responsible for cardiac complications that hamper TRZ clinical application. In this study we investigated the involvement of FcγRs in the TRZ cardiotoxicity. We used a recombinant antigen-binding fragment (Fab) of TRZ (rFab-HER2) to examine whether the absence of the Fc region resulted in fewer cardiomyocyte toxicity while preserving TRZ’s ability to inhibit HER2. When exposed to rFab-HER2, AC16 human adult ventricular cardiomyocytes were less vulnerable to damage and death, than to TRZ. Specifically, TRZ exhibited cytotoxicity at a lower concentration (150 µg/mL, corresponding to ~1 µM) compared to rFab-HER2 (250 µg/mL, corresponding to ~5 µM). Like TRZ, rFab-HER2 negatively modulated HER2 levels in cardiomyocyte (without inducing cytotoxic activity in BJ human fibroblast cells that either did not express or express very low levels of HER2) and inhibited the downstream ERK/AKT cascades. But rFab-HER2 did not alter cardiomyocyte mitochondrial dynamic balance, and affect apoptosis and inflammation, while it limited cytosolic and mitochondrial ROS indicators. On contrary, the Fc region (50−250 μg/mL) exerted direct cytotoxic action on cardiomyocytes (but not on human fibroblasts that lacked Fc receptors). TRZ (150 μg/mL) markedly upregulated the expression level of FcγRIIA (a FcγRs strongly involved in TRZ-induced antibody-dependent cellular toxicity) in cardiomyocytes, whereas the Fab fragment (150 μg/mL) had no effect. Our results demonstrate that Fc region plays an important pathogenic role in TRZ-induced cardiomyocyte toxicity. In addition, targeting FcγRIIA might contribute to the off-target effects of TRZ therapy.

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Fig. 1: Effects of TRZ or rFab-HER2 on cell viability and cytotoxicity in AC16 human cardiomyocytes.
Fig. 2: Effect of TRZ, rFab-HER2 or IgG on Human Epidermal Growth Factor Receptor 2 (HER2) expression in AC16 human cardiomyocytes.
Fig. 3: Effects of TRZ or rFab-HER2 on cell viability in BJ human fibroblast cells.
Fig. 4: Effects of TRZ or rFab-HER2 on cardiomyocyte signaling pathways related to cell survival, mitochondrial dynamics, and inflammation, in AC16 cells.
Fig. 5: Effects of TRZ or rFab-HER2 on cardiomyocyte apoptosis in AC16 cells.
Fig. 6: Effect of TRZ or rFab-HER2 on indicators of cellular and mitochondrial ROS in AC16 human cardiomyocytes.
Fig. 7: Effects of the Fc region on AC16 and BJ cells viability, and effect of TRZ or rFab-HER2 on FcγRIIA expression in AC16 human cardiomyocytes.
Fig. 8: Proposed schematic representation of TRZ effects (red arrows) versus rFab-HER2 effects (blue symbols) in adult human ventricular cardiomyocytes.

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Acknowledgements

The authors acknowledge Dr. Francesca Giordano (Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy) for her technical support in the flow cytometry analysis. This research was supported by “SI.F.I.PA.CRO.DE. – Sviluppo e industrializzazione farmaci innovativi per terapia molecolare personalizzata PA.CRO.DE” (PON ARS01_00568).

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  1. These authors contributed equally: Carmine Rocca, Tommaso Angelone

Authors and Affiliations

  1. Department of Biology, E. and E. S. (DiBEST), Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, University of Calabria, Cosenza, Italy

    Anna De Bartolo, Naomi Romeo, Alessandro Marrone, Maria Concetta Granieri, Carmine Rocca & Tommaso Angelone

  2. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Cosenza, Italy

    Vittoria Rago

  3. Department of Biology, E. and E. S. (DiBEST), University of Calabria, Rende, Italy

    Maria Luigia Vommaro

  4. Department of Biology, E. and E. S. (DiBEST), Organ and System Physiology Laboratory, University of Calabria, Cosenza, Italy

    Arianna Cupelli & Maria Carmela Cerra

  5. Department of Biology, E. and E. S. (DiBEST), Unit of Biochemistry, Molecular Biotechnology, and Molecular Biology, University of Calabria, Cosenza, Italy

    Cesare Indiveri

  6. CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnology, Bari, Italy

    Cesare Indiveri

  7. BIOVIIIX, Napoli, Italy

    Raffaele Ronca, Maria Cantile & Riccardo Sanna

  8. National Institute of Cardiovascular Research (INRC), Bologna, Italy

    Carmine Rocca & Tommaso Angelone

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Contributions

ADB, NR, AM, VR, MCG, MLV, AC, RR, MC, and RS performed the experiments, contributed to prepare, collect, and analyze the data; ADB and CR wrote the first draft of the manuscript; MCC and CI contributed to supervision of the experiments, review and edit the manuscript. CR and TA conceived the project, analyzed data, supervisioned and validated the experiments, reviewed and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Carmine Rocca or Tommaso Angelone.

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De Bartolo, A., Romeo, N., Marrone, A. et al. A recombinant fragment antigen-binding (Fab) of trastuzumab displays low cytotoxic profile in adult human cardiomyocytes: first evidence and the key implication of FcγRIIA receptor. Acta Pharmacol Sin 46, 618–631 (2025). https://doi.org/10.1038/s41401-024-01397-3

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