Trastuzumab-induced Cardiotoxicity involves Antibody Dependent Cell Cytotoxicity (ADCC) — ASN Events
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  2. Poster Session One
  3. Trastuzumab-induced Cardiotoxicity involves Antibody Dependent Cell Cytotoxicity (ADCC)

Trastuzumab-induced Cardiotoxicity involves Antibody Dependent Cell Cytotoxicity (ADCC) (#134)

Liam J Griffiths 1 , Uda Ho 1 , Kelsey Burt 1 , Sophie Watson 1 , Kinjal Patel 1 , Julia Bradford 1 , Yuanzhao Cao 2 , Clarissa Tan 2 , Melissa Elliott 3 , Nathan J Palpant 2 , Fernando Guimaraes 3 , Sherry Y Wu 1 , Melissa E Reichelt 1 , Walter G Thomas 1
  1. School of Biomedical Sciences , The University of Queensland, Brisbane, Queensland, Australia
  2. Institute of Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
  3. Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia

Introduction: Human Epidermal Growth Factor Receptor 2 (HER2) is amplified in approximately 20% of breast cancers and is associated with uncontrolled cell proliferation and poor prognosis. The HER2-targeting antibody Trastuzumab, in combination with the anthracycline Doxorubicin, significantly improves overall survival in patients with HER2-positive breast cancer. However, Trastuzumab’s effectiveness is hindered by the occurrence of cardiotoxicity, which is exacerbated when used alongside anthracyclines. Despite efforts to limit its on-target effects on the heart, cardiac dysfunction remains a dose-limiting side effect of treatment. The mechanism underlying this toxicity remains poorly understood.

Aims: We hypothesised that Trastuzumab- and Doxorubicin-induced cardiotoxicity is mediated by Antibody-Dependent Cell Cytotoxicity (ADCC) driven by Natural Killer (NK) cells. Furthermore, we proposed that a functionally active, yet Trastuzumab-resistant HER2 receptor could mitigate the cardiac side effects associated with Trastuzumab.

Results: We mutated the Trastuzumab-binding domain of HER2 and confirmed Trastuzumab-resistance via immunofluorescence in HEK293T cells. We used Bioluminescence Resonance Energy Transfer (BRET) to confirm function of the HER2 mutant (via recruitment of Grb2 to HER2 as part of a heterodimer with EGFR). We delivered both mutant and wild-type HER2 into Human-induced Pluripotent Stem Cell-derived Cardiomyocytes (HiPSC-CM) with an adeno-associated virus and treated with combinations IgG or Trastuzumab, Doxorubicin and purified NK cells. Cardiac function and cytotoxicity were evaluated using LDH release and the CardioExcyte96 platform and demonstrated that clinically relevant dosages of Trastuzumab could mediate cardiotoxicity in the presence of NK cells. Notably, ADCC was exacerbated by the transduction of extra WT-HER2, but not the Trastuzumab-resistant HER2, suggesting that Trastuzumab-bound endogenous HER2 could drive these effects.

Conclusion: We present the first evidence of ADCC as a mechanism underlying Trastuzumab-induced cardiotoxicity. Detailed understanding of this mechanism could offer an avenue for the development of cardioprotective therapies, with the potential to enhance efficacy and safety profiles, thereby improving patient outcomes.