Role of Fcγ receptors in HER2-targeted breast cancer therapy

Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (Fc gamma R)-dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. Fc gamma Rs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating Fc gamma RIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating Fc gamma RIIa (CD32A) and Fc gamma RIIIa on macrophages are important for mediating ADCP. Polymorphisms in Fc gamma RIIIa and Fc gamma RIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential Fc gamma R-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance Fc gamma R-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating Fc gamma RIIIa and decrease binding to inhibitory Fc gamma RIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell-mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms.

Automated summary

Fc gamma R-mediated activities play a crucial role in the treatment of HER2+ breast cancer, but variations in Fc-gammaR can lead to differential therapeutic outcomes.