Role of Fcγ receptors in HER2-targeted breast cancer therapy

Abstract

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 (FcγR)-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. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-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 FcγR-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 FcγRIIIa and decrease binding to inhibitory FcγRIIb (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.

Keywords: adaptive immunity; breast neoplasms; immunity; innate; review.

Figure 1

Mechanism of action of anti-HER2 mAbs: antiproliferative effects and immune activation. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; FcγR, fragment crystallizable gamma receptor; HER2, human epidermal growth factor receptor 2; mAb, monoclonal antibody; MHC II, major histocompatibility complex class II; NK, natural killer; TAA, tumor-associated antigen. The red X in the left panel indicates inhibition.

Figure 2

FcγRs differ in their function, cell distribution, immune response, signaling motifs, and affinity for IgG molecules. ^aDendritic cells internalize Ag:Ab immune complexes and present Ag to T cells. ^bCD32B is expressed on NK cells in ~3% of humans due to an FCGR2C-FCGR3B gene deletion that links the FCGR2C promoter to the FCGR2B coding sequence. ^cCD32C is expressed in ~20% of humans due to an unequal crossover of FCGR2A and FCGR2B genes. ^dSame ECD as CD16A but lacks intracellular signaling motifs. ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; ECD, extracellular domain; FcγR, fragment crystallizable gamma receptor; GPI, glycophosphatidylinositol; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; NK, natural killer; NKT, natural killer T cell.

Figure 3

Classical granzyme/perforin-mediated apoptosis pathway (adapted from Bots and Medema76). Bid, BH3 interacting domain death agonist; CAD, caspase-activated DNase; ER, endoplasmic reticulum; FcγR, fragment crystallizable gamma receptor; HER2, human epidermal growth factor receptor 2; HMG2, high-mobility group protein 2; ICAD, inhibitor of caspase-activated DNase; mAb, monoclonal antibody; Mcl-1, myeloid-cell leukemia 1; NK, natural killer; PI-9, proteinase inhibitor 9; ROS, reactive oxygen species; tBid, truncated Bid.