IgG1 anti‐epidermal growth factor receptor antibodies induce CD8‐dependent antitumor activity

Abstract

Anti-EGFR monoclonal antibodies (mAb) like Cetuximab are commonly used for treatment of EGFR 1 solid tumors mainly by exerting their therapeutic effect through inhibition of signal transduction. Additionally, IgG1 is a potent mediator of antibodydependent cytotoxicity (ADCC). In case of the IgG1, Cetuximab induction of ADCC in vivo is controversially discussed. In our study, we investigated the efficiency of Cetuximab-mediated ADCC in a humanized mouse tumor model in vivo and analyzed the contribution of immunologic processes toward antitumor activity. Therefore, we used immunodeficient NOD/Scid mice transgenic for human MHC class I molecule HLA-A2 and adoptively transferred human HLA-A2 1 PBMC after engraftment of human epidermoid cell carcinoma A431. Here, we show that high doses of anti-EGFR mAb induced strong tumor regression independent of the immune system. However, tumor regression by low doses of anti-EGFR mAb treatment was ADCC dependent and mediated by tumor infiltrating CD8 1 T effector cells. This novel mechanism of ADCC conducted by CD8 1 T effector cells was restricted to IgG1 anti-EGFR mAb, dependent of binding to CD16 on T cells and could be inhibited after EGFR blockade on tumor cells. Furthermore, CD8 1 T effector cell-mediated ADCC was enhanced in the presence of IL-15 and strongly improved after glycosylation of anti-EGFR mAb indicating the potential of glycoengineered therapeutic mAb as efficient biologicals in cancer therapy.

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

“…9 However, zalutumumab, as an IgG1 molecule, could induce both NK and myeloid effector cell-mediated ADCC, which shows the advantage of the IgG1 subclass in activating ADCC activity. 9 Moreover, Kubach et al 20 provide strong evidence of a novel mechanism of CD8 C T cell-mediated cytotoxicity induced by anti-EGFR mAb with an IgG1 isotype. Recently, Dillon et al 26 revealed that the heterogeneity of human IgG2 antibodies can affect structure and function, although additional studies are required to further characterize how this heterogeneity specifically affects panitumumab and its biological functions.…”

“…9 Recent studies have suggested that the lack of ADCC activity could limit the efficacy of panitumumab in vivo mouse model. 19,20 The IgG2 isotype of panitumumab was chosen to minimize potential toxicity to EGFR-expressing normal tissues from ADCC and CDC. 15 Consequently, the construction of a novel ADCC-enhanced mAb by engineering panitumumab has not been reported, potentially due to concerns that improving the effector functions of panitumumab might increase the severity of additional side effects.…”

Anti-tumor immunity of BAM-SiPc-mediated vascular photodynamic therapy in a BALB/c mouse model

“…In a human HER2 transgenic mouse model, anti-HER2 monoclonal antibody treatment of murine D5 melanoma transfected with full-length human HER2 led to tumor regression and the development of immunological memory against the original tumor. 67,68 The effects of antibodies can be affected by the antibodies' subclass, glycosylation state, and affinity toward various tumor-derived antigens; [69][70][71] therefore, it remains unknown whether tumor-reactive antibodies generated in vivo possess similar functions to those used in monoclonal antibody therapy.…”

Targeted Therapies: Immunologic Effects and Potential Applications Outside of Cancer

“…In line with the above concept, there is evidence that the specific isotype and/or glycosylation status of an individual therapeutic mAb is relevant in this regard because these differences influence the aforementioned interactions . For example, the immunoglobulin G (IgG) isotype of EGFR‐specific mAbs is thought to be important in determining which lineage of cells predominates in mediating ADCC .…”