GA201, a novel humanized, glycoengineered EGFR antibody with enhanced ADCC and superior in vivo efficacy in xenograft models
Authors: Christian Gerdes, Monika Patre, Valeria Nicolini, Ekkehard Moessner, Gabriele Klingner, Peter Bruenker, Samuel Moser, Roger Grau, Carla Schmidt, Barbara Guarino, Peter Sondermann, Christiane Jaegar, Susanne Preiss, Erwin van Puijenbroek, Birgit Bossenmaier, Carola Ries, Thomas Friess, Pablo Umana
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3973 

The epidermal growth factor receptor (EGFR, HER1) is a clinically validated target for unconjugated antibodies in the treatment of cancer. It is over-expressed in a large variety of tumors for example in non-small cell lung cancer (NSCLC), head and neck, colorectal, gastric, pancreatic, renal cell, breast and prostate cancer as well as in gliomas. One anti-EGFR antibody, cetuximab, is already approved for the treatment of refractory metastatic colorectal cancer (mCRC) and of locally advanced and recurrent head and neck cancer. A second EGFR antibody, panitumumab has also been approved for mCRC. Several more EGFR antibodies are currently in clinical development. Response rates and times to progression with these drugs are modest (e.g., 11% and 1.5 months for cetuximab alone and 23 % and 4.1 months in combination with chemotherapy in mCRC) which means there is a significant need to improve on these results.    Anti-EGFR antibodies can work via various mechanisms including: (1) blocking of ligand (EGF, TGF-α, epiregulin, amphiregulin and additional EGF-like ligands) binding to the receptor, (2) blocking of homo- and heterodimerization among HER family members (HER 1-4), (3) receptor downregulation, and (4) immune effector functions such as antibody-dependent cellular cytotoxicity (ADCC). Mechanisms 1 to 3 lead to inhibition of EGFR phosphorylation and of downstream signaling, leading to inhibition of tumor cell growth, VEGF secretion, tumor cell migration, and resistance to apoptosis, while ADCC is a mechanism of direct target cell killing by immune effector cells (e.g., NK cells, macrophages) triggered upon cross-linking of Fc receptors.    GA201 is a novel humanized and glycoengineered IgG1 antibody which targets EGFR. Similar to cetuximab, its mechanism of action involves high affinity binding to EGFR, which subsequently results in ligand binding and heterodimerization blockade preventing receptor phosphorylation. This leads to inhibition of cell growth, tumor cell migration, VEGF secretion and resistance to apoptosis. However, a unique feature of GA201 that differentiates it from other EGFR antibodies, including cetuximab, is its ability to bind to human FcgRIIIa on immune effector cells with a 50-fold higher affinity than standard, IgG1 antibodies, a property conferred by the engineered glycosylation of the antibody Fc region. Consequently, GA201 exhibits superior potency and efficacy in ADCC, as shown in vitro using different EGFR expressing cell lines and in its Fc mediated anti-tumor effect in a murine models compared to other anti-EGFR Abs. The enhanced ADCC capability renders GA201 a promising new therapy compared to the other anti-EGFR MAbs on the market and currently in clinical development for the treatment of solid tumors.