GA201: A Novel Humanized and Glycoengineered Anti-EGFR Antibody—Letter
Authors: Helmout Modjtahedi, Suzanne Eccles
Journal: Clinical Cancer Research (2014)

We read with great interest the article by Gerdes and colleagues, reporting the production of a novel, humanized anti-EGFR antibody GA201 (RG7160) with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and superior in vivo efficacy compared with cetuximab (1). In particular, we noticed that GA201 is the humanized version of our well characterized rat anti-EGFR monoclonal antibody (mAb) ICR62 (2). We have shown previously that ICR62 (i) inhibits the growth in vitro and in vivo of a wide range of human tumor cell lines by blocking the binding of ligands to the EGF receptor (EGFR) and by inducing terminal differentiation; and ADCC (ii) inhibits the growth of tumors overexpressing the EGFRvIII deletion mutant and (iii) localizes to metastatic lesions in patients with head and neck or lung cancer, 24 hours post treatment (2–4). Only 2 out of 20 patients developed anti-idiotypic responses (4). In their study, Gerdes and colleagues established the humanized version of ICR62 by transferring the three complementarity determining regions (CDRs) from the heavy and light variable domains of ICR62 into a human immunoglobulin G (IgG)1 framework. To enhance its binding to FcRγIIIA, they have also glycoengineered the Fc portion of GA201 to contain bisected, afucosylated carbohydrate. They report that GA201 inhibited the binding EGFR to the EGFR, EGFR/HER-2 heterodimerization, downstream signaling, and cell proliferation to a similar extent to cetuximab. In contrast, GA201 was found to have superior antitumor activity in vivo against both KRAS wild-type and KRAS-mutant cancer cells (1). On the basis of their data, they concluded that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and that this could be due to its enhanced ADCC ability. Although the data presented here are interesting, there are important questions that require further clarifications by the authors.The authors have stated that “The humanized GA201 construct showed identical EGFR-binding behavior compared with the parent rat antibody (i.e., “Engineering and characterization of GA201” in the Results section). They have also stated that “Glycoengineering of GA201 resulted in bisected, afucosylated Fc-region carbohydrates and a concomitant increase in the affinity for FcrγIIIA compared with the parental ICR62 antibody (“Glycoengineering of the Fc region” in the Results section). However, there are no data with the parental rat anti-EGFR mAb ICR62 to support such claims. The authors should address and clarify these points. In addition, they show that although cetuximab did not have a significant effect on the survival of mice bearing tumors with low level EGFR expression, they found that GA201 had a significant effect (Fig. 4C) highlighting the fact that the superiority of GA201 compared with cetuximab is independent of EGFR expression levels. What is going to be the potential limitation of this engineered antibody? EGFR is a tumor-associated antigen, but there is also low level of expression in several normal tissues and organs (e.g., skin, liver) and these are responsible for some of the side effects (e.g., skin rash) associated with both anti-EGFR mAbs and small-molecule EGFR tyrosine kinase inhibitors (5). Will the increased therapeutic effect obtained with this humanized form of ICR62, which has been glycoengineered for enhanced ADCC via NK cells, not be accompanied by increased toxicities to normal tissues? The results of future studies should determine whether treatment with repeated doses of GA201, or any other humanized versions of our mAb ICR62, will be more efficacious, less immunogenic, and less toxic than cetuximab, panitumumab, or our parental ICR62 in patients with cancer. Finally, it is important to remember that the binding sites of ICR62, and consequently GA201, are different from those of cetuximab. Consequently, the superiority of GA201 compared with cetuximab could also be due to the differences in the binding sites of the ICR62/GA201 and cetuximab on the extracellular domain of the EGFR. The glycoengineering of cetuximab or its parental mouse anti-EGFR mAb with enhanced binding to FcRγIIIA would determine whether the superiority of GA201 over cetuximab is due to differences in their binding sites or glycoengineering of the Fc portion of the antibody.See the Response, p. 1055No potential conflicts of interest were disclosed.Conception and design: H. ModjtahediDevelopment of methodology: H. ModjtahediWriting, review, and/or revision of the manuscript: H. Modjtahedi, S. Eccles