Abstract
To improve efficacy and minimize toxicity of EGFR inhibition treatment, we developed Ame55, a novel anti-EGFR IgG1 with lower affinity to EGFR than cetuximab (C225) from a human phage library. Ame55 had lower bioactivity than cetuximab in vitro but similar antitumor efficacy as cetuximab in vivo. Moreover, Ame55 was more efficacious than cetuximab in a Lovo cell xenograft tumor model when combined with irinotecan (CPT-11). Ame55 concentrates in the mouse xenograft tumor and has less toxicity than cetuximab in cynomolgus monkeys in an overdose study.
Highlights
Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) and a member of the ErbB (human epidermal receptor (HER)) receptor family
EGFR is overexpressed in about one third of all human cancers [1, 2], and EGFR-mediated activation of downstream signaling pathways is associated with poor patient outcomes [3]
The results indicated that Ame55 binding to EGFR could be inhibited by EGF in a similar manner to cetuximab and nimotuzumab (Figure 2(a))
Summary
Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) and a member of the ErbB (human epidermal receptor (HER)) receptor family. To assure adequate tumor inhibition effectiveness, the US Food and Drug Administration (FDA) has approved only three EGFR-targeted mAbs drugs, including cetuximab (C225) [5, 6], panitumumab [7, 8], and necitumumab [9, 10]. These all have high-level receptor-binding affinity and undesirable side effects, such as serious diarrhea and skin rash [4]. Exploring new anti-EGFR antibodies with a good balance of affinity-efficacy-toxicity is very urgent for clinical treatment of epithelial cancer. A series of in vitro assays and in vivo tests were conducted to explore its affinity, binding specificity, xenograft tumor inhibition, combined efficacy, and general toxicity
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