Human Domain Antibodies to Conserved Epitopes on HER2 Potently Inhibit Growth of HER2-Overexpressing Human Breast Cancer Cells In Vitro

Abstract

The FDA approval of two anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, and an antibody-drug conjugate, trastuzumab emtansine, has transformed clinical practice for HER2-positive cancers. However, not all patients respond to therapy, and the majority of responders eventually develop resistance. In addition, cardiotoxicity is a major safety concern for their clinical use. Thus, there remains a need for the discovery and development of novel classes of HER2-targeted therapeutics with high efficacy and specificity. In this study, we report the identification and characterization of fully human single-domain antibodies (dAbs) targeting HER2 epitopes that are highly conserved among various species and non-overlapping with those of trastuzumab and pertuzumab. An Fc-fusion protein of the best binder demonstrated much higher inhibitory activity against HER2-amplified human breast cancer cell lines than trastuzumab and pertuzumab. Unlike the latter, however, it did not have an effect on gastric and ovarian cancer cell lines with HER2 overexpression. The dAb-Fc fusion protein showed poor pharmacokinetics in mice, thus limiting its potential for therapeutic use. It could be useful as an agent for the exploration of functionally important conserved structures on HER2 with implications for the design of novel therapeutics and elucidation of mechanisms of HER2-mediated tumorigenesis.

A Triptolide Loaded HER2-Targeted Nano-Drug Delivery System Significantly Suppressed the Proliferation of HER2-Positive and BRAF Mutant Colon Cancer

“…Anti-HER2 antibodies have improved clinical treatment effects for metastatic CRC patients. 43 So far, the Food and Drug Administration has approved two anti-EGFR drugs cetuximab and panitumumab for the treatment of colorectal cancer, so EGFR can be used as an important and clinically relevant therapeutic target for colon cancer. However, the duration of response to anti-HER2 antibodies lasts short.…”

Novel single-domain antibodies against the EGFR domain III epitope exhibit the anti-tumor effect

“…Third, because human sdAb is small, it can access a hidden epitope that is not accessible to the large-size conventional mAb [20,21].…”

“…It has good tissue and tumor penetration [19]. It can access an epitope inaccessible to the large-size conventional mAb [20,21]. Moreover, human sdAb can be easily manufactured in bacteria at a very low cost.…”

Honokiol Suppression of Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Gastric Cancer Cell Biological Activity and Its Mechanism

“…Usually, HER2 protein is expressed only in the fetal period, and in a few tissues at a low level or not expressed in adulthood, but it is overexpressed in many tumor tissues. It has been confirmed that 12–35% of gastric cancers have HER2 overexpression, and HER2 is an independent prognostic factor of gastric cancer [ 21 ]. The results of Roy et al [ 22 ] showed that HER2 protein expression in patients with gastric cancer combined with lymph node metastasis was significantly higher than that in those without lymph node metastasis; HER2 protein expression in patients with infiltration reaching beyond the serosa was significantly higher than in those with infiltration within the serosa, and HER2 protein in lymph node metastasis of gastric cancer was highly expressed.…”