Dataset Information

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.

SUBMITTER: Wang H

PROVIDER: S-EPMC6640707 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Wang Hongqian H Wang Yanping Y Xiao Zuoxiang Z Li Wei W Dimitrov Dimiter S DS Chen Weizao W

Antibodies (Basel, Switzerland) 20190318 1

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 ...[more]

PMID: 31544831

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Project description:Filoviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members of Filoviridae such as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models.Filoviruses are among the most deadly human pathogens. The 2014-2015 outbreak of Ebola virus disease (EVD) led to more than 27,000 cases and 11,000 fatalities. While there are five species of Ebolavirus and several strains of marburgvirus, the current immunotherapeutics primarily target Ebola virus. Since the nature of future outbreaks cannot be predicted, there is an urgent need for therapeutics with broad protective efficacy against multiple filoviruses. Here we describe a set of monoclonal antibodies cross-reactive with multiple filovirus species. These antibodies target novel conserved epitopes within the envelope glycoprotein and exhibit protective efficacy in mice. We further present novel concepts for combination of cross-reactive antibodies against multiple epitopes that show enhanced efficacy compared to monotherapy and provide complete protection in mice. These findings set the stage for further evaluation of these antibodies in nonhuman primates and development of effective pan-filovirus immunotherapeutics for use in future outbreaks.

Dataset Information

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

Publications

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

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