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- Publisher Website: 10.1158/1535-7163.MCT-13-0558
- Scopus: eid_2-s2.0-84892598423
- PMID: 24227890
- WOS: WOS:000329815200010
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Article: Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor
Title | Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor |
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Authors | |
Issue Date | 2014 |
Publisher | American Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/ |
Citation | Molecular Cancer Therapeutics, 2014, v. 13 n. 1, p. 90-100 How to Cite? |
Abstract | The humanized anti-HER2 monoclonal antibody (mAb) trastuzumab (Herceptin; Genentech) effectively inhibits human epidermal growth factor receptor 2 (HER2)-positive breast tumors. However, many patients responding to treatment often develop resistance. Cross-talk between type I insulin-like growth factor receptor (IGF-IR) and HER2 and elevated IGF-IR signaling have been implicated in tumor cell resistance to trastuzumab therapy. Previously, we reported that the anti-IGF-IR mAb m590 inhibits proliferation and migration of breast cancer MCF-7 cells in vitro. Here, we generated a 'knobs-into-holes' bispecific antibody (Bi-Ab) against HER2 and IGF-IR by engineering trastuzumab and m590. We compared the effects of Bi-Ab treatment in vitro and in SKOV-3 HER2- and IGF-IR-overexpressing cancer xenograft mouse model with those of m590 and trastuzumab treatment alone or in combination. Bi-Ab effectively inhibited proliferation of HER2- and IGF-IR-overexpressing ovarian cancer SKOV-3 cells in vitro by ablating receptor phosphorylation and downstream PI3K/Akt and mitogen-activated protein kinase signaling. Bi-Ab more effectively inhibited cancer growth in SKOV-3 HER2- and IGF-IR-overexpressing cancer xenograft mouse model than m590 and trastuzumab alone or in combination. Mice bearing SKOV-3 HER2- and IGF-IR-overexpressing xenografts showed extensive and sustainable tumor regression when treated with Bi-Ab. Our results suggest that Bi-Ab has superior antitumor activity compared with monospecific antibodies, and cotargeting HER2 and IGF-IR may be clinically beneficial in minimizing the acquired resistance to trastuzumab therapy. Mol Cancer Ther; 13(1); 90-100. (c)2013 AACR. |
Persistent Identifier | http://hdl.handle.net/10722/193753 |
ISSN | 2023 Impact Factor: 5.3 2023 SCImago Journal Rankings: 2.270 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Chen, C | - |
dc.contributor.author | Zhang, Y | - |
dc.contributor.author | Zhang, Y | - |
dc.contributor.author | Li, J | - |
dc.contributor.author | Tsao, GSW | - |
dc.contributor.author | Zhang, M | - |
dc.date.accessioned | 2014-01-27T06:15:07Z | - |
dc.date.available | 2014-01-27T06:15:07Z | - |
dc.date.issued | 2014 | - |
dc.identifier.citation | Molecular Cancer Therapeutics, 2014, v. 13 n. 1, p. 90-100 | - |
dc.identifier.issn | 1535-7163 | - |
dc.identifier.uri | http://hdl.handle.net/10722/193753 | - |
dc.description.abstract | The humanized anti-HER2 monoclonal antibody (mAb) trastuzumab (Herceptin; Genentech) effectively inhibits human epidermal growth factor receptor 2 (HER2)-positive breast tumors. However, many patients responding to treatment often develop resistance. Cross-talk between type I insulin-like growth factor receptor (IGF-IR) and HER2 and elevated IGF-IR signaling have been implicated in tumor cell resistance to trastuzumab therapy. Previously, we reported that the anti-IGF-IR mAb m590 inhibits proliferation and migration of breast cancer MCF-7 cells in vitro. Here, we generated a 'knobs-into-holes' bispecific antibody (Bi-Ab) against HER2 and IGF-IR by engineering trastuzumab and m590. We compared the effects of Bi-Ab treatment in vitro and in SKOV-3 HER2- and IGF-IR-overexpressing cancer xenograft mouse model with those of m590 and trastuzumab treatment alone or in combination. Bi-Ab effectively inhibited proliferation of HER2- and IGF-IR-overexpressing ovarian cancer SKOV-3 cells in vitro by ablating receptor phosphorylation and downstream PI3K/Akt and mitogen-activated protein kinase signaling. Bi-Ab more effectively inhibited cancer growth in SKOV-3 HER2- and IGF-IR-overexpressing cancer xenograft mouse model than m590 and trastuzumab alone or in combination. Mice bearing SKOV-3 HER2- and IGF-IR-overexpressing xenografts showed extensive and sustainable tumor regression when treated with Bi-Ab. Our results suggest that Bi-Ab has superior antitumor activity compared with monospecific antibodies, and cotargeting HER2 and IGF-IR may be clinically beneficial in minimizing the acquired resistance to trastuzumab therapy. Mol Cancer Ther; 13(1); 90-100. (c)2013 AACR. | - |
dc.language | eng | - |
dc.publisher | American Association for Cancer Research. The Journal's web site is located at http://mct.aacrjournals.org/ | - |
dc.relation.ispartof | Molecular Cancer Therapeutics | - |
dc.title | Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor | en_US |
dc.type | Article | en_US |
dc.identifier.email | Li, J: joyli@hku.hk | - |
dc.identifier.email | Tsao, GSW: gswtsao@hku.hk | - |
dc.identifier.email | Zhang, M: zhangmy@hku.hk | - |
dc.description.nature | postprint | - |
dc.identifier.doi | 10.1158/1535-7163.MCT-13-0558 | - |
dc.identifier.pmid | 24227890 | - |
dc.identifier.scopus | eid_2-s2.0-84892598423 | - |
dc.identifier.hkuros | 227417 | - |
dc.identifier.volume | 13 | - |
dc.identifier.issue | 1 | - |
dc.identifier.spage | 90 | - |
dc.identifier.epage | 100 | - |
dc.identifier.isi | WOS:000329815200010 | - |
dc.publisher.place | United States | - |
dc.identifier.issnl | 1535-7163 | - |