Fully human HER2/cluster of differentiation 3 bispecific antibody triggers potent and specific cytotoxicity of T lymphocytes against breast cancer

Zhou,Yan; Gou,Lan‑Tu; Guo,Zhi‑Hui; Liu,Hai‑Rong; Wang,Jiang‑Man; Zhou,Shu‑Xian; Yang,Jin‑Liang; Li,Xiao‑An

doi:10.3892/mmr.2015.3441

Fully human HER2/cluster of differentiation 3 bispecific antibody triggers potent and specific cytotoxicity of T lymphocytes against breast cancer

Authors:
- Yan Zhou
- Lan‑Tu Gou
- Zhi‑Hui Guo
- Hai‑Rong Liu
- Jiang‑Man Wang
- Shu‑Xian Zhou
- Jin‑Liang Yang
- Xiao‑An Li
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Affiliations: Gastroenterology Tumor and Microenvironment Laboratory, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610041, P.R. China, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: March 5, 2015 https://doi.org/10.3892/mmr.2015.3441
Pages: 147-154
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The use of a bispecific antibody (BsAb) is a promising and highly specific approach to cancer therapy. In the present study, a fully human recombinant single chain variable fragment BsAb against human epidermal growth factor receptor (HER)2 and cluster of differentiation (CD)3 was constructed with the aim of developing an effective treatment for breast cancer. HER2/CD3 BsAb was expressed in Chinese hamster ovary cells and purified via nickel column chromatography. Flow cytometry revealed that the HER2/CD3 BsAb was able to specifically bind to HER2 and CD3‑positive cells. HER2/CD3 BsAb was able to stimulate T-cell activation and induce the lysis of cultured SKBR‑3 and BT474 cells in the presence of unstimulated T lymphocytes. HER2/CD3 BsAb efficiently inhibited the growth of breast cancer tissue by activating and inducing the proliferation of tumor tissue infiltrating lymphocytes. Therefore, HER2/CD3 BsAb is a potent tool which may be a suitable candidate for the treatment of breast cancer.

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1	El Saghir NS and Anderson BO: Breast cancer early detection and resources: where in the world do we start? Breast. 21:423–425. 2012. View Article : Google Scholar : PubMed/NCBI
2	Yu ZG, Jia CX, Liu LY, et al: The prevalence and correlates of breast cancer among women in Eastern China. PLoS One. 7:e377842012. View Article : Google Scholar : PubMed/NCBI
3	Oliva S, Cioffi G, Frattini S, et al: Administration of angiotensin-converting enzyme inhibitors and β-blockers during adjuvant trastuzumab chemotherapy for nonmetastatic breast cancer: marker of risk or cardioprotection in the real world? Oncologist. 17:917–924. 2012. View Article : Google Scholar :
4	de Hoon JP, Veeck J, Vriens BE, Calon TG, van Engeland M and Tjan-Heijnen VC: Taxane resistance in breast cancer: a closed HER2 circuit? Biochim Biophys Acta. 1825.197–206. 2012.
5	Arapantoni-Dadioti P, Valavanis C, Gavressea T, Tzaida O, Trihia H and Lekka I: Discordant expression of hormone receptors and HER2 in breast cancer. A retrospective comparison of primary tumors with paired metachronous recurrences or metastases. J BUON. 17:277–283. 2012.PubMed/NCBI
6	Baselga J, Bradbury I, Eidtmann H, et al: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 379:633–640. 2012. View Article : Google Scholar : PubMed/NCBI
7	Boulaamane L, Boutayeb S and Errihani H: Bevacizumab based chemotherapy in first line treatment of HER2 negative metastatic breast cancer: results of a Moroccan observational institutional study. BMC Res Notes. 5:1622012. View Article : Google Scholar : PubMed/NCBI
8	Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 244:707–712. 1989. View Article : Google Scholar : PubMed/NCBI
9	Blok EJ, Kuppen PJ, van Leeuwen JE and Sier CF: Cytoplasmic overexpression of HER2: a key factor in colorectal cancer. Clin Med Insights Oncol. 7:41–51. 2013. View Article : Google Scholar : PubMed/NCBI
10	Conti M, Hsieh M, Park JY and Su YQ: Role of the epidermal growth factor network in ovarian follicles. Mol Endocrinol. 20:715–723. 2006. View Article : Google Scholar
11	Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 131:18–43. 2007.PubMed/NCBI
12	Larbouret C, Robert B, Navarro-Teulon I, et al: In vivo therapeutic synergism of anti-epidermal growth factor receptor and anti-HER2 monoclonal antibodies against pancreatic carcinomas. Clin Cancer Res. 13:3356–3362. 2007. View Article : Google Scholar : PubMed/NCBI
13	Burstein HJ: The distinctive nature of HER2-positive breast cancers. N Engl J Med. 353:1652–1654. 2005. View Article : Google Scholar : PubMed/NCBI
14	Bayoudh L, Afrit M, Daldoul O, et al: Trastuzumab (herceptin) for the medical treatment of breast cancer. Tunis Med. 90:6–12. 2012.PubMed/NCBI
15	Wang CX, Koay DC, Edwards A, Lu Z, Mor G, Ocal IT and Digiovanna MP: In vitro and in vivo effects of combination of Trastuzumab (Herceptin) and Tamoxifen in breast cancer. Breast Cancer Res Treat. 92:251–263. 2005. View Article : Google Scholar : PubMed/NCBI
16	Rugo H, Brammer M, Zhang F and Lalla D: Effect of trastuzumab on health-related quality of life in patients with HER2-positive metastatic breast cancer: data from three clinical trials. Clin Breast Cancer. 10:288–293. 2010. View Article : Google Scholar : PubMed/NCBI
17	Shepard HM, Jin P, Slamon DJ, et al: Herceptin. Handb Exp Pharmacol. 181:183–219. 2008.
18	Wolf E, Hofmeister R, Kufer P, et al: BiTEs: bispecific antibody constructs with unique anti-tumor activity. Drug Discovery Today. 10:1237–1244. 2005. View Article : Google Scholar : PubMed/NCBI
19	Seimetz D, Lindhofer H and Bokemeyer C: Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev. 36:458–67. 2010. View Article : Google Scholar : PubMed/NCBI
20	Bargou R, Leo E, Zugmaier G, et al: Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 321:974–977. 2008. View Article : Google Scholar : PubMed/NCBI
21	Yamamoto K, Trad A, Baumgart A, et al: A novel bispecific single-chain antibody for ADAM17 and CD3 induces T-cell-mediated lysis of prostate cancer cells. Biochem J. 445:135–144. 2012. View Article : Google Scholar : PubMed/NCBI
22	Wu G, Fan X, Wu H, et al: Bioscreening of phage display antibody library and expression of a humanized single-chain variable fragment antibody against human connective tissue growth factor (CTGF/CCN2). Biotechnol Appl Biochem. 56:95–102. 2010. View Article : Google Scholar : PubMed/NCBI
23	Petsch S, Gires O, Rüttinger D, Denzel S, Lippold S, Baeuerle PA and Wolf A: Concentrations of EpCAM ectodomain as found in sera of cancer patients do not significantly impact redirected lysis and T-cell activation by EpCAM/CD3-bispecific BiTE antibody MT110. MAbs. 3:31–37. 2011. View Article : Google Scholar :
24	Jäger M, Schoberth A, Ruf P, et al: Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3). Cancer Res. 72:24–32. 2012. View Article : Google Scholar
25	Reusch U, Sundaram M, Davol PA, et al: Anti-CD3 anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model. Clin Cancer Res. 12:183–190. 2006. View Article : Google Scholar : PubMed/NCBI
26	Kasuya K, Shimazu M, Suzuki M, Itoi T, Aoki T and Tsuchida A: Bispecific anti-HER2 and CD16 single-chain antibody production prolongs the use of stem cell-like cell transplantation against HER2-overexpressing cancer. Int J Mol Med. 25:209–215. 2010.PubMed/NCBI
27	Stebbings R, Findlay L, Edwards C, et al: ‘Cytokine storm’ in the phase I trial of monoclonal antibody TGN1412: better understanding the causes to improve preclinical testing of immunotherapeutics. J Immunol. 179:3325–3331. 2007. View Article : Google Scholar : PubMed/NCBI
28	McLaughlin P, Grillo-López AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 16:2825–2833. 1998.PubMed/NCBI
29	Finn RS and Slamon DJ: Monoclonal antibody therapy for breast cancer: herceptin. Cancer Chemother Biol Response Modif. 21:223–233. 2003.