Download PDF
CC BY 4.0 · Pharmaceutical Fronts 2023; 05(03): e187-e196
DOI: 10.1055/s-0043-1772703
Original Article

A Potential Antibody–Drug Conjugate Targeting Human LIV1 for the Treatment of Triple-Negative Breast Cancer

Wei Zhang
1   Department of Biology, China State Institute of Pharmaceutical Industry Co., Ltd., People's Republic of China
,
Hong Liu
1   Department of Biology, China State Institute of Pharmaceutical Industry Co., Ltd., People's Republic of China
,
Wei-Liang Zhuang
1   Department of Biology, China State Institute of Pharmaceutical Industry Co., Ltd., People's Republic of China
,
Yuan Li
1   Department of Biology, China State Institute of Pharmaceutical Industry Co., Ltd., People's Republic of China
,
Li-Ping Xie
1   Department of Biology, China State Institute of Pharmaceutical Industry Co., Ltd., People's Republic of China
,
You-Jia Hu
1   Department of Biology, China State Institute of Pharmaceutical Industry Co., Ltd., People's Republic of China
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Abstract

Triple-negative breast cancer (TNBC), which accounts for 15 to 20% of incidents of breast cancer, is the only breast cancer subtype that lacks targeted treatments. It was reported in the literature that LIV1 was highly expressed in TNBC and other solid tumors. This makes LIV1 a potential target for the treatment of TNBC. This study aimed to develop an anti-LIV1 antibody for the treatment of TNBC. In this study, a novel anti-LIV1 antibody Ab1120 was developed and conjugated with monomethyl auristatin E (MMAE) to obtain the antibody–drug conjugate, Ab1120-vcMMAE. The Cell Counting Kit-8 method was used to assess the killing effect of the antibody–drug conjugate on cell lines MDA-MB−231 (high LIV1 expression of breast cancer cell line), MDA-MB-468 (low LIV1 expression of breast cell line), and 293C18 (LIV1-negative human embryonic kidney cell). The antitumor effect of Ab1120-vcMMAE on an MDA-MB-231 xenograft model was determined by evaluating the tumor volume and body weight after its treatment. In vitro analysis showed that Ab1120-vcMMAE is a potent inhibitor against the proliferation of a LIV1 overexpression cell line. The in vivo results demonstrated its antitumor activity in the cell-derived xenograft breast tumor mouse model. The results of this study suggest that Ab1120-vcMMAE may be used as a new therapeutic drug for patients with LIV1 high-expression breast cancer.

Keywords

triple-negative breast cancer - LIV1 - anti-LIV1 antibody - antibody–drug conjugates

Ethical Approval

All animal experiments were approved by the Animal Ethical Committee at the China State Institute of Pharmaceutical Industry, which conformed to the National Institutes of Health Guidelines on Laboratory Research and Guide for the Care and Use of Laboratory Animals (Eighth Edition, 2011). This article does not contain any studies with human participants performed by any of the authors.




Publication History

Received: 30 March 2023

Accepted: 24 July 2023

Article published online:
24 August 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
    CrossrefPubMedGoogle Scholar
  • 2 Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther 2022; 7 (01) 93
    CrossrefPubMedGoogle Scholar
  • 3 Saravanan R, Balasubramanian V, Swaroop Balamurugan SS. et al. Zinc transporter LIV1: a promising cell surface target for triple negative breast cancer. J Cell Physiol 2022; 237 (11) 4132-4156
    CrossrefPubMedGoogle Scholar
  • 4 Lopez V, Kelleher SL. Zip6-attenuation promotes epithelial-to-mesenchymal transition in ductal breast tumor (T47D) cells. Exp Cell Res 2010; 316 (03) 366-375
    CrossrefPubMedGoogle Scholar
  • 5 Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson RI. Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J 2003; 375 (Pt 1) 51-59
    CrossrefPubMedGoogle Scholar
  • 6 Manning DL, Daly RJ, Lord PG, Kelly KF, Green CD. Effects of oestrogen on the expression of a 4.4 kb mRNA in the ZR-75-1 human breast cancer cell line. Mol Cell Endocrinol 1988; 59 (03) 205-212
    CrossrefPubMedGoogle Scholar
  • 7 Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005; 17 (05) 548-558
    CrossrefPubMedGoogle Scholar
  • 8 Taylor KM, Hiscox S, Nicholson RI. Zinc transporter LIV-1: a link between cellular development and cancer progression. Trends Endocrinol Metab 2004; 15 (10) 461-463
    CrossrefPubMedGoogle Scholar
  • 9 Sussman D, Smith LM, Anderson ME. et al. SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Mol Cancer Ther 2014; 13 (12) 2991-3000
    CrossrefPubMedGoogle Scholar
  • 10 Unno J, Satoh K, Hirota M. et al. LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells. Int J Oncol 2009; 35 (04) 813-821
    PubMedGoogle Scholar
  • 11 Tozlu S, Girault I, Vacher S. et al. Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. Endocr Relat Cancer 2006; 13 (04) 1109-1120
    CrossrefPubMedGoogle Scholar
  • 12 Greenfield EA. Standard Immunization of Mice, Rats, and Hamsters. Cold Spring Harb Protoc 2020; 2020 (03) 100297
    CrossrefPubMedGoogle Scholar
  • 13 Smith ML, Sussman D, Arthur W, Nesterova A. Humanized Antibodies To LIV-1 And Use Of Same To Treat Cancer. U.S. Patent 20130259860A1. June, 2011
    Google Scholar
  • 14 Jones PT, Dear PH, Foote J, Neuberger MS, Winter G. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 1986; 321 (6069) 522-525
    CrossrefPubMedGoogle Scholar
  • 15 Smith ML, Sussman D, Arthur W, Nesterova A. Humanized antibodies to LIV-1 and use of same to treat cancer. US Patent 9228026. January, 2016
    PubMedGoogle Scholar
  • 16 Lyon RP, Meyer DL, Setter JR, Senter PD. Conjugation of anticancer drugs through endogenous monoclonal antibody cysteine residues. Methods Enzymol 2012; 502: 123-138
    CrossrefPubMedGoogle Scholar
  • 17 Kovtun YV, Audette CA, Ye Y. et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res 2006; 66 (06) 3214-3221
    CrossrefPubMedGoogle Scholar
  • 18 Boghaert ER, Khandke K, Sridharan L. et al. Tumoricidal effect of calicheamicin immuno-conjugates using a passive targeting strategy. Int J Oncol 2006; 28 (03) 675-684
    PubMedGoogle Scholar
  • 19 Parray HA, Shukla S, Samal S. et al. Hybridoma technology a versatile method for isolation of monoclonal antibodies, its applicability across species, limitations, advancement and future perspectives. Int Immunopharmacol 2020; 85: 106639
    CrossrefPubMedGoogle Scholar
  • 20 Klee GG. Human anti-mouse antibodies. Arch Pathol Lab Med 2000; 124 (06) 921-923
    CrossrefPubMedGoogle Scholar
  • 21 Francisco JA, Cerveny CG, Meyer DL. et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 2003; 102 (04) 1458-1465
    CrossrefPubMedGoogle Scholar
  • 22 Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules 2020; 25 (20) 4764
    CrossrefPubMedGoogle Scholar
  • 23 Li JY, Perry SR, Muniz-Medina V. et al. A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 2016; 29 (01) 117-129
    CrossrefPubMedGoogle Scholar
  • 24 Krop IE, Kim SB, Martin AG. et al. Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 2017; 18 (06) 743-754
    CrossrefPubMedGoogle Scholar
  • 25 Grattan BJ, Freake HC. Zinc and cancer: implications for LIV-1 in breast cancer. Nutrients 2012; 4 (07) 648-675
    CrossrefPubMedGoogle Scholar
  • 26 Lue HW, Yang X, Wang R. et al. LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated ERK signaling. PLoS One 2011; 6 (11) e27720
    CrossrefPubMedGoogle Scholar
  • 27 Romero I, Garrido C, Algarra I. et al. MHC intratumoral heterogeneity may predict cancer progression and response to immunotherapy. Front Immunol 2018; 9: 102
    CrossrefPubMedGoogle Scholar
  • 28 Vitale I, Shema E, Loi S, Galluzzi L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat Med 2021; 27 (02) 212-224
    CrossrefPubMedGoogle Scholar