RSS-Feed abonnieren
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0042-1749334
Generating a Bispecific Antibody Drug Conjugate Targeting PRLR and HER2 with Improving the Internalization
Funding This work was supported by the National Natural Science Foundation of China (Grant No. 81773621 and 82073751) and Shanghai Science and Technology Commission project (Grant No. 20S11904900).![](https://www.thieme-connect.de/media/10.1055-s-00043364/202202/lookinside/thumbnails/10-1055-s-0042-1749334_2200005oa-1.jpg)
Abstract
Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. The bispecific targeting could improve the specificity, affinity, and internalization of the ADC molecules. Prolactin preceptor (PRLR) and HER2 have crosstalk signaling in breast cancer, and PRLR undergoes a rapid internalization compared with HER2. To improve the efficacy of HER2 ADCs with enhancing the target specificity and internalization, we constructed a PRLR/HER2-targeting bispecific ADC (BsADC). We evaluated the characterization of PRLR × HER2 BsADC from the affinity and internalization, and further assessed its in vitro cytotoxicity in human breast-cancer cell lines (BT474, T47D, and MDA-MB-231) using Cell Count Kit-8 analysis. Our data demonstrated that PRLR × HER2 BsADC kept the affinity to two targeting antigens after conjugating drugs and exhibited higher internalization efficiency in comparison to HER2 ADC. Furthermore, PRLR × HER2 BsADC demonstrated to have superior antitumor activity in human breast cancer in vitro. In conclusion, our findings indicate that it is feasible through increasing the internalization of target antibody to enhance the antitumor activity and therapeutic potential that could be further evaluated in in vivo animal model.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Publikationsverlauf
Eingereicht: 16. Februar 2022
Angenommen: 15. April 2022
Artikel online veröffentlicht:
04. Juli 2022
© 2022. 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 Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules 2020; 25 (20) 4764
- 2 Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov 2017; 16 (05) 315-337
- 3 Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody-drug conjugates: a comprehensive review. Mol Cancer Res 2020; 18 (01) 3-19
- 4 Joubert N, Beck A, Dumontet C, Denevault-Sabourin C. Antibody-drug conjugates: the last decade. Pharmaceuticals (Basel) 2020; 13 (09) 245
- 5 Mei X, Chen J, Wang J, Zhu J. Immunotoxins: targeted toxin delivery for cancer therapy. Pharm Fronts 2019; 01 (01) e33-e45
- 6 Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet 2019; 394 (10200): 793-804
- 7 de Goeij BE, Vink T, Ten Napel H. et al. Efficient payload delivery by a bispecific antibody-drug conjugate targeting HER2 and CD63. Mol Cancer Ther 2016; 15 (11) 2688-2697
- 8 Andreev J, Thambi N, Perez Bay AE. et al. Bispecific antibodies and antibody-drug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol Cancer Ther 2017; 16 (04) 681-693
- 9 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
- 10 Piazza TM, Lu JC, Carver KC, Schuler LA. SRC family kinases accelerate prolactin receptor internalization, modulating trafficking and signaling in breast cancer cells. Mol Endocrinol 2009; 23 (02) 202-212
- 11 Anderson MG, Zhang Q, Rodriguez LE. et al. ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition. BMC Cancer 2021; 21 (01) 681
- 12 Zhou Y, Zong H, Han L. et al. A novel bispecific antibody targeting CD3 and prolactin receptor (PRLR) against PRLR-expression breast cancer. J Exp Clin Cancer Res 2020; 39 (01) 87
- 13 Kelly MP, Hickey C, Makonnen S. et al. Preclinical activity of the novel anti-prolactin receptor (PRLR) antibody-drug conjugate REGN2878-DM1 in PRLR-positive breast cancers. Mol Cancer Ther 2017; 16 (07) 1299-1311
- 14 Nagini S. Breast cancer: current molecular therapeutic targets and new players. Anticancer Agents Med Chem 2017; 17 (02) 152-163
- 15 Kavarthapu R, Anbazhagan R, Dufau ML. Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer. Cancers (Basel) 2021; 13 (18) 4685
- 16 Han L, Zong H, Zhou Y. et al. Naturally split intein Npu DnaE mediated rapid generation of bispecific IgG antibodies. Methods 2019; 154: 32-37
- 17 Pan Z, Chen J, Xiao X. et al. Characterization of a novel bispecific antibody targeting tissue factor-positive tumors with T cell engagement. Acta Pharm Sin B 2022; 12 (04) 1928-1942
- 18 Sun R, Zhou Y, Han L. et al. A rational designed novel bispecific antibody for the treatment of GBM. Biomedicines 2021; 9 (06) 640
- 19 Wang J, Han L, Chen J, Xie Y, Jiang H, Zhu J. Reduction of non-specific toxicity of immunotoxin by intein mediated reconstitution on target cells. Int Immunopharmacol 2019; 66: 288-295
- 20 Ge Q, Sun T, Bian Y, Xiao X, Zhu J. Generating a novel bispecific nanobody to enhance antitumor activity. Pharmaceutical Fronts 2020; 02 (02) e100-e108
- 21 Liu X, Sun T, Ge Q, Zhu J. Construction of novel bispecific single-domain antibodies (BiSdAbs) with potent antiangiogenic activities. Pharmaceutical Fronts 2020; 02 (01) e64-e76
- 22 Han L, Chen J, Ding K. et al. Efficient generation of bispecific IgG antibodies by split intein mediated protein trans-splicing system. Sci Rep 2017; 7 (01) 8360
- 23 Ding K, Han L, Zong H, Chen J, Zhang B, Zhu J. Production process reproducibility and product quality consistency of transient gene expression in HEK293 cells with anti-PD1 antibody as the model protein. Appl Microbiol Biotechnol 2017; 101 (05) 1889-1898
- 24 Zhu J. Mammalian cell protein expression for biopharmaceutical production. Biotechnol Adv 2012; 30 (05) 1158-1170
- 25 Shen BQ, Xu K, Liu L. et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat Biotechnol 2012; 30 (02) 184-189
- 26 Junutula JR, Raab H, Clark S. et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 2008; 26 (08) 925-932
- 27 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
- 28 Kovtun Y, Noordhuis P, Whiteman KR. et al. IMGN779, a novel CD33-targeting antibody-drug conjugate with DNA-alkylating activity, exhibits potent antitumor activity in models of AML. Mol Cancer Ther 2018; 17 (06) 1271-1279
- 29 Zong H, Han L, Chen J. et al. Kinetics study of the natural split Npu DnaE intein in the generation of bispecific IgG antibodies. Appl Microbiol Biotechnol 2022; 106 (01) 161-171