A Novel Anti-HER2 Bispecific Antibody With Potent Tumor Inhibitory Effects and

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Mar 8

PMID 33679691

Citations 9

Authors

Mehdi Mohammadi

Mahmood Jeddi-Tehrani

Forough Golsaz-Shirazi

Mohammad Arjmand

Tannaz Bahadori

Mohammad Ali Judaki

Fariba Shiravi

Hengameh Ahmadi Zare

Farzaneh Notash Haghighat

Maryam Mobini

Mohammad Mehdi Amiri

Fazel Shokri

Affiliations

Soon will be listed here.

Abstract

Overexpression of HER2 has been reported in many types of cancer, making it a perfect candidate for targeted immunotherapy. The combination of two FDA approved monoclonal antibodies (mAbs), trastuzumab and pertuzumab, has more robust anti-tumor activity in patients with HER2-overexpressing breast cancer. We recently produced a new humanized anti-HER2 mAb, hersintuzumab, which recognizes a different epitope than trastuzumab and pertuzumab on HER2. This mAb, in combination with trastuzumab, exhibits more potent anti-tumor activity than each parental mAb alone. Here we have developed a novel bispecific anti-HER2 antibody (BsAb) designated as trasintuzumab, composed of trastuzumab and hersintuzumab, using dual variable domain immunoglobulin (DVD-Ig) technology. Both variable domains of trasintuzumab are fully functional and have similar affinities to the parental mAbs and are also able to bind to natural HER2 on the surface of several HER2-expressing cell lines. Trasintuzumab was found to inhibit the growth of different types of tumor cell lines through suppression of the AKT and ERK signaling pathways as efficiently as the combination of the parental mAbs. It also induced tumor regression as potently as the combination of the two mAbs in nude mice bearing ovarian and gastric cancer xenografts. Our data suggest that trasintuzumab may be a promising BsAb therapeutic candidate for the treatment of HER2-overexpressing cancers.

Citing Articles

Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo.

Wang Z, Liu Y, Xu Y, Lu L, Zhu Z, Lv B MAbs. 2024; 16(1):2412881.

PMID: 39381966 PMC: 11469434. DOI: 10.1080/19420862.2024.2412881.

Preclinical assessment of a recombinant RBD-Fc fusion protein as SARS-CoV-2 candidate vaccine.

Dashti N, Golsaz-Shirazi F, Soltanghoraee H, Zarnani A, Mohammadi M, Imani D Eur J Microbiol Immunol (Bp). 2024; 14(3):228-242.

PMID: 38753442 PMC: 11393645. DOI: 10.1556/1886.2024.00045.

Hyperthermia in Combination with Emerging Targeted and Immunotherapies as a New Approach in Cancer Treatment.

Logghe T, van Zwol E, Immordino B, Van den Cruys K, Peeters M, Giovannetti E Cancers (Basel). 2024; 16(3).

PMID: 38339258 PMC: 10854776. DOI: 10.3390/cancers16030505.

Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment.

Guo X, Wu Y, Xue Y, Xie N, Shen G Front Immunol. 2023; 14:1291836.

PMID: 38106416 PMC: 10722299. DOI: 10.3389/fimmu.2023.1291836.

No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations.

Han S, Yu J, You B, Kim S, Bae M, Chae H Int J Mol Sci. 2023; 24(23).

PMID: 38068999 PMC: 10706748. DOI: 10.3390/ijms242316677.

References

McGaraughty S, Davis-Taber R, Zhu C, Cole T, Nikkel A, Chhaya M . Targeting Anti-TGF- Therapy to Fibrotic Kidneys with a Dual Specificity Antibody Approach. J Am Soc Nephrol. 2017; 28(12):3616-3626. PMC: 5698069. DOI: 10.1681/ASN.2017010013. View

Gu J, Ghayur T . Generation of dual-variable-domain immunoglobulin molecules for dual-specific targeting. Methods Enzymol. 2012; 502:25-41. DOI: 10.1016/B978-0-12-416039-2.00002-1. View

Craig R, Summa C, Corti M, Pincus S . Anti-HIV double variable domain immunoglobulins binding both gp41 and gp120 for targeted delivery of immunoconjugates. PLoS One. 2012; 7(10):e46778. PMC: 3464217. DOI: 10.1371/journal.pone.0046778. View

McDonagh C, Huhalov A, Harms B, Adams S, Paragas V, Oyama S . Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Mol Cancer Ther. 2012; 11(3):582-93. DOI: 10.1158/1535-7163.MCT-11-0820. View

Kiewe P, Hasmuller S, Kahlert S, Heinrigs M, Rack B, Marme A . Phase I trial of the trifunctional anti-HER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer. Clin Cancer Res. 2006; 12(10):3085-91. DOI: 10.1158/1078-0432.CCR-05-2436. View

Zhang Y, Wang L, Chong X, Yu X, Meng Y, Dong J . A bispecific anti-ErbB2 antibody potently induces ErbB2 internalization and suppresses ErbB2-overexpressing tumor growth. Biochem Biophys Res Commun. 2016; 477(4):755-760. DOI: 10.1016/j.bbrc.2016.06.131. View

Meng Y, Zheng L, Yang Y, Wang H, Dong J, Wang C . A monoclonal antibody targeting ErbB2 domain III inhibits ErbB2 signaling and suppresses the growth of ErbB2-overexpressing breast tumors. Oncogenesis. 2016; 5:e211. PMC: 4815051. DOI: 10.1038/oncsis.2016.25. View

Tai W, Mahato R, Cheng K . The role of HER2 in cancer therapy and targeted drug delivery. J Control Release. 2010; 146(3):264-75. PMC: 2918695. DOI: 10.1016/j.jconrel.2010.04.009. View

Hinner M, Aiba R, Jaquin T, Berger S, Durr M, Schlosser C . Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343. Clin Cancer Res. 2019; 25(19):5878-5889. DOI: 10.1158/1078-0432.CCR-18-3654. View

10.

Shu M, Yan H, Xu C, Wu Y, Chi Z, Nian W . A novel anti-HER2 antibody GB235 reverses Trastuzumab resistance in HER2-expressing tumor cells in vitro and in vivo. Sci Rep. 2020; 10(1):2986. PMC: 7031383. DOI: 10.1038/s41598-020-59818-2. View

11.

Fleischmann R, Bliddal H, Blanco F, Schnitzer T, Peterfy C, Chen S . A Phase II Trial of Lutikizumab, an Anti-Interleukin-1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis. Arthritis Rheumatol. 2019; 71(7):1056-1069. DOI: 10.1002/art.40840. View

12.

Adams C, Allison D, Flagella K, Presta L, Clarke J, Dybdal N . Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2005; 55(6):717-27. PMC: 11030689. DOI: 10.1007/s00262-005-0058-x. View

13.

Kosloski M, Goss S, Wang S, Liu J, Loebbert R, Medema J . Pharmacokinetics and Tolerability of a Dual Variable Domain Immunoglobulin ABT-981 Against IL-1α and IL-1β in Healthy Subjects and Patients With Osteoarthritis of the Knee. J Clin Pharmacol. 2016; 56(12):1582-1590. DOI: 10.1002/jcph.764. View

14.

Wu C, Ying H, Grinnell C, Bryant S, Miller R, Clabbers A . Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol. 2007; 25(11):1290-7. DOI: 10.1038/nbt1345. View

15.

Li Y, Hickson J, Ambrosi D, Haasch D, Foster-Duke K, Eaton L . ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models. Mol Cancer Ther. 2018; 17(5):1039-1050. DOI: 10.1158/1535-7163.MCT-17-0800. View

16.

Lacy S, Wu C, Ambrosi D, Hsieh C, Bose S, Miller R . Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig(TM)) molecule that specifically and potently neutralizes both IL-1α and IL-1β. MAbs. 2015; 7(3):605-19. PMC: 4622731. DOI: 10.1080/19420862.2015.1026501. View

17.

Golsaz-Shirazi F, Amiri M, Farid S, Bahadori M, Bohne F, Altstetter S . Construction of a hepatitis B virus neutralizing chimeric monoclonal antibody recognizing escape mutants of the viral surface antigen (HBsAg). Antiviral Res. 2017; 144:153-163. DOI: 10.1016/j.antiviral.2017.06.013. View

18.

Tahmasebi F, Kazemi T, Amiri M, Khoshnoodi J, Mahmoudian J, Bayat A . In vitro assessment of the effects of anti-HER2 monoclonal antibodies on proliferation of HER2-overexpressing breast cancer cells. Immunotherapy. 2013; 6(1):43-9. DOI: 10.2217/imt.13.156. View

19.

Vaishampayan U, Thakur A, Rathore R, Kouttab N, Lum L . Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. Prostate Cancer. 2015; 2015:285193. PMC: 4352947. DOI: 10.1155/2015/285193. View

20.

Liu J, Wu X, Lin L, Pan H, Wang Y, Li Y . Bp-Bs, a Novel T-cell Engaging Bispecific Antibody with Biparatopic Her2 Binding, Has Potent Anti-tumor Activities. Mol Ther Oncolytics. 2019; 14:66-73. PMC: 6475711. DOI: 10.1016/j.omto.2019.03.009. View