Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer-Reference-Cited by-同舟云学术

Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer

Published:2024-07-09 Issue:1 Volume:22 Page:
ISSN:1479-5876
Container-title:Journal of Translational Medicine
language:en
Short-container-title:J Transl Med

Author:

Wei Ruicheng,Zhang Wenli,Yang Futang,Li Qianhao,Wang Qingyu,Liu Ningshu,Zhu Jun,Shan Yongqiang

Abstract

Abstract Background Trastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer. Methods We developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Results HLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-β-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo. Conclusions These results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.

Funder

Shanghai Henlius Biotech, Inc.

Publisher

Springer Science and Business Media LLC

Link

https://link.springer.com/content/pdf/10.1186/s12967-024-05453-8.pdf

Reference34 articles.

1. Hudis CA. Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39–51. https://doi.org/10.1056/NEJMra043186.

2. Capelan M, Pugliano L, De Azambuja E, Bozovic I, Saini KS, Sotiriou C, et al. Pertuzumab: new hope for patients with HER2-positive breast cancer. Ann Oncol. 2013;24(2):273–82. https://doi.org/10.1093/annonc/mds328.

3. Richard S, Selle F, Lotz JP, Khalil A, Gligorov J, Soares DG. Pertuzumab and trastuzumab: the rationale way to synergy. An Acad Bras Cienc. 2016;88(Suppl 1):565–77. https://doi.org/10.1590/0001-3765201620150178.

4. Fabi A, Mottolese M, Segatto O. Therapeutic targeting of ERBB2 in breast cancer: understanding resistance in the laboratory and combating it in the clinic. J Mol Med. 2014;92(7):681–95. https://doi.org/10.1007/s00109-014-1169-7.

5. Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018;19(10):1372–84. https://doi.org/10.1016/S1470-2045(18)30481-9.