Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

SIBP-03, a novel anti-HER3 antibody, exerts antitumor effects and synergizes with EGFR- and HER2-targeted drugs

Acta Pharmacologica Sinica volume 45, pages 857–866 (2024)Cite this article

Abstract

HER3 (human epidermal growth factor receptor 3) acts through heterodimerization with EGFR (epidermal growth factor receptor) or HER2 to play an essential role in activating phosphoinositide 3-kinase (PI3K) and AKT signaling—a crucial pathway that promotes tumor cell survival. HER3 is a promising target for cancer therapy, and several HER3-directed antibodies have already entered into clinical trials. In this study we characterized a novel anti-HER3 monoclonal antibody, SIBP-03. SIBP-03 (0.01−10 μg/mL) specifically and concentration-dependently blocked both neuregulin (NRG)-dependent and -independent HER3 activation, attenuated HER3-mediated downstream signaling and inhibited cell proliferation. This antitumor activity was dependent, at least in part, on SIBP-03–induced, cell-mediated cytotoxicity and cellular phagocytosis. Importantly, SIBP-03 enhanced the antitumor activity of EGFR- or HER2-targeted drugs (cetuximab or trastuzumab) in vitro and in vivo. The mechanisms underlying this synergy involve increased inhibition of HER3-mediated downstream signaling. Collectively, these results demonstrated that SIBP-03, which is currently undergoing a Phase I clinical trial in China, may offer a new treatment option for patients with cancers harboring activated HER3, particularly as part of a combinational therapeutic strategy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: SIBP-03 specifically binds to HER3 protein.
Fig. 2: SIBP-03 efficiently inhibits ligand-independent and ligand-dependent HER3 activation in vitro.
Fig. 3: Anti-proliferative effects of SIBP-03 in vitro.
Fig. 4: SIBP-03–induced CDC, ADCC, and ADCP in vitro.
Fig. 5: Antitumor activity of SIBP-03 in vivo.
Fig. 6: SIBP-03 synergizes with HER2- and EGFR-targeted drugs to potentiate antitumor activity.

Similar content being viewed by others

References

  1. Kumagai S, Koyama S, Nishikawa H. Antitumour immunity regulated by aberrant ERBB family signalling. Nat Rev Cancer. 2021;21:181–97.

    Article  CAS  PubMed  Google Scholar 

  2. Liu X, Liu S, Lyu H, Riker AI, Zhang Y, Liu B. Development of effective therapeutics targeting HER3 for cancer treatment. Biol Proced Online. 2019;21:5.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell. 2002;110:775–87.

    Article  CAS  PubMed  Google Scholar 

  4. Uliano J, Corvaja C, Curigliano G, Tarantino P. Targeting HER3 for cancer treatment: a new horizon for an old target. ESMO Open. 2023;8:100790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci USA. 2010;107:7692–7.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kilroy MK, Park S, Feroz W, Patel H, Mishra R, Alanazi S, et al. HER3 alterations in cancer and potential clinical implications. Cancers (Basel). 2022;14:6174.

    Article  CAS  PubMed  Google Scholar 

  7. Prigent SA, Gullick WJ. Identification of c-erbB-3 binding sites for phosphatidylinositol 3’-kinase and SHC using an EGF receptor/c-erbB-3 chimera. EMBO J. 1994;13:2831–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Drago JZ, Ferraro E, Abuhadra N, Modi S. Beyond HER2: targeting the ErbB receptor family in breast cancer. Cancer Treat Rev. 2022;109:102436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Haikala HM, Janne PA. Thirty years of HER3: From basic biology to therapeutic interventions. Clin Cancer Res. 2021;27:3528–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yonesaka K, Tanizaki J, Maenishi O, Haratani K, Kawakami H, Tanaka K, et al. HER3 augmentation via blockade of EGFR/AKT signaling enhances anticancer activity of HER3-targeting patritumab deruxtecan in EGFR-mutated non-small cell lung cancer. Clin Cancer Res. 2022;28:390–403.

    Article  CAS  PubMed  Google Scholar 

  11. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Engelman JA, Janne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C, et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA. 2005;102:3788–93.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Suenaga A, Takada N, Hatakeyama M, Ichikawa M, Yu X, Tomii K, et al. Novel mechanism of interaction of p85 subunit of phosphatidylinositol 3-kinase and ErbB3 receptor-derived phosphotyrosyl peptides. J Biol Chem. 2005;280:1321–6.

    Article  CAS  PubMed  Google Scholar 

  14. Scharpenseel H, Hanssen A, Loges S, Mohme M, Bernreuther C, Peine S, et al. EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients. Sci Rep. 2019;9:7406.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  15. Gandullo-Sanchez L, Ocana A, Pandiella A. HER3 in cancer: from the bench to the bedside. J Exp Clin Cancer Res. 2022;41:310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liles JS, Arnoletti JP, Kossenkov AV, Mikhaylina A, Frost AR, Kulesza P, et al. Targeting ErbB3-mediated stromal-epithelial interactions in pancreatic ductal adenocarcinoma. Br J Cancer. 2011;105:523–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Berghoff AS, Magerle M, Ilhan-Mutlu A, Dinhof C, Widhalm G, Dieckman K, et al. Frequent overexpression of ErbB–receptor family members in brain metastases of non-small cell lung cancer patients. APMIS. 2013;121:1144–52.

    Article  CAS  PubMed  Google Scholar 

  18. Srinivasan R, Benton E, Mccormick F, Thomas H, Gullick WJ. Expression of the c-erbB-3/HER-3 and c-erbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 alpha, neuregulin-1 beta, and betacellulin, in normal endometrium and endometrial cancer. Clin Cancer Res. 1999;5:2877–83.

    CAS  PubMed  Google Scholar 

  19. Defazio A, Chiew YE, Sini RL, Janes PW, Sutherland RL. Expression of c-erbB receptors, heregulin and oestrogen receptor in human breast cell lines. Int J Cancer. 2000;87:487–98.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang Z, Karthaus WR, Lee YS, Gao VR, Wu C, Russo JW, et al. Tumor microenvironment-derived NRG1 promotes antiandrogen resistance in prostate cancer. Cancer Cell. 2020;38:279–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Laskin J, Liu SV, Tolba K, Heining C, Schlenk RF, Cheema P, et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020;31:1693–703.

    Article  CAS  PubMed  Google Scholar 

  22. Zhuo W, Kang Y. Lnc-ing ROR1-HER3 and Hippo signalling in metastasis. Nat Cell Biol. 2017;19:81–83.

    Article  CAS  PubMed  Google Scholar 

  23. Orme JJ, Huang H. Microenvironment-mediated resistance to anti-androgen therapy. Cancer Cell. 2020;38:155–7.

    Article  CAS  PubMed  Google Scholar 

  24. De Boeck A, Pauwels P, Hensen K, Rummens JL, Westbroek W, Hendrix A, et al. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. Gut. 2013;62:550–60.

    Article  PubMed  Google Scholar 

  25. Kol A, Terwisscha Van Scheltinga AG, Timmer-Bosscha H, Lamberts LE, Bensch F, De Vries EG, et al. HER3, serious partner in crime: therapeutic approaches and potential biomarkers for effect of HER3-targeting. Pharmacol Ther. 2014;143:1–11.

    Article  CAS  PubMed  Google Scholar 

  26. Jacob W, James I, Hasmann M, Weisser M. Clinical development of HER3-targeting monoclonal antibodies: Perils and progress. Cancer Treat Rev. 2018;68:111–23.

    Article  CAS  PubMed  Google Scholar 

  27. Kawakami H, Okamoto I, Yonesaka K, Okamoto K, Shibata K, Shinkai Y, et al. The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells. Oncotarget. 2014;5:11847–56.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Duvvuri U, George J, Kim S, Alvarado D, Neumeister VM, Chenna A, et al. Molecular and clinical activity of CDX-3379, an anti-ErbB3 monoclonal antibody, in head and neck Squamous cell carcinoma patients. Clin Cancer Res. 2019;25:5752–8.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chen X, Liu P, Wang Q, Li Y, Fu L, Fu H, et al. DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp90-Cdc37 interaction. Cancer Lett. 2018;434:70–80.

    Article  CAS  PubMed  Google Scholar 

  30. Yang CY, Wang L, Sun X, Tang M, Quan HT, Zhang LS, et al. SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models. Acta Pharmacol Sin. 2019;40:971–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li Y, Li L, Fu H, Yao Q, Wang L, Lou L. Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers. Am J Cancer Res. 2023;13:161–75.

    PubMed  PubMed Central  Google Scholar 

  32. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15:429–40.

    Article  CAS  PubMed  Google Scholar 

  33. Kiavue N, Cabel L, Melaabi S, Bataillon G, Callens C, Lerebours F, et al. ERBB3 mutations in cancer: biological aspects, prevalence and therapeutics. Oncogene. 2020;39:487–502.

    Article  CAS  PubMed  Google Scholar 

  34. Hanker AB, Brown BP, Meiler J, Marin A, Jayanthan HS, Ye D, et al. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity. Cancer Cell. 2021;39:1099–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Recondo G, Bahcall M, Spurr LF, Che J, Ricciuti B, Leonardi GC, et al. Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors in patients with MET exon 14-mutant NSCLC. Clin Cancer Res. 2020;26:2615–25.

    Article  CAS  PubMed  Google Scholar 

  36. Chen W, Yuan Y, Jiang X. Antibody and antibody fragments for cancer immunotherapy. J Control Release. 2020;328:395–406.

    Article  CAS  PubMed  Google Scholar 

  37. Cascone T, Fradette J, Pradhan M, Gibbons DL. Tumor immunology and immunotherapy of non-small-cell lung cancer. Cold Spring Harb Perspect Med. 2022;12:a037895.

    Article  CAS  PubMed  Google Scholar 

  38. Wilson TR, Lee DY, Berry L, Shames DS, Settleman J. Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell. 2011;20:158–72.

    Article  CAS  PubMed  Google Scholar 

  39. Citri A, Skaria KB, Yarden Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res. 2003;284:54–65.

    Article  CAS  PubMed  Google Scholar 

  40. Leung HY, Weston J, Gullick WJ, Williams G. A potential autocrine loop between heregulin-alpha and erbB-3 receptor in human prostatic adenocarcinoma. Br J Urol. 1997;79:212–6.

    Article  CAS  PubMed  Google Scholar 

  41. Koumakpayi IH, Diallo JS, Le Page C, Lessard L, Gleave M, Begin LR, et al. Expression and nuclear localization of ErbB3 in prostate cancer. Clin Cancer Res. 2006;12:2730–7.

    Article  CAS  PubMed  Google Scholar 

  42. Muller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwable J, et al. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer. Cancer Res. 2005;65:1778–82.

    Article  PubMed  Google Scholar 

  43. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878–87.

    Article  CAS  PubMed  Google Scholar 

  44. Van Lengerich B, Agnew C, Puchner EM, Huang B, Jura N. EGF and NRG induce phosphorylation of HER3/ERBB3 by EGFR using distinct oligomeric mechanisms. Proc Natl Acad Sci USA. 2017;114:E2836–45.

    PubMed  PubMed Central  Google Scholar 

  45. Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, et al. An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res. 2013;73:6024–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci USA. 2012;109:2718–23.

    Article  ADS  CAS  PubMed  Google Scholar 

  47. Sanchez-Martin M, Pandiella A. Differential action of small molecule HER kinase inhibitors on receptor heterodimerization: therapeutic implications. Int J Cancer. 2012;131:244–52.

    Article  CAS  PubMed  Google Scholar 

  48. Diwanji D, Trenker R, Thaker TM, Wang F, Agard DA, Verba KA, et al. Structures of the HER2-HER3-NRG1beta complex reveal a dynamic dimer interface. Nature. 2021;600:339–43.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from the Science and Technology Commission of Shanghai Municipality (No 18DZ2293200) and the Yunnan Province Sciences and Technology plan (No 202102AA310026).

Author information

Authors and Affiliations

  1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Wen-jing Li, Cheng-ying Xie, Xi Zhu, Jiao Tang, Lei Wang & Li-guang Lou

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Wen-jing Li & Li-guang Lou

Authors
  1. Wen-jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cheng-ying Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiao Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li-guang Lou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LGL conceived and designed the research. WJL and CYX performed the experiments. WJL, CYX, LW, and LGL contributed to the acquisition and analysis of the data. WJL prepared the figures, tables, and manuscript. XZ and JT partly supervised the research. LW and LGL revised and approved the manuscript. All authors approved the final manuscript.

Corresponding authors

Correspondence to Lei Wang or Li-guang Lou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Wj., Xie, Cy., Zhu, X. et al. SIBP-03, a novel anti-HER3 antibody, exerts antitumor effects and synergizes with EGFR- and HER2-targeted drugs. Acta Pharmacol Sin 45, 857–866 (2024). https://doi.org/10.1038/s41401-023-01221-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01221-4

Keywords

Search

Advanced search

Quick links