Targeting HER3 Using Mono- and Bispecific Antibodies or Alternative Scaffolds

Overview

Journal MAbs

Specialty Allergy & Immunology

Date 2016 Aug 18

PMID 27532938

Citations 27

Authors

Magdalena Malm

Fredrik Y Frejd

Stefan Stahl

John Lofblom

Affiliations

Soon will be listed here.

Abstract

The human epidermal growth factor receptor 3 (HER3) has in recent years been recognized as a key node in the complex signaling network of many different cancers. It is implicated in de novo and acquired resistance against therapies targeting other growth factor receptors, e.g., EGFR, HER2, and it is a major activator of the PI3K/Akt signaling pathway. Consequently, HER3 has attracted substantial attention, and is today a key target for drugs in clinical development. Sophisticated protein engineering approaches have enabled the generation of a range of different affinity proteins targeting this receptor, including antibodies and alternative scaffolds that are either mono- or bispecific. Here, we describe HER3 and its role as a key tumor target, and give a comprehensive review of HER3-targeted proteins currently in development, including discussions on the opportunities and challenges of targeting this receptor.

Citing Articles

HER3-targeted therapeutic antibodies and antibody-drug conjugates in non-small cell lung cancer refractory to EGFR-tyrosine kinase inhibitors.

Larsen M, Lyu H, Liu B Chin Med J Pulm Crit Care Med. 2024; 1(1):11-17.

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HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs.

Zeng H, Wang W, Zhang L, Lin Z Cancer Drug Resist. 2024; 7:14.

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DB-1310, an ADC comprised of a novel anti-HER3 antibody conjugated to a DNA topoisomerase I inhibitor, is highly effective for the treatment of HER3-positive solid tumors.

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Hyperstable Synthetic Mini-Proteins as Effective Ligand Scaffolds.

Blanchard P, Knick B, Whelan S, Hackel B ACS Synth Biol. 2023; 12(12):3608-3622.

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HER3 functions as an effective therapeutic target in triple negative breast cancer to potentiate the antitumor activity of gefitinib and paclitaxel.

Lyu H, Shen F, Ruan S, Tan C, Zhou J, Thor A Cancer Cell Int. 2023; 23(1):204.

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References

Berger M, Mendrola J, Lemmon M . ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett. 2004; 569(1-3):332-6. DOI: 10.1016/j.febslet.2004.06.014. View

Muyldermans S . Nanobodies: natural single-domain antibodies. Annu Rev Biochem. 2013; 82:775-97. DOI: 10.1146/annurev-biochem-063011-092449. View

Uhlen M, Guss B, Nilsson B, Gatenbeck S, Philipson L, Lindberg M . Complete sequence of the staphylococcal gene encoding protein A. A gene evolved through multiple duplications. J Biol Chem. 1984; 259(3):1695-702. View

Wurch T, Pierre A, Depil S . Novel protein scaffolds as emerging therapeutic proteins: from discovery to clinical proof-of-concept. Trends Biotechnol. 2012; 30(11):575-82. DOI: 10.1016/j.tibtech.2012.07.006. View

LaFleur D, Abramyan D, Kanakaraj P, Smith R, Shah R, Wang G . Monoclonal antibody therapeutics with up to five specificities: functional enhancement through fusion of target-specific peptides. MAbs. 2013; 5(2):208-18. PMC: 3893231. DOI: 10.4161/mabs.23043. View

Schoeberl B, Pace E, Fitzgerald J, Harms B, Xu L, Nie L . Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis. Sci Signal. 2009; 2(77):ra31. DOI: 10.1126/scisignal.2000352. View

Ridgway J, Presta L, Carter P . 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996; 9(7):617-21. DOI: 10.1093/protein/9.7.617. View

Lazrek Y, Dubreuil O, Garambois V, Gaborit N, Larbouret C, Le Clorennec C . Anti-HER3 domain 1 and 3 antibodies reduce tumor growth by hindering HER2/HER3 dimerization and AKT-induced MDM2, XIAP, and FoxO1 phosphorylation. Neoplasia. 2013; 15(3):335-47. PMC: 3593156. DOI: 10.1593/neo.121960. View

Nagata Y, Lan K, Zhou X, Tan M, Esteva F, Sahin A . PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004; 6(2):117-27. DOI: 10.1016/j.ccr.2004.06.022. View

10.

Jost C, Schilling J, Tamaskovic R, Schwill M, Honegger A, Pluckthun A . Structural basis for eliciting a cytotoxic effect in HER2-overexpressing cancer cells via binding to the extracellular domain of HER2. Structure. 2013; 21(11):1979-91. DOI: 10.1016/j.str.2013.08.020. View

11.

Sierke S, Cheng K, Kim H, Koland J . Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (HER3) receptor protein. Biochem J. 1997; 322 ( Pt 3):757-63. PMC: 1218252. DOI: 10.1042/bj3220757. View

12.

Boersma Y, Chao G, Steiner D, Wittrup K, Pluckthun A . Bispecific designed ankyrin repeat proteins (DARPins) targeting epidermal growth factor receptor inhibit A431 cell proliferation and receptor recycling. J Biol Chem. 2011; 286(48):41273-41285. PMC: 3308840. DOI: 10.1074/jbc.M111.293266. View

13.

Wang S, Huang X, Lee C, Liu B . Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene. 2010; 29(29):4225-36. DOI: 10.1038/onc.2010.180. View

14.

Xiao Z, Carrasco R, Schifferli K, Kinneer K, Tammali R, Chen H . A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response. Mol Cancer Ther. 2016; 15(4):689-701. DOI: 10.1158/1535-7163.MCT-15-0555. View

15.

Vlacich G, Coffey R . Resistance to EGFR-targeted therapy: a family affair. Cancer Cell. 2011; 20(4):423-5. PMC: 3616495. DOI: 10.1016/j.ccr.2011.10.006. View

16.

Klein C, Sustmann C, Thomas M, Stubenrauch K, Croasdale R, Schanzer J . Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies. MAbs. 2012; 4(6):653-63. PMC: 3502232. DOI: 10.4161/mabs.21379. View

17.

Beck A, Wurch T, Bailly C, Corvaia N . Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010; 10(5):345-52. DOI: 10.1038/nri2747. View

18.

Travis A, Pinder S, Robertson J, Bell J, Wencyk P, Gullick W . C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators. Br J Cancer. 1996; 74(2):229-33. PMC: 2074568. DOI: 10.1038/bjc.1996.342. View

19.

Rosestedt M, Andersson K, Mitran B, Tolmachev V, Lofblom J, Orlova A . Affibody-mediated PET imaging of HER3 expression in malignant tumours. Sci Rep. 2015; 5:15226. PMC: 4609989. DOI: 10.1038/srep15226. View

20.

SALA G, Traini S, DEgidio M, Vianale G, Rossi C, Piccolo E . An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling. Oncogene. 2011; 31(10):1275-86. DOI: 10.1038/onc.2011.322. View