Details of the BTS

General Information of Binding Target of SBP (BTS) (ID: ST00015)
BTS Name	Epidermal growth factor receptor
Synonyms	EC 2.7.10.1; Proto-oncogene c-ErbB-1; Receptor tyrosine-protein kinase erbB-1
BTS Type	Protein
Family	Protein kinase superfamily; Tyr protein kinase family; EGF receptor subfamily
Gene Name	EGFR
Organism	Homo sapiens (Human)
Function	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules May also activate the NF-kappa-B signaling cascade Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration Plays a role in enhancing learning and memory performance (By similarity).; Isoform 2 may act as an antagonist of EGF action.; (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins.
UniProt ID	P00533
UniProt Entry	EGFR_HUMAN
PFam	PF00757 ; PF14843 ; PF07714 ; PF01030
Gene ID	1956
Sequence	MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEV VLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALA VLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDF QNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGC TGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYV VTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFK NCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAF ENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKL FGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCN LLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVM GENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVV ALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGS GAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGI CLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAA RNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPK FRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQ QGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTED SIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLN TVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRV APQSSEFIGA
Sequence Length	1210

Synthetic Binding Protein (SBP) Targeting This BTS

SBP Name	Highest Status	Mechanism	Affinity	Application	Details	Ref
Affibody ABY-029	Phase I	Binder	Kd: 3 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[1], [2]
Affibody anti-EGFR Z(EGFR:1853)	Research	binder	Kd: 9.2 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[3]
Affibody anti-EGFR Z(EGFR:1868)	Research	binder	Kd: 8.9 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[3]
Affibody anti-EGFR Z(EGFR:1877)	Research	binder	Kd: 5.8 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[3]
Affibody anti-EGFR Z(EGFR:1907)	Research	binder	Kd: 5.4 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[3]
Affibody anti-EGFR Z(EGFR:1908)	Research	binder	Kd: 5.5 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[3]
Affibody anti-EGFR ZB05	Research	binder	Kd: 568 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[4]
Affibody anti-ERBB1 Z(EGFR:1907)	Research	Binder	Kd: 5.4 nM	Imaging agent for patients with cancer	SBP Info	[5]
Affibody anti-ERBB1 Z(EGFR:955)	Research	Binder	Kd: 130-185 nM	Imaging agent for patients with cancer	SBP Info	[5]
Affibody anti-HER2 Z(HER2:2395)	Research	binder	Kd: 0.027 nM	Ovarian cancer [ICD-11: 2C73.Z]; Prostate cancer [ICD-11: 2C82.Z]	SBP Info	[6]
Affibody anti-HER2 Z(HER2:342)	Research	binder	Kd: 0.022 nM	Ovarian cancer [ICD-11: 2C73.Z]; Breast cancer [ICD-11: 2C6Z]	SBP Info	[6], [7]
Affibody anti-HER2 Z(HER2:4)	Research	binder	Kd: 50 nM	Ovarian cancer [ICD-11: 2C73.Z]	SBP Info	[6], [7]
Affibody anti-HER2 Z(HER2:41071)	Phase I	binder	Kd: 0.058 nM	Ovarian cancer [ICD-11: 2C73.Z]; Breast cancer [ICD-11: 2C6Z]	SBP Info	[6], [8]
Affibody anti-HER2 Z(HER2:V2)	Research	binder	Kd: 0.15 nM	Ovarian cancer [ICD-11: 2C73.Z]; Lung cancer [ICD-11: 2C25.Z]	SBP Info	[6]
Affibody anti-Her3 ZHer3	Research	binder	N.A.	Cancers [ICD-11: 2D4Z]	SBP Info	[9]
Affitin anti-ERBB1 B10	Research	Binder	Kd: 27.6 nM	Imaging agent	SBP Info	[10]
Bicyclic peptide anti-ERBB1 cp23G	Research	Inhibitor	Kd: 252000 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[11]
BiTE Etevritamab	Phase I; Discontinued	Stimulator	N.A.	Glioblastoma [ICD-11: XH7F82]	SBP Info	[12], [13], [14]
Centyrin anti-ERBB1 83v2	Research	Inhibitor	Kd: 0.1 nM	Tools for targeted delivery	SBP Info	[15]
Centyrin anti-ERBB1 83v2 variant	Research	Binder	Kd: 0.01 nM	Tools for targeted delivery	SBP Info	[15]
DARPin anti-ERBB1 E01	Research	Binder	Kd: 0.5 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[16], [17]
DARPin anti-ERBB1 E67	Research	Binder	Kd: 7.3 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[18], [19]
DARPin anti-ERBB1 E68	Research	Binder	Kd: 0.7 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[18], [19]
DARPin anti-ERBB1 E69	Research	Binder	N.A.	Cancers [ICD-11: 2D4Z]	SBP Info	[20], [18], [19]
DARPin anti-ERBB1 PSC099	Research	Modulator	Kd: 0.02 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[21]
DARPin anti-ERBB1 PSC099-DGN549	Research	Modulator	N.A.	Cancers [ICD-11: 2D4Z]	SBP Info	[21]
DARPin anti-ERBB1 PSC106	Research	Modulator	Kd: 0.08 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[21]
DARPin anti-ERBB1 PSC106-DGN549	Research	Modulator	N.A.	Cancers [ICD-11: 2D4Z]	SBP Info	[21]
DARPin anti-ERBB1 PSC108-DGN549	Research	Binder	N.A.	Cancers [ICD-11: 2D4Z]	SBP Info	[21]
DARPin MP0274	Phase I	Antagonist	N.A.	Solid tumour/cancer [ICD-11: 2A00-2F9Z]	SBP Info	[22], [23], [24]
Diabody anti-ERBB1/CD16 hEx16-3G/5	Research	Activator	Kd: 1430 nM	Research tool	SBP Info	[25]
Diabody anti-ERBB1/CD16 hEx16-5/3G	Research	Activator	Kd: 213 nM	Research tool	SBP Info	[25]
Diabody anti-ERBB1/CD16 hEx16-HL	Research	Activator	Kd: 85.7 nM	Research tool	SBP Info	[25]
Diabody anti-ERBB1/CD16 hEx16-LH	Research	Activator	Kd: 132 nM	Research tool	SBP Info	[25]
Diabody anti-ERBB1/CD3 hEx3	Research	Binder	N.A.	Imaging agent for patients with cancer; Cancers [ICD-11: 2D4Z]	SBP Info	[26], [27]
EGFRc minibinder	Research	binder	Kd: 6.8 nM	Research tool	SBP Info	[28]
EGFRn minibinder	Research	inhibitor	Kd: 1.2 nM	Tools for inhibiting EGF-induced ERK and AKT phosphorylation	SBP Info	[28]
Gp2-based binder anti-ERBB1 GalphaEGFR(2.2.3)	Research	Binder	Kd: 18 nM	Research tool	SBP Info	[29]
Human VH dAb anti-ERBB1 aEG1B4	Research	Inhibitor	N.A.	Tumors [ICD-11: XH1N44]	SBP Info	[30]
Human VH dAb anti-ERBB1 aEG2C7	Research	Inhibitor	N.A.	Tumors [ICD-11: XH1N44]	SBP Info	[30]
Human VH dAb anti-ERBB1 aEG2E12	Research	Inhibitor	N.A.	Tumors [ICD-11: XH1N44]	SBP Info	[30]
Human VH dAb anti-ERBB1 aEG4D9	Research	Inhibitor	N.A.	Tumors [ICD-11: XH1N44]	SBP Info	[30]
Human VH dAb anti-ERBB1 aEG6B2	Research	Inhibitor	N.A.	Tumors [ICD-11: XH1N44]	SBP Info	[30]
Monobody anti-ERBB1 clone 1	Research	Antagonist	Kd: 2 nM	Tools as argeted biologics	SBP Info	[31], [32]
Monobody anti-ERBB1 pAdHM72-alphaE-L2	Research	Inhibitor	Kd: 0.7 nM	Targeted gene therapy	SBP Info	[33]
Nanobody anti-ERBB1 EGa1	Research	Antagonist	Kd: 2.1 nM	Cancers [ICD-11: 2D4Z]	SBP Info	[34]
Nanobody anti-HER2 MIRC213	Research	Inhibitor	IC50: 17.09 nM	Tools for prolonging nanobody-based radiotracer plasma half-life and enhancing the efficacy of tumor-targeted radionuclide therapy	SBP Info	[35]
Nanobody anti-HER2 MIRC213-213	Research	Inhibitor	IC50: 4.22 nM	Tools for prolonging nanobody-based radiotracer plasma half-life and enhancing the efficacy of tumor-targeted radionuclide therapy	SBP Info	[35]
Nanobody anti-HER2 MIRC213-709	Research	Inhibitor	IC50: 29.47 nM	Tools for prolonging nanobody-based radiotracer plasma half-life and enhancing the efficacy of tumor-targeted radionuclide therapy	SBP Info	[35]
Peptide aptamer anti-ERBB1 KDI1	Research	Blocker	N.A.	Tumors [ICD-11: XH1N44]	SBP Info	[36], [37]
Repebody anti-ERBB1 rAC1	Research	Binder	N.A.	Research tool	SBP Info	[38]
Repebody anti-ERBB1 rEgH9	Research	Binder	Kd: 0.3 nM	Tools for detecting biodistribution and localization	SBP Info	[38]
Repebody anti-ERBB1 rEgH9CCaaX	Research	Binder	Kd: 0.3 nM	Targeted therapies	SBP Info	[38]
scFv anti-EGFRvIII	Research	Binder	N.A.	Glioblastoma [ICD-11: XH7F82]	SBP Info	[39]
scFv anti-ERBB1 225	Research	Binder	Kd: 12 nM	EGFR-specific cancer	SBP Info	[40], [41]
scFv anti-ERBB1 72000	Research	Binder	N.A.	EGFR-specific cancer	SBP Info	[40], [42]
Scfv anti-HER2 4D5-L-ABD	Research	binder	EC50: 1.50 nM	Tools for prolonging scfv Serum Half-Life	SBP Info	[43]
Scfv anti-HER2 4D5-S-ABD	Research	binder	EC50: 1.95 nM	Tools for prolonging scfv Serum Half-Life	SBP Info	[43]

References

1	Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use. Mol Imaging Biol. 2017 Aug;19(4):512-521.
2	AffibodyAB. Product Development Pipeline. 2021.
3	Directed evolution to low nanomolar affinity of a tumor-targeting epidermal growth factor receptor-binding affibody molecule. J Mol Biol. 2008 Mar 7;376(5):1388-402.
4	Generation of an anti-idiotypic affibody-based masking domain for conditional activation of EGFR-targeting. N Biotechnol. 2023 Mar 25;73:9-18.
5	Analysis of Progress and Challenges of EGFR-Targeted Molecular Imaging in Cancer With a Focus on Affibody Molecules. Mol Imaging. Jan-Dec 2019;18:1536012118823473.
6	Advances in the Application of Radionuclide-Labeled HER2 Affibody for the Diagnosis and Treatment of Ovarian Cancer. Front Oncol. 2022 Jun 15;12:917439
7	Selection and characterization of HER2/neu-binding affibody ligands. Protein Eng Des Sel. 2004 May;17(5):455-62.
8	Preclinical Evaluation of 99mTc-ZHER2:41071, a Second-Generation Affibody-Based HER2-Visualizing Imaging Probe with a Low Renal Uptake. Int J Mol Sci. 2021 Mar 9;22(5):2770.
9	Her3-specific affibody mediated tumor targeting delivery of ICG enhanced the photothermal therapy against Her3-positive tumors. Int J Pharm. 2022 Apr 5;617:121609.
10	Nanofitin as a New Molecular-Imaging Agent for the Diagnosis of Epidermal Growth Factor Receptor Over-Expressing Tumors. Bioconjug Chem. 2017 Sep 20;28(9):2361-2371.
11	Toward a Novel Drug To Target the EGF-EGFR Interaction: Design of Metabolically Stable Bicyclic Peptides. Chembiochem. 2018 Jan 4;19(1):76-84.
12	Amgen. Product Development Pipeline. 2021.
13	The BiTE (bispecific T-cell engager) platform: Development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. 2020 Jul 15;126(14):3192-3201.
14	Single-Chain Variable Fragment-Based Bispecific Antibodies: Hitting Two Targets with One Sophisticated Arrow. Mol Ther Oncolytics. 2019 Mar 23;14:38-56.
15	Engineering a targeted delivery platform using Centyrins. Protein Eng Des Sel. 2016 Dec;29(12):563-572.
16	Multispecific Targeting with Synthetic Ankyrin Repeat Motif Chimeric Antigen Receptors. Clin Cancer Res. 2019 Dec 15;25(24):7506-7516.
17	Bifunctional Reagents for Formylglycine Conjugation: Pitfalls and Breakthroughs. Chembiochem. 2020 Dec 11;21(24):3580-3593.
18	Recent progress in protein-protein interaction study for EGFR-targeted therapeutics. Expert Rev Proteomics. 2016 Sep;13(9):817-32.
19	Efficient selection of DARPins with sub-nanomolar affinities using SRP phage display. J Mol Biol. 2008 Oct 24;382(5):1211-27.
20	Bispecific designed ankyrin repeat proteins (DARPins) targeting epidermal growth factor receptor inhibit A431 cell proliferation and receptor recycling. J Biol Chem. 2011 Dec 2;286(48):41273-41285.
21	ImmunoGen. Product Development Pipeline. 2021.
22	DARPins: Promising Scaffolds for Theranostics. Acta Naturae. Oct-Dec 2019;11(4):42-53.
23	In vitro-engineered non-antibody protein therapeutics. Protein Cell. 2018 Jan;9(1):3-14.
24	Beyond Antibodies: The DARPin ? Drug Platform. BioDrugs. 2020 Aug;34(4):423-433.
25	Functional Domain Order of an Anti-EGFR G Anti-CD16 Bispecific Diabody Involving NK Cell Activation. Int J Mol Sci. 2020 Nov 24;21(23):8914.
26	Humanization of the bispecific epidermal growth factor receptor x CD3 diabody and its efficacy as a potential clinical reagent. Clin Cancer Res. 2006 Jul 1;12(13):4036-42.
27	Domain order of a bispecific diabody dramatically enhances its antitumor activity beyond structural format conversion: the case of the hEx3 diabody. Protein Eng Des Sel. 2013 May;26(5):359-67.
28	Design of protein-binding proteins from the target structure alone
29	A 45-Amino-Acid Scaffold Mined from the PDB for High-Affinity Ligand Engineering. Chem Biol. 2015 Jul 23;22(7):946-56.
30	Novel single-domain antibodies against the EGFR domain III epitope exhibit the anti-tumor effect. J Transl Med. 2020 Oct 6;18(1):376.
31	Structures of adnectin/protein complexes reveal an expanded binding footprint. Structure. 2012 Feb 8;20(2):259-69.
32	Anti-tumor effect of CT-322 as an adnectin inhibitor of vascular endothelial growth factor receptor-2. MAbs. Mar-Apr 2010;2(2):199-208.
33	A targeted adenovirus vector displaying a human fibronectin type III domain-based monobody in a fiber protein. Biomaterials. 2013 May;34(16):4191-4201.
34	Capillary electrophoresis-based assessment of nanobody affinity and purity. Anal Chim Acta. 2014 Mar 25;818:1-6.
35	IgG-Binding Nanobody Capable of Prolonging Nanobody-Based Radiotracer Plasma Half-Life and Enhancing the Efficacy of Tumor-Targeted Radionuclide Therapy. Bioconjug Chem. 2022 Jul 20;33(7):1328-1339.
36	Sequence-specific peptide aptamers, interacting with the intracellular domain of the epidermal growth factor receptor, interfere with Stat3 activation and inhibit the growth of tumor cells. J Biol Chem. 2003 Sep 26;278(39):37610-21.
37	Peptide aptamers with biological and therapeutic applications. Curr Med Chem. 2011;18(27):4215-22.
38	Enzymatic prenylation and oxime ligation for the synthesis of stable and homogeneous protein-drug conjugates for targeted therapy. Angew Chem Int Ed Engl. 2015 Oct 5;54(41):12020-4. doi: 10.1002/anie.201505964. Epub 2015 Aug 28.
39	Immunotoxins with increased activity against epidermal growth factor receptor vIII-expressing cells produced by antibody phage display. Clin Cancer Res. 2000 Jul;6(7):2835-43.
40	Peptide mimotopes recognized by antibodies cetuximab and matuzumab induce a functionally equivalent anti-EGFR immune response. Oncogene. 2010 Aug 12;29(32):4517-27.
41	EGF receptor and p185erbB-2-specific single-chain antibody toxins differ in their cell-killing activity on tumor cells expressing both receptor proteins. Int J Cancer. 1995 Jan 3;60(1):137-44.
42	Display of heterologous proteins on the surface of microorganisms: from the screening of combinatorial libraries to live recombinant vaccines. Nat Biotechnol. 1997 Jan;15(1):29-34.
43	Computation-Aided Design of Albumin Affibody-Inserted Antibody Fragment for the Prolonged Serum Half-Life. Pharmaceutics. 2022 Aug 24;14(9):1769.