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Ep 2501716 B1 (19) TZZ Z___T (11) EP 2 501 716 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 14/00 (2006.01) C12N 9/00 (2006.01) 21.01.2015 Bulletin 2015/04 C12N 9/12 (2006.01) C12N 9/14 (2006.01) C12N 9/22 (2006.01) C12N 9/50 (2006.01) (21) Application number: 10803492.7 (86) International application number: (22) Date of filing: 19.11.2010 PCT/IB2010/003127 (87) International publication number: WO 2011/061625 (26.05.2011 Gazette 2011/21) (54) Compositions for increasing polypeptide stability and activity, and related methods Zusammensetzungen zur erhöhung der Polypeptidstabilität und -aktivität sowie zugehörige Verfahren Compositions pour augmenter la stabilité et l’activité d’un polypeptide, et procédés apparentés (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB US-A1- 2005 037 412 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR • EUI NAM LEE ET AL: "Stabilizing Peptide Fusion Designated Extension States: for Solving the Stability and Solubility Problems BA ME of Therapeutic Proteins", PHARMACEUTICAL RESEARCH,KLUWER ACADEMIC PUBLISHERS- (30) Priority: 19.11.2009 US 262919 P PLENUM PUBLISHERS, NL, vol. 22, no. 10, 1 01.06.2010 US 350457 P October 2005 (2005-10-01), pages 1735-1746, 18.06.2010 US 356541 P XP019370712, ISSN: 1573-904X, DOI: DOI: 07.10.2010 US 390857 P 10.1007/S11095-005-6489-4 • KIM YOUNG MOK ET AL: "Expression of human (43) Date of publication of application: interferon alpha-1 with enhanced stability via the 26.09.2012 Bulletin 2012/39 tagging system of a stabilizing peptide", PROTEINEXPRESSION AND PURIFICATION, vol. (60) Divisional application: 63, no. 2, February 2009 (2009-02), pages 140-146, 14198178.7 XP002635174, ISSN: 1046-5928 • FAGAIN CIARAN O: "Understanding and (73) Proprietor: Solis BioDyne OÜ increasing protein stability", BIOCHIMICA ET 51014 Tartu (EE) BIOPHYSICA ACTA, vol. 1252, no. 1, 1995, pages 1-14, XP002635175, ISSN: 0006-3002 (72) Inventors: • SOLIS BIODYNE: "FIREPol DNA Polymerase", • KAHRE, Olev INTERNET CITATION, 4 May 2011 (2011-05-04), EE-51014 Tartu (EE) XP007918521, Retrieved from the Internet: URL: • ARTMA, Kadri http://www.sbd.ee/index.php?lan=EN&sid EE-51014 Tartu (EE) =70&tid=33&active=62&active1=99 [retrieved on • KAHRE, Tiina 2011-05-04] EE-51014 Tartu (EE) Remarks: (74) Representative: Kremer, Simon Mark et al Thefile contains technical information submitted after Mewburn Ellis LLP the application was filed and not included in this 33 Gutter Lane specification London EC2V 8AS (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 501 716 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 501 716 B1 Description BACKGROUND OF THE INVENTION 5 [0001] There is a need in the art for methods and compositions that enhance the stability of proteins. There is particularly a need for compositions that enhance the stability of polymerases such as Taq polymerases so that they can retain enzymatic activity after short-term or long-term exposure to temperatures above freezing. There is also a need in the art for compositions that enhance polymerase fidelity, sensitivity, and yield. Stabilized fusion proteins having the acidic tail of synuclein are described in Lee et al. Pharmaceutical Research 22, 10 (2005) 1735-1746. 10 SUMMARY OF THE INVENTION [0002] The invention is as defined in the claims. [0003] This disclosure provides peptides, polypeptides, fusion polypeptides, compositions, and methods for enabling 15 the retention of activity of an enzyme (e.g., DNA polymerase, RNA polymerase, nuclease, reverse transcriptase, DNA deaminase, RNA deaminase, protease) or a protein (e.g., erythropoietin, human Leukemia Inhibitor Factor (hLIF), gran- ulocyte macrophage colony-stimulating factor (GM-CSF), insulin, vascular endothelial growth factor (VEGF), leptin, bevacizumab) after short-term or long-term exposure to a temperature of from about -20 °C to about 35 °C. Peptides, polypeptides, fusion polypeptides, or compositions provided herein may enhance stability of an enzyme or protein at 20 room temperature. An enzyme or protein provided herein may be any nucleic acid binding protein, e.g., a DNA binding protein, a RNA binding protein, a fragment thereof, or any combination thereof. An enzyme or protein provided herein may bind to other proteins, e.g., hormone receptors. [0004] In some embodiments, polypeptides, fusion polypeptides, or compositions provided herein retain activity at a temperature between -20°C and 50 °C. In some embodiments, polypeptides, fusion polypeptides, or compositions retain 25 enzymatic activity or hormone activity at a temperature between -20 °C and 50 °C. In some embodiments, the enzymatic activity or hormone activity of the polypeptides, fusion polypeptides, or compositions after exposure to a temperature between -20 °C and 50 °C is at least 50% of the enzymatic activity of the polypeptide prior to exposure to said temperature. [0005] Peptide tags provided herein increase stability of the polypeptides. In some embodiments, peptide tags inhibit loss of enzymatic activity of the polypeptides. In some embodiments, peptide tags inhibit degradation of the polypeptides 30 fusion polypeptides, or compositions. In some embodiments, peptide tags increase stability or inhibit loss of enzymatic activity of the polypeptides for at least one day. In some embodiments, peptide tags increase stability or inhibit loss of enzymatic activity of the polypeptides for at least one week. In some embodiments, peptide tags increase stability or inhibit loss of enzymatic activity of the polypeptides for at least one month. [0006] In some embodiments, polypeptides provided herein demonstrate enhanced stability, enzymatic activity, or 35 hormone activity when compared to a similar polypeptide that does not comprise a peptide tag provided herein. In some embodiments, polypeptides have at least 50%, 60%, 70%, 80%, 90%, or 95% of the enzymatic activity or hormone activity of a similar polypeptide that does not comprise a peptide tag provided herein. In some embodiments, polypeptides have at least 50%, 60%, 70%, 80%, 90%, or 95% of the enzymatic activity or hormone activity of a similar polypeptide that does not comprise a peptide tag provided herein, after exposure to a temperature between -20 °C and 50 °C. In 40 some embodiments, polypeptides have at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% greater enzymatic activity or hormone activity than the enzymatic activity or hormone activity of a similar polypeptide that does not comprise a peptide tag provided herein, after exposure to a temperature between -20 °C and 50 °C. [0007] The polypeptides are linked to a peptide tag that has an amino acid sequence that is at least 70% identical to 45 SEQ ID NO: 1. In some embodiments, the peptide tag has an amino acid sequence as shown in SEQ ID NO: 1, SEQ ID NO: 13, or SEQ ID NO: 14. Also provided herein are peptide tags having an amino acid sequence that is at least 70% identical to SEQ ID NO: 13 or SEQ ID NO: 14. In some embodiments, polypeptides, linked to peptide tags provided herein comprise an amino acid sequence that is at least 70% identical to SEQ ID NO: 6, SEQ ID NO: 8, or SEQ ID NO: 11. In some embodiments, polypeptides, linked to peptide tags provided herein comprise an amino acid sequence as 50 shown in SEQ ID NO: 6, SEQ ID NO: 8, or SEQ ID NO: 11. In some embodiments, the polypeptide comprises an amino acid sequence that is at least 70% identical to SEQ ID NO: 1, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22. In some embodiments, polypeptides; do not have the amino acid sequence as shown in SEQ ID NO: 2, SEQ ID NO: 6, or SEQ ID NO: 11. [0008] In some embodiments, polypeptides provided herein are linked to a peptide tag that is encoded by a nucleotide 55 sequence that is at least 70% identical to SEQ ID NO: 3 or SEQ ID NO: 15. In some embodiments, polypeptides provided herein are linked to a peptide tag that is encoded by a nucleotide sequence as shown in SEQ ID NO:3 or SEQ ID NO: 15. Also provided herein is a polypeptide encoded by a nucleotide sequence that is at least 70% identical to SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, or SEQ ID NO: 12. Also provided herein is a polypeptide encoded by a nucleotide 2 EP 2 501 716 B1 sequence as shown in SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, or SEQ ID NO: 12. [0009] Also provided herein is a polypeptide that has an amino acid sequence that is at least 70% identical to SEQ ID NO: 10. Also provided herein is a polypeptide that has an amino acid sequence as shown in SEQ ID NO: 10. Also provided herein is a polypeptide comprising a sequence motif that binds to a double stranded DNA. Also provided herein 5 is a polypeptide that is encoded by a nucleotide sequence that is at least 70% identical to SEQ ID NO: 9.
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