Title:
NOVEL NUCLEIC ACIDS AND PROTEINS WITH p53 ACTIVITY AND ALTERED TETRAMERIZATION DOMAINS
Document Type and Number:
WIPO Patent Application WO/2000/068384
Kind Code:
A2
Abstract:
The invention relates to novel p53 proteins with altered tetramerization domains (tet-p53) proteins and nucleic acids. The invention further relates to the use of the tet-p53 proteins in the treatment of p53 related disorders.
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Inventors:
FIEBIG KLAUS
Application Number:
PCT/US2000/013248
Publication Date:
November 16, 2000
Filing Date:
May 12, 2000
Export Citation:
Assignee:
XENCOR INC (US)
International Classes:
C12N15/09; A61K31/7125; A61K35/76; A61K38/00; A61K48/00; A61P35/00; C07K14/47; C12N1/15; C12N1/19; C12N1/21; C12N5/10; C12N15/12; C12P21/02; A61K39/00; (IPC1-7): C12N15/12; C07K14/47; C12N1/21; A61K38/00; A61K39/00
Domestic Patent References:
| WO1996016989A1 | 1996-06-06 | |||
| WO1998031703A1 | 1998-07-23 | |||
| WO2000022115A2 | 2000-04-20 |
Other References:
MATEU MAURICIO G ET AL: "Mutually compensatory mutations during evolution of the tetramerization domain of tumor suppressor p53 lead to impaired hetero-oligomerization." PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES, vol. 96, no. 7, 30 March 1999 (1999-03-30), pages 3595-3599, XP002152303 March 30, 1999 ISSN: 0027-8424
MATEU MAURICIO G ET AL: "Nine hydrophobic side chains are key determinants of the thermodynamic stability and oligomerization status of tumour suppressor p53 tetramerization domain." EMBO (EUROPEAN MOLECULAR BIOLOGY ORGANIZATION) JOURNAL, vol. 17, no. 10, 15 May 1998 (1998-05-15), pages 2748-2758, XP002152304 ISSN: 0261-4189 cited in the application
STAVRIDI ELENA S ET AL: "Change in oligomerization specificity of the p53 tetramerization domain by hydrophobic amino acid substitutions." PROTEIN SCIENCE, vol. 8, no. 9, September 1999 (1999-09), pages 1773-1779, XP002152305 ISSN: 0961-8368 cited in the application
MATEU MAURICIO G ET AL: "Nine hydrophobic side chains are key determinants of the thermodynamic stability and oligomerization status of tumour suppressor p53 tetramerization domain." EMBO (EUROPEAN MOLECULAR BIOLOGY ORGANIZATION) JOURNAL, vol. 17, no. 10, 15 May 1998 (1998-05-15), pages 2748-2758, XP002152304 ISSN: 0261-4189 cited in the application
STAVRIDI ELENA S ET AL: "Change in oligomerization specificity of the p53 tetramerization domain by hydrophobic amino acid substitutions." PROTEIN SCIENCE, vol. 8, no. 9, September 1999 (1999-09), pages 1773-1779, XP002152305 ISSN: 0961-8368 cited in the application
Attorney, Agent or Firm:
Silva, Robin M. (CA, US)
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Claims:
CLAIMS We claim:
| 1. | A nonnaturally occurring tetp53 protein comprising an amino acid sequence that is less than about 97% identical to the tetramerization domain of human p53, wherein said tetp53 protein will preferentially tetramerize with itself to form homotetramers rather than tetramerize with the tetramerization domain of wildtype p53 to form heterotetramers. |
| 2. | A nonnaturally occurring tetp53 protein according to claim 1 wherein said tetp53 has at least about 5 amino acid substitutions as compared to human p53 sequence. |
| 3. | A nonnaturally occurring tetp53 protein comprising at least three amino acid substitutions as compared to human p53 protein, wherein at least three of said substitutions are selected from the amino acid residues at positions selected from positions 341,343,344, 345,348,349 and 350. |
| 4. | The nonnaturally occurring tetp53 protein according to claim 3, wherein said substitutions are selected from the group of substitutions consisting of F328Y, F328W, F328L, L3301; 1332V, 1332L; R337L, F338Y, M340L, M3401, F341 1, F341 L, F341 V; E343R, E343T, E343V, E343K, E343Q, E343W, E343F, E343N, L344M, N345Y, N345F, N345L, N345V, N345W, L348F, L348M, L348W, E349R, E349L, E349Q, E349W, E3491, E349N, E349L, L3501, L350Y, 1350F, 1350W and 1350V. |
| 5. | A recombinant nucleic acid encoding the nonnaturally occurring tetp53 protein of claim 1. |
| 6. | An expression vector comprising the recombinant nucleic acid of claim 5. |
| 7. | A host cell comprising the recombinant nucleic acid of claim 5. |
| 8. | A host cell comprising the expression vector of claim 6. |
| 9. | A method of producing a nonnaturally occurring tetp53 protein comprising culturing the host cell of claim 7 under conditions suitable for expression of said nucleic acid. |
| 10. | The method according to claim 19 further comprising recovering said tetp53 protein. |
| 11. | A pharmaceutical composition comprising a tetp53 protein according to claim 1 and a pharmaceutical carrier. |
| 12. | A pharmaceutical composition comprising a nucleic acid encoding a tetp53 protein according to claim 1 and a pharmaceutical carrier. |
| 13. | A method for treating an p53 responsive condition comprising administering a tetp53 nucleic acid encoding a tetp53 protein according to claim 1 to a patient. |
| 14. | The method according to claim 13, wherein said condition is cancer. |
Description:
INTERNATIONAL SEARCH REPORT , a iion No Me oM) AppttcaOon No PCT/US 00/13248 C. (Continwtlon) DOCUMEN1'S CONSIDERED TO BE RELEVANT Category 7y'Citation of document, with indication, where appropriate, of the relevant passages Relevant to daim No. X MATEU MAURICIO G ET AL:"Nine hydrophobic 1,5-10, side chains are key determinants of the 13,14 thermodynamic stability and oligomerization status of tumour suppressor p53 tetramerization domain." EMBO (EUROPEAN MOLECULAR BIOLOGY ORGANIZATION) JOURNAL, vol. 17, no. 10,15 May 1998 (1998-05-15), pages 2748-2758, XP002152304 ISSN: 0261-4189 cited in the application the whole document X WO 96 16989 A (WISTAR INST; HALAZONETIS 1-3,5-14 THANOS D (US)) 6 June 1996 (1996-06-06) page 13-page 17; claims 1-3,7,8,11,18,19,21,34-39; examples 1B10,3,7 page 31-page 37 X WO 98 31703 A (WISTAR INST ; HALAZONETIS 1,3,5-14 THANOS D (US)) 23 July 1998 (1998-07-23) page 3-page 19; claims 1-7,9-21; examples 1,3 P, X STAVRIDI ELENA S ET AL:"Change in 1-3, oligomerization specificity of the p53 5-10,13, tetramerization domain by hydrophobic 14 amino acid substitutions." PROTEIN SCIENCE, vol. 8, no. 9, September 1999 (1999-09), pages 1773-1779, XP002152305 ISSN: 0961-8368 cited in the application the whole document P, X WO 00 22115 A (UNIV TEXAS; ADVANCED RES & 1,3,5-14 TECH INST (US); ELLINGTON ANDREW D (US)) 20 April 2000 (2000-04-20) the whole document 1 INTERNATIONAL SEARCH REPORT tntt ; ona) AppOcatton No IMormatlon on patenttamily members PCT/US 00/13248 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9616989 A 06-06-1996 US 5721340 A 24-02-1998 US 5573925 A 12-11-1996 AU 4288496 A 19-06-1996 EP 0799243 A 08-10-1997 WO 9831703 A 23-07-1998 AU 6027898 A 07-08-1998 WO 0022115 A 20-04-2000 AU 1115300 A 01-05-2000