WO1998024923B1 - Inactivation of hiv co-receptors as therapy for hiv infection - Google Patents
Inactivation of hiv co-receptors as therapy for hiv infectionInfo
- Publication number
- WO1998024923B1 WO1998024923B1 PCT/US1997/022198 US9722198W WO9824923B1 WO 1998024923 B1 WO1998024923 B1 WO 1998024923B1 US 9722198 W US9722198 W US 9722198W WO 9824923 B1 WO9824923 B1 WO 9824923B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chemokine
- receptor
- expression vector
- cell
- retention signal
- Prior art date
Links
- 208000005721 HIV Infections Diseases 0.000 title abstract 2
- 201000001820 human immunodeficiency virus infectious disease Diseases 0.000 title 1
- 230000002779 inactivation Effects 0.000 title 1
- 238000002560 therapeutic procedure Methods 0.000 title 1
- 210000004027 cells Anatomy 0.000 claims abstract 16
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 claims abstract 5
- 102000005962 receptors Human genes 0.000 claims 21
- 108020003175 receptors Proteins 0.000 claims 21
- 230000031852 maintenance of location in cell Effects 0.000 claims 11
- 229920001184 polypeptide Polymers 0.000 claims 11
- 210000002472 Endoplasmic Reticulum Anatomy 0.000 claims 8
- 102000009410 chemokine receptors Human genes 0.000 claims 5
- 108050000299 chemokine receptors Proteins 0.000 claims 5
- 230000003834 intracellular Effects 0.000 claims 5
- 230000000717 retained Effects 0.000 claims 5
- 210000000130 stem cell Anatomy 0.000 claims 5
- 102000019388 CXC chemokine Human genes 0.000 claims 4
- 108050006947 CXC chemokine Proteins 0.000 claims 4
- 102100016449 CCL5 Human genes 0.000 claims 3
- 108010055166 Chemokine CCL5 Proteins 0.000 claims 3
- 210000004698 Lymphocytes Anatomy 0.000 claims 3
- 210000002540 Macrophages Anatomy 0.000 claims 3
- 210000001616 Monocytes Anatomy 0.000 claims 3
- 201000009910 diseases by infectious agent Diseases 0.000 claims 3
- 108010089256 lysyl-aspartyl-glutamyl-leucine Proteins 0.000 claims 3
- 210000002288 Golgi Apparatus Anatomy 0.000 claims 2
- 210000003712 Lysosomes Anatomy 0.000 claims 2
- 102000004965 antibodies Human genes 0.000 claims 2
- 108090001123 antibodies Proteins 0.000 claims 2
- 230000004927 fusion Effects 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 2
- 230000001868 lysosomic Effects 0.000 claims 2
- 230000014759 maintenance of location Effects 0.000 claims 2
- 102000004169 proteins and genes Human genes 0.000 claims 2
- 108090000623 proteins and genes Proteins 0.000 claims 2
- 230000001177 retroviral Effects 0.000 claims 2
- 230000003612 virological Effects 0.000 claims 2
- 102000004500 CCR1 Receptors Human genes 0.000 claims 1
- 108010017319 CCR1 Receptors Proteins 0.000 claims 1
- 102000004499 CCR3 Receptors Human genes 0.000 claims 1
- 108010017316 CCR3 Receptors Proteins 0.000 claims 1
- 102000004274 CCR5 Receptors Human genes 0.000 claims 1
- 108010017088 CCR5 Receptors Proteins 0.000 claims 1
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 claims 1
- 210000000265 Leukocytes Anatomy 0.000 claims 1
- 210000003463 Organelles Anatomy 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 230000000903 blocking Effects 0.000 claims 1
- 230000001413 cellular Effects 0.000 claims 1
- 210000002865 immune cell Anatomy 0.000 claims 1
- 101700005465 mip-1 Proteins 0.000 claims 1
- 108020004707 nucleic acids Proteins 0.000 claims 1
- 150000007523 nucleic acids Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 claims 1
- 108010006908 signal sequence receptor Proteins 0.000 claims 1
- 230000002463 transducing Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract 2
- 230000002265 prevention Effects 0.000 abstract 1
Abstract
The present invention provides compositions and methods for the treatment and/or prevention of HIV-1 infection. In particular, the present invention employs novel compositions and methods for preventing the cell surface expression of a co-receptor necessary for the binding of HIV to its target cells.
Claims
1. An expression vector, wherein the expression region comprises: a promoter; an intracellular retention signal sequence encoding region; and a chemokine encoding gene; wherein at least one intracellular retention signal sequence and chemokine encoding gene are expressed from said promoter as a transcript encoding an intracellularly retained chemokine.
2. The expression vector of claim 1, further comprising a gene encoding a secreted chemokine.
3. The expression vector of claim 2, wherein said gene encoding said secreted chemokine is expressed from an internal ribosome entry site.
4. The expression vector of claim 1, further defined as a retroviral vector.
5. The expression vector of claim 1, wherein said intracellular retention signal sequence is an endoplasmic reticulum retention signal sequence.
6. The expression vector of claim 5, wherein said endoplasmic reticulum retention signal sequence is a KDEL sequence.
7. The expression vector of claim 6, wherein said KDEL sequence has the amino acid sequence SEKDEL, SEQ ID NO:6.
8. The expression vector of claim 1, wherein said chemokine gene encodes a chemokine that binds to at least one receptor ofthe group consisting of a C-C chemokine 5 receptor, C-C chemokine 3 receptor, C-C chemokine 1 receptor, and CXR4 receptor.
9. The expression vector of claim 1, wherein said chemokine gene encodes a chemokine that binds to a C-C chemokine 5 receptor. -59-
10. The expression vector of claim 1, wherein said CC chemokine gene encodes a chemokine that binds to a C-C chemokine 3 receptor.
11. The expression vector of claim 1, wherein said CC chemokine gene encodes a chemokine that binds to a C-C chemokine 1 receptor.
12. The expression vector of claim 1, wherein said CXC chemokine gene encodes a chemokine that binds to a CXR4 receptor.
13. The expression vector of claim 2, wherein the secreted chemokine is RANTES, MlP-l╬▒ or SDF.
14. The expression vector of claim 2, wherein said secreted chemokine binds to the same chemokine receptor as an intracellularly retained chemokine.
15. The expression vector of claim 14, wherein one or more amino acids are deleted from the N-terminus ofthe intracellularly retained chemokine and/or the secreted chemokine.
16. The expression vector of claim 1, wherein said intracellular retention signal sequence directs the expressed protein to the endoplasmic reticulum, Golgi apparatus, a lysosome, an intracellular vesicle or other cellular compartment.
17. A method of inhibiting phenotypic expression of a chemokine receptor in a cell, wherein the method comprises blocking cell surface expression of said chemokine receptor by expressing a polypeptide in said cell, that binds said receptor and directs it to an intracellular compartment.
18. The method of claim 17, further defined as comprising the steps of: obtaining a vector comprising a nucleic acid segment encoding a promoter, an intracellular retention signal sequence and a chemokine receptor binding polypeptide gene; and transducing said vector into said cell; wherein said vector expresses said intracellular retention signal sequence and chemokine receptor binding polypeptide gene under the transcriptional control of said promoter to produce a fusion polypeptide when transduced into said cell. - -
19. The method of claim 18, wherein said polypeptide is a chemokine, a chemokine analog, an antibody, a cytokine, or a peptide.
20. The method of claim 19, wherein said polypeptide is a chemokine.
21. The method of claim 18, wherein said polypeptide is RANTES, MIP- 1 , SDF, HIV gp 120 or the V3 region of HTV gp 120.
22. The method of claim 20, wherein said chemokine is RANTES, MlP-l╬▒ or SDF.
23. A method of inhibiting HTV infection of a cell comprising phenotypic knock-out of at least one HTV co-receptor in said cell by expressing a polypeptide in said cell, that binds said receptor and directs it to an intracellular compartment.
24. The method of claim 23, wherein said co-receptor is at least one of the group consisting of a C-C chemokine 5 receptor, C-C chemokine 3 receptor, C-C chemokine 1 receptor or CXR4 receptor.
25. The method of claim 23, further defined as expressing a receptor binding polypeptide fused to an intracellular retention signal sequence in said cell.
26. The method of claim 25, wherein said intracellular retention signal sequence directs the fusion polypeptide to the endoplasmic reticulum, Golgi apparatus, a lysosome, an intracellular vesicle or intracellular organelle.
27. The method of claim 26, wherein said intracellular retention signal sequence is a KDEL sequence.
28. The method of claim 25, wherein said receptor binding polypeptide is a CC-chemokine, a CXC chemokine, an analog of a CC or CXC chemokine, a single chain antibody, an HIV gp 120 protein, a V3 region of HIV gp 120 or a peptide that binds to the receptor. -61-
29. The method of claim 24, wherein said cell is transduced with a CC-chemokine gene fused to an endoplasmic reticulum (ER)-retention signal to intracellularly block the transport and the surface expression of at least one endogeneous CC receptor.
30. The method of claim 25, wherein said expression is from a viral vector.
31. The method of claim 30, wherein said viral vector is a retroviral vector.
32. The method of claim 23, wherein said cell is a lymphocyte, monocyte, macrophage or a stem cell.
33. The method of claim 29, wherein said CC receptor includes at least one of the CCR5, CCR3 and CCR1 receptors.
34. The method of claim 24, wherein said cell is transduced with a CXC-chemokine gene fused to an endoplasmic reticulum (ER)-retention signal to intracellularly block the transport and surface expression of at least one endogenous CXR4 receptor.
35. An expression vector for treatment of an HTV infection in a subject, wherein said expression vector includes: an expression region which comprises: a promoter; an intracellular retention signal sequence encoding region; and a chemokine encoding gene; wherein an intracellular retention signal sequence and chemokine encoding gene are expressed as a transcript encoding an intracellularly retained chemokine from said promoter;
and wherein said expression vector is administered to lymphocytes, monocytes, macrophages or stem cells of said subject and wherein said cells exhibit a phenotypic knock out of at least one HIV coreceptor.
36. The expression vector of claim 35, wherein said cells are transduced ex vivo with said vector. -62-
37. The expression vector of claim 36, wherein said stem cells are autologous stem cells.
38. The expression vector of claim 35, contained in a pharmaceutically acceptable solution.
39. A method of increasing white blood cell count in a subject with an HTV infection comprising administering to said subject a pharmaceutical composition comprising lymphocytes, monocytes, macrophages, or stem cells transduced with a vector of claim 1.
STATEMENT UNDER ARTICLE 19(1)
Substitute pages 53-57, provided herewith, contain certain amendments to claims 1, 8, 13-15, 17, 19, 23-25, and 33-35 in order to further clarify the subject matter ofthe claims. In particular, claims 1, 8, 13-15 and 35 have been amended to clarify what was meant by the term "intrakine" as defined in the specification at page 3, and to more clearly define and distinguish an intracellularly retained chemokine and a secreted chemokine as used in the claims. Claims 17, 23-25, 33, and 34 are amended in order to more clearly delineate the methods of phenotypic knockout of those claims. Claims 35 is also amended to correct an informality in the claim as originally filed.
It is Applicants' belief that these amendments do no not go beyond the disclosure in the international application as filed.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU53724/98A AU721121B2 (en) | 1996-12-02 | 1997-12-02 | Inactivation of HIV co-receptors as therapy for HIV infection |
| JP52495998A JP2001505055A (en) | 1996-12-02 | 1997-12-02 | Inactivation of HIV co-receptors as a treatment for HIV infection |
| CA002273192A CA2273192A1 (en) | 1996-12-02 | 1997-12-02 | Inactivation of hiv co-receptors as therapy for hiv infection |
| EP97950829A EP0963441A4 (en) | 1996-12-02 | 1997-12-02 | Inactivation of hiv co-receptors as therapy for hiv infection |
| IL13016097A IL130160A0 (en) | 1996-12-02 | 1997-12-02 | Inactivation of HIV co-receptors as therapy for HIV infection |
| IL130160A IL130160A (en) | 1996-12-02 | 1999-05-27 | Expression vector for blocking hiv entry into a cell and compositions comprising cells transduced with such vector |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3227796P | 1996-12-02 | 1996-12-02 | |
| US60/032,277 | 1996-12-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1998024923A1 WO1998024923A1 (en) | 1998-06-11 |
| WO1998024923B1 true WO1998024923B1 (en) | 1998-07-16 |
Family
ID=21864069
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/022198 WO1998024923A1 (en) | 1996-12-02 | 1997-12-02 | Inactivation of hiv co-receptors as therapy for hiv infection |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0963441A4 (en) |
| JP (1) | JP2001505055A (en) |
| AU (1) | AU721121B2 (en) |
| CA (1) | CA2273192A1 (en) |
| IL (2) | IL130160A0 (en) |
| WO (1) | WO1998024923A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001042308A2 (en) * | 1999-12-08 | 2001-06-14 | Novartis Ag | Methods and compositions useful for inhibiting ccr5-dependent infection of cells by hiv-1 |
| JP4836451B2 (en) | 2002-07-18 | 2011-12-14 | メルス ベー ヴェー | Recombinant production of antibody mixtures |
| USRE47770E1 (en) | 2002-07-18 | 2019-12-17 | Merus N.V. | Recombinant production of mixtures of antibodies |
| US20100069614A1 (en) | 2008-06-27 | 2010-03-18 | Merus B.V. | Antibody producing non-human mammals |
| CA2527694C (en) | 2003-05-30 | 2015-07-14 | Hendricus Renerus Jacobus Mattheus Hoogenboom | Fab library for the preparation of anti vegf and anti rabies virus fabs |
| JP6272299B2 (en) | 2012-04-20 | 2018-01-31 | メルス ナムローゼ フェンノートシャップ | Methods for producing Ig-like molecules, mixtures of Ig-like molecules, recombinant host cells, pharmaceutical compositions, methods for making host cells, and cultures |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09511916A (en) * | 1994-11-01 | 1997-12-02 | ベルス，ビンフリート | Nucleic acid transfer system |
| WO1998020135A2 (en) * | 1996-11-06 | 1998-05-14 | The Government Of The United States Of America, Represented By The Secretary Of The Department Of Health And Human Services | Protease-activatable pseudomonas exotoxin a-like proproteins |
| US6100387A (en) * | 1997-02-28 | 2000-08-08 | Genetics Institute, Inc. | Chimeric polypeptides containing chemokine domains |
| US6214540B1 (en) * | 1997-03-26 | 2001-04-10 | University Of Maryland Biotechnology Institute | Chemokines that inhibit immunodeficiency virus infection and methods based thereon |
| GB9718609D0 (en) * | 1997-09-02 | 1997-11-05 | Imp College Innovations Ltd | Fusion protein |
| MXPA00003885A (en) * | 1997-10-22 | 2004-04-23 | Inst Genetics Llc | Chimeric polypeptides containing chemokine domains. |
| US6110695A (en) * | 1997-12-02 | 2000-08-29 | The Regents Of The University Of California | Modulating the interaction of the chemokine, B Lymphocyte Hemoattractant, and its Receptor, BLR1 |
-
1997
- 1997-12-02 IL IL13016097A patent/IL130160A0/en active IP Right Grant
- 1997-12-02 JP JP52495998A patent/JP2001505055A/en active Pending
- 1997-12-02 EP EP97950829A patent/EP0963441A4/en not_active Withdrawn
- 1997-12-02 CA CA002273192A patent/CA2273192A1/en not_active Abandoned
- 1997-12-02 WO PCT/US1997/022198 patent/WO1998024923A1/en not_active Application Discontinuation
- 1997-12-02 AU AU53724/98A patent/AU721121B2/en not_active Ceased
-
1999
- 1999-05-27 IL IL130160A patent/IL130160A/en not_active IP Right Cessation
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