ANTIBODY COMPLEXES

• US 20070036783A1
• Filed: 06/16/2006
• Published: 02/15/2007
• Est. Priority Date: 06/16/2005
• Status: Abandoned Application

• Current Assignee: VIRxSYS Corporation
• Original Assignee: VIRxSYS Corporation
• Inventors: Humeau, Laurent, Paszkiet, Brian, Lemiale, Franck
• Application Number:
  US11/424,637
• Publication Number:
  US 20070036783A1
• Time in Patent Office: Days
• US Class Current: 424/143.100
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2818 against CD28 or CD152

Abstract

This invention is directed to a soluble complex of ligands that binds to surface molecules of hemopoietic cells and result in their activation or expansion. The complex may be used in the activation and/or expansion of hemopoietic cells, optionally in combination with their transduction. The complex of ligands bind at least two cell surface molecules, such as one that plays a role in cell-cell adhesion and one that may or may not activate or stimulate the cell to promote growth and/or proliferation after binding to a ligand. A complex of ligands that bind two hemopoietic cell stimulatory molecules is also provided. The invention further provides for the use of the complex to target vectors to hemopoietic cells.

Claims

1. A soluble complex comprising a first ligand and a second ligand which binds a first and a second cell surface molecule, respectively, on the same target hemopoietic cell.

2. The complex according to claim 1 wherein each of said first and second ligands is an antibody or a fragment thereof which binds said first and second cell surface molecules, respectively.

3. The complex according to claim 1 wherein said target cell is a T cell.

4. The complex according to claim 1 wherein the first ligand binds CD28.

5. The complex according to claim 4 wherein the second ligand binds a ligand selected from B7-H1 (also called PD-L1);

B7-H2;

B7-H3 (also called B7RP-2);

B7-H4;

CD2;

CD3;

CD11a;

CD26;

CD27;

CD30L;

CD32;

CD38;

CD40L (also called CD154);

CD45;

CD49;

CD50 (also called ICAM-3);

CD54 (also called ICAM-1);

CD58 (also called LFA-3);

CD70;

CD80 (also called B7.1);

CD86 (also called B7.2);

CD100;

CD122;

CD137L (also called 4-1BB Ligand);

CD153;

CTLA-4;

ICOS;

OX40L (also called CD134);

PD-1;

PD-L2 (also called B7-DC);

SLAM (also called CD150);

TIM-1;

TIM-2;

TIM-3;

TIM-4;

2B4 (also called CD244);

CD28;

CD7;

ICOS-L;

ICAM;

CD40;

CD83;

HLA-G;

MICA;

MICB;

HVEM;

lymphotoxin beta receptor;

ILT3;

ILT4;

3/TR6;

4-IBB;

OX40;

CD30;

CD40;

ICOS;

LFA-1;

CD7;

LIGHT;

NKG2C;

BTLA;

a Toll ligand receptor;

or CD83.

6. The complex according to claim 1 wherein said first and second ligands are covalently linked or linked by one or more antibodies that bind both.

7. The complex according to claim 6 wherein said one or more antibodies are bi-specific antibodies, each of which bind both said first and second ligands.

8. The complex according to claim 1 wherein at least one of said first and second cell surface molecules is a transmembrane molecule.

9. The complex according to claim 1 wherein said first and second cell surface molecules are individually selected from B7-H1 (also called PD-L1);

B7-H2;

B7-H3 (also called B7RP-2);

B7-H4;

CD2;

CD3 or CD3/TCR complex;

CD11a;

CD26;

CD27;

CD28;

CD30L;

CD32;

CD38;

CD40L (also called CD154);

CD45;

CD49;

CD50 (also called ICAM-3);

CD54 (also called ICAM-1);

CD58 (also called LFA-3);

CD70;

CD80 (also called B7.1);

CD86 (also called B7.2);

CD100;

CD122;

CD137L (also called 4-1BB Ligand);

CD153;

CTLA-4;

ICOS;

OX40L (also called CD134);

PD-1;

PD-L2 (also called B7-DC);

SLAM (also called CD150);

TIM-1;

TIM-2;

TIM-3;

TIM-4;

or 2B4 (also called CD244).

10. A method of activating a hemopoietic cell, said method comprising

contacting said cell with a complex according to claim 1, wherein said contacting is optionally in vitro or ex vivo.

11. The method of claim 10 wherein said cell is a T cell.

12. A method of transducing a hemopoietic cell, said method comprising

introducing a nucleic acid molecule into said cell before, while, or after said cell is contacted with a complex according to claim 1, wherein said introducing is optionally in vitro or ex vivo.

13. The method of claim 12 wherein said cell is a T cell.

14. The method of claim 12 wherein said nucleic acid molecule is a viral vector.

15. A method of directing an enveloped vector to a target hemopoietic cell, said method comprising

contacting said target cell, optionally a T cell, with a combination of said enveloped vector and a complex according to claim 1 to form a vector-complex combination,

wherein said complex comprises a first ligand which binds a cell surface molecule in the envelope of said vector and a second ligand which binds a cell surface molecule of said target cell.

16. A method of directing a vector particle to a target hemopoietic cell, said method comprising

contacting said target cell, optionally a T cell, with a combination of said vector particle and a complex according to claim 1 to form a vector particle-complex combination,

wherein said complex comprises a first ligand which binds said particle and a second ligand which binds a cell surface molecule of said target cell.

17. The method of claim 14 wherein said viral vector is selected from a retroviral or lentiviral vector, optionally derived from avian reticuloendotheliosis virus (duck infectious anaemia virus, spleen necrosis virus, Twiehaus-strain reticuloendotheliosis virus, C-type retrovirus, reticuloendotheliosis virus Hungary-2 (REV-H-2)), and feline leukemia virus (FeLV)), human immunodeficiency viruses (HIV-1 and HIV-2), feline immunodeficiency virus (FIV), simian immunodeficiency virus (SIV), Maedi/Visna virus, caprine arthritis/encephalitis virus, equine infectious anaemia virus (EIAV), and bovine immunodeficiency virus (BIV);

avian type C retroviruses, such as the avian leukosis virus (ALV);

HTLV-BLV retroviruses, such as bovine leukaemia virus (BLV), human T-cell lymphotropic virus (HTLV), and simian T-cell lymphotropic virus;

mammalian type B retroviruses, such as the mouse mammary tumor virus (MMTV);

mammalian type C retroviruses, such as the murine leukaemia virus (MLV), feline sarcoma virus (FeSV), murine sarcoma virus, Gibbon ape leukemia virus, guinea pig type C virus, porcine type C virus, wooly monkey sarcoma virus, and viper retrovirus;

spumavirus (foamy virus group), such as human spumavirus (HSRV), feline synctium-forming virus (FeSFV), human foamy virus, simian foamy virus, and bovine syncytial virus; and

type D retroviruses, such as Mason-Pfizer monkey virus (MPMV), squirrel monkey retrovirus, and langur monkey virus.

18. The method of claim 17 wherein said viral vector is pseudotyped.

19. A method for ex vivo expansion of cells in the preparation of a medicament, said method comprising cell isolation and expansion after contact with the complex of claim 1.

20. The method of claim 19 where the cells are genetically modified, optionally with a retroviral vector.