Dendritic cell co-stimulatory molecules

• US 8,053,558 B2
• Filed: 10/31/2007
• Issued: 11/08/2011
• Est. Priority Date: 04/28/2000
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Gorski, Kevin S., Tsuchiya, Haruo, Pardoll, Drew M., Tseng, Su-Yi
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US11/931,653
• Publication Number:
  US 20080226662A1
• Time in Patent Office: 1,469 Days
• Field of Search: None
• US Class Current: 530/350
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/5152 Tumor cells
• CPC Class Codes: A61K 2039/5156 expressing foreign proteins
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/57 characterised by the type of response, e.g. Th1, Th2
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4632 T-cell receptors [TCR]; antibody T-cell receptor constructs
• CPC Class Codes: A61K 39/464838 Viral antigens
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 14/70532 B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

A novel costimulatory protein molecule, B7-DC, which is a member of the B7 family, is described as is DNA coding therefor and expression vectors comprising this DNA. B7-DC protein, fragments, fusion polypeptides/proteins and other functional derivatives, and transformed cells expressing B7-DC are useful in vaccine compositions and methods. Compositions and methods are disclosed for inducing potent T cell mediated responses that can be harnessed for anti-tumor and anti-viral immunity.

Claims

1. A fusion polypeptide comprising a first fusion partner consisting of all or part of a B7-DC protein extracellular domain which

(i) is fused directly to a second polypeptide or

(ii) is fused to a linker peptide sequence that is fused to the second polypeptide,

wherein the B7-DC protein has at least 70% sequence identity to SEQ ID NO:

2.

2. A dimeric or trimeric fusion polypeptide which is a dimer or trimer of the fusion polypeptide of claim 1.

3. A vaccine composition useful for inducing an immune response against an antigen associated with a pathogenic cell or microorganism, comprising

(a) the fusion protein of claim 1;

(b) the antigen; and

(c) a pharmaceutically and immunologically acceptable excipient or carrier.

4. The fusion protein of claim 1, wherein the second polypeptide comprises one or more domains of an Ig heavy chain constant region.

5. The fusion protein of claim 4, wherein the one or more domains of the Ig heavy chain comprise C_H2 or C_H3 regions of a human immunoglobulin Cγ

1 chain.

6. The fusion protein of claim 1, wherein the first fusion partner is the extracellular domain encoded by nucleotides 58-663 of SEQ ID NO:

1.

7. The fusion protein of claim 1, wherein the extracellular domain comprises amino acids from about position 20-221 of SEQ ID NO:

2.

8. The fusion protein of claim 1, wherein the fusion protein binds to Programmed Death-1 (PD-1).

9. The fusion protein of claim 1, wherein the fusion protein co-stimulates T cells in the presence of an adequate stimulus to the T cell receptor to proliferate or to produce and secrete cytokines.

10. The fusion protein of claim 4, wherein the fusion protein is a dimeric fusion protein formed by covalent bonding of Cys residues in C_H regions of two Ig heavy chains.

11. The fusion protein of claim 10 wherein the Cys residues are the same Cys residues that are disulfide linked in dimerized Ig heavy chains.

20. The fusion polypeptide of claim 1 wherein the extracellular domain comprises an amino acid sequence extending from the cysteine at position 42 of SEQ ID NO:

2 to the cysteine at position 102 of SEQ ID NO;

2.

21. The fusion polypeptide of claim 1 wherein the extracellular domain comprises an amino acid sequence extending from the cysteine at position 42 of SEQ ID NO:

2 to the cysteine at position 192 of SEQ ID NO;

2.

22. The fusion polypeptide of claim 1 wherein the extracellular domain comprises an IgV domain.

23. The fusion polypeptide of claim 1 wherein the extracellular domain comprises an IgV and an IgC domain.

25. The vaccine composition of claim 3 further comprising a general immunostimulatory agent or adjuvant.

12. A fusion polypeptide of the extracellular domain of murine or human B7-DC, wherein the B7-DC polypeptide is selectively expressed on dendritic cells as compared to activated macrophages, wherein murine B7-DC polypeptide has 32% homology to human B7-H1, wherein the B7-DC polypeptide comprises single IgV and IgC domains, wherein the B7-DC polypeptide comprises a single transmembrane domain, wherein the murine B7-DC polypeptide comprises an intracytoplasmic tail 4 amino acids in length, wherein the B7-DC polypeptide does not bind to CD28 or CTLA-4 and does not include the CD28/CTLA-4 binding motifs, and wherein the 137-DC polypeptide is capable of co-stimulating T cells, with a second polypeptide.

13. The fusion polypeptide of claim 12 wherein the second polypeptide comprises:

(a) one or more domains of an Ig heavy chain constant region;

(b) two C domains of an IgG heavy chain constant region;

or (c) the hinge, C_H2 and C_H3 regions of a human immunoglobulin Cγ

1 chain.

14. The fusion polypeptide of claim 12 wherein the fusion polypeptide binds to a binding partner molecule on T cells and co-stimulates the T cells.

15. The fusion polypeptide of claim 14 wherein the binding partner molecule is a receptor on T cells that is not CD28 or CTLA-4.

16. The fusion polypeptide of claim 12, wherein the second polypeptide comprises one or more domains of an Ig heavy chain constant region.

31. The fusion polypeptide of claim 12, wherein the fusion protein binds to Programmed Death-1 (PD-1).

17. A mature polypeptide comprising a first fusion partner and a second fusion partner, wherein the first fusion partner consists of an extracellular domain of a B7-DC protein comprising an IgV domain,

wherein the B7-DC protein has at least 70% sequence identity to SEQ ID NO:

2.

19. The mature polypeptide of claim 17, wherein the polypeptide co-stimulates T cells.

24. The mature polypeptide of claim 17 wherein the extracellular domain of B7-DC comprises an IgV domain and an IgC domain.

18. A mature polypeptide comprising a first fusion partner and a second fusion partner, wherein the first fusion partner consists of an extracellular domain of B7-DC comprising amino acid residues 20-221 of SEQ ID NO:

2.

26. A fusion polypeptide comprising a first fusion partner consisting of amino acids 20-221 of SEQ ID NO:

2 and a second fusion partner consisting of the hinge, C_H2 and C_H3 regions of a human immunoglobulin Cγ

1 chain.

27. The fusion polypeptide of claim 26 further comprising a linker between the first and second fusion partners.

28. The fusion polypeptide of claim 26 wherein the first fusion partner is directly linked to the second fusion partner.

29. The fusion polypeptide of claim 28, wherein the fusion polypeptide is a dimeric fusion protein formed by covalent bonding of Cys residues in at least one C_H region of a first second fusion partner with at least one C_H region of a second fusion partner.

30. A pharmaceutical composition comprising the fusion polypeptide of any one of claims 26 to 29.