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Co-stimulatory polypeptides Number:7,094,875 from the United States Patent and Trademark Office (PTO) owispatent

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Title: Co-stimulatory polypeptides

Abstract: The invention provides polynucleotides and polypeptides encoded therefrom having advantageous properties, including an ability of the polypeptides to preferentially bind a CD28 or CTLA-4 receptor at a level greater or less than the ability of human B7-1 to bind CD28 or CTLA-4, or to induce or inhibit altered level of T cell proliferation response greater compared to that generated by human B7-1. The polypeptides and polynucleotides of the invention are useful in therapeutic and prophylactic treatment methods, gene therapy applications, and vaccines.

Patent Number: 7,094,875 Issued on 08/22/2006 to Punnonen,   et al.


Inventors: Punnonen; Juha (Belmont, CA), Lazetic; Alexandra L. L. (San Jose, CA), Leong; Steven R. (Berkeley, CA), Chang; Chia-Chun (Los Gatos, CA)
Assignee: Maxygen, Inc. (Redwood City, CA)
Appl. No.: 09/888,324
Filed: June 22, 2001


Current U.S. Class: 530/350 ; 435/69.1; 530/351; 530/387.1
Current International Class: C07K 14/725 (20060101); C12P 21/00 (20060101)
Field of Search: 530/350,351,387.1 514/21


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Primary Examiner: Gambel; Phillip
Assistant Examiner: Ouspenski; Ilia
Attorney, Agent or Firm: Powers; Margaret A. Kruse; Norman J.

Government Interests



STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

This work was supported in part by a grant from the Defense Advanced Research Projects Agency (DARPA) (Grant No. N65236-98-1-5401). The Government may have certain rights in this invention.
Parent Case Text



CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to and benefit of U.S. Provisional Patent Application Ser. Nos. 60/213,946, filed on Jun. 23, 2000, and 60/241,245, filed on Oct. 17, 2000, the disclosure of each of which is incorporated herein by reference in its entirety for all purposes.
Claims



What is claimed is:

1. An isolated or recombinant polypeptide comprising an extracellular domain, said extracellular domain comprising an amino acid sequence having at least 91% sequence identity to a subsequence of the polypeptide sequence set forth in SEQ ID NO:66, wherein the subsequence is the extracellular domain of SEQ ID NO:66, and wherein the isolated or recombinant polypeptide has a human CD28/human CTLA-4 binding affinity ratio equal to or greater than the human CD28/human CTLA-4 binding affinity ratio of human B7-1 when said isolated or recombinant polypeptide is expressed on a cell or bound to a cell membrane.

2. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide is expressed on a cell or bound to a cell membrane.

3. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide comprises an extracellular domain which comprises an amino acid sequence having at least 95% sequence identity to the extracellular domain of SEQ ID NO:66, wherein said extracellular domain of SEQ ID NO:66 comprises at least amino acid residues 35 244 of SEQ ID NO:66.

4. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide comprises an extracellular domain which comprises an amino acid sequence having at least 95% sequence identity to the extracellular domain of SEQ ID NO:66, wherein the extracellular domain of SEQ ID NO;66 comprises at least amino acid residues 35 245 of SEQ ID NO:66.

5. The isolated or recombinant polypeptide of claim 3, wherein the polypeptide comprises art extracellular domain comprising at least amino acid residues 35 244 of SEQ ID NO:66.

6. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide further comprises a signal peptide.

7. The isolated or recombinant polypeptide of claim 6, wherein the signal peptide comprises an amino acid sequence that has at least 90% sequence identity to the amino acid sequence comprising residues 1 34 of SEQ ID NO:66.

8. The isolated or recombinant polypeptide of claim 6, wherein the signal peptide has an amino acid sequence comprising amino acid residues 1 34 of SEQ ID NO:66.

9. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide comprises a transmembrane domain.

10. The isolated or recombinant polypeptide of claim 9, wherein the polypeptide comprises the transmembrane domain of SEQ ID NO:66.

11. The isolated or recombinant polypeptide of claim 10, wherein the transmembrane domain comprises an amino acid sequence having at least 90% sequence identity to an amino acid sequence comprising at least amino acid residues 245 268 or 246 272 of SEQ ID NO:66.

12. The isolated or recombinant polypeptide of claim 11, wherein the transmembrane domain comprises an amino acid sequence comprising at least amino acid residues 245 268 or 246 272 of SEQ ID NO:66.

13. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide further comprises a cytoplasmic domain.

14. The isolated or recombinant polypeptide of claim 13, wherein the polypeptide comprises the cytoplasmic domain of SEQ ID NO:66.

15. The isolated or recombinant polypeptide of claim 13, wherein the cytoplasmic domain comprises an amino acid sequence having at least 90% sequence identity to an amino acid sequence comprising at least amino acid residues 269 303 or 273 303 of SEQ ID NO:66.

16. The isolated or recombinant polypeptide of claim 15, wherein the cytoplasmic domain comprises an amino acid sequence comprising at least amino acid residues 269 303 or 273 303 of SEQ ID NO:66.

17. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence comprising a mature domain of SEQ ID NO:66.

18. The isolated or recombinant polypeptide of claim 17, wherein the mature domain comprises amino acid residues 35 303 of SEQ ID NO:66.

19. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence corresponding to the signal peptide, extracellular domain and transmembrane domain of SEQ ID NO:66 which comprises at least amino acid residues 1 268 or 1 272 of SEQ ID NO:66.

20. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide has at least 91% sequence identity to the full length amino acid sequence of SEQ ID NO:66.

21. The isolated or recombinant polypeptide of claim 20, wherein the polypeptide comprises the full length amino acid sequence of SEQ ID NO:66.

22. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide has a human CD28/human CTLA-4 binding affinity ratio greater than the human CD28/human CTLA-4 binding affinity ratio of human B7-1.

23. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide has a binding affinity for CD28 that is greater than the binding affinity of human B7-1 for CD28.

24. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide has a binding affinity for CTLA-4 that is less than the binding affinity of human B7-1 for CTLA-4.

25. The isolated or recombinant polypeptide of claim 1, wherein the polypeptide has an ability to induce a T-cell proliferation response equal to or greater than the T-cell proliferation response induced by human B7-1.

26. An isolated or recombinant polypeptide comprising an extracellular domain, said extracellular domain comprising an amino acid sequence having at least 91% sequence identity to a subsequence of SEQ ID NO:66, said subsequence comprising at least amino acid residues 35 244 or 35 245 of SEQ ID NO:66, wherein said polypeptide induces a T-cell proliferation response equal to or greater than the T-cell proliferation response induced by human B7-1 when said polypeptide is expressed on a cell or bound to a cell membrane.

27. The isolated or recombinant polypeptide of claim 26, wherein the extracellular domain of said polypeptide comprises an amino acid sequence having at least 95% sequence identity to the subsequence of SEQ ID NO:66 that comprises at least amino acid residues 35 244.

28. The isolated or recombinant polypeptide of claim 26, wherein the polypeptide comprises one or more of a signal peptide, transmembrane domain, and cytoplasmic domain.

29. The isolated or recombinant polypeptide of claim 28, wherein the polypeptide comprises an amino acid sequence having at least 95% sequence identity to the full length amino acid sequence of SEQ ID NO:66.

30. The isolated or recombinant polypeptide of claim 1, wherein the cell is an antigen-presenting cell.

31. The polypeptide of claim 1, comprising at least one modified amino acid.

32. The polypeptide of claim 30, wherein the modified amino acid is selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivariting agent.

33. An isolated or recombinant polypeptide comprising an amino acid sequence according to the formula: MGHTM-X6-W-X8-SLPPK-X14-PCL-X18-X19-X20-QLLVLT-X27-LFYFCSGITPKSVTKRVKETVM- LSCDY-X55-TSTE-X60-LTSLRIYW-X69-KDSKMVLAILPGKVQVWPEYKNRTITDMNDN-X101-RIVI-- X106-ALR-X110-SD-X113-GTYTCV-X120-QKP-X124-LKGAYKLEHL-X135-SVRLMIRADFPVP-X- 149-X150-X151-DLGNPSPNIRRLICS-X167-X168-X169-GFPRPHL-X177-WLENGEELNATNTT-X- 192-SQDP-X197-T-X199-LYMISSEL-X208-FNVTNN-X215-SI-X218-CLIKYGEL-X227-VSQIF- PWSKPKQEPPIDQLPF-X249-VIIPVSGALVL-X261-A-X263-VLY-X267-X268-ACRH-X273-ARWK- RTRRNEETVGTE RLSPIYLGSAQSSG (SEQ ID NO:284), or a extracellullar domain subsequence thereof comprising amino acid residues at positions 35 244, wherein the amino acid residue at position X6 is Lys or Glu; position X8 is Arg or Gly; position X14 is Arg or Cys; position X18 is Trp or Arg; position X19 is Pro or Leu; position X20 is Ser or Pro; position X27 is Asp or Gly; position X55 is Asn or Ser; position X60 is Glu or Lys; position X69 is Gln or Mg; position X101 is Pro or Leu; position X106 is Leu or Gln; position X110 is Pro or Leu; position X113 is Lys or Ser; position 120 is Val or Ile; position X124 is Val or Asp; position X135 is Thr or Ala; position X149 is Thr, Ser, or deleted; position X150 is Ile or deleted; position X151 is Asn or Thr; position X167 is Thr or deleted; position X169 is Ser or deleted; position X169 is Gly or deleted; position X117 is Cys or Tyr; position X192 is Val or Leu; position X197 is Gly or Glu; position X199 is Glu or Lys; position X208 is Gly or Asp; position X215 is His or Arg; position X218 is Ala or Val; position X227 is Ser or Leu; position X249 is Trp, Leu, or Arg; position X261 is Ala or Thr; position X263 is Val Ala, or Ile; position X267 is Arg or Cys; position X268 is Pro or Leu; and position X273 is Gly or Val, and wherein the polypeptide has a human CD28/human CTLA-4 binding affinity ratio equal to or greater than the human CD28/human CTLA-4 binding affinity ratio of human B7-1 and/or induces a T-cell proliferation or activation response when the isolated or recombinant polypeptide is expressed on a cell or bound to a cell membrane.

34. The isolated or recombinant polypeptide of claim 33, wherein the polypeptide has a human CD28/human CTLA-4 binding affinity ratio greater than the human CD28/human CTLA-4 binding affinity ratio of human B7-1.

35. The isolated or recombinant polypeptide of claim 33, wherein the polypeptide induces a T-cell proliferation response equal to, or greater than that induced by human B7-1.

36. The isolated or recombinant polypeptide of claim 33, comprising three or more of: Lys at position X6; Arg at position X8; Arg at position X14; Trp at position X18; Pro at position X19; Ser at position X20; Asp at position X27; Asn at position X55; Len at position X106; Pro at position X110; Lys at position X113; Val at position X120; Val at position X124; Thr at position X135; Asn at position X151; Cys at position X177; Val at position X192; Gly at position X197; Glu at position X199; Gly at position X208; His at position 215; Ala at position X218; Trp at position X249; Ala at position X261; Val at position X263; Arg at position X267; Pro at position X268; and Gly at position X273.

37. The isolated or recombinant polypeptide of claim 36, comprising three or more of: Arg at position X8; Arg at position X14; Trp at position X18; Pro at position X19; Ser at position X20; Pro at position X110; Val at position X120; Val at position X124; Cys at position X177; Val at position X192; Gly at position X197; Glu at position X199; Gly at position X208; His at position X215; Ala at position X218; Trp at position X249; Ala at position X261; and Val at position X263.

38. The isolated or recombinant polypeptide of claim 37, comprising amino acid residues 35 244 of SEQ ID NO:66.

39. An isolated or recombinant polypeptide comprising an amino acid sequence having at least 91% sequence identity to the complete amino acid sequence set forth in SEQ ID NO:66, wherein said polypeptide when expressed on a cell or bound to a cell membrane has a human CD28/human CTLA-4 binding affinity ratio at least equal to the human CD28/human CTLA-4 binding affinity ratio of human B7-1 or induces a T-cell proliferation or activation response.

40. A phamaceutical composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.

41. An isolated or recombinant polypeptide comprising an amino acid sequence comprising at least amino acid residues 245 268 or 246 272 of SEQ ID NO:66.

42. An isolated or recombinant polypeptide comprising an amino acid sequence comprising at least amino acid residues 269 303 or 273 303 of SEQ ID NO:66.

43. The isolated or recombinant polypeptide of claim 6, wherein the polypeptide comprises an amino acid sequence comprising at least amino acid residues 1 244 or 1 245 of SEQ ID NO:66.

44. The isolated or recombinant polypeptide of claim 27, wherein said extracellular domain comprises an amino acid sequence having at least 97% sequence identity to the subsequence of SEQ ID NO:66 comprising at least amino acid residues 35 244.

45. The isolated or recombinant polypeptide of claim 27, wherein said polypeptide when expressed on a cell or bound to a cell membrane induces a T-cell proliferation response greater than the T-cell proliferation response induced by human B7-1.

46. The isolated or recombinant polypeptide of claim 39, wherein said polypeptide comprises an amino acid sequence having at least 95% sequence identity to the complete amino acid sequence of SEQ ID NO:66, and wherein said polypeptide when expressed on a cell or bound to a cell membrane has a human CD28/human CTLA-4 binding affinity ratio that is at least equal to the human CD28/CTLA-4 binding affinity ratio of human B7-1.

47. The isolated or recombinant polypeptide of claim 46, wherein said polypeptide when expressed on a cell or bound to a cell membrane has a human CD28/human CTLA-4 binding affinity ratio that is greater than the human CD28/CTLA-4 binding affinity ratio of human B7-1.

48. The isolated or recombinant polypeptide of claim 39, wherein said polypeptide comprises an amino acid sequence having at least 95% sequence identity to the complete amino acid sequence of SEQ ID NO:66, and wherein said polypeptide when expressed on a cell or bound to a cell membrane induces a T-cell proliferation or activation response.

49. The isolated or recombinant polypeptide of claim 48, wherein said polypeptide comprises an amino acid sequence having at leas 95% sequence identity to the complete amino acid sequence of SEQ ID NO:66, and wherein said polypeptide when expressed on a cell or bound to a cell membrane induces a T-cell proliferation or activation response.

50. The isolated or recombinant polypeptide of claim 49, wherein said polypeptide when expressed on a cell or bound to a cell membrane induces a T-cell proliferation or activation response greater than that induced by human B7-1.

51. A pharmaceutical composition comprising a polypeptide of claim 39 and a pharmaceutically acceptable excipient.

52. A pharmaceutical composition comprising a polypeptide of claim 44 and a pharmaceutically acceptable excipient.

53. A pharmaceutical composition comprising a polypeptide of claim 46 and a pharmaceutically acceptable excipient.
Description



COPYRIGHT NOTIFICATION

Pursuant to 37 C.F.R. 1.71(e), Applicants note that a portion of this disclosure contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.

FIELD OF THE INVENTION

The present invention relates generally to polynucleotides and polypeptides encoded therefrom, as wells as vectors, cells, antibodies, and methods for using and producing the polynucleotides and polypeptides.

BACKGROUND OF THE INVENTION

T cells are a crucial component of the immune system. Not only is T cell activation required for all specific immune responses against infectious agents, but T cells also play an important role in tumor immunity and in autoimmune and allergic diseases. T cell activation is initiated when T cells recognize their specific antigen (Ag) in the context of major histocompatibility complex (MHC) molecules. T cell activation is well known by those of ordinary skill in the art and is characterized by such things as, e.g., cytokine synthesis, induction of various activation markers such as CD25 (interleukin-2 (IL-2) receptor), etc. CD4+T cells recognize their immunogenic peptides in the context of MHC class II molecules, whereas CD8+T cells recognize their immunogenic peptides in the context of MHC class I molecules. For induction of T cell activation, cytokine synthesis or effector function, a second signal, mediated through CD28, is required. Two ligands for CD28 are B7-1 (CD80) and B7-2 (CD86). B7-1 and B7-2 are termed co-stimulatory molecules and are typically expressed on professional antigen-presenting cells (APCs). In addition to binding the CD28 receptor, B7-1 and B7-2 also bind the CTLA-4 (CD152) receptor on T cells.

B7 molecules mediate both positive and negative signals to T cells by binding to CD28 and CTLA-4 (CD152) molecules on T cells. CTLA-4 is a negative regulator of the immune system. In general, wild-type (WT) B7-1, e.g., human B7-1, preferentially binds CTLA-4 more strongly than it binds CD28. Typically, wild-type B7-1, e.g., human B7-1, binds CTLA-4 with about 100 times greater affinity than it binds CD28. Binding of B7-1 or B7-2 to CTLA-4 suppresses activation of T cells, resulting in reduced T cell proliferation and cytokine production (see, e.g., Walunas, T. L. et al. (1994) Immunity 1(5):405 413; Alegre, M. L. et al. (1998) J Immunol 161(7):3347 3356). Interaction between B7-1 or B7-2 and CTLA-4 expressed on T cells down-regulates T cell responses and raises thresholds required for activation by CD28. Blockade of CTLA-4/ligand interactions can also augment in vivo tumor immunity (Leach, D. et al. (1996) Science 271:1734 1736). Consequently, CD28 and CTLA-4 play a pivotal role in the regulation of T cell activation and both are essential for proper functioning of the immune system. For example, CD28 deficient mice are severely immunodeficient and show poor antigen specific T cell responses, while CTLA-4 deficient mice die of lymphoproliferative disease, show T cell expansion mediated by CD28 signaling and have a lack of down-regulation of T cell receptor signaling. Upon ligation by the co-stimulatory molecules B7-1 or B7-2, CD28 mediates a co-stimulatory signal that synergizes with T cell receptor signaling to induce, e.g., proliferation, cytokine production and effector functions by both CD4+ and CD8+T cells (proliferation/activation). Ligation of CTLA-4 with B7-1 (CD80) or B7-2 (CD86), however, dampens the CD80 or CD86 activating signal through CD28, resulting in down-regulation of T cell activation. CD28 ligation reduces the inhibition mediated through the CTLA-4 signaling. CTLA-4 ligation mediates tolerance and anergy.

CD28 and CTLA-4 are both involved in the generation of an immune response to genetic vaccinations (e.g., nucleic acid vaccinations (NAV), DNA vaccinations, and viral vectors). CD28 deficient mice are unable to mount T cell or antibody responses against Beta-galactosidase (Beta-gal) when immunized with a plasmid encoding the Beta-gal gene, and CTLA-4 ligation suppresses the antibody response to Beta-gal in immunized wild-type mice (Horspool, J. et al. (1998), J Immunol 160:2706 2714). Expression of B7-1 on human myeloma cells (Wendtner, C. et al. (1997) Gene Therapy 4(7):726 735), murine mammary tumors (Martin-Fontecha, A. et al.(2000) J Immunol 164(2):698 704) or murine sarcoma (Indrova et al. (1998) Intl J Onc 12(2):387 390) enhances anti-tumor immunity. Furthermore, transfection of human APCs with retroviral vectors encoding B7-1 and tumor antigens induces a stronger cytotoxic T-lymphocyte (CTL) response than transfection with similar vectors encoding the tumor antigens alone (Zajac, P. et al. (1998) Cancer Res 58(20):4567 4571). Anti-viral responses are also modulated by co-stimulatory molecules. For example, DNA vaccination of chimpanzees and mice with HIV antigens in conjunction with B7-2 augmented anti-viral responses (Kim, J. et al. (1998) Vaccine 16(19):1828 1835; Tsuji et al. (1997) Eur J Immunol 27(3):782 787).

The binding properties of B7-1 and B7-2 have limited their usefulness in clinical applications. The present invention addresses needs for molecules having varied abilities to preferentially bind to and/or signal through either CD28 or CTLA-4 receptor and methods of using such molecules for selected and differential manipulation of T cell responses in vitro, ex vivo, and in vivo methods. Such molecules would be of beneficial use in a variety of applications, including, e.g., therapeutic and prophylactic treatments and vaccinations. The present invention fulfills these and other needs.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel co-stimulatory molecules (abbreviated as "NCSM") molecules, including polypeptides and proteins, related fusion polypeptide or fusion protein molecules, or functional equivalents thereof, homologues, and fragments of said polypeptide and protein molecules or equivalents, analogs, or derivatives thereof. The invention also provides nucleic acids encoding any of these polypeptides, proteins, fragments or variants thereof. In addition, the invention provides vectors comprising such nucleic acids, and uses of such NCSM polypeptides and NCSM nucleic acids; and other features are apparent upon further review.

Generally speaking, a "co-stimulatory molecule" refers to a molecule that acts in association or conjunction with, or is involved with, a second molecule or with respect to an immune response in a co-stimulatory pathway. In one aspect, a co-stimulatory molecule may be an immunomodulatory molecule that acts in association or conjunction with, or is involved with, another molecule to stimulate or enhance an immune response. In another aspect, a co-stimulatory molecule is immunomodulatory molecule that acts in association or conjunction with, or is involved with, another molecule to inhibit or suppress an immune response. A "co-stimulatory molecule" need not act simultaneously with or by the same mechanism as the second molecule.

The term "NCSM" in reference to a molecule is not intended to limit the molecule to only those molecules that have positive co-stimulatory properties (e.g., that stimulate or augment T cell proliferation). In the initial recombination procedures described below, libraries of recombinant molecules were generated by recombining nucleotide sequences of parental co-stimulatory molecules (CSM) as discussed herein. As shown by the data and analyses presented herein, novel recombinant molecules having a variety of properties were identified and selected. For example, molecules that enhance an immune response, such as by inducing T cell activation or proliferation (e.g., agonists), and molecules that down-regulate or inhibit an immune response, such as by inhibiting T cell activation or proliferation (e.g., antagonists) were identified and selected. Further, molecules that preferentially bind and/or signal through either or both the CD28 and CTLA-4 receptor were identified and selected. Thus, the term "NCSM" is not limited to molecules having the co-stimulatory properties of the parent sequences, but is intended to refer collectively to all polypeptides of the invention, and nucleic acids encoding them, and other embodiments as described herein, unless specifically noted otherwise.

In one aspect, the invention includes isolated or recombinant NCSM polypeptides, variants, homologues, derivatives, analogs, and fragments thereof. The invention includes recombinant NCSM polypeptides having varied abilities to preferentially bind to and/or signal through CD28 and/or CTLA-4 receptor and provide for selected and differential manipulation of T cell responses in vitro, ex vivo, and in vivo. The invention also includes isolated or recombinant NCSM nucleic acids, variants, homologues, derivatives, analogs, and fragments thereof that encode polypeptides having varied abilities and uses described above. Such NCSM polypeptide and polynucleotides are useful in a variety of applications, including e.g., therapeutic and prophylactic treatment methods, vaccinations, and diagnostic assays described below. The invention also provides NCSM polypeptides, and polynucleotide encoding such polypeptides, that strongly or preferentially bind at least one of CD28 or CTLA-4, but do not effectuate signaling; such molecules are useful in methods as potential antagonists of endogenous molecules, such as e.g., endogenous co-stimulatory molecules. Further, the invention provides NCSM polypeptides, and polynucleotides encoding them, having improved or altered receptor/ligand binding affinities and methods of using such molecules, including in pharmaceutical, prophylactic, therapeutic, vaccine, and diagnostic applications.

In one aspect, the invention provides an isolated or recombinant polypeptide comprising an extracellular domain sequence, said extracellular domain sequence having at least about 75% amino acid sequence identity to an extracellular domain sequence of, or the full-length sequence of, at least one of SEQ ID NOS:48 68, 174 221, 283 285, and 290 293, and is not a naturally-occurring extracellular domain sequence, and wherein said polypeptide has a CD28/CTLA-4 binding affinity ratio equal to or greater than the CD28/CTLA-4 binding affinity ratio of human B7-1. Some such polypeptides induce T-cell proliferation or T-cell activation or both T-cell proliferation and T-cell activation. In some embodiments, the T cell activation or proliferation response is at least equal to or greater than that caused by WT hB7-1. Other such polypeptides modulate T-cell activation, but do not induce proliferation of purified T-cells activated by soluble anti-CD3 mAbs.

In another aspect, the invention provides an isolated or recombinant polypeptide, which polypeptide comprises a non-naturally-occurring amino acid sequence encoded by a nucleic acid comprising a polynucleotide sequence selected from the group of: (a) a polynucleotide sequence selected from SEQ ID NOS:1 21 and 95 142, or a complementary polynucleotide sequence thereof; (b) a polynucleotide sequence encoding a polypeptide selected from SEQ ID NOS:48 68, 174 221, 283 285, and 290 293, or a complementary polynucleotide sequence thereof; (c) a polynucleotide sequence which hybridizes under highly stringent conditions over substantially the entire length of polynucleotide sequence (a) or (b); (d) a polynucleotide sequence comprising all or a fragment of (a), (b), or (c), wherein the fragment encodes a polypeptide having a CD28/CTLA-4 binding affinity ratio equal to or greater than the CD28/CTLA-4 binding affinity ratio of human B7-1; (e) a polynucleotide sequence encoding a polypeptide, the polypeptide comprising an amino acid sequence which is substantially identical over at least about 150 contiguous amino acid residues of any one of SEQ ID NOS:48 68, 174 221, 283 285, and 290 293; and (f) a polynucleotide sequence encoding a polypeptide that has a CD28/CTLA-4 binding affinity ratio equal to or greater than the CD28/CTLA-4 binding affinity ratio of human B7-1, which polynucleotide sequence has at least about 70% identity to at least one polynucleotide sequence of (a), (b), (c), or (d).

Also provided is an isolated or recombinant polypeptide comprising a sequence according to the formula: MGHTM-X6-W-X8-SLPPK-X14-PCL-X18-X19-X20-QLLVLT-X27-LFYFCSGITPKSVTKRVKETVM- LSCDY-X55-TSTE-X60-LTSLRIYW-X69-KDSKMVLAILPGKVQVWPEYKNRTITDMNDN-X101-RIVI-- X106-ALR-X110-SD-X113-GTYTCV-X120-QKP-X124-LKGAYKLEHL-X135-SVRLMIRADFPVP-X- 149-X150-X151-DLGNPSPNIRRLICS-X167-X168-X169-GFPRPHL-X177-WLENGEELNATNTT-X- 192-SQDP-X197-T-X199-LYMISSEL-X208-FNVTNN-X215-SI-X218-CLIKYGEL-X227-VSQIF- PWSKPKQEPPIDQLPF-X249-VIIPVSGALVL-X261-A-X263-VLY-X267-X268-ACRH-X273-ARWK- RTRRNEETVGTE RLSPIYLGSAQSSG (SEQ ID NO:284), or a subsequence thereof comprising the extracellular domain, wherein position X6 is Lys or Glu; position X8 is Arg or Gly; position X14 is Arg or Cys; position X18 is Trp or Arg; position X19 is Pro or Leu; position X20 is Ser or Pro; position X27 is Asp or Gly; position X55 is Asn or Ser; position X60 is Glu or Lys; position X69 is Gln or Arg; position X101 is Pro or Leu; position X106 is Leu or Gln; position X110 is Pro or Leu; position X113 is Lys or Ser; position X120 is Val or Ile; position X124 is Val or Asp; position X135 is Thr or Ala; position X149 is Thr, Ser, or del; position X150 is Ile or del; position X151 is Asn or Thr; position X167 is Thr or del; position X169 is Ser or del; position X169 is Gly or del; position X177 is Cys or Tyr; position X192 is Val or Leu; position X197 is Gly or Glu; position X199 is Glu or Lys; position X208 is Gly or Asp; position X215 is His or Arg; position X218 is Ala or Val; position X227 is Ser or Leu; position X249 is Trp, Leu, or Arg; position X261 is Ala or Thr; position X263 is Val, Ala, or Ile; position X267 is Arg or Cys; position X268 is Pro or Leu; and position X273 is Gly or Val.

In yet another aspect, the invention provides an isolated or recombinant polypeptide comprising a subsequence of an amino acid sequence set forth in any of SEQ ID NOS:48 68, 174 182, 184 221, 283 285, and 290 293, wherein the subsequence is the extracellular domain of said amino acid sequence.

The invention further provides isolated or recombinant polypeptides comprising a sequence having at least about 95% identity to at least one of SEQ ID NOS:69 92, 222 252, 286 289, or a subsequence thereof comprising the extracellular domain, wherein said sequence (a) is a non naturally-occurring sequence, and (b) comprises at least one of: Gly at position 2; Thr at position 4; Arg at position 5; Gly at position 8; Pro at position 12; Met at position 25; Cys at position 27; Pro at position 29; Leu at position 31; Arg at position 40; Leu at position 52; His at position 65; Ser at position 78; Asp at position 80; Tyr at position 87; Lys at position 120; Asp at position 122; Lys at position 129; Met at position 135; Phe at position 150; Ile at position 160; Ala at position 164; His at position 172; Phe at position 174; Leu at position 176; Asn at position 178; Asn at position 186; Glu at position 194; Gly at position 196; Thr at position 199; Ala at position 210; His at position 212; Arg at position 219; Pro at position 234; Asn at position 241; Leu at position 244; Thr at position 250; Ala at position 254; Tyr at position 265; Arg at position 266; Glu at position 273; Lys at position 275; Ser at position 276; an amino acid deletion at position 276; or Thr at position 279, wherein the position number corresponds to that of the human B7-1 amino acid sequence (SEQ ID NO:278), wherein said polypeptide has a CTLA-4/CD28 binding affinity ratio equal to or greater than the CTLA-4/CD28 binding affinity ratio of human B7-1.

In another aspect, the invention provides isolated or recombinant polypeptides comprising a sequence that differs from a primate B7-1 sequence in at least one mutation selected from: Ser 12 Pro; Leu 25 Met; Gly 27 Cys; Ser 29 Pro; Lys 40 Arg; His 52 Leu; Tyr 65 His; Glu 122 Asp; Glu 129 Lys; Thr 135 Met; Thr 164 Ala; Ser 174 Phe; Glu 196 Gly; Ala 199 Thr; Thr 210 Ala; Lys 219 Arg; Thr 234 Pro; Asp 241 Asn; Val 254 Ala; Arg 275 Lys; Arg 276 Ser; or Arg 279 Thr; the mutation being indicated relative to human B7-1 with the amino acid sequence shown in SEQ ID NO:278, wherein said sequence does not occur in nature, and wherein said polypeptide has a CTLA-4/CD28 binding affinity ratio equal to or great


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