Human FC&ggr; receptor III

Details Human FC&ggr; receptor III Human FC&ggr; receptor III

1999-01-19

2001-09-25

Spector, Lorraine (Department: 1646)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C435S007100, C435S007200, C435S356000, C435S365000, C530S350000, C436S501000, C436S503000, C436S504000, C436S536000, C436S542000

Reexamination Certificate

active

06294347

ABSTRACT:

FIELD OF THE INVENTION
The invention relates generally to therapeutic compounds, and more particularly to soluble and membrane-bound forms of a low-affinity receptor for human immunoglobulin G, nucleic acids encoding the same, and diagnostic and therapeutic uses of such receptors.
BACKGROUND
Receptors for the Fc portion of immunoglobulin G (IgG) play a central role in cellular immune defenses. Three types of such receptors have been identified: A 72 kilodalton (D) receptor with high affinity for monomeric IgG is found on monocytes and some macrophages, a 40 D receptor with low affinity for monomeric IgG is found on monocytes, neutrophils, eosinophils, platelets, and certain human tumor-cell lines, and a 50-70 D receptor with low affinity for monomeric IgG is found on neutrophils, eosinophils, natural killer cells, and macrophages. These three types of Fc&ggr; receptor are referred to as Fc&ggr;RI, Fc&ggr;RII, and Fc&ggr;RIII, respectively: Unkeless et al.,
Ann. Rev. Immunol.
, Vol. 6 , pgs. 251-281 (1988).
It is believed that Fc&ggr;RIII-mediated removal of IgG-coated platelets plays an important part in the pathogenesis of immune thrombocytopenic purpura (ITP), a platelet-deficiency condition characterized by excessive bleeding: von dem Borne, pgs. 222-256, in
Immunohaematology
, Engelfriet et al., eds. (Elsevier, Amsterdam, 1984). Clerkson et al.,
New England J. Med.,
Vol. 314,pgs. 1236-1239 (1986) , report that the infusion of ligand-blocking anti-Fc&ggr;RIII antibody into a patient with refractory ITP resulted in transient increase in platelet count. This observation suggests that the most deleterious manifestation of ITP could be temporarily ameliroated by the administration of agents that block or compete with Fc&ggr;RIII for binding sites on IgG-coated platelets.
In a separate area of clinical immunology, elevated serum levels of aggregates consisting of immunoglobulin and antigen (so-called “immune complexes”) have been correlated with a wide variety of disorders, particularly autoimmune diseases, such as systemic lupus erythematosus (SLE), and rheumatoid arthritis. The level of such complexes has become an important diagnostic for presence of autoimmune disorder; e.g. Theofilopoulos et al.,
Am.J. Pathol
., Col. 100, pgs. 531-591 (1980).
Present assays for the serum level of immune complexes include solid-phase assays which take advantage of the affinity of the complexes for certain complement or rheumatoid factor proteins, and cellular assays which take advantage of the property of Raji cells to preferentially bind immune complexes; Theofilopoulos et al., chapter 28, and Toth et al., chapter 29, in Rose et al., eds.
Manual of Clinical Immunology,
3rd Ed. (American Society for Microbiology, Washington, D.C., 1986). Unfortunately, like many mammalian-cell based assays, the Raji-cell assay is difficult to perform, and requires elaborate controls and standards because of the inherent variability of Raji-cell binding to immune complexes.
In light of the foregoing, it would be advantageous for the medical community to have alternative assay methods for immune complexes utilizing well characterized, widely available, and conveniently cultured cell lines. It would also be advantageous if soluble Fc&ggr;Rs could be produced in sufficient quantity to permit practical emergency therapy for refractory cases of ITP.
SUMMARY OF THE INVENTION
The present invention is directed to soluble and membrane-bound human Fc&ggr;RIII polypeptides, their muteins, nucleic acids capable of encoding the same, and diagnostic and therapeutic uses of such polypeptides and muteins.
The invention is based on the discovery of a cDNA encoding a human Fc&ggr;RIII. A cDNA clone, pcD(SR&agr;) containing the Fc&ggr;RIII-encoding insert (illustrated in
FIG. 1
) is deposited in
E. coli
K12 strain MC1061 with the American Type Culture Collection (ATCC), Rockville, Md. USA, under accession number 67707.
The invention therefore provides a protein consisting of soluble or membrane-bound human Fc&ggr;RIII and having the the amino acid sequence:
Arg - Thr - Glu - Asp - Leu - Pro - Lys - Ala -

Val - Val - Phe - Leu - Glu - Pro - Gln - Trp -

Tyr - Arg - Val - Leu - Glu - Lys - Asp - Ser -

Val - Thr - Leu - Lys - Cys - Gln - Gly - Ala -

Tyr - Ser - Pro - Glu - Asp - Asn - Ser - Thr -

Gln - Trp - Phe - His - Asn - Glu - Asn - Leu -

Ile - Ser - Ser - Gln - Ala - Ser - Ser - Tyr -

Phe - Ile - Asp - Ala - Ala - Thr - Val - Asp -

Asp - Ser - Gly - Glu - Tyr - Arg - Cys - Gln -

Thr - Asn - Leu - Ser - Thr - Leu - Ser - Asp -

Pro - Val - Gln - Leu - Glu - Val - His - Val -

Gly - Trp - Leu - Leu - Leu - Gln - Ala - Pro -

Arg - Trp - Val - Phe - Lys - Glu - Glu - Asp -

Pro - Ile - His - Leu - Arg - Cys - His - Ser -

Trp - Lys - Asn - Thr - Ala - Leu - His - Lys -

Val - Thr - Tyr - Leu - Gln - Asn - Gly - Lys -

Asp - Arg - Lys - Tyr - Phe - His - His - Asn -

Ser - Asp - Phe - His - Ile - Pro - Lys - Ala -

Thr - Leu - Lys - Asp - Ser - Gly - Ser - Tyr -

Phe - Cys - Arg - Gly - Leu - Val - Gly - Ser -

Lys - Asn - Val - Ser - Ser - Glu - Thr - Val -

Asn - Ile - Thr - Ile - Ser - Ser - Phe - Ser -

Pro - Pro - Gly
Formula I

or

Arg - Thr - Glu - Asp - Leu - Pro - Lys - Ala -

Val - Val - Phe - Leu - Glu - Pro - Gln - Trp -

Tyr - Arg - Val - Leu - Glu - Lys - Asp - Ser -

Val - Thr - Leu - Lys - Cys - Gln - Gly - Ala -

Tyr - Ser - Pro - Glu - Asp - Asn - Ser - Thr -

Gln - Trp - Phe - His - Asn - Glu - Asn - Leu -

Ile - Ser - Ser - Gln - Ala - Ser - Ser - Tyr -

Phe - Ile - Asp - Ala - Ala - Thr - Val - Asp -

Asp - Ser - Gly - Glu - Tyr - Arg - Cys - Gln -

Thr - Asn - Leu - Ser - Thr - Leu - Ser - Asp -

Pro - Val - Gln - Leu - Glu - Val - His - Val -

Gly - Trp - Leu - Leu - Leu - Gln - Ala - Pro -

Arg - Trp - Val - Phe - Lys - Glu - Glu - Asp -

Pro - Ile - His - Leu - Arg - Cys - His - Ser -

Trp - Lys - Asn - Thr - Ala - Leu - His - Lys -

Val - Thr - Tyr - Leu - Gln - Asn - Gly - Lys -

Asp - Arg - Lys - Tyr - Phe - His - His - Asn -

Ser - Asp - Phe - His - Ile - Pro - Lys - Ala -

Thr - Leu - Lys - Asp - Ser - Gly - Ser - Tyr -

Phe - Cys - Arg - Gly - Leu - Val - Gly - Ser -

Lys - Asn - Val - Ser - Ser - Glu - Thr - Val -

Asn - Ile - Thr - Ile - Ser - Ser - Phe - Phe -

Pro - Pro - Gly;
Formula II
together with variant proteins wherein one amino acid residue is deleted, and 0-2 amino acid residues, other than Cys, Phe, Trp and Tr, are replaced according to the following substitution Table:
Amino Acid
Can be replaced by
Ala
Ser, Thr or Gly
Arg
Lys
Asn
Asp or Ser
Asp
Glu or Asn
Gln
Glu
Glu
Asp or Gln
Gly
Ala or Ser
His
Asn
Ile
Val or Leu
Leu
Val or Ile
Lys
Arg or Asn
Met
Leu
Pro
Ala
Ser
Ala, Thr, Gly or Asn
Thr
Ser, Ala or Lys
Val
Ile, Ala or Leu.
For the variant proteins, this substitution Table presents the group of additional L-amino acids that are synonymous to the amino acids that can be replaced. Synonymous amino acids within a group have sufficiently similar physiochemical properties for substitution between members of the group to preserve the biological function of the molecule, Grantham,
Science
, Vol. 185, pgs. 862-864 (1974); and Dayhoff et al.,
Atlas of Protein Sequence and Structure
1972, Vol. 5, pgs. 89-99.
Furthermore, it is clear that deletions of amino acids may also be made in the above-identified sequences without altering biological function, particularly if only one amino acid is acid is deleted and amino acids that are critical to a functional conformation are not removed or displaced, e.g. some cysteine residues: Anfinsen, “Principles That Govern The Folding of Protein Chains”,
Science
, Vol. 181, pgs. 223-230 (1973). Proteins and muteins produced by deletions are within the purview of the present invention. Whenever an amino acid residue of a protein of Formula I or II is referred to herein by number, such a number is in reference to the N-terminus of the protein.
In particular, 1-2 amino acid residues (especially 1) other than Arg, Gln, His, Met and Pro, can be replaced according to the following substitution Ta

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