Abstract: Single-chain forms of the glycoprotein hormone quartet, at least some members of which are found in most vertebrates, are disclosed. In one embodiment of these single-chain forms, the .alpha. and .beta. subunits of the wild-type heterodimers or their variants are covalently linked, optionally through a linker moiety. A drug may further be included within the linker moiety to be targeted to receptors for these hormones. Some of the single-chain forms are agonists and others antagonists of the glycoprotein hormone activity. Another embodiment of the single-chain compounds of the invention comprises two .beta. subunits of the glycoprotein hormones, which .beta. subunits are the same or different. These "two-.beta." forms are antagonists of glycoprotein hormone activity.

Abstract: The invention is directed to a glycosylated or nonglycosylated protein which is composed of the amino acid sequence of a first .alpha. subunit common to the glycoprotein hormones linked covalently, optionally through a linker moiety, to the amino acid sequence of a second .alpha. subunit of said hormones, wherein said first and second .alpha. subunits consist of the native amino acid sequences or variants of said amino acid sequences. These proteins are useful as agonists or antagonists of glycoprotein hormone activity.

Abstract: "Partial" and "complete" CTP units are used to modify biologically active proteins and peptides to alter their clearance patterns. "Complete" CTP units have the amino acid sequence found at positions 112-118 to position 145 of the .beta.-subunit of human chorionic gonadotropin; "partial" CTP units are missing at least one amino acid in the region of position 118-145 inclusive. Variants of these CTP units contain 1-5 conservative amino acid substitutions which do not destroy activity. Suitable peptides or proteins which may be modified in this manner include various hormones and cytokines.

Abstract: "Partial" and "complete" CTP units are used to modify biologically active proteins and peptides at the aminoterminus to alter their clearance patterns. "Complete" CTP units have the amino acid sequence found at positions 112-118 to position 145 of the .beta.-subunit of human chorionic gonadotropin; "partial" CTP units are missing at least one amino acid in the region of position 118-145 inclusive. Variants of these CTP units contain 1-5 conservative amino acid substitutions which do not destroy activity. Suitable peptides or proteins which may be modified in this manner include various hormones and cytokines.

Abstract: A method to determine the site on a receptor or its cognate signaling pathway at which an antagonist acts is disclosed. The method comprises first, (a) determining the effect of an antagonist on a first cell that has been modified to display a mutant form of said receptor. The mutant form constituitively activates the cognate signaling pathway of said receptor. Second, (b) the effect of the antagonist is determined on a second host cell that has been modified to display a tethered form of the receptor. The tethered form is composed of an agonist for said receptor covalently bound thereto whereby said agonist activates the cognate signaling pathway of said receptor. The effect on the cells is determined by measuring the level of an intracellular event that is responsive to the cognate signaling pathway. An antagonist that inhibits the intracellular event in (b) acts at the site of binding for an agonist to the receptor.

Abstract: Modified protein pharmaceuticals extended with a CTP unit retain their biological activity and they had extended biological half-lives. The CTP extension represents an amino acid sequence derived from that of positions 112-118 to 145 of human chorionic gonadotropin.

Abstract: Single-chain forms of the glycoprotein hormone quartet, at least some members of which are found in most vertebrates, are disclosed. The single chain compounds of the invention comprise two .beta. subunits of the glycoprotein hormones, which .beta. subunits are the same or different. These "two-.beta." forms are antagonists of glycoprotein hormone activity.

Abstract: Extended forms of beta subunits of human glycoproteins wherein the amino acid sequence of a carboxy terminal peptide (CTP) representing positions from about 112-118 to 145 of the human CG-beta subunit or a variant form thereof is appended to the C-terminus are disclosed. Recombinant materials for the production of these extended human glycoprotein beta subunits and production of the modified hormones containing the extended beta subunits are also described. Pharmaceutical compositions containing the modified forms of these hormones are useful in pharmacological applications analogous to those of the unmodified forms.

Abstract: Expression constructs for the alpha subunit common to the four human reproductive hormones are disclosed which have enhanced efficiency. These constructs are characterized by the presence of only one intron interrupting the coding sequence for the alpha subunit.

Abstract: The invention provides recombinant native and mutein forms of human reproductive hormones with characteristic glycosylation patterns which are influential in the metabolic activity of the protein. The invention also provides recombinant mutant forms of the human alpha subunit common to FSH, LH, CG, and TSH, to obtain hormones which also have unique glycosylation patterns. Also provided are recombinant materials to produce these subunits separately or together to obtain complete heterodimeric hormones of regulated glycosylation pattern and activity. Modified forms of LH and FSH beta subunits which enhance the rate of dimerization and secretion of the dimers or individual chains are also disclosed.

Abstract: The invention provides recombinant native and mutein forms of human reproductive hormones with characteristic glycosylation patterns which are influential in the metabolic activity of the protein. The invention also provides recombinant mutant forms of the human alpha subunit common to FSH, LH, CG, and TSH, to obtain hormones which also have unique glycosylation patterns. Also provided are recombinant materials to produce these subunits separately or together to obtain complete heterodimeric hormones of regulated glycosylation pattern and activity. Modified forms of LH and FSH beta subunits which enhance the rate of dimerization and secretion of the dimers or individual chains are also disclosed.