Washington University

David Ben-Menahem

Irving Boime

Forms of differentially acting glycoprotein hormones are disclosed. These compositions are of the formula&#x3b2;-(linker)-&#x3b1;-(linker)-&#x3b2;;&#x2003;&#x2003;(1)&#x3b2;-(linker)-&#x3b2;-(linker)-&#x3b1;;&#x2003;&#x2003;(2)&#x3b1;-(linker)-&#x3b2;-(linker)-&#x3b2;;&#x2003;&#x2003;(3)&#x3b2;&#x2248;&#x3b1;-(linker)-&#x3b2;; or&#x2003;&#x2003;(4)&#x3b2;-(linker)-&#x3b1;&#x2248;&#x3b2;&#x2003;&#x2003;(5) wherein each of &#x3b2;and &#x3b2;has the amino acid sequence of the &#x3b2; subunit of a vertebrate glycoprotein hormone or a variant of said amino acid sequence, as variants are defined herein. '&#x3b1;' designates the &#x3b1; subunit of a vertebrate glycoprotein hormone or a variant thereof, 'linker' refers to a covalently linked moiety that spaces the &#x3b2;and &#x3b2;subunits at appropriate distances from the &#x3b1; subunit and from each other. &#x201c;&#x2248;&#x201d; is a noncovalent link. Each of m and n is independently 0 or 1.

Glycoprotein hormone compositions containing two &#x3b2; subunits

Glycoprotein hormone compositions comprising two &bgr; subunits and methods of use thereof

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.

Single-chain .beta. subunit dimers of the glycoprotein hormones and

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.

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St. Louis, MO, United States of America

David Ben-Menahem