Hoffmann-la Roche Inc.

Roche Diagnostics Gmbh

F. Hoffmann-la Roche Ag

Bernd Hilger

Josef Burg

Hans-Peter Josel

Wilhelm Tischer

Alfred Engel

Reinhard Franze

Hartmut Ernst Schurig

Manfred Wozny

The present invention refers to conjugates of erythropoietin with poly(ethylene glycol) comprising an erythropoietin glycoprotein having an N-terminal &#x3b1;-amino group and having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells and selected from the group consisting of human erythropoietin and analogs thereof which have the sequence of human erythropoietin modified by the addition of from 1 to 6 glycosylation sites or a rearrangement of at least one glycosylation site; said glycoprotein being covalently linked to one poly(ethylene glycol) group of the formula&#x2014;CO&#x2014;(CH)&#x2014;(OCHCH)&#x2014;ORwherein the &#x2014;CO of the poly(ethylene glycol) group forms an amide bond with said N-terminal &#x3b1;-amino group; and wherein R is lower alkyl; x is 2 or 3; and m is from about 450 to about 1350.

Erythropoietin conjugates

Erythropoietin glycoprotein products are disclosed which have the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells. The present conjugates have an increased circulating half-life and plasma residence time, decreased clearance, and increased clinical activity in vivo. In addition, compared with conventional PEG-EPO conjugates, the conjugates of this invention have superior clinical properties. The present invention also includes a method for the treatment of anemia in a human employing the novel erythropoietin glycoprotein products as well as a method for preparing the erythropoietin glycoprotein products.

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Penzberg, Germany

Bernd Hilger