Hybritech Incorporated

Eli Lilly and Company

Molecular Biosystems, Inc.

Leslie D Anderson

Kenneth J Widder

Gary S David

Clarence Nathaniel Ahlem

Michele C Smith

Diane M Szaflarski

Ann E Huang

Willem P Stemmer

Mary S Kasher

Susan M Hochschwender

James A Cook

Janeth M Bartlett

A chelating agent is covalently bonded to a biologically active molecule such as an enzyme or antibody, the biologically active molecule is contacted with a support containing a bound transition metal ion whereby the metal ion is chelated by the chelating agent and the oxidation state of the metal ion is changed by treatment with an oxidizing or a reducing agent to provide a kinetically inert: oxidation state to immobilize the biologically active molecule on the support. The transition metal ion is preferably Co(II), Cr(II) or Ru(III) and the oxidation state of the metal ion is changed to Co(III), Cr(III) or Ru(II), respectively. The chelating agent can be iminodiacetic acid, nitrilotriacetic acid, terpyridine, bipyridine, triethylenetetraamine, biethylenetriamine, 1,4,7-triazacyclonane or a chelating peptide. Certain chelating agents can immobilize more than one biologically active molecule at a metal ion site on the support. The immobilized biologically active molecules can be used in affinity chromatography or in assay systems.

Immobilization of biologically active molecules by changing the

A method for enhanced ultrasonic imaging of the tissues defining the gastrointestinal tract and the upper abdominal organs wherein the gastrointestinal tract is filled with a chemically defined essentially sonolucent ultrasound contrast agent that is stable under gastric conditions and has a gastric emptying time of at least about twenty minutes, thus causing the lumen of the upper gastrointestinal tract to appear dark relative to the positive image of the gastrointestinal tract walls and upper abdominal organs.

Method of ultrasonic imaging of the gastrointestinal tract and upper

The present invention is directed to a method for extending the length of one of the three linker arms of the compound of Formula I in the production of novel trifunctional antibody-like compounds. Formula I is defined as follows: ##STR1## wherein X is ##STR2## wherein k=1 or 0; wherein Z is ##STR3## wherein s=1 or 0; wherein n=1 or 0; wherein q=1 or 0; wherein Y is ##STR4## wherein Y' is ##STR5## wherein p or m may be the same or different and are integers ranging from 0 to 20 with the provisos that when n=0, the sum of m and p is an integer ranging from 1 to 20, whereas when n=1, p and m are each an integer that is at least 1 and the sum of p and m is an integer ranging from 2 to 20; wherein R.sup.1 is straight or branched chain lower alkyl having from 1 to 6 carbon atoms or lower alkoxy having from 1-6 carbon atoms; and wherein R.sup.2 is hydrogen, phenyl, --COOH, or straight or branched chain lower alkyl having from 1-6 carbon atoms, with the proviso that the lower alkyl moiety may be mono substituted by --NH.sub.2, --OH, or --COOH. The compound of the present invention is useful as a trivalent coupling agent for linking Fab'-like fragments to form both bifunctional and trifunctional antibody-like compounds.

Method for the synthesis of trifunctional maleimide-antibody complex

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Encinitas, CA, United States of America

Leslie D Anderson