American Cyanamid Company

Wyeth Holdings Corporation

Irwin J Hollander

Philip R Hamann

Martin J Weiss

Hwei-Ru Tsou

William A Hallett

Lois M Hinman

Ryan Holcomb

Semiramis Ayral-Kaloustian

Arthur Kunz

Ann Aulabaugh

Martin P Kunstmann

Martin P Kuntsmann

5-Substituted-3(2H)-furanones useful for inhibition of farnesyl-protein transferase

This invention describes carrier-drug conjugates prepared from disulfide analogs of the calicheamicin family of potent antitumor antibiotics and their derivatives, as well as similar analogs from related antitumor antibiotics such as the esperamicins. The carrier can be an antibody, growth factor, or steroid which targets an undesired population of cells, such as those of a tumor. Whole protein carriers as well as their antigen-recognizing fragments and their chemically or genetically manipulated counterparts are useful for the targeting portion of the conjugates. This invention includes compounds required for the synthesis of these conjugates, appropriate pharmaceutical compositions of the carrier-drug conjugates, and their method of use.

Process for preparing conjugates of methyltrithio antitumor agents

Conjugates of methyltrithio antitumor agents and intermediates for their

Linkers useful for the synthesis of conjugates of methyltrithio

Enediyne derivatives useful for the synthesis of conjugates of

A method is provided for preparing monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and decreased aggregation. These conjugates are prepared by incubating a calicheamicin derivative and a proteinaceous carrier in a solution comprising a non-nucleophilic, protein-compatible, buffered solution, a cosolvent selected from the group consisting of propylene glycol, ethanol, DMSO, and combinations thereof, and an additive comprising at least one C.sub.6 -C.sub.18 carboxylic acid having a pH in the range from about 4.0 to 8.5 and at a temperature ranging from about 25.degree. C. to about 37.degree. C. for a period of time ranging from about 15 minutes to about 24 hours, and recovering monomeric calicheamicin derivative/carrier conjugates. Alternatively, the conjugates can be prepared by incubating the calicheamicin derivative and a proteinaceous carrier in a solution comprising a non-nucleophilic, protein-compatible, buffered solution and a cosolvent comprising t-butanol.

Methods for the preparation of monomeric calicheamicin

A method is provided for preparing monomeric calicheamicin derivative/carrier conjugates with higher drug loading/yield and decreased aggregation. These conjugates are prepared by incubating a calicheamicin derivative and a proteinaceous carrier in a solution comprising a phosphate buffered solution, a cosolvent comprising propylene glycol, an additive comprising at least one C.sub.6 -C.sub.25 carboxylic acid, preferably having a pH in the range from about 7.0 to 8.5, and at a temperature ranging from about 25.degree. C. to about 37.degree. C. for a period of time ranging from about 2 hours to about 18 hours, and recovering monomeric calicheamicin derivative/carrier conjugates. Alternatively, the conjugates can be prepared by incubating the calicheamicin derivative and a proteinaceous carrier in a solution comprising a phosphate buffered solution and a cosolvent comprising t-butanol.

Method for the preparation of substantiallly monomeric calicheamicin

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Monsey, NY, United States of America

Irwin J Hollander