Sloan-Kettering Institute for Cancer Research

Centrose, LLC

Sloan-Kettering Institute for Cancer

Jon S Thorson

James Robert Prudent

Charles R Hutchinson

Dimitar B Nikilov

Charles B Hutchinson

Jill Hutchinson Bollettieri

The present invention relates to, inter alia, extracellular drug conjugates (EDC) in which an antibody or other targeting agent (e.g. a targeting moiety) is linked to a drug through a linker (e.g. a non-cleavable linker). These conjugates are useful in the treatment of disease and/or as a tool in the evaluation of biological systems.

Extracellular targeted drug conjugates

The present invention provides mutant nucleotidylyl-transferases, such as E, having altered substrate specificity; methods for their production; and methods of producing nucleotide sugars, which utilize these nucleotidylyl-transferases. The present invention also provides methods of synthesizing desired nucleotide sugars using natural and/or modified Eor other nucleotidyltransferases; and nucleotide sugars synthesized by the present methods. The present invention further provides new glycosyl phosphates, and methods for making them.

Active-site engineering of nucleotidylyltransferases and general enzymatic methods for the synthesis of natural and 'unnatural' UDP- and TDP-nucleotide sugars

The present invention provides mutant nucleotidylyl-transferases, such as E, having altered substrate specificity; methods for their production; and methods of producing nucleotide sugars, which utilize these nucleotidylyl-transferases. The present invention also provides methods of synthesizing desired nucleotide sugars using natural and/or modified Ep or other nucleotidyltransferases; and nucleotide sugars sythesized by the present methods. The present invention further provides new glycosyl phosphates, and methods for making them.

The present invention provides combinatorial methods for rapidly generating a diverse library of glycorandomized structures, comprising incubating one or more aglycons and a pool of NDP-sugars in the presence of a glycosyltransferase. The glycosyltransferase may be one that is associated with or involved in production of natural secondary metabolites, or one which is putatively associated with or involved in production of natural secondary metabolites. The glycosyltransferase may show significant flexibility with respect to its NDP-sugar donors and/or its aglycons. NDP-sugar donors may be commercially available, or may be produced by utilizing mutant or wild type nucleotidyltransferases significant flexibility with respect to their substrates.

Glycorandomization and the production of novel erythronolide and coumarin analogs

An isolated gene cluster of which codes for calicheamicin biosynthesis. The biosynthetic gene cluster contains genes encoding proteins and enzymes used in the biosynthetic production of calicheamicin, including the aryltetrasaccharide and aglycone. The gene cluster also includes the gene coding for the protein conferring calicheamicin resistance. The invention also provides isolated genes of the biosynthetic cluster and their corresponding proteins. In addition, the invention relates to DNA hybridizing with the calicheamicin gene cluster and the isolated genes of that cluster. Expression vectors containing genes of the biosynthetic gene and their functional variants are also provided. The invention also relates to host cells conjugated with DNA isolated from the spp. calichensis genome.

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Madison, WI, United States of America

Jon S Thorson