Water-Soluble Polymer Conjugates of Topotecan
AssigneeNektar Therapeutics
InventorsXuyuan Gu, Jennifer Riggs-Sauthier, Michael D. Bentley, Tacey X. Viegas
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Abstract
Provided herein are water-soluble polymer conjugates of topotecan, along with compositions comprising the conjugates and related methods of making and using the same.
Claims44
A water-soluble polymer conjugate of topotecan having two or more topotecan molecules covalently attached to a water-soluble polymer.
A water-soluble polymer conjugate of topotecan having a structure encompassed by the formula:
- wherein:
- y=0 or 1, such that when y=0, —CyH′H″ is absent, and when y=1, Cy is present;
- m is a positive integer from 1 to about 12;
- X1 and X2, when present, are each an amino acid linker, such that the amino acid carboxyl carbon of the linker is adjacent to the TPN-oxygen (O);
- each POLY1 is a water-soluble, non-peptidic polymer;
- q=1, 2, 3, or 4;
- r=0 or 1;
- and
- “TPN-O˜” corresponds to
- and pharmaceutically acceptable salts thereof,
- where the following apply:
- when r=1, q does not equal 4;
- when r=0, q is selected from 2, 3, and 4, and
- when r+q does not equal 4, then H′ and optionally H″ are present to bring the valence on Cy to four.
A conjugate-containing composition comprising four-arm conjugates, wherein at least 80% of the four-arm conjugates in the composition have a structure encompassed by the formula:
- where n is a positive integer ranging from 10 to about 400, and pharmaceutically acceptable salts thereof.
A method comprising reacting a water-soluble, non-peptidic polymer structure having 2, 3 or 4 polymer arms, each individual polymer arm having a reactive carboxylic acid group or activated ester thereof at its terminus, with “q” moles or greater of a compound having the following structure, where “q” corresponds to the number of reactive carboxylic acid or activated ester functionalities in the reactive polymeric structure:
- wherein G is H or —C(O)—CHR″—NH2, where R″ is selected from H, C1-C6 alkyl, C1-C6 alkylaryl, and substituted C1-C6 alkyl.
Dependencies are inferred from the claim text.