Anti-staphylococcus aureus antibody rifamycin conjugates and uses thereof
AssigneeGenentech, Inc.
InventorsEric Brown, Wouter Hazenbos, Isidro Hotzel, Kimberly Kajihara, Sophie M. Lehar, Sanjeev Mariathasan, Thomas Pillow, Leanna Staben, Vishal Verma, Binqing Wei, Min Xu
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Abstract
The invention provides anti-Staphylococcus aureus antibody rifamycin antibiotic conjugates and methods of using same.
Claims53
An antibody-antibiotic conjugate compound comprising an anti-wall teichoic acid (WTA) monoclonal antibody, wherein the anti-wall teichoic acid monoclonal antibody binds to Staphylococcus aureus, and covalently attached by a protease-cleavable, non-peptide linker to a rifamycin-type antibiotic, the antibody-antibiotic conjugate compound having the formula:
- Ab-(PML-abx)p
- wherein:
- Ab is the anti-wall teichoic acid antibody:
- PML is the protease-cleavable, non-peptide linker having the formula:
- -Str-PM-Y-
- where Str is a stretcher unit:
- PM is a peptidomimetic unit, and Y is a spacer unit;
- abx is the rifamycin-type antibiotic;
- and
- p is an integer from 1 to 8.
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An antibiotic-linker intermediate having Formula II:
- wherein:
- the dashed lines indicate an optional bond;
- R is H, C1-C12 alkyl, or C(O)CH3;
- R1 is OH;
- R2 is CH═N-(heterocyclyl), wherein the heterocyclyl is optionally substituted with one or more groups independently selected from C(O)CH3, C1-C12 alkyl, C1-C12 heteroaryl, C2-C20 heterocyclyl, C6-C20 aryl, and C3-C12 carbocyclyl;
- or R1 and R2 form a five- or six-membered fused heteroaryl or heterocyclyl, and optionally forming a spiro or fused six-membered heteroaryl, heterocyclyl, aryl, or carbocyclyl ring, wherein the spiro or fused six-membered heteroaryl, heterocyclyl, aryl, or carbocyclyl ring is optionally substituted H, F, Cl, Br, I, C1-C12 alkyl, or OH;
- PML is a protease-cleavable, non-peptide linker attached to R2 or the fused heteroaryl or heterocyclyl formed by R1 and R2, and having the formula:
- -Str-PM-Y-
- where Str is a stretcher unit;
- PM is a peptidomimetic unit, and Y is a spacer unit;
- and
- X is a reactive functional group selected from maleimide, thiol, amino, bromide, bromoacetamido, iodoacetamido, p-toluenesulfonate, iodide, hydroxyl, carboxyl, pyridyl disulfide, and N-hydroxysuccinimide.
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Dependencies are inferred from the claim text.