Binding protein drug conjugates comprising anthracycline derivatives
Inventors
Grawunder, Ulf • BEERLI, Roger Renzo
Assignees
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Publication Number
US-10517959-B2
Publication Date
2019-12-31
Expiration Date
Abstract
The present invention relates to an anthracycline (PNU) derivative conjugate comprising a derivative of the anthracycline PNU-159682 having the formula (i) or formula (ii) which further comprises a linker structure X-L1-L2-L3-Y.
Core Innovation
The disclosure describes anthracycline (PNU) derivative conjugates built from derivatives of PNU-159682, where the conjugate comprises a linker structure X–L1–L2–L3–Y at a wavy-line position. The linker comprises linkers L1–L3, in which two of L1–L3 are mandatory, and X and Y further represent each one or more optional linkers. The conjugate is framed as a binding protein drug conjugate (BPDC) and includes an anthracycline-derived drug component and defined linker architecture.
A key aspect is the use of a sortase-mediated, site-specific conjugation (SMAC) approach to form the linker and enable conjugation through a defined linker chain rather than maleimide/thiol chemistry. The linker L3 is described as being processed from a sortase enzyme recognition motif (LPXTG, LPXSG, or LAXTG), with cleavage generating a processed L3 structure. The disclosure emphasizes homogeneous drug-to-antibody ratio behavior and improved serum stability in comparison to maleimide-linked references.
The payload embodiments are based on PNU-159682 derivatives that lack specified C14 hydroxyl and/or C13/C14 carbonyl/hydroxyl features, and the linker chain includes ethylenediamino (EDA)/(CH2)m–NH2 type spacers and an oligo-glycine peptide (Gly_n) component having a free N-terminus. The conjugation architecture is described to include a free amino terminus of Gly_n and a processed sortase motif-derived peptide segment for L3, supporting binding protein attachment through defined linker placement.
Claims Coverage
The partial claim set provided lists one independent claim (clm-00001). The independent claim covers an anthracycline (PNU) derivative conjugate defined by a PNU-159682 derivative and a specific multi-part linker structure at a wavy-line position, with additional inventive refinements stated in the dependent claims focusing on the linker composition and sortase motif constraints.
PNU-159682 derivative conjugate with X–L1–L2–L3–Y linker at a wavy-line position
An anthracycline (PNU) derivative conjugate comprising a derivative of the anthracycline PNU-159682 having a specified formula (i) or formula (ii), where the conjugate comprises at its wavy line a linker structure X–L1–L2–L3–Y, with L1–L3 representing linkers in which two of L1–L3 are mandatory and X and Y representing each one or more optional linkers.
Across the provided claims, the core inventive coverage centers on a PNU-159682-derived anthracycline conjugate with a defined X–L1–L2–L3–Y linker at a wavy-line position, with dependent refinements specifying an oligo-glycine peptide linker featuring a free amino terminus and constraining its length, and defining L3 through sortase enzyme recognition motifs with explicit sequence patterns (LPXTG/LPXSG/LAXTG).
Stated Advantages
Improved serum stability compared with maleimide-linked references.
Homogeneous drug-to-antibody ratio behavior is emphasized.
Higher mono-DAR behavior (reported as mono-DAR ~4) is described for specific embodiments.
Markedly improved in vitro/in vivo stability versus maleimide-linked Kadcyla/T-DM1 is described.
Potent TSA-dependent cytotoxicity is reported in connection with specific embodiments.
Documented Applications
Binding protein drug conjugates/antibody drug conjugates are described, including conjugates involving trastuzumab (HER-2) and brentuximab (CD30).
In vitro and in vivo testing contexts are described for the disclosed conjugates, including reported stability comparisons and cytotoxicity behavior.
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