Site specific antibody-drug conjugates with peptide-containing linkers
Inventors
Lowinger, Timothy B. • DAMELIN, Marc I. • Toader, Dorin
Assignees
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Publication Number
US-11786605-B2
Publication Date
2023-10-17
Expiration Date
Abstract
The present disclosure relates generally to antibody-drug conjugates comprising peptide-containing linkers and to methods of using these conjugates as therapeutics and/or diagnostics. Also disclosed herein are peptide-containing scaffolds useful to conjugate with a targeting moiety (e.g., an antibody), a drug, or both to produce the antibody-drug conjugates.
Core Innovation
The invention relates to an antibody-drug conjugate of Formula in which GlcNAc is present, Fuc is present, GalNAc is present, and d13 is 2. The antibody comprises one or more asparagine group at N297 being connected to the rest of the conjugate, defining a glycan-defined antibody scaffold with an N297 connection to the conjugate framework.
The disclosure further specifies embodiments in which the antibody is a NaPi2b antibody defined by CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino-acid sequences. The conjugate architecture is also described with site-specific preparation concepts in which terminal GlcNAc at site N297 is generated and then modified using a GalNAc transfer system involving an enzyme, with steps (a) and (b) conducted concurrently.
The document also describes releasable and cleavable components, including linker and payload regions, variable carbonyl-containing moieties, peptide-based linker moieties, and a divalent assembly unit. Additional embodiments reference pharmaceutical composition and treatment scope for NaPi2b-expressing cancers, including non-small cell lung cancer sub-typed as adenocarcinoma.
Claims Coverage
The claim coverage centers on a single independent structural claim for an antibody-drug conjugate with defined glycan components and an N297 asparagine connected to the rest of the conjugate. Dependent claims refine the antibody identity, describe site-specific conjugate preparation, and add pharmaceutical composition and NaPi2b-expressing cancer treatment scope, including NSCLC adenocarcinoma.
Glycan-defined antibody-drug conjugate with N297 asparagine connection
An antibody-drug conjugate of Formula wherein GlcNAc, Fuc, and GalNAc are present, d13 is 2, and the antibody comprises one or more asparagine group at N297 being connected to the rest of the conjugate.
NaPi2b antibody defined by CDR amino-acid sequences
The conjugate includes a NaPi2b antibody defined by CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino-acid sequences.
Site-specific conjugate preparation using Endo SH and GalNAc transfer
A method prepares a site-specific antibody-drug conjugate by generating terminal GlcNAc at site N297 using Endo SH and then modifying with 4-AzGalNAc-UDP with a β-(1,4)-GalNAcT enzyme, with steps (a) and (b) conducted concurrently.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprises the conjugate and a pharmaceutically acceptable carrier.
Cancer treatment limited to NaPi2b-expressing cancers
A method for treating cancer is limited to NaPi2b-expressing cancers selected from ovarian cancer, non-small cell lung cancer, endometrial cancer, papillary renal cell cancer, salivary duct cancer, papillary thyroid cancer, clear cell renal cancer, breast cancer, kidney cancer, cervical cancer, and cholangiocarcinoma.
NSCLC adenocarcinoma subtype restriction
The method further specifies that the non-small cell lung cancer is sub-typed as adenocarcinoma.
Overall, the claims are anchored by a structural antibody-drug conjugate defined by GlcNAc, Fuc, GalNAc, d13 being 2, and N297 asparagine connectivity. The dependent claims further specify a NaPi2b antibody, a site-specific preparation workflow, pharmaceutical composition scope, and treatment of NaPi2b-expressing cancers including NSCLC adenocarcinoma.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of cancer in NaPi2b-expressing cancers selected from ovarian cancer, non-small cell lung cancer, endometrial cancer, papillary renal cell cancer, salivary duct cancer, papillary thyroid cancer, clear cell renal cancer, breast cancer, kidney cancer, cervical cancer, and cholangiocarcinoma.
Treatment of non-small cell lung cancer sub-typed as adenocarcinoma.
Use in a pharmaceutical composition comprising the conjugate and a pharmaceutically acceptable carrier.
Diagnostic use is mentioned at a general level in the partial content.
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