Antibody peptide conjugates that have agonist activity at both the glucagon and glucagon-like peptide 1 receptors
Inventors
Carrington, Paul E. • Ermakov, Grigori • Garbaccio, Robert M. • Seghezzi, Wolfgang • Bianchi, Elisabetta • Orvieto, Federica • Gately, Dennis • Knudsen, Nick • Manibusan, Anthony
Assignees
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Publication Number
US-11773150-B2
Publication Date
2023-10-03
Expiration Date
Abstract
Described are antibody peptide conjugates (APCs) comprising an antibody conjugated to a peptide analog of glucagon, which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to have agonist activity at the glucagon (GCG) receptor and the glucagon-like peptide 1 (GLP-1) receptor and the use of such APCs for treatment of metabolic disorders such as diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity.
Core Innovation
The invention relates to an antibody peptide conjugate in which an antibody having a light chain with the amino acid sequence of SEQ ID NO:64 and a heavy chain with the amino acid sequence of SEQ ID NO:65 is conjugated to a peptide having the amino acid sequence of SEQ ID NO:63. The peptide contains a defined His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-... sequence with specified residue identities at multiple positions, including Lys31 within the peptide.
A key feature is a site-specific covalent linkage involving the epsilon amino group of Lys31. Lys31 is covalently linked at its epsilon amino group to an aminooxy acid residue of the peptide, and the aminooxy acid residue is covalently linked to a para-acetylphenylalanine residue of the antibody.
The construct also specifies that either the light chain includes a substitution at position 125 or 142 with pAcF, or the heavy chain includes a substitution at position 16, 32, 33, 56, 114, 179, 198, or 211 with AcF. The linkage architecture may include polyethylene glycol spacers or γGlu-based spacers, and PEG spacer embodiments include PEG2, PEG4, PEG6, PEG8, PEG24, and PEG36.
Claims Coverage
The independent claim is directed to a specific antibody peptide conjugate architecture defined by antibody light/heavy chain sequences, a defined peptide sequence, and a covalent linkage through Lys31 to an aminooxy residue that is covalently linked to pAcF on the antibody. Six inventive features are captured across the merged claim set, with dependent claims further refining linkage architecture, spacer embodiments, and pharmaceutical composition and treatment subject matter.
Covalently linked antibody peptide conjugate with defined sequences
An antibody having a light chain with the amino acid sequence of SEQ ID NO:64 and a heavy chain with the amino acid sequence of SEQ ID NO:65 is conjugated to a peptide having the amino acid sequence of SEQ ID NO:63 comprising the specified His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-... sequence with defined residue identities and Lys at position 31.
Lys31 epsilon amino to aminooxy residue and pAcF linkage
Lys31 is covalently linked at its epsilon amino group to an aminooxy acid residue, wherein the aminooxy acid residue is covalently linked to the pAcF residue of the antibody.
DPP-IV cleavage resistance residue definition
Xaa2 is α-aminoisobutyric acid or D-Ser, with Xaa16 as aib, within the peptide sequence framework of the conjugate.
pAcF substitution placement on the antibody
Either the light chain includes a substitution at position 125 or 142 with pAcF or the heavy chain includes a substitution at position 16, 32, 33, 56, 114, 179, 198, or 211 with AcF.
Spacer-defined linkage architecture
The linkage between Lys31 and the aminooxy acid residue can be direct or provided via polyethylene glycol spacers or γGlu/γGlu-γGlu spacers, with PEG embodiments including PEG2, PEG4, PEG6, PEG8, PEG24, and PEG36.
Pharmaceutical composition and treatment method
A pharmaceutical composition includes the antibody peptide conjugate with a pharmaceutically acceptable carrier, and a method treats a metabolic disease or disorder by administering the pharmaceutical composition to a patient in need.
Overall, the claim set covers a highly specific antibody peptide conjugate with defined antibody and peptide sequences, anchored by a covalent Lys31 to aminooxy residue to pAcF linkage. The dependent claims refine linkage architectures, including PEG and γGlu spacers, and additionally cover pharmaceutical compositions and treatment of metabolic disease, including diabetes subtypes.
Stated Advantages
Improved peptide stability/solubility/half-life.
DPP-IV cleavage resistance.
Extended in vivo half-life.
Documented Applications
Therapeutic use for metabolic disorders including diabetes (type 1, type 2, gestational), NAFLD/NASH, and obesity.
A method for treating a metabolic disease or disorder by administering a pharmaceutical composition to a patient in need.
Diabetes treatment specifically for Type 1 diabetes, Type II diabetes, or gestational diabetes.
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