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Publication Number
US-12269801-B2
Publication Date
2025-04-08
Expiration Date
Abstract
Provided herein are modified amino acids comprising an azido group, polypeptides, antibodies and conjugates comprising the modified amino acids, and methods of producing the polypeptides, antibodies and conjugates comprising the modified amino acids. The polypeptides, antibodies and conjugates are useful in methods of treatment and prevention, methods of detection and methods of diagnosis.
Core Innovation
The disclosure relates to modified amino acids bearing an azido group, including compounds defined by Formula I, Formula Ia, and Formula II, together with pharmaceutically acceptable salts. The modified amino acids are characterized by substituent definitions including D, Ar, W1, W2, W3, X1, Y1, Y2, Z1, Z2, Z3, and related formula features, and may be L-, D-, or racemic.
The disclosure further relates to polypeptides, including antibodies and antibody fragments, and to conjugates constructed by incorporating a modified amino acid at a site-specific position. The incorporation uses an orthogonal tRNA system, including an orthogonal tRNA synthetase and aminoacylated tRNA, configured to incorporate the modified amino acid into a polypeptide, enabling azide-dependent conjugation outcomes and selective bioconjugation.
Selective bioconjugation is enabled by Huisgen [3+2] cycloaddition between the azide group on the modified amino acid and an alkyne-containing second compound, forming a triazole linkage. The disclosure also addresses PEG-derivative structures and polymer payloads for conjugating polypeptides containing non-natural amino acids, including azide-terminal PEG, alkyne-terminal PEG, and branched PEG.
Claims Coverage
The consolidated claim coverage provides three independent inventive features.
Compound defined by formula with W4 and R
A compound according to a specified formula, wherein W4 is C1–C10 alkylene and R is hydrogen or methyl.
Preparing a formula compound using an acylase
A method of preparing a compound according to a specified formula by treating a precursor compound with an acylase, wherein W4 is C1–C10 alkylene.
Preparing a formula compound using NaN3
A method of preparing a compound according to a specified formula by treating a precursor compound with NaN3.
The inventive coverage is directed to a formula-defined compound and to preparation methods using either an acylase or NaN3 to generate the specified compound.
Stated Advantages
Enables more uniform site-specific labeling and payload attachment, addressing limitations of heterogeneous conjugation.
Documented Applications
Site-specific incorporation of azide-bearing modified-amino-acid residues into polypeptides and antibodies, including conjugates with a payload.
Azide-dependent conjugation outcomes in contexts including GFP and turboGFP and an orthogonal tRNA system incorporating an azide-bearing amino acid.
PEGylation and polymer payload conjugation of polypeptides containing non-natural amino acids.
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