Antibody molecule-drug conjugates and uses thereof
Inventors
Shriver, Zachary • Plante, Obadiah Joseph • Li, Kai • Viswanathan, Karthik • Delaney, James C. • Ramakrishnan, Boopathy • Wollacott, Andrew M.
Assignees
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Publication Number
US-11890319-B2
Publication Date
2024-02-06
Expiration Date
Abstract
Antibody molecule-drug conjugates (ADCs) that specifically bind to lipopolysaccharides (LPS) are disclosed. The antibody molecule-drug conjugates can be used to treat, prevent, and/or diagnose bacterial infections and related disorders.
Core Innovation
The invention relates to antibody molecule-drug conjugates (ADC) comprising an anti-LPS antibody molecule and a covalently coupled antimicrobial peptide. The antibody molecule comprises one or more motifs defined by a specific amino-acid motif formula in which FGly′ is a 2-formylglycine residue, a cysteine, or a serine, Z2 is a proline or alanine, X1, X2, and X3 are each independently any amino acid, and Z3 is a basic amino acid.
The antibody molecule further comprises a heavy chain with a heavy chain variable region (VH) having defined HCDR1, HCDR2, and HCDR3 sequence options, and a light chain with a light chain variable region (VL) having defined LCDR1, LCDR2, and LCDR3 sequence options. These defined variable-region elements are described in connection with targeting LPS and maintaining anti-LPS binding functionality.
The antimicrobial peptide is defined by the amino acid sequence GGGKFFRKLKKSVKKRAKEFFKKPRVIGVSIPF (SEQ ID NO: 156) and is covalently coupled to the anti-LPS antibody molecule. The disclosed antigen scope is LPS from Gram-negative bacteria, including Enterobacteriaceae, Pseudomonas, and Acinetobacter, with epitopes described using Kdo residues and Hep residues.
Claims Coverage
The independent claim coverage defines one anti-LPS antibody-drug conjugate with four inventive features tied to the ADC architecture, motif definition, specific antibody variable-region CDR sequence options, and the antimicrobial peptide sequence.
Motif-defined anti-LPS ADC with covalently coupled antimicrobial peptide
An antibody molecule-drug conjugate (ADC) comprising an anti-LPS antibody molecule and a covalently coupled antimicrobial peptide, wherein the antibody molecule comprises one or more motifs defined by the formula in which FGly′ is a 2-formylglycine residue, a cysteine, or a serine, Z2 is a proline or alanine residue, X1, X2, and X3 are each independently any amino acid, and Z3 is a basic amino acid.
Heavy-chain variable-region CDR sequence options
The antibody molecule comprises a heavy chain comprising a heavy chain variable region (VH) comprising HCDR1 comprising the amino acid sequence of SEQ ID NO: 108, HCDR2 comprising SEQ ID NO: 146, and HCDR3 comprising SEQ ID NO: 107, or HCDR1 comprising SEQ ID NO: 105, HCDR2 comprising SEQ ID NO: 106, and HCDR3 comprising SEQ ID NO: 107.
Light-chain variable-region CDR sequence options
The antibody molecule comprises a light chain comprising a light chain variable region (VL) comprising LCDR1 comprising SEQ ID NO: 138, LCDR2 comprising SEQ ID NO: 142, and LCDR3 comprising the amino acid sequence of any of SEQ ID NO: 112.
Specified antimicrobial peptide sequence covalently coupled to the antibody molecule
The antimicrobial peptide comprises the amino acid sequence GGGKFFRKLKKSVKKRAKEFFKKPRVIGVSIPF (SEQ ID NO: 156).
Independent claim coverage centers on an anti-LPS ADC that covalently couples the antimicrobial peptide sequence SEQ ID NO: 156 to an antibody molecule containing one or more motifs defined by the specified motif formula and containing constrained heavy-chain and light-chain variable-region CDR sequence options.
Stated Advantages
Controlled stoichiometry and more homogeneous ADC populations.
Reduced toxicity.
Activity against Gram-negative and multi-drug resistant strains.
Antibacterial activity in anti-LPS targeting, including Pseudomonas aeruginosa.
Documented Applications
Treatment or prevention of bacterial infections, including Gram-negative bacterial infections and infections associated with Pseudomonas aeruginosa.
In vivo evaluation in a murine acute pneumonia model.
In vivo evaluation in a neutropenic infection model.
ADC with an anti-LPS antibody molecule covalently coupled to an antimicrobial peptide, including antibody component specifications such as constant-region/Fc engineering and variable-region/CDr frameworks.
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