Antibody molecule-drug conjugates and uses thereof
Inventors
Plante, Obadiah Joseph • Delaney, James C. • Viswanathan, Karthik • Ramakrishnan, Boopathy • Shriver, Zachary Holmes • Wollacott, Andrew M.
Assignees
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Publication Number
US-11168131-B2
Publication Date
2021-11-09
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 an antibody molecule-drug conjugate (ADC) that comprises an antibody molecule binding to Pseudomonas lipopolysaccharide (LPS) and an antimicrobial peptide. The antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 117 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 135, and the antimicrobial peptide comprises the amino acid sequence of SEQ ID NO: 156.
The disclosure describes antibody variable-region specifications and permissive variants for VH and VL, including HCDRs and LCDRs defined using Chothia and Kabat systems, CDR homology or identity relative to antibody 3D6, and frameworks from human or human-derived sources. Humanized antibody formats and VH/VL combinations are described to form antibodies that retain binding to Gram-negative targets, with explicit VH and VL sequence examples and combinations.
The antibody-binding component is linked to an antimicrobial peptide payload to form an ADC, including configurations that provide multi-peptide valency and options for fusion orientation and coupling via constant regions or sortase. The disclosure further associates these constructs with anti-LPS binding and additional antimicrobial peptide properties including cysteine cross-linking and D-amino-acid content.
Claims Coverage
The independent claim coverage centers on an ADC with two main inventive components: an antibody molecule that binds Pseudomonas LPS with defined VH and VL sequences, and an antimicrobial peptide defined by a specific sequence. Six inventive features are present across the claims, with dependent claims refining peptide structure, conjugation, multiplicity, and formulation scope.
Pseudomonas LPS-binding ADC with defined VH, VL, and antimicrobial peptide sequence
An antibody molecule-drug conjugate (ADC) comprising an antibody molecule that binds Pseudomonas lipopolysaccharide (LPS) and an antimicrobial peptide, wherein the antibody molecule comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 117 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 135, and wherein the antimicrobial peptide comprises the amino acid sequence of SEQ ID NO: 156.
Cysteine cross-linked antimicrobial peptide in the ADC
The ADC wherein the antimicrobial peptide comprises a first cysteine residue and a second cysteine residue, and wherein the first cysteine residue is cross-linked to the second cysteine residue.
Indirect fusion of at least two to four antimicrobial peptides via constant region and/or linker
The ADC comprising at least two, three, or four antimicrobial peptides each comprising the amino acid sequence of SEQ ID NO: 156, each of which is fused to the VH or VL indirectly via a constant region, a linker, or both.
Antimicrobial peptide with constrained D-amino-acid content
The ADC wherein the antimicrobial peptide comprises 28, 29, 30, 31, 32, 33, or more D-amino acids, or at least 80%, 90%, 95%, or 100%, of the amino acid residues in the antimicrobial peptide are D-amino acids.
Sortase-mediated fusion to the antimicrobial peptide
The ADC wherein the antibody molecule is fused to the antimicrobial peptide by a sortase.
Pharmaceutical composition including the ADC
A pharmaceutical composition comprising the ADC and a pharmaceutically acceptable carrier.
Overall, the claims center on an ADC defined by a Pseudomonas LPS-binding antibody with VH SEQ ID NO: 117 and VL SEQ ID NO: 135, conjugated to an antimicrobial peptide with SEQ ID NO: 156, with dependent claim refinements covering cysteine cross-linking, multi-peptide valency with indirect fusion, D-amino-acid content constraints, sortase-mediated fusion, and a pharmaceutically acceptable carrier formulation.
Stated Advantages
Higher affinity and kinetic binding performance are reported for the constructs using metrics including Kd, Koff, and Kon.
Improvements in MIC and MBC for the ADC are reported versus components.
Documented Applications
Treating, preventing, or diagnosing bacterial infections, including those involving multidrug-resistant strains.
Targeting bacterial organisms associated with Gram-negative pathogens, including Pseudomonas and other Gram-negative bacteria.
Anti-LPS targeting and antimicrobial activity directed to Gram-negative bacteria, including Pseudomonas spp., via an ADC that binds Pseudomonas lipopolysaccharide (LPS).
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