Antibody molecule-drug conjugates and uses thereof
Inventors
Viswanathan, Karthik • Johnson, Kenneth Douglas • Plante, Obadiah Joseph • Delaney, James C. • Koch, Tyree J. • Tissire, Hamid • Wollacott, Andrew M. • Ramakrishnan, Boopathy
Assignees
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Publication Number
US-11969476-B2
Publication Date
2024-04-30
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 (ADCs) comprising an antibody molecule and a covalently coupled peptide. The antibody molecule is capable of binding to lipopolysaccharide (LPS) on Pseudomonas aeruginosa and comprises a heavy chain variable region (VH) and a light chain variable region (VL) with defined complementarity determining regions. A peptide having the amino acid sequence of SEQ ID NO: 257 is covalently coupled to the antibody molecule.
The disclosed ADCs use specific VH and VL complementarity determining region sequences, with the VH comprising either HCDR1/HCDR2/HCDR3 sequences of SEQ ID NO: 105/106/107 or SEQ ID NO: 108/146/107, and the VL comprising LCDR1/LCDR2/LCDR3 sequences of SEQ ID NO: 138/142/112. Certain embodiments further require coupling architecture involving a (Gly-Ser)n linker with n=2 to 20, and other disclosed embodiments include peptide coupling via enzymatic ligation through a sortase recognition sequence.
The described approach is directed to LPS on Pseudomonas aeruginosa and is associated with broad activity across multiple Gram-negative strains, including MDR/pan-resistant Pseudomonas aeruginosa. The disclosure states advantages such as inhibition of LPS/TLR4 signaling, reduced mammalian cytotoxicity/hemolysis, and improved biodistribution.
Claims Coverage
The consolidated set includes two independent claims. Across these independent claims, the main inventive features are an anti-LPS ADC with specified VH and VL complementarity determining region sequences and a covalently coupled peptide of SEQ ID NO: 257, with one independent claim further requiring two VHs and two VLs and C-terminal peptide coupling via a (Gly-Ser)n linker where n=2 to 20.
Lps-binding adc with defined vh and vl complementarity determining regions
An antibody molecule-drug conjugate (ADC) comprising an antibody molecule and a covalently coupled peptide, wherein the antibody molecule is capable of binding to lipopolysaccharide (LPS) on Pseudomonas aeruginosa and comprises a heavy chain variable region (VH) with HCDR1/HCDR2/HCDR3 sequences of SEQ ID NO: 105/106/107 or SEQ ID NO: 108/146/107, and a light chain variable region (VL) with LCDR1/LCDR2/LCDR3 sequences of SEQ ID NO: 138/142/112.
Covalent coupling to peptide seq id no: 257
The ADC wherein the peptide comprises the amino acid sequence of SEQ ID NO: 257.
ADC with two VHs and two VLs and (Gly-Ser)n linker to VH C-terminus
An ADC comprising an antibody molecule comprising two VHs and two VLs, wherein the VH is covalently coupled with a peptide comprising the amino acid sequence of SEQ ID NO: 257, and wherein the peptide is coupled to the C-terminus of the VH via a (Gly-Ser)n linker where n=2 to 20 (SEQ ID NO: 262), with the VH HCDR sequences of SEQ ID NO: 105/106/107 or SEQ ID NO: 108/146/107 and the VL LCDR sequences of SEQ ID NO: 138/142/112.
Across the independent claims, the coverage is directed to ADCs that bind Pseudomonas aeruginosa LPS and carry a covalently coupled peptide with SEQ ID NO: 257. The key inventive aspects are the specific VH and VL complementarity determining region sequence sets and, in the second independent claim, a defined coupling of the peptide to the VH C-terminus via a (Gly-Ser)n linker with n=2 to 20.
Stated Advantages
Inhibition or reduction of bacterial viability across broad Gram-negative taxa.
Bactericidal activity supported by the ADC design.
Membrane disruption activity is described as an evaluation endpoint.
Opsonophagocytic activity is described as an evaluation endpoint.
Low hemolysis is described as part of antimicrobial peptide selection criteria.
Inhibition of LPS/TLR4 signaling.
Reduced mammalian cytotoxicity/hemolysis.
Improved biodistribution.
Broad activity against multiple Gram-negative strains, including MDR/pan-resistant Pseudomonas aeruginosa.
Documented Applications
Treating or preventing a bacterial infection by administering an ADC to a subject in an amount effective to treat or prevent the infection.
Methods of treating or preventing bacterial infection by administering the ADC of claim 1 to a subject in an amount effective to treat or prevent the infection.
Use of pharmaceutical compositions containing the ADC, including dosing routes such as intravenous, subcutaneous, intranasal, and inhalation [procedural detail omitted for safety].
Kits and nucleic acids/vectors/cells associated with the disclosed compositions and uses.
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