Bacterial-binding peptides for treatment of infectious diseases and related inflammatory processes
Inventors
Lozano Soto, Francisco • MARTÍNEZ FLORENSA, Mario
Assignees
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Publication Number
US-11660326-B2
Publication Date
2023-05-30
Expiration Date
Abstract
The present invention relates to the field of medicine and provides pharmaceutical compositions comprising one or more of the following isolated amino acid sequences comprising or, alternatively, consisting of, SEQ. ID No.: 3, and/or SEQ. ID No.: 1, and/or SEQ ID No.: 2, kits and conjugates comprising one or more of the above mentioned amino acid sequences. In addition, the present invention relates to the use of the pharmaceutical compositions, kits and conjugates of the present invention as a medicament, in particular in the treatment of an infectious disease, or of an inflammatory condition related to an infectious disease, or of an inflammatory disease related to the presence of a product derived from an infectious agent. The present invention also provides a device for selective binding and separation of at least one component from an aqueous solution wherein the device comprises one or more of the above mentioned amino acid sequences.
Core Innovation
The invention relates to bacterial-binding 11-mer peptides derived from the scavenger-like CD6 receptor, including peptide sequences consisting of SEQ ID NO: 3, SEQ ID NO: 1, and SEQ ID NO: 2, and derivatives thereof. These peptides bind PAMPs from Gram− and Gram+ bacteria, notably LPS and LTA.
The disclosed peptides induce bacterial agglutination and modulate cytokine release, including effects on pro-inflammatory cytokines and anti-inflammatory cytokines. Binding and affinity analyses are reported, together with ex vivo cytokine effects.
The disclosure further reports in vivo efficacy in a CLP-induced septic shock model, including dose- and time-dependent survival benefit and reduced pro-inflammatory cytokines and bacterial load. CD6.PD3 is identified as showing the survival benefit in the described in vivo context.
The invention also discloses compositions, pharmaceutical compositions with carriers/salts/adjuvants/excipients, and conjugates including polyethylene glycol or albumin, as well as kit-of-parts combining the peptides with antibiotic Imipenem and enzyme inhibitor Cilastatin. In addition, device concepts are disclosed for extracorporeal adsorption/removal of bacterial endotoxin components (LPS/LTA/PGN) from aqueous or biological fluids using peptide-immobilized supports such as Eupergit® beads.
Claims Coverage
The independent claims cover three claim categories: pharmaceutical compositions of specific 11-mer peptide sequences and their derivatives, conjugates comprising those peptides with defined derivative types, and kit-of-parts that combine those peptides with an antibiotic and optionally an inhibitor. Across the independent claims, the inventive features focus on selecting SEQ ID NO: 3, SEQ ID NO: 1, SEQ ID NO: 2 (and derivatives) and limiting the derivative forms to defined terminal modifications and/or L-to-D replacements and/or polyethylene glycol or albumin conjugation.
Pharmaceutical composition with CD6-derived 11-mer sequences and defined derivatives
A pharmaceutical composition comprising one or more isolated amino acid sequences selected from SEQ ID NO: 3, SEQ ID NO: 1, SEQ ID NO: 2, and derivatives thereof, where derivatives are a peptide consisting of SEQ ID NO: 3, SEQ ID NO: 1, or SEQ ID NO: 2 with one modification of a C-terminal end selected from C-amidation and C-esterification and/or one modification of an N-terminal end selected from N-acylation and N-alkylation, replacement of one or more L-amino acids with corresponding D-amino acids, conjugation with polyethylene glycol or albumin, or combinations of any of (i), (ii), or (iii).
Conjugate comprising CD6-derived 11-mer sequences with defined derivative forms
A conjugate comprising one or more isolated amino acid sequences comprising an 11-mer amino acid sequence selected from SEQ ID NO: 3, SEQ ID NO: 1, SEQ ID NO: 2, and derivatives thereof, where derivatives are SEQ ID NO: 3, SEQ ID NO: 1, or SEQ ID NO: 2 with one modification of a C-terminal end selected from C-amidation and C-esterification and/or one modification of an N-terminal end selected from N-acylation and N-alkylation, replacement of one or more L-amino acids with corresponding D-amino acids, or combinations of (i) or (ii).
Kit-of-parts combining CD6-derived 11-mer sequences with antibiotic and defined derivatives
A kit-of-parts comprising one or more isolated amino acid sequences consisting of a sequence selected from SEQ ID NO: 3, SEQ ID NO: 1, SEQ ID NO: 2, and derivatives thereof and an antibiotic, where derivatives are a peptide consisting of SEQ ID NO: 3, SEQ ID NO: 1, or SEQ ID NO: 2 with one modification of a C-terminal end selected from C-amidation and C-esterification and/or one modification of an N-terminal end selected from N-acylation and N-alkylation, replacement of one or more L-amino acids with corresponding D-amino acids, conjugation with polyethylene glycol or albumin, or combinations of any of (i), (ii), or (iii).
Across the independent claims, the patent claims CD6-derived 11-mer peptide sequences selected from SEQ ID NO: 3, SEQ ID NO: 1, and SEQ ID NO: 2 (and derivatives), where derivative scope is defined by specified terminal modifications and/or L-to-D amino acid replacements and/or conjugation with polyethylene glycol or albumin. The independent claims further distinguish whether the peptides are provided as pharmaceutical compositions, as conjugates, or as kit-of-parts that include an antibiotic.
Stated Advantages
Induces bacterial agglutination.
Modulates cytokine release, including reducing pro-inflammatory cytokines.
Provides dose- and time-dependent survival benefit in CLP-induced septic shock.
Reduces bacterial load in the CLP-induced septic shock context.
Enables adsorption/removal of bacterial endotoxin components (LPS/LTA/PGN) from aqueous/biological fluids using peptide-immobilized supports.
Documented Applications
In vitro binding/affinity analysis and ex vivo cytokine modulation for bacterial PAMPs, notably LPS and LTA.
In vivo treatment context using CLP-induced septic shock, with survival benefit and reduced pro-inflammatory cytokines and bacterial load.
Device/hemadsorption/hemoperfusion-style extracorporeal removal of endotoxin components (LPS/LTA/PGN) from aqueous/biological fluids using peptide-immobilized supports such as Eupergit® beads.
Combination use with antibiotic Imipenem and enzyme inhibitor Cilastatin as a kit-of-parts.
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