Peptides and analogs for use in the treatment of oral mucositis
Inventors
Donini, Oreola • Rozek, Annett • Lee, Jackson • North, John • Abrams, Michael
Assignees
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Publication Number
US-9850279-B2
Publication Date
2017-12-26
Expiration Date
Abstract
Preclinical data obtained in models of chemotherapy-induced mucositis, radiation-induced mucositis, neutropenic infection and colitis indicate oral mucositis is a promising indication for Innate Defense Regulator (IDR) peptides. Preclinical efficacy results obtained with IDRs in mouse and hamster models of mucositis indicate that dosing every third day should be able to cover the mucositis “window” with seven to fourteen doses, depending on the duration of chemotherapy or radiation exposure. IDRs have also shown efficacy in mouse models of chemotherapy-induced oral and gastrointestinal mucositis, consistent with the response of the innate immune response to chemotherapy and/or radiation damage. IDRs are also effective at reducing bacterial burden and improve survival in the presence or absence of antibiotic treatment in various murine infection models.
Core Innovation
The invention relates to Innate Defense Regulator (IDR) short peptides, including peptides comprising specific amino acid sequences selected from SEQ ID NOs: 5, 7, 10, 14, 17, 18, 22, 23, 24, 27, 28, 31, 34, 35, 63, 64, 66-69, 72, 76, 77, 90, 91, and 92, and a peptide comprising an amino acid sequence of up to 7 amino acids having the sequence pattern X1X2X3P where SEQ ID NO: 56 is the first four amino acids at the N-terminus of the peptide. The peptides are used to modulate innate immune responses in subjects exposed to damaging radiation or chemotherapeutic agents.
The problem addressed is reducing the incidence, severity and/or duration of oral mucositis in a subject exposed to a damaging amount of radiation or chemotherapeutic agents, and treating an individual suffering from mucositis and colitis or exposure to acute radiation. The disclosed rationale links mucositis and acute radiation syndrome to innate defense and DAMP/PAMP-driven inflammatory cascades, and describes anti-inflammatory cytokine/chemokine profile changes.
The disclosed approaches include administering an effective amount of an IDR peptide as a pharmaceutical salt, ester or amide and with a pharmaceutically-acceptable carrier, diluent, or excipient. The partial content also describes preclinical and human evidence supporting modulation of innate immune responses, including mouse/hamster models of fractionated radiation-induced oral mucositis, chemotherapy-induced mucositis, DSS-induced colitis, and infection models with Gram-positive and Gram-negative bacteria, along with a Phase 1 study in humans reporting rapid clearance and tolerability in the tested dosing range.
Claims Coverage
The partial content provides two independent claims, covering methods centered on administering Innate Defense Regulator (IDR) short peptides to reduce oral mucositis caused by radiation or chemotherapeutic agents, and to treat mucositis/colitis or exposure to acute radiation.
Reducing oral mucositis with up to 7 amino acid IDR peptides
A method of reducing the incidence, severity and/or duration of oral mucositis in a subject exposed to a damaging amount of radiation or chemotherapeutic agents, comprising administering an effective amount of a peptide comprising an amino acid sequence of up to 7 amino acids with the sequence pattern X1X2X3P, wherein X1 is R; X2 is I or V; X3 is I or V; P is proline or a proline analogue; and wherein SEQ ID NO: 56 is the first four amino acids at the N-terminus of the peptide, or a peptide comprising the amino acid sequence of any of SEQ ID NOs: 5, 7, 10, 14, 17, 18, 22, 23, 24, 27, 28, 31, 34, 35, 63, 64, 66-69, 72, 76, 77, 90 and 92.
Treating mucositis and colitis or exposure to acute radiation with selected IDR peptides
A method of treating an individual suffering from a disease selected from the group consisting of mucositis and colitis or exposure to acute radiation comprising administering to the individual a peptide consisting of an amino acid sequence of SEQ ID NOs: 5, 7, 10, 14, 17, 18, 22, 23, 24, 27, 28, 31, 34, 35, 63, 64, 66-69, 72, 76, 77, 90, 91 and 92.
Across the independent claims, the inventive core is the use of specified Innate Defense Regulator short peptides, including a defined X1X2X3P pattern linked to SEQ ID NO: 56 and/or peptide sequences corresponding to listed SEQ ID NOs, to reduce oral mucositis due to radiation or chemotherapeutic exposure, and to treat mucositis/colitis or exposure to acute radiation.
Stated Advantages
Reduces the incidence, severity and/or duration of oral mucositis.
Treats mucositis and colitis.
Treats exposure to acute radiation.
Documented Applications
Reducing fractionated radiation-induced oral mucositis in mouse/hamster models.
Reducing oral/GI mucositis in chemotherapy models.
Efficacy in DSS-induced colitis.
Antimicrobial/host-directed effects in MRSA and other Gram-positive/Gram-negative infection models, including synergy with suboptimal antibiotics, with dose-responsive survival benefits.
A Phase 1 study in humans reporting rapid clearance and tolerability up to the tested IV doses, including ex vivo anti-inflammatory cytokine/chemokine profile changes.
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