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-10253068-B2
Publication Date
2019-04-09
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) peptides, including the peptides RIVPA (SEQ ID NO. 5) and related sequences and analogs. The disclosed peptides include isolated peptides defined by specific amino acid sequences and pharmaceutical salts, esters, or amides thereof.
The invention addresses dysregulated innate immune signaling that is triggered by chemotherapy or radiation, together with secondary bacterial burden. The disclosed approach uses IDR peptides (SEQ ID NO. 91 and SEQ ID NO. 92) to treat oral mucositis and related mucosal and infectious complications associated with chemotherapy-induced mucositis and radiation-induced mucositis.
The document further reports preclinical efficacy in chemotherapy- and radiation-induced oral mucositis models, as well as DSS-induced colitis and multiple murine infection models. The reported infection coverage includes Gram-positive and Gram-negative bacteria, with emphasis on models including MRSA and Klebsiella, and the utility includes combination with antibiotics such as vancomycin for treatment of neutropenic infection-related bacterial burdens.
The disclosed peptides are presented together with formulations and administration routes, including intravenous administration, and dosing schedules intended to cover the mucositis window. Safety and supporting clinical pharmacology are described, including rapid clearance and selective innate modulation, as well as safety pharmacology/toxicology findings in mice and nonhuman primates and human tolerability up to tested doses.
Claims Coverage
The claim set includes four independent claims that cover isolated peptide sequence identity and two specific isolated peptide sequence structures defined by modified residues/links, plus a method of treating specified diseases or acute radiation exposure by administering one of the two sequences. Across these independent claims, the inventive features focus on exact peptide identity and a defined therapeutic use for mucositis, colitis, bacterial infection, and acute radiation exposure.
Isolated peptide defined by SEQ ID NO. 91 or SEQ ID NO. 92
An isolated peptide comprising the amino acid SEQ ID NO. 91 or SEQ ID NO. 92 or a pharmaceutical salt, ester or amide thereof.
Isolated peptide with R(tBg)V1KR(tBg)V2 defined by tert-butyl glycine and an amide linkage
An isolated peptide consisting of the amino acid sequence of R(tBg)V1KR(tBg)V2, where tBg=tert-butyl glycine, wherein R(tBg)V2 is linked via an amide bond between V2 and the lysine amino group in the side chain (SEQ ID NO. 91).
Isolated peptide with RIV(mp2)A-NH2 defined by mp2 and carboxy-terminal NH2
An isolated peptide consisting of the amino acid sequence of RIV(mp2)A-NH2, wherein mp2=4-Amino-1-methyl-1H-pyrrole-2-carboxylic acid.
Method of treating bacterial infection, mucositis, colitis, or acute radiation exposure by administering SEQ ID NO. 91 or SEQ ID NO. 92
A method of treating an individual suffering from a disease selected from the group consisting of bacterial infection, mucositis and colitis or exposure to acute radiation comprising administering to the individual a peptide wherein the peptide comprises the amino acid sequence is SEQ ID NO. 91 or SEQ ID NO. 92.
Overall, the independent claims cover isolated peptides defined by SEQ ID NO. 91 or SEQ ID NO. 92, including specific modified-residue sequence structures, and a therapeutic method of administering these peptides to treat bacterial infection, mucositis, colitis, or exposure to acute radiation.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating oral mucositis and related mucosal/infectious complications associated with chemotherapy-induced mucositis and radiation-induced mucositis.
Treating DSS-induced colitis.
Treating bacterial infection and neutropenic infection in murine infection models, including Gram-positive and Gram-negative infections (including MRSA and Klebsiella).
Treating individuals exposed to acute radiation.
Combination utility with antibiotics such as vancomycin for treating infectious complications associated with the disclosed disease contexts.
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