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-11311598-B2
Publication Date
2022-04-26
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) peptides for treating conditions associated with radiation or chemotherapy, including oral mucositis and acute radiation syndrome (ARS). In particular, the description focuses on an IDR peptide comprising SEQ ID NO: 5 (RIVPA) and also addresses IDR peptides defined by an amino acid sequence motif (SEQ ID NO: 56) with specified X1, X2, X3 and P positions, including pharmaceutical salts, esters, or amides.
The problem being solved is radiation- and chemotherapy-associated tissue injury and infection risk, including oral mucositis caused by chemotherapy or fractionated radiation and complications of acute radiation syndrome. The described rationale links innate immune modulation by the IDR peptides to reduced inflammatory cascade effects associated with PAMPs and DAMPs and signaling through Toll-like receptors (TLRs).
The description reports preclinical evidence in mouse and hamster models showing that dosing every third day covers the mucositis window and that RIVPA improves outcomes across mucositis, colitis, neutropenic infections, and skin injury. Reported infection outcomes include reductions relevant to Gram-positive and Gram-negative bacteria, including MRSA, and supporting nonclinical and early human safety, pharmacokinetics, and pharmacodynamics data are also described.
Claims Coverage
The partial content identifies one independent claim directed to treating infection in an individual suffering from acute radiation syndrome using an effective amount of a specified short IDR peptide or a peptide comprising SEQ ID NO: 5, including pharmaceutically acceptable salts and formulations. The claim coverage is structured around two alternative peptide definitions.
Treating acute radiation syndrome infection with IDR peptides
A method of treating an infection in an individual suffering from Acute Radiation Syndrome by administering an effective amount of either a peptide comprising an amino acid sequence of up to 7 amino acids with the amino acid sequence X1 X2 X3 P (SEQ ID NO: 56) having X1=R; X2 is I or V wherein X2 can be N-methylated; X3 is I or V wherein X3 can be N-methylated; P is proline or a proline analogue, where SEQ ID NO: 56 is the first four amino acids at the N-terminus of the peptide, or a pharmaceutical salt, ester or amide thereof and a pharmaceutically-acceptable carrier, diluent, or excipient; or a peptide comprising the amino acid sequence of SEQ ID NO: 5 or a pharmaceutical salt, ester or amide thereof and a pharmaceutically-acceptable carrier, diluent or excipient.
The claim coverage centers on administering an effective amount of an IDR peptide for infection associated with acute radiation syndrome, using either a defined SEQ ID NO: 56 motif peptide or a peptide comprising SEQ ID NO: 5, each in pharmaceutically acceptable forms and carriers.
Stated Advantages
Improves outcomes in oral mucositis associated with chemotherapy and/or fractionated radiation.
Mitigates complications associated with acute radiation syndrome, including infection burden.
Reduces inflammatory cascade effects associated with PAMPs and DAMPs through innate immune modulation.
Improves outcomes across mucositis, colitis, neutropenic infections, and skin injury.
Describes a safety and tolerability profile with no DLTs in the cited Phase 1 context and observes anti-inflammatory status changes in cytokine/chemokine ex vivo assays.
Documented Applications
Treating oral mucositis caused by chemotherapy or fractionated radiation.
Treating infection in an individual suffering from Acute Radiation Syndrome.
Mitigating acute radiation syndrome (ARS) and reducing infection burden.
Improving outcomes in GI mucositis and related inflammatory injury contexts described as mucositis across models.
Addressing colitis associated with the described radiation/immune injury setting.
Managing neutropenic infections, including MRSA and other Gram-positive/Gram-negative bacteria, in the described model contexts.
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