Co-administration of an agent linked to an internalization peptide with an anti-inflammatory
Inventors
Tymianski, Michael • Garman, Jonathan David • Cui, Hong
Assignees
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Publication Number
US-8933013-B2
Publication Date
2015-01-13
Expiration Date
Abstract
The invention provides methods of delivering pharmacologic agents linked to an internalization peptide, in which an inflammatory response inducible by the internalization peptide is inhibited by co-administration of an anti-inflammatory or by linking the internalization peptide to biotin or similar molecule. Such methods are premised in part on the results described in the examples whereby administration of a pharmacological agent linked to tat at high dosages is closely followed by an inflammatory response, which includes mast cell degranulation, histamine release and the typical sequelae of histamine release, such as redness, heat, swelling, and hypotension.
Core Innovation
The patent addresses delivering a pharmacological agent linked to an internalization peptide comprising RKKRRQRRR (SEQ ID NO:51) to a subject having or at risk of a disease treatable by the pharmacological agent. The internalization peptide induces mast cell degranulation, which leads to an inflammatory response within 60 minutes of administering the pharmacologic agent linked to the internalization peptide.
To reduce this mast cell degranulation-induced inflammatory response, the patent discloses administering a mast cell degranulation inhibitor and/or an anti-histamine in connection with administration of the peptide-linked pharmacologic agent. The disclosure also describes embodiments in which an anti-inflammatory agent inhibits an inflammatory response from mast cell degranulation induced by the internalization peptide.
The document further states that reducing inflammatory potential may be achieved by conjugating the internalization peptide to biotin or similar molecules, and it provides stroke/excitotoxicity context involving PSD-95/NR2B2B-binding inhibitory peptides linked to Tat together with mast cell inhibitors and/or anti-histamines.
Claims Coverage
The document includes two independent claims. Both focus on delivering a pharmacologic agent linked to an internalization peptide comprising RKKRRQRRR (SEQ ID NO:51) while co-administering an agent that inhibits mast cell degranulation-induced inflammatory response within 60 minutes; the second independent claim frames the co-administered agent more generally as an anti-inflammatory agent.
Timed co-administration to reduce mast cell degranulation inflammation from RKKRRQRRR-linked agents
Administering a pharmacological agent linked to an internalization peptide comprising RKKRRQRRR (SEQ ID NO:51) to a subject treatable by the pharmacological agent, and administering a mast cell degranulation inhibitor and/or an anti-histamine thereby reducing an inflammatory response due to mast cell degranulation induced by the internalization peptide, wherein the inflammatory response occurs within 60 minutes of administering the pharmacologic agent linked to the internalization peptide.
Anti-inflammatory inhibition of mast cell degranulation inflammatory response from RKKRRQRRR-linked agents
Administering the pharmacologic agent linked to an internalization peptide having an amino acid sequence comprising RKKRRQRRR (SEQ ID NO:51) to the subject; and administering an anti-inflammatory agent whereby the anti-inflammatory agent inhibits an inflammatory response from mast cell degranulation induced by the internalization peptide, wherein the inflammatory response occurs within 60 minutes of administering the pharmacologic agent linked to the internalization peptide.
Across both independent claims, the core inventive theme is pairing delivery of an RKKRRQRRR (SEQ ID NO:51)-linked pharmacologic agent with an agent that inhibits the mast cell degranulation-induced inflammatory response occurring within 60 minutes after administration.
Stated Advantages
Reducing an inflammatory response due to mast cell degranulation induced by the internalization peptide.
Inhibiting an inflammatory response from mast cell degranulation induced by the internalization peptide.
Documented Applications
Stroke/excitotoxicity context involving combinations of PSD-95/NR2B2B-binding inhibitory peptides linked to Tat with mast cell inhibitors and/or anti-histamines.
Endovascular surgery timing window context referenced in relation to the Tat-linked delivery approach and inflammatory timing constraints.
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