Compositions containing a pharmacophore with selectivity to diseased tissue and methods of making same
Inventors
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Assignees
Sanford Burnham Prebys Medical Discovery Institute • Vascular Biosciences Inc
Member
Vascular BioSciencesVascular BioSciences is a biopharmaceutical and medical device company focused on developing targeted therapeutics, minimally invasive interventional devices, and advanced molecular diagnostics for cardiovascular, pulmonary, and inflammatory diseases. The company leverages targeted peptide drug delivery, endovascular tissue sampling, molecular profiling, and bioinformatics to advance personalized medicine for difficult-to-treat diseases. Its operations span California and North Carolina with expertise in biologics, device engineering, and translational research.
Vascular BioSciences is a biopharmaceutical and medical device company focused on developing targeted therapeutics, minimally invasive interventional devices, and advanced molecular diagnostics for cardiovascular, pulmonary, and inflammatory diseases. The company leverages targeted peptide drug delivery, endovascular tissue sampling, molecular profiling, and bioinformatics to advance personalized medicine for difficult-to-treat diseases. Its operations span California and North Carolina with expertise in biologics, device engineering, and translational research.
Publication Number
US-11642391-B2
Publication Date
2023-05-09
Expiration Date
Abstract
Compositions and methods useful for delivery of targeted therapies for pulmonary arterial hypertension, sepsis, cancer and cachexia. The compositions and methods are based on peptide pharmacophores that selectively bind to and home to diseased tissue and enable targeted therapies to affect a beneficial therapeutic result. Peptide pharmacophores may selectively target tumor vasculature, regenerating tissue, wounded tissue, inflamed tissue, fibrotic tissue, remodeled tissue, tissue characterized by elevated heparanase levels, and have the ability to internalize into such diseased cells.
Core Innovation
The invention relates to a “CAR pharmacophore” comprising cyclic, linear, or truncated peptides, including peptides containing SEQ ID NO:1, SEQ ID NO:12, and SEQ ID NO:24, and variants including SEQ ID NOs:2–8 and SEQ ID NOs:16–33. The CAR pharmacophore selectively homes to diseased tissue and internalizes into diseased cells, and the targeting behavior is attributed to disease-associated alterations such as heparanase-mediated glycocalyx remodeling.
The core concept is that the conserved CAR pharmacophore is identified and defined through cell binding and internalization assays and in silico superimposition modeling. This enables broad composition scope for peptide/protein variants and cyclized forms, including conservative and unconservative substitutions, while maintaining the disease-homing and internalization characteristics.
The disclosure further provides conjugate scope in which the CAR pharmacophore is used with therapeutic or diagnostic payloads, including examples with human serum albumin (HSA) and other conjugates. The approach is presented as providing enhanced therapeutic targeting and efficacy across multiple disease contexts, including sepsis and kidney injury/chronic kidney disease targeting, cancer cachexia and tumor efficacy when combined with paclitaxel, and potentiation of imatinib in monocrotaline-induced pulmonary arterial hypertension.
Claims Coverage
The provided independent claim covers a pharmacophore defined by a peptide sequence set (SEQ ID NOs: 2–8) for administration to an individual suffering from a disease. The independent claim is narrowed by a dependent claim to specific disease categories, including pulmonary arterial hypertension, sepsis, kidney disease, cancer, or cachexia.
Disease-administered CAR pharmacophore defined by SEQ ID NOs 2-8
A pharmacophore for administration to an individual suffering from a disease, wherein the pharmacophore comprises a peptide comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 2-8.
Treatment of selected diseases including pulmonary arterial hypertension, sepsis, kidney disease, cancer, or cachexia
The pharmacophore is for treating a disease selected from pulmonary arterial hypertension, sepsis, kidney disease, cancer, or cachexia.
Across the independent and dependent claim coverage, the claim centers on a CAR pharmacophore whose composition is defined by peptide sequences from SEQ ID NOs 2–8, and whose intended use is directed to treatment of selected diseases including pulmonary arterial hypertension, sepsis, kidney disease, cancer, or cachexia.
Stated Advantages
Selective homing to diseased tissue and internalization into diseased cells.
Enhanced therapeutic targeting and efficacy in sepsis, including improved survival when co-administered with sivelestat, ATIII, or hydrocortisone, and also improved survival as a stand-alone.
Enhanced targeting in kidney injury/chronic kidney disease contexts, including association with acute kidney injury marker KIM-1.
Enhanced cancer-related efficacy in cancer cachexia and tumor efficacy when combined with paclitaxel.
Potentiation of imatinib in monocrotaline-induced pulmonary arterial hypertension, with associated improvements in right-heart hypertrophy, pulmonary muscularization, and bodyweight.
Documented Applications
Sepsis, including LPS-induced mouse sepsis.
Kidney injury and chronic kidney disease targeting, associated with acute kidney injury marker KIM-1.
Cancer cachexia and tumor efficacy, including triple-negative breast cancer (MDA-MB-231) with paclitaxel.
Pulmonary arterial hypertension, including monocrotaline-induced pulmonary arterial hypertension with imatinib and associated improvements including right-heart hypertrophy and pulmonary muscularization.
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