Modulators of parathyroid hormone receptor (PTHR1)
Inventors
Mata-Fink, Jordi • Ngo, Le Phuong • GRIGORYAN, Gevorg • MacKenzie, Craig Owen • Hopson, Kristen Park
Assignees
Flagship Pioneering Inc • Flagship Pioneering Innovations VI Inc • Generate Biomedicines Inc
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Publication Number
US-12344649-B2
Publication Date
2025-07-01
Expiration Date
Abstract
The invention provides, inter alia, synthetic parathyroid hormones (sPTHs) that can modulate the activity of parathyroid hormone receptor, such as parathyroid hormone receptor 1 (PTHR1). The invention also provides methods of modulating PTHR activity using these sPTHs, e.g., in a cell, such as a cell in an organism.
Core Innovation
The invention relates to synthetic parathyroid hormone receptor (PTHR/PTHR1) modulators based on synthetic parathyroid hormones (sPTHs). The disclosed polypeptides specifically bind Parathyroid Hormone Receptor (PTHR), wherein the sPTH comprises an amino acid sequence selected from SEQ ID NOs: 102-106 and SEQ ID NOs: 132-155.
The disclosure provides a structural design space for sPTHs including 14- and 32-amino-acid variants with defined polar/charged residue constraints and allowed substitutions, supporting multiple functional classes of PTHR modulation. The disclosure further characterizes PTHR signaling modulation classes for sPTH polypeptides, including agonist, biased agonist, inverse agonist, and antagonist.
The disclosed signaling readouts include pathways and recruitment/activation assays such as Gs/cAMP/PKA, Gq/PLC/Ca2+/PKC, G12/13/RhoA, and β-arrestin/ERK1/2, with functional assays described using β-arrestin recruitment assays and cAMP accumulation assays. In addition to polypeptides, the disclosure provides downstream embodiments aligned with PTHR modulation, including fusion proteins, conjugates, polynucleotides, expression vectors, host cells, and pharmaceutical compositions.
The document describes intended treatment contexts including osteoporosis and calcium homeostasis disorders, and it reports experimental testing frameworks and example assay results for numerous SEQ ID NO peptides, including an ovariectomized rat osteoporosis model.
Claims Coverage
The independent claim set contains 1 independent claim. It includes an sPTH-based PTHR-binding polypeptide defined by specific SEQ ID NO sequence selections, with additional dependent claim refinements that introduce quantitative binding comparisons and functional activity limitations.
PTHR-binding polypeptide comprising sPTH from defined SEQ ID NO ranges
A polypeptide that specifically binds Parathyroid Hormone Receptor (PTHR), wherein the polypeptide comprises a synthetic parathyroid hormone (sPTH), wherein the sPTH comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 102-106 and SEQ ID NOs: 132-155.
Quantified binding affinity comparison to reference SEQ ID NOs
The polypeptide comprises an sPTH that binds to PTHR with an affinity at least about 5% higher than polypeptides having amino acid sequences corresponding to SEQ ID NOs 1-5.
sPTH defined as a PTHR agonist
The polypeptide comprises an sPTH that acts as an agonist of PTHR.
sPTH sequence length constraint
The polypeptide comprises an sPTH that consists of 28-36 amino acids.
Across the claim coverage provided, the core scope is a PTHR-binding polypeptide defined by sPTH sequence selection from SEQ ID NOs 102-106 and 132-155, with further narrowing by sPTH length and agonist activity, and with quantitative binding affinity comparisons to reference sequences.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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