Molecular degraders of extracellular proteins
Inventors
Caianiello, David • DERAMON, Edward • Spiegel, David
Assignees
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Publication Number
US-12234256-B2
Publication Date
2025-02-25
Expiration Date
2042-08-26
Abstract
The disclosure describes compounds of Formula Ia, which in non-limiting aspects contain an asialoglycoprotein receptor (ASGPR) binding moiety and an anti-β1AR binding moiety. Compounds of Formula Ia are useful in preventing, treating, and/or ameliorating heart failure in a subject when administered in therapeutically effective amounts.
Core Innovation
The invention provides compounds of Formula Ia, which consist of an asialoglycoprotein receptor (ASGPR) binding moiety linked to an anti-β1AR binding moiety. These compounds are structured to possess at least 80% homology to a defined amino acid sequence (SEQ ID NO: 1) and optionally include specific structural features in their linker, carbohydrate units, and ring systems, enhancing binding specificity.
This invention addresses the need for more selective and rapidly active treatments for dilated cardiomyopathy (DCM) and heart failure. Pathogenic anti-β1ECII (the second extracellular loop of the β1 adrenergic receptor) autoantibodies have been shown to induce DCM and other forms of heart failure, and removal or neutralization of these antibodies can alleviate disease. Existing treatments like β1-AR blockers and whole IgG depletion can result in undesirable side effects such as fatigue, dizziness, poor circulation, gastrointestinal symptoms, and sexual dysfunction.
By employing a bifunctional molecule that binds both anti-β1AR antibodies and the ASGPR on hepatocytes, the invention enables selective endocytosis and degradation of the pathogenic antibodies. As described, the compound forms a ternary complex with the antibody and ASGPR on hepatocytes, leading to endocytosis and subsequent degradation of the harmful autoantibodies, while the ASGPR and bifunctional molecule are recycled. This process provides a means to prevent, treat, or ameliorate heart failure in a subject by efficiently targeting specific extracellular pathogenic proteins.
Claims Coverage
The patent includes two independent claims: one covering the novel compound of Formula Ia and one covering the method of treating heart failure using the compound. Each claim contains core inventive features.
Novel ASGPR- and anti-β1AR-binding compound of Formula Ia
A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, comprises: - An asialoglycoprotein receptor (ASGPR) binding moiety. - An anti-β1AR binding moiety containing an amino acid sequence at least 80% homologous to SEQ ID NO: 1 (DEARRCYNDPKCSDFVQ). - A specific molecular scaffold and linkers as defined, including options for different chemical configurations (such as ring A and various substituents). - The compound optionally includes particular structures for carbohydrate units, peptide cycles, and linkers, allowing precise customization as outlined in detailed formulae. This design enables bifunctional binding, targeting both the ASGPR on hepatocytes and anti-β1AR antibodies.
Method for ameliorating heart failure using the compound of Formula Ia
A method of ameliorating heart failure in a subject in need thereof by: 1. Administering a therapeutically effective amount of a compound of Formula Ia (as described in the compound claim). 2. The method includes administration by various possible routes, including but not limited to oral, intravenous, transdermal, transmucosal, and more, as covered in dependent claims. 3. The subject is a mammal, optionally a human. The method is explicitly applicable to heart failure, including dilated cardiomyopathy (DCM). Administration dosage is included within a specified range, and compositions may include a pharmaceutically acceptable carrier.
In summary, the claims protect a specifically designed bifunctional molecule for targeted removal of pathogenic anti-β1AR antibodies and the broad method of using this molecule to treat heart failure, including specific structural and usage details.
Stated Advantages
The compounds provide a more selective and rapidly active treatment for dilated cardiomyopathy and related heart failure, addressing shortcomings of existing therapies.
Use of the compounds enables targeted removal of pathogenic anti-β1AR antibodies, potentially reducing undesirable side effects associated with non-specific treatments such as β1-AR blockers and whole IgG depletion.
The compounds can be combined with existing heart failure therapies, which may allow lowering doses and subsequently reducing side effects of those therapies.
Documented Applications
Prevention, treatment, and/or amelioration of heart failure in a subject, including but not limited to dilated cardiomyopathy.
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