Modified relaxin polypeptides and their uses
Inventors
Kraynov, Vadim • Knudsen, Nick • HEWET, Amha • DE DIOS, Kristine • PINKSTAFF, Jason • SULLIVAN, Lorraine
Assignees
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Publication Number
US-11786578-B2
Publication Date
2023-10-17
Expiration Date
Abstract
Modified relaxin polypeptides and their uses thereof are provided. Exemplary embodiments provide relaxin polypeptides which include one or more amino acid substitutions with natural or non-naturally encoded amino acids, and/or linkage to a water-soluble polymer, such as polyethylene glycol. Additionally, use of said relaxin polypeptides for treatment of disease, such as heart failure, is also provided.
Core Innovation
The invention relates to biologically active modified relaxin polypeptides comprising a relaxin A chain polypeptide and a relaxin B chain polypeptide, where the relaxin A chain polypeptide has a sequence at least 95% identical to SEQ ID NO: 4 and the relaxin B chain polypeptide has a sequence at least 95% identical to SEQ ID NO: 6. A non-naturally encoded amino acid is substituted in the A chain polypeptide at residue 1, and the modified relaxin polypeptide further comprises a non-naturally encoded amino acid linked to a linker or polymer.
The linkage is formed by reaction of a first functional group and a second functional group that are not identical and each comprise a carbonyl group, an aminooxy group, a hydrazide group, a hydrazine group, a semicarbazide group, an azide group, or an alkyne group. The resultant covalent linkage comprises a triazole or an oxime linkage, and the disclosed framework includes PEGylation and other polymer:protein conjugates.
The patent describes biologically active modified relaxin polypeptides for intravenous or subcutaneous administration to a human subject in need thereof. The modified relaxin polypeptide comprises a relaxin A chain polypeptide and a relaxin B chain polypeptide, and the patent further describes serum half-life extension strategies for relaxin by linking the modified relaxin polypeptide to linker or polymer components, including poly(ethylene glycol) and albumin fusion proteins or albumin-binding domains.
Claims Coverage
The consolidated independent claim coverage centers on three inventive features: a modified relaxin polypeptide with defined A and B chain sequence identity and a residue-1 non-naturally encoded amino acid substitution, covalent linkage of that non-naturally encoded amino acid to a linker or polymer to form a triazole or an oxime linkage, and pharmaceutical compositions for intravenous or subcutaneous administration, including heart failure treatment embodiments.
Modified relaxin polypeptide with defined sequence identity and residue-1 substitution
A biologically active modified relaxin polypeptide comprising a relaxin A chain polypeptide and a relaxin B chain polypeptide, wherein the relaxin A chain polypeptide has a sequence at least 95% identical to SEQ ID NO: 4 and the relaxin B chain polypeptide has a sequence at least 95% identical to SEQ ID NO: 6, and the non-naturally encoded amino acid is substituted in the A chain polypeptide at residue 1.
Covalent linkage to linker or polymer yielding triazole or oxime
The non-naturally encoded amino acid is linked to a linker or polymer, wherein the non-naturally encoded amino acid comprises a first functional group and the linker or polymer comprises a second functional group, the first and second functional groups are not identical and each comprise a carbonyl group, an aminooxy group, a hydrazide group, a hydrazine group, a semicarbazide group, an azide group, or an alkyne group, and the resultant covalent linkage created by the reaction comprises a triazole or an oxime linkage.
Intravenous or subcutaneous pharmaceutical composition with carrier or excipient
A composition for intravenous or subcutaneous administration to a human subject in need thereof, comprising the biologically active modified relaxin polypeptide and a pharmaceutically acceptable carrier and/or excipient.
Heart failure treatment composition
A composition for intravenous or subcutaneous administration for treating heart failure in a human subject in need thereof, comprising the biologically active modified relaxin polypeptide and a pharmaceutically acceptable carrier and/or excipient.
The claims collectively cover pharmaceutical compositions for intravenous or subcutaneous administration containing a biologically active modified relaxin polypeptide with defined relaxin A and B chain sequence identity, a residue-1 non-naturally encoded amino acid substitution, and covalent attachment to a linker or polymer through a triazole or oxime linkage, including embodiments directed to treating heart failure.
Stated Advantages
Retains relaxin receptor activation and anti-fibrotic activity.
Greatly increased in vivo half-life.
Increased in vivo half-life by at least 2-fold relative to the human relaxin polypeptides of SEQ ID NO: 4 and SEQ ID NO: 5.
Selective protein modification.
Site-specific labeling.
Photocrosslinking.
X-ray phasing.
Cycloaddition reactivity.
Modulated immunogenicity.
Extends serum half-life of relaxin.
Documented Applications
Treating heart failure in a human subject via intravenous or subcutaneous administration.
Fibrotic disorders, including cardiac fibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, coronary fibrosis, bone marrow fibrosis, dermatological fibrosis, and a fibrotic eye disorder.
Anti-fibrotic activity.
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