Relaxin polypeptides comprising non-naturally encoded amino acids

Abstract

Modified relaxin polypeptides and their uses are provided. In one aspect, the disclosure provides a relaxin polypeptide comprising one or more non-naturally encoded amino acids. The polypeptide may be linked to a linker, polymer, or biologically active molecule. The serum half-life of the relaxin polypeptide may be enhanced relative to the unconjugated form. In another aspect, the disclosure provides methods of treating a patient having a disorder modulated by relaxin.

Description

FIELD OF THE INVENTION[0001]This invention relates to relaxin polypeptides optionally modified with at least one non-naturally encoded amino acid.SEQUENCE LISTING[0002]This application includes a sequence listing which has been submitted via EFS-Web in a file named “AMBX017400US.txt” created on Oct. 18, 2012 and having a size of 50,180 bytes, which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0003]Mature human relaxin is a hormonal peptide of approximately 6000 daltons known to be responsible for remodelling the reproductive tract before parturition, thus facilitating the birth process. This protein appears to modulate the restructuring of connective tissues in target organs to obtain the required changes in organ structure during pregnancy and parturition. See, Hisaw, F. L., Proc. Soc. Exp. Biol. Med., 23: 661-663 (1926); Schwabe, C., et al., Biochem. Biophys. Res. Comm, 75: 503-570 (1977); James, R. et al., Nature, 267: 544-546 (1977). A concise ...

AI Technical Summary

Benefits of technology

[0049]In an additional embodiment of the present invention, it is possible to use the technology disclosed herein for the production of relaxin analogs with increased pharmacokinetic and pharacodynamic properties for patient use via administration to the lung, resulting in elevated blood levels of relaxin that are sustained for at least 6 hours, and more typically for at least 8, 10, 12, 14, 18, 24 hours or greater post-administration. Another embodiment of the present invention allows for advantageous mixtures of relaxin analogs suitable for therapeutic formulations designed to be administered to patients as an inhalant.

[0090]The present invention also provides methods of increasing therapeutic half-life, serum half-life or circulation time of relaxin polypeptides. The present invention also provides methods of modulating immunogenicity of relaxin polypeptides. In some embodiments, the methods comprise substituting a non-naturally encoded amino acid for any one or more amino acids in naturally occurring relaxin polypeptides and / or linking the relaxin polypeptide to a linker, a polymer, a water soluble polymer, or a biologically active molecule.

Problems solved by technology

Decreases in pumping ability arise most often from loss or damage of myocardial tissue.

As a result, ventricular emptying is suppressed which leads to an increase in ventricular filling pressure and ventricular wall stress, and to a decrease in cardiac output.

Although these reflex responses tend to enhance cardiac output initially, they are detrimental in the long term.

These changes, together with the increased sympathetic stimulation of the heart, lead to further and often decompensating demands on the remaining functional myocardium.

Congestive heart failure, which is a common end point for many cardiovascular disorders, results when the heart is unable to adequately perfuse the peripheral tissues.

Current therapy therefore depends on balancing the effects of multiple drugs to achieve the clinical needs of individual patients, and is plagued by adverse reactions to the drugs used.

For example, diuretics decrease plasma concentrations of potassium and magnesium and increase the incidence of arrhythmias in patients receiving digitalis.

Alpha adrenergic antagonists can lead to marked falls in systemic arterial pressure that compromise coronary perfusion.

Angiotensin converting enzyme inhibitors can have similar effects on arterial pressure and additionally lead to excessive increases in plasma concentrations of potassium.

Drugs that lead to positive inotropy, such as digitalis and beta adrenergic antagonists, have the potential to provoke arrhythmias.

In addition, digitalis has a narrow therapeutic index and the catecholamine analogs all tend to loose their effectiveness rapidly, due to receptor downregulation.

Scleroderma is a disease involving an imbalance in tissue reformation giving rise to the overproduction of collagen, and ultimately resulting in swelling and hardening of the skin (and affected organs).