Long-acting polypeptides and methods of producing same
Inventors
Assignees
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Publication Number
US-10030060-B2
Publication Date
2018-07-24
Expiration Date
Abstract
A polypeptide and polynucleotides encoding same comprising one carboxy-terminal peptide (CTP) of chorionic gonadotrophin attached to an amino terminus of a cytokine and two carboxy-terminal peptides (CTP) of chorionic gonadotrophin attached to a carboxy terminus of a cytokine are disclosed. Pharmaceutical compositions comprising the polypeptide and polynucleotides of the invention and methods of using same are also disclosed.
Core Innovation
The invention relates to polypeptides comprising an interferon and chorionic gonadotropin carboxy terminal peptide (CTP) moieties. A first CTP is attached to the amino terminus of the interferon, and a second and a third CTP are attached to the carboxy terminus of the interferon in tandem, with the third CTP attached in tandem to the second CTP. Optional signal peptide inclusion is described.
The document further characterizes the interferon-CTP polypeptides by stating that the CTP amino acid sequences can be selected from named SEQ ID NOs, and that at least one of the CTPs can be truncated. The disclosure also describes glycosylation options, including glycosylation of the interferon and/or the chorionic gonadotropin carboxy terminal peptides.
The CTP unit is described as functioning as a protectant against degradation and clearance, thereby increasing pharmacokinetic parameters and extending duration in vivo. The described effects include increases in Cmax/Tmax and biological half-life, and the ability to enhance in vivo potency while maintaining receptor binding.
Claims Coverage
The partial claim set includes two independent claims. Across the independent claims, there are two inventive features centered on positional attachment of CTPs to interferon termini and on extending interferon biological half-life by attaching two or three CTPs with defined positional rules.
Interferon polypeptide with amino-terminus CTP and tandem carboxy-terminus CTPs
A polypeptide consisting of an interferon and optionally a signal peptide, wherein a first chorionic gonadotropin carboxy terminal peptide is attached to the amino terminus of said interferon, and a second and third chorionic gonadotropin carboxy terminal peptide are attached to the carboxy terminus of said interferon, wherein said third chorionic gonadotropin carboxy terminal peptide is attached in tandem to said second chorionic gonadotropin carboxy terminal peptide.
Extending interferon biological half-life by attaching two or three CTPs
A method of extending the biological half-life of an interferon, comprising attaching two or three chorionic gonadotropin carboxy terminal peptides to said interferon, wherein a first chorionic gonadotropin carboxy terminal peptide is attached to an amino terminus of said interferon, and either only a second chorionic gonadotropin carboxy terminal peptide is attached to the carboxy terminus of said interferon or two chorionic gonadotropin carboxy terminal peptides are attached to a carboxy terminus of said interferon, thereby extending the biological half-life of said interferon.
Across the independent claims, the document covers interferon polypeptides where CTPs are attached to specific interferon termini, including tandem attachment of the third CTP to the second at the carboxy terminus, and it covers extending interferon biological half-life by attaching two or three CTPs with one at the amino terminus and either one or two at the carboxy terminus.
Stated Advantages
CTP is described as acting as a protectant against degradation and clearance.
The engineered polypeptides are described as increasing Cmax/Tmax.
The engineered polypeptides are described as increasing biological half-life.
The disclosure states that potency can be enhanced in vivo while maintaining receptor binding.
Extending the biological half-life of an interferon.
Documented Applications
Therapeutic use rationales are described for anemia for EPO and for multiple sclerosis and viral/cancer/inflammatory diseases for interferons, along with metabolic and growth effects for hGH/GLP-1.
Example data are described for engineered EPO-CTP variants using TF-1 potency via MTT assay and in vivo mouse hematocrit/reticulocyte responses, including once-weekly dosing durability.
Extending the biological half-life of an interferon (as the stated purpose of the method claim).
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