IP Library › Granted Patent US 9,382,304
Granted Patent B2
US 9,382,304 · App. 14/129,815 · Granted Jul 5, 2016

Engineered polypeptides having enhanced duration of action with reduced immunogenicity

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Quick Facts
Patent No.
US 9,382,304
App. No.
14/129,815
Granted
Jul 5, 2016
Kind
B2
Abstract

Compounds are provided having inter alia good duration of action, high potency and/or convenient dosing regimens including oral administration, and reduced immunogenicity. The compounds are engineered polypeptides which incorporate an albumin binding domain in combination with one or more biologically active polypeptides. Also provided are pharmaceutical compositions and methods of treatment for diseases and disorders including obesity and overweight, diabetes, dyslipidemia, hyperlipidemia, Alzheimer's disease, fatty liver disease, Short Bowel Syndrome, Parkinson's disease, and cardiovascular disease.

Claims (97)

1. An engineered polypeptide comprising:

an albumin binding domain polypeptide (ABD), and

a first peptide hormone domain (HD1) comprising an exendin sequence, an exendin analog sequence or an active fragment sequence thereof,

wherein said ABD comprises at least 95% identity to SEQ ID NO:300, with the proviso that X 7 is not L, E or D; or alternatively, with the proviso that the amino acid sequence is not SEQ ID NO:679.

2. The engineered polypeptide according to claim 1 , further comprising a first linker (L1) covalently linking said HD1 and said ABD.

3. The engineered polypeptide according to claim 1 , wherein said HD1 is exendin-4(1-28) (SEQ ID NO: 980), exendin-4(1-29) (SEQ ID NO: 981), exendin-4(1-30) (SEQ ID NO: 680), exendin-4(1-31) (SEQ ID NO: 982) or exendin-4(1-32) (SEQ ID NO: 983).

4. The engineered polypeptide according to claim 1 , wherein said HD1 is selected from the group of sequences consisting of:

(SEQ ID NO: 2)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS,

(SEQ ID NO: 3)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPS,

(SEQ ID NO: 4)

HGEGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKEIIS,

(SEQ ID NO: 2)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS,

(SEQ ID NO: 111)

HGEGTFTSDLSKQMEEEAVRLFIEWLKQGGPSKEIIS,

(SEQ ID NO: 112)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPS,

(SEQ ID NO: 113)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPS,

(SEQ ID NO: 114)

HGEGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKEIISKKKKKK,

(SEQ ID NO: 115)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSKKKKKK,

(SEQ ID NO: 116)

HGEGTFTSDLSKQMEEEAVRLFIEWLKQGGPSKEIISKKKKKK,

(SEQ ID NO: 117)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK

and

(SEQ ID NO: 118)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK.

5. The engineered polypeptide according to claim 1 , wherein the ABD is selected from the group consisting of: SEQ ID NOs: 301-463, 500-502, and 862-950.

6. The engineered polypeptide according to claim 1 , having affinity for serum albumin with a dissociation constant less than about 10 −6 mol/L.

7. The engineered polypeptide according to claim 1 , wherein the engineered polypeptide is selected from the group consisting of:

(SEQ ID NO: 727)

HGEGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKEIISTGGGGSASGSLAEAKEAANAELD

SYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;

(SEQ ID NO: 728)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPKSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;

(SEQ ID NO: 729)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;

(SEQ ID NO: 730)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;

(SEQ ID NO: 731)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAANAELDSYGV

SDFYKRLIDKAKTVEGVEALKDAILAALP;

(SEQ ID NO: 732)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;

(SEQ ID NO: 733)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAANAELDSYGV

SDFYKRLIDKAKTVEGVEALKDAILAALP;

(SEQ ID NO: 734)

HGEGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKEIISTGGGGSASGSLAEAKEAANAELD

SYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;

(SEQ ID NO: 735)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPKSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;

(SEQ ID NO: 736)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;

(SEQ ID NO: 737)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;

(SEQ ID NO: 738)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAANAELDSYGV

SDFYKRLIDKAKTVEGVEALKDAILAAL;

(SEQ ID NO: 739)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAANAELDSYGV

SDFYKRLIDKAKTVEGVEALKDAILAAL;

(SEQ ID NO: 740)

HGEGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKEIISTGGGGSASGSLAEAKEAANAELD

SYGVSDFYKRLIDKAKTVEGVEALKDAILAA;

(SEQ ID NO: 741)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPKSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;

(SEQ ID NO: 742)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;

(SEQ ID NO: 743)

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAANAELDSYGV

SDFYKRLIDKAKTVEGVEALKDAILAA;

(SEQ ID NO: 744)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSLAEAKEAANA

ELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;

and

(SEQ ID NO: 745)

HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAANAELDSYGV

SDFYKRLIDKAKTVEGVEALKDAILAA.

8. A polynucleotide encoding an engineered polypeptide according to claim 1 .

9. An expression vector comprising a polynucleotide according to claim 8 .

10. A host cell comprising an expression vector according to claim 9 .

11. A method of producing the engineered polypeptide of claim 1 , the method comprising expressing a polynucleotide encoding the engineered polypeptide or synthesizing the polypeptide by non-biological peptide synthesis.