TRANSMUCOSAL DELIVERY OF ENGINEERED POLYPEPTIDES
Formulations are provided that comprise compounds having inter alia good duration of action, high potency and/or convenient dosing regimens, and a permeation enhancer for transmucosal administration. The compounds are engineered polypeptides which incorporate an albumin binding domain in combination with one or more biologically active polypeptides. The pharmaceutical compositions provided are suitable for 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, cardiovascular disease, and other and disorders of the central nervous system.
1 . A pharmaceutical composition comprising (a) an engineered polypeptide comprising an Albumin Binding Domain polypeptide (ABD) sequence, and a first peptide hormone domain (HD1) sequence selected from an exendin sequence, an exendin analog sequence, an exendin active fragment sequence or an exendin analog active fragment sequence, and (b) a mucosal permeation enhancer, with the proviso that the composition does not comprise a Phosphate Buffered Saline comprising propylene glycol (50:50 v/v).
2 . The composition according to claim 1 , where the engineered polypeptide further comprises a first linker (L1) covalently linking said ABD sequence and said HD1 sequence.
3 . The composition according to claim 1 , wherein said engineered polypeptide comprises said ABD sequence as a C-terminal moiety and said HD1 sequence as an N-terminal moiety.
4 - 5 . (canceled)
6 . The composition according to claim 1 , wherein said HD1 sequence is said exendin sequence or said exendin analog sequence.
7 - 13 . (canceled)
14 . The composition according to claim 1 , wherein said exendin analog sequence comprises from 1 to 5 amino acid modifications relative to exendin-4 sequence, said modifications independently selected from any one or combination of an insertion, deletion, addition and substitution.
15 . The composition according to claim 1 , wherein said ABD sequence comprises an Albumin Binding Motif (ABM) sequence, an ABD1 sequence or an ABD2 sequence.
16 - 33 . (canceled)
34 . The composition according to claim 1 , wherein said ABD sequence comprises an amino acid sequence selected from the amino acid sequence comprising:
formula (iii)
(SEQ ID NO: 594)
LA X3 AK X6 X7 AN X10 ELD X14 YGVSDF YKRLIDKAKT V
EGVEALKDA ILAALP
wherein independently of each other
X3 is selected from E, S, Q and C;
X6 is selected from E, S and C;
X7 is selected from A and S;
X10 is selected from A, S and R;
X14 is selected from A, S, C and K;
the leucine at position 45 is present or absent; and
the proline at position 46 is present or absent;
formula (iv) an amino acid sequence which has at least 95% identity to the sequence defined in (iii),
with the proviso that X7 is not L, E or D;
or alternatively,
with the proviso that the amino acid sequence is not defined by the following sequence:
(SEQ ID NO: 593)
LAEAK Xa Xb A Xc Xd EL Xe KY GVSD X5 YK X8 X9 I
X11 X12 A X14 TVEGV X20 AL X23 X24 X25 ILAALP
wherein independently of each other,
Xa is selected from V and E;
Xb is selected from L, E and D;
Xc is selected from N, L and I;
Xd is selected from R and K;
Xe is selected from D and K;
X5 is selected from Y and F;
X8 is selected from N, R and S;
X9 is selected from V, I, L, M, F and Y;
X11 is selected from N, S, E and D;
X12 is selected from R, K and N;
X14 is selected from K and R;
X20 is selected from D, N, Q, E, H, S, R and K;
X23 is selected from K, I and T;
X24 is selected from A, S, T, G, H, L and D; and
X25 is selected from H, E and D.
35 . The composition according to claim 15 , wherein said ABD sequence comprises an amino acid sequence comprising:
formula (iii)
(SEQ ID NO: 594)
LA X3 AK X6 X7 AN X10 ELD X14 YGVSDF YKRLIDKAKT
VEGVEALKDA ILAALP
wherein independently of each other
X3 is selected from E, S, Q and C;
X6 is selected from E, S and C;
X7 is selected from A and S;
X10 is selected from A, S and R;
X14 is selected from A, S, C and K;
the leucine at position 45 is present or absent; and
the proline at position 46 is present or absent.
36 . The composition according to claim 15 , wherein said ABD sequence comprises an amino acid sequence comprising formula (iv) or an amino acid sequence which has at least 95% identity to the sequence defined in (iii), with the proviso that X7 is not L, E or D; or alternatively, with the proviso that the amino acid sequence is not defined by the following sequence:
(SEQ ID NO: 593)
LAEAK Xa Xb A Xc Xd EL Xe KY GVSD X5 YK X8 X9 I
X11 X12 A X14 TVEGV X20 AL X23 X24 X25 ILAALP
wherein independently of each other, Xa is selected from V and E; Xb is selected from L, E and D; Xc is selected from N, L and I; Xd is selected from R and K; Xe is selected from D and K; and X5 is selected from Y and F; X8 is selected from N, R and S; X9 is selected from V, I, L, M, F and Y; X11 is selected from N, S, E and D; X12 is selected from R, K and N; X14 is selected from K and R; X20 is selected from D, N, Q, E, H, S, R and K; X23 is selected from K, I and T; X24 is selected from A, S, T, G, H, L and D; and X25 is selected from H, E and D.
37 - 67 . (canceled)
68 . The composition according to claim 1 , wherein the ABD sequence is selected from SEQ ID NOs:301-463 or SEQ ID NOs:500-733.
69 - 102 . (canceled)
103 . The composition of claim 1 , wherein the engineered polypeptide comprises (SEQ ID NO:40), (SEQ ID NO:41), (SEQ ID NO:42), (SEQ ID NO:43), (SEQ ID NO:51), (SEQ ID NO:163), (SEQ ID NO:99), (SEQ ID NO:169), (SEQ ID NO:170), (SEQ ID NO:95), (SEQ ID NO:97), (SEQ ID NO:96), (SEQ ID NO:55), (SEQ ID NO:53), (SEQ ID NO:62), (SEQ ID NO:67), (SEQ ID NO:166), (SEQ ID NO:167), (SEQ ID NO:51), (SEQ ID NO:52), (SEQ ID NO:53), (SEQ ID NO:54), (SEQ ID NO:55), (SEQ ID NO:56), (SEQ ID NO:57), (SEQ ID NO:58), (SEQ ID NO:59), (SEQ ID NO:60), (SEQ ID NO:61), (SEQ ID NO:62), (SEQ ID NO:63), (SEQ ID NO:64), (SEQ ID NO:65), (SEQ ID NO:66), (SEQ ID NO:67), (SEQ ID NO:68), (SEQ ID NO:70), (SEQ ID NO:71), (SEQ ID NO:72), (SEQ ID NO:73), (SEQ ID NO:74), (SEQ ID NO:75), (SEQ ID NO:76), (SEQ ID NO:77), (SEQ ID NO:78), (SEQ ID NO:79), (SEQ ID NO:80), (SEQ ID NO:81), (SEQ ID NO:82), (SEQ ID NO:83), (SEQ ID NO:84), (SEQ ID NO:85), (SEQ ID NO:86), (SEQ ID NO:87), (SEQ ID NO:88), (SEQ ID NO:89), (SEQ ID NO:90), (SEQ ID NO:91), (SEQ ID NO:92), (SEQ ID NO:93), (SEQ ID NO:94), (SEQ ID NO:95), (SEQ ID NO:96), (SEQ ID NO:97), (SEQ ID NO:98), (SEQ ID NO:99), (SEQ ID NO:100) (SEQ ID NO:101), (SEQ ID NO:102), (SEQ ID NO:103), (SEQ ID NO:104), (SEQ ID NO:105), (SEQ ID NO:106), (SEQ ID NO:107), (SEQ ID NO:108) or (SEQ ID NO:109).
104 - 107 . (canceled)
108 . The composition of claim 1 , wherein the engineered polypeptide is selected from the group consisting of:
(SEQ ID NO: 620)
HGEGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKERSTGGGGSASGSLAEA
KEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;
(SEQ ID NO: 621)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPKSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;
(SEQ ID NO: 622)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;
(SEQ ID NO: 623)
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;
(SEQ ID NO: 624)
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAA
NAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;
(SEQ ID NO: 625)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;
(SEQ ID NO: 626)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAA
NAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAALP;
(SEQ ID NO: 627)
HGEGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKERSTGGGGSASGSLAEA
KEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;
(SEQ ID NO: 628)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPKSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;
(SEQ ID NO: 629)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;
(SEQ ID NO: 630)
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;
(SEQ ID NO: 631)
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAA
NAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;
(SEQ ID NO: 632)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAA
NAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAAL;
(SEQ ID NO: 633)
HGEGTFTSDLSKQLEEEAVRLFIEWLKQGGPSKERSTGGGGSASGSLAEA
KEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;
(SEQ ID NO: 634)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPKSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;
(SEQ ID NO: 635)
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSTGGGGSASGSL
AEAKEAANAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;
(SEQ ID NO: 636)
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAA
NAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA;
and
(SEQ ID NO: 637)
HGEGTFTSDLSKQLEEEAVRLFIEWLKNGGPSSGAPPPSGGSLAEAKEAA
NAELDSYGVSDFYKRLIDKAKTVEGVEALKDAILAA.
109 - 110 . (canceled)
111 . The composition according to claim 1 , wherein the engineered polypeptide has at least 95% sequence identity with Cmpd 2-5, Cmpd 2-9 or Cmpd 2-11.
112 - 122 . (canceled)
123 . The composition according to claim 1 , wherein said engineered polypeptide has a plasma half-life of at least 40 hours.
124 - 129 . (canceled)
130 . The composition according to claim 1 , wherein the permeation enhancer enhances paracellular permeation, opens cell tight junctions, enhances transcellular permeation, inhibits an intestinal protease, enhances solubility of a different permeation enhancer and/or is a mucoadhesive.
131 - 167 . (canceled)
168 . The composition according to claim 130 , further comprising a permeation enhancer that is a salt of a medium chain fatty acid which has a carbon chain length of the carboxylate moiety of from 6 to 20 carbon atoms.
169 - 204 . (canceled)
205 . The composition according to claim 1 , wherein the permeation enhancer is a salt, ester or ether of a medium chain fatty acid which has a carbon chain length of the carboxylate moiety of from 6 to 20 carbon atoms.
206 - 220 . (canceled)
221 . The composition according to claim 1 , wherein the permeation enhancer is a cationic, anionic or nonionic surfactant, or mixture thereof.
222 - 280 . (canceled)
281 . A pharmaceutical composition according to claim 1 , for use in treating a disease or disorder in a subject in need of such treatment.
282 - 284 . (canceled)
285 . A method for treating a disease or disorder in a subject, comprising administering a composition according to claim 1 to a subject in need thereof in an amount effective to treat said disease or disorder.
286 - 294 . (canceled)