OB fusion protein compositions and methods
First Claim
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1. A protein having a formula selected from the group consisting of:
- R1-R2 and R1-L-R2, wherein;
R1 is an Fc protein selected from the group consisting of;
(a) amino acids 1-233 of SEQ ID NO;
9, amino acids 1-233 of SEQ ID NO;
12, amino acids 1-228 of SEQ ID NO;
15, or amino acids 1-228 of SEQ ID NO;
18;
(b) the amino acid sequence of subpart (a) having a different amino acid substituted or deleted in one or more of the following positions (using the numbering according to SEQ. ID. NO.
9);
(i) one or more cysteine residues replace by an alanine or serine residue;
(ii) one or more tyrosine residues replaced by a phenylalanine residue;
(iii) the amino acid at position 15 replaced with an glutamate;
(iv) the amino acid at position 20 replaced with glutamate;
(v) the amino acid at position 103 replaced with an alanine;
(vi) the amino acid at position 105 replaced with an alanine;
(vii) the amino acid at position 107 replaced with an alanine;
(viii) the amino acids at positions 1, 2, 3, 4, and/or 5 deleted;
(ix) the amino acid at position 15 replaced to ablate the Fc receptor binding site;
(x) one or more amino acids at positions 98, 100, and 102 replaced to ablate the complement (C1q) binding site; and
(xi) a combination of subparts i-x;
(c) the amino acid sequence of subparts (a) or (b) having a methionyl residue at the N-terminus;
(d) the amino acid sequence of subparts (a) through (c) wherein the Fc protein is connected to a water soluble polymer moiety selected from the group consisting of;
polyethylene glycol, an ethylene glycol/propylene glycol copolymer, a carboxymethylcellulose, a dextran, a polyvinyl alcohol, a polyvinyl pyrolidone, a poly-1,3-dioxolane, a poly-1,3,6-trioxane, an ethylene/maleic anhydride copolymer, a polyaminoacid homopolymer, a polyaminoacid random copolymer, an albumin, a polylysine moiety, a poly(n-vinyl pyrolidone)polyethylene glycol, a propylene glycol homopolymer, a polypropylene oxide/ethylene oxide copolymer, a polyoxyethylated polyol, a polyethylene glycol propionaldehyde, a succinate, and a styrene;
(e) the amino acid sequence of subpart (d) wherein said water soluble polymer moiety is polyethylene glycol;
(f) the amino acid sequence of subpart (d) wherein said water soluble polymer is a polyamino acid-selected from the group consisting of an albumin, and a polylysine moiety; and
(g) the amino acid sequence of subpart (d) wherein said water soluble polymer moiety is attached at solely the N-terminus of said Fc protein;
R2 is an OB protein selected from the group consisting of;
(A) the amino acid sequence 1-146 as set forth in SEQ. ID. NO. 3 or SEQ. ID. NO. 6;
(B) the amino acid sequence 1-146 as set forth in SEQ. ID. NO. 6 having a lysine residue at position 35 and an isoleucine residue at position 74;
(C) the amino acid sequence of subpart (B) wherein one or more of the following positions (using the numbering according to SEQ. ID. NO.
6);
4, 8, 32, 33, 35, 48, 50, 53, 60, 64, 66, 67, 68, 71, 74, 77, 78, 89, 97, 100, 102, 105, 106, 107, 108, 111, 112, 118, 136, 138, 142, and 145;
is substituted with the corresponding amino acid at the corresponding position as set forth in SEQ ID NO;
3;
(D) the amino acid sequence of subpart (B) wherein one or more of the following positions (using the numbering according to SEQ. ID. NO.
6) is substituted according to the following;
(i) the amino acid at position 8 replaced with a serine;
(ii) the amino acid at position 35 replaced with an arginine;
(iii) the amino acid at position 48 replaced with a valine;
(iv) the amino acid at position 53 replaced with a glutamine;
(v) the amino acid at position 60 replaced with an isoleucine;
(vi) the amino acid at position 66 replaced with an isoleucine;
(vii) the amino acid at position 67 replaced with an asparagine;
(viii) the amino acid at position 68 replaced with a leucine;
(ix) the amino acid at position 89 replaced with a leucine;
(x) the amino acid at position 100 replaced with a leucine;
(xi) the amino acid at position 108 replaced with a glutamate;
(xii) the amino acid at position 112 replaced with an aspartate; and
(xiii) the amino acid at position 118 replaced with a leucine;
(E) the amino acid sequence of subparts (A), (B), (C), or (D) optionally lacking a glutaminyl residue at position 28;
(F) the amino acid sequence of subparts (A), (B), (C), (D), or (E) having a methionyl residue at the N-terminus,(G) the OB protein of subpart (A) through (F) wherein the OB protein comprises a water soluble polymer moiety selected from the group consisting of;
polyethylene glycol, an ethylene glycol/propylene glycol copolymer, a carboxymethylcellulose, a dextran, a polyvinyl alcohol, a polyvinyl pyrolidone, a poly-1,3-dioxolane, a poly-1,3,6-trioxane, an ethylene/maleic anhydride copolymer, a polyaminoacid homopolymer, a polyaminoacid random copolymer, an albumin, a polylysine moiety, a poly(n-vinyl pyrolidone)polyethylene glycol, a propylene glycol homopolymer, a polypropylene oxide/ethylene oxide copolymer, a polyoxyethylated polyol, a polyethylene glycol propionaldehyde, a succinate, and a styrene;
(H) the OB protein of subpart (G) wherein said water soluble polymer moiety is polyethylene glycol;
(I) the OB protein of subpart (G) wherein said water soluble polymer is a polyamino acid selected from the group consisting of an albumin, and a polylysine moiety; and
(J) the OB protein of subpart (G) wherein said water soluble polymer moiety is attached at solely the N-terminus of said OB protein; and
L is a linker.
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Abstract
The present invention relates to Fc-OB fusion protein compositions, methods of preparation of such compositions and uses thereof. In particular, the present invention relates to a genetic or chemical fusion protein comprising the Fc immunoglobulin region, derivative or analog fused to the N-terminal portion of the OB protein, derivative or analog.
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Citations
4 Claims
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1. A protein having a formula selected from the group consisting of:
- R1-R2 and R1-L-R2, wherein;
R1 is an Fc protein selected from the group consisting of; (a) amino acids 1-233 of SEQ ID NO;
9, amino acids 1-233 of SEQ ID NO;
12, amino acids 1-228 of SEQ ID NO;
15, or amino acids 1-228 of SEQ ID NO;
18;(b) the amino acid sequence of subpart (a) having a different amino acid substituted or deleted in one or more of the following positions (using the numbering according to SEQ. ID. NO.
9);(i) one or more cysteine residues replace by an alanine or serine residue; (ii) one or more tyrosine residues replaced by a phenylalanine residue; (iii) the amino acid at position 15 replaced with an glutamate; (iv) the amino acid at position 20 replaced with glutamate; (v) the amino acid at position 103 replaced with an alanine; (vi) the amino acid at position 105 replaced with an alanine; (vii) the amino acid at position 107 replaced with an alanine; (viii) the amino acids at positions 1, 2, 3, 4, and/or 5 deleted; (ix) the amino acid at position 15 replaced to ablate the Fc receptor binding site; (x) one or more amino acids at positions 98, 100, and 102 replaced to ablate the complement (C1q) binding site; and (xi) a combination of subparts i-x; (c) the amino acid sequence of subparts (a) or (b) having a methionyl residue at the N-terminus; (d) the amino acid sequence of subparts (a) through (c) wherein the Fc protein is connected to a water soluble polymer moiety selected from the group consisting of;
polyethylene glycol, an ethylene glycol/propylene glycol copolymer, a carboxymethylcellulose, a dextran, a polyvinyl alcohol, a polyvinyl pyrolidone, a poly-1,3-dioxolane, a poly-1,3,6-trioxane, an ethylene/maleic anhydride copolymer, a polyaminoacid homopolymer, a polyaminoacid random copolymer, an albumin, a polylysine moiety, a poly(n-vinyl pyrolidone)polyethylene glycol, a propylene glycol homopolymer, a polypropylene oxide/ethylene oxide copolymer, a polyoxyethylated polyol, a polyethylene glycol propionaldehyde, a succinate, and a styrene;(e) the amino acid sequence of subpart (d) wherein said water soluble polymer moiety is polyethylene glycol; (f) the amino acid sequence of subpart (d) wherein said water soluble polymer is a polyamino acid-selected from the group consisting of an albumin, and a polylysine moiety; and (g) the amino acid sequence of subpart (d) wherein said water soluble polymer moiety is attached at solely the N-terminus of said Fc protein; R2 is an OB protein selected from the group consisting of; (A) the amino acid sequence 1-146 as set forth in SEQ. ID. NO. 3 or SEQ. ID. NO. 6; (B) the amino acid sequence 1-146 as set forth in SEQ. ID. NO. 6 having a lysine residue at position 35 and an isoleucine residue at position 74; (C) the amino acid sequence of subpart (B) wherein one or more of the following positions (using the numbering according to SEQ. ID. NO.
6);
4, 8, 32, 33, 35, 48, 50, 53, 60, 64, 66, 67, 68, 71, 74, 77, 78, 89, 97, 100, 102, 105, 106, 107, 108, 111, 112, 118, 136, 138, 142, and 145;
is substituted with the corresponding amino acid at the corresponding position as set forth in SEQ ID NO;
3;(D) the amino acid sequence of subpart (B) wherein one or more of the following positions (using the numbering according to SEQ. ID. NO.
6) is substituted according to the following;(i) the amino acid at position 8 replaced with a serine; (ii) the amino acid at position 35 replaced with an arginine; (iii) the amino acid at position 48 replaced with a valine; (iv) the amino acid at position 53 replaced with a glutamine; (v) the amino acid at position 60 replaced with an isoleucine; (vi) the amino acid at position 66 replaced with an isoleucine; (vii) the amino acid at position 67 replaced with an asparagine; (viii) the amino acid at position 68 replaced with a leucine; (ix) the amino acid at position 89 replaced with a leucine; (x) the amino acid at position 100 replaced with a leucine; (xi) the amino acid at position 108 replaced with a glutamate; (xii) the amino acid at position 112 replaced with an aspartate; and (xiii) the amino acid at position 118 replaced with a leucine; (E) the amino acid sequence of subparts (A), (B), (C), or (D) optionally lacking a glutaminyl residue at position 28; (F) the amino acid sequence of subparts (A), (B), (C), (D), or (E) having a methionyl residue at the N-terminus, (G) the OB protein of subpart (A) through (F) wherein the OB protein comprises a water soluble polymer moiety selected from the group consisting of;
polyethylene glycol, an ethylene glycol/propylene glycol copolymer, a carboxymethylcellulose, a dextran, a polyvinyl alcohol, a polyvinyl pyrolidone, a poly-1,3-dioxolane, a poly-1,3,6-trioxane, an ethylene/maleic anhydride copolymer, a polyaminoacid homopolymer, a polyaminoacid random copolymer, an albumin, a polylysine moiety, a poly(n-vinyl pyrolidone)polyethylene glycol, a propylene glycol homopolymer, a polypropylene oxide/ethylene oxide copolymer, a polyoxyethylated polyol, a polyethylene glycol propionaldehyde, a succinate, and a styrene;(H) the OB protein of subpart (G) wherein said water soluble polymer moiety is polyethylene glycol; (I) the OB protein of subpart (G) wherein said water soluble polymer is a polyamino acid selected from the group consisting of an albumin, and a polylysine moiety; and (J) the OB protein of subpart (G) wherein said water soluble polymer moiety is attached at solely the N-terminus of said OB protein; and L is a linker. - View Dependent Claims (2, 3, 4)
- R1-R2 and R1-L-R2, wherein;
Specification