Heregulin variants
AssigneeGenentech, Inc.
InventorsMarcus D. Ballinger, Jennifer T. Jones, Wayne J. Fairbrother, Mark X. Sliwkowski, James A. Wells
Life of this patent
Estimating the term…
Abstract
The present invention provides heregulin variants that are capable of binding an ErbB receptor. Included in the invention are variants of human heregulins, and, in particular, variants of human heregulin-.beta.1 having enhanced affinity for the ErbB-3 and ErbB-4 receptors. These variants include at least one amino acid substitution and can include further modifications. The invention also provides nucleic acid molecules encoding heregulin variants and related vectors, host cells, pharmaceutical compositions, and methods.
Claims32
A variant of heregulin, said variant having an amino acid sequence not found in nature and the ability to bind an ErbB receptor, wherein said variant comprises a different amino acid than in said heregulin wherein:
- at residue number 177 said different amino acid is A, F, W, or Y;
- at residue number 178 said different amino acid is A, D, E, G, L, N, P, Q, R, T V, or W;
- at residue number 179 said different amino acid is A, G, L, M, P, S or V;
- at residue number 180 said different amino acid is A, D, E, G, H, I, K, M, N, P, Q, or R;
- at residue number 181 said different amino acid is A, G, I, L, P, or V;
- at residue number 183 said different amino acid is A, G, I, L, M, S, or T;
- at residue number 184 said different amino acid is A, F, G, H, I, K, L, M, N, P, Q, R, S, V, or W;
- at residue number 185 said different amino acid is A, G, H, I, K, L, M, N, P, Q, S, T, or V;
- at residue number 186 said different amino acid is A, K, R, or S;
- at residue number 187 said different amino acid is A, E, G, I, L, M, N, P, Q, S, or T;
- at residue number 188 said different amino acid is A, H, K, N, or R;
- at residue number 195 said different amino acid is A, H, N, Q, R, or S;
- at residue number 197 said different amino acid is A, F, L, V, or W;
- at residue number 198 said different amino acid is A, H, K, R, or S;
- at residue number 200 said different amino acid is A, H, R, or S;
- at residue number 201 said different amino acid is G, H, I, L, M, P, R, S, T, or V;
- at residue number 205 said different amino acid is A, F, H, I, K, R, T, V, W, or Y;
- at residue number 206 said different amino acid is A, F, G, H, I, K, L, M, P, R, S, V, W, or Y;
- at residue number 207 said different amino acid is F, H, I, L, P, R, V, W, or Y;
- at residue number 208 said different amino acid is A, H, K, R, or S;
- at residue number 209 said different amino acid is G, M, P, S, T, or V;
- at residue number 211 said different amino acid is A, H, R, or S;
- at residue number 213 said different amino acid is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, W, or Y;
- at residue number 214 said different amino acid is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, W, or Y;
- at residue number 215 said different amino acid is A, C, D, F, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y;
- at residue number 216 said different amino acid is A, G, L, M, P, or V;
- at residue number 223 said different amino acid is A, F, H, R, S, or W;
- or
- at residue number 226 said different amino acid is A, G, L, or P;
- wherein said residue numbers correspond to residue numbers of native human heregulin-.beta.1 (SEQ ID NO:
- 93) numbered from the N-terminus;
- and
- wherein said heregulin variant comprises a portion that is at least 70% identical to the portion from about residue 175 to about residue 230 of native human heregulin-.beta.1 (SEQ ID NO:
- 93).
A variant of human heregulin-.beta.1, said variant having an amino acid sequence not found in nature and the ability to bind an ErbB receptor, wherein said variant comprises an amino acid substitution selected from the group consisting of;
- S177W;
- H117E, R, or A;
- V180Q, I, or E;
- K181P or A;
- A183G;
- E184V, W, R, G, or N;
- K185S, Q, or G;
- E186R;
- K187E or A;
- E195Q;
- M198R or K;
- D201T or I;
- P205T or Y;
- S206K, H, G, P, or R;
- R207Y;
- Y208R or L;
- L209M or G;
- K211R;
- P213S, T, N, or K;
- N214L, K, S, or E;
- F216M;
- and
- N223H or W;
- wherein said residue numbers correspond to residue numbers of native human heregulin-.beta.1 (SEQ ID NO:
- 93) numbered from the N-terminus;
- and
- wherein said heregulin variant comprises a portion that is at least 70% identical to the portion from about residue 175 to about residue 230 of native human heregulin-.beta.1 (SEQ ID NO:
- 93).
A heregulin variant having an amino acid sequence not found in nature and the ability to bind an ErbB receptor,
- wherein said variant comprises a methionine residue in place of amino acid residues corresponding to residue numbers 228 to 231 of native human heregulin-.beta.1 (SEQ ID NO:
- 93) numbered from the N-terminus and
- said heregulin variant comprises a portion that is at least 70% identical to the portion from about residue 175 to about residue 230 of native human heregulin-.beta.1 (SEQ ID NO:
- 93),
- said heregulin variant having a greater specificity for the ErbB-4 receptor, relative to the ErbB-3 receptor, than a heregulin that differs from the heregulin variant only in that the heregulin comprises said amino acid residues corresponding to residue numbers 228 to 231 in place of said methionine.
Dependencies are inferred from the claim text.