Antibody fusion with IL-12 proteins with disrupted heparin-binding activity
AssigneeThe Regents of the University of California
InventorsManuel L. Penichet, Rosendo Luria-Perez, Gustavo Helguera
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Abstract
Disclosed herein are polypeptides which comprise all or part of an antibody linked to all or part of a cytokine. The cytokine sequences of the polypeptides have a modified heparin binding region which disrupts, inhibits, or reduces the ability of the cytokine to bind a heparin compound as compared to a corresponding cytokine having an unmodified heparin binding region. Also disclosed are methods of treating cancer, inducing cell proliferation, and reducing the non-specific binding and/or non-specific localization of the polypeptides.
Claims17
A polypeptide which comprises an antibody sequence, said antibody sequence specific for a tumor associated antigen, linked or fused to a modified cytokine which (a) has a modified heparin binding region which disrupts, inhibits, or reduces the ability of the cytokine to bind a heparin compound as compared to an unmodified heparin binding region of the wild type cytokine corresponding to the modified cytokine, and (b) exhibits immunostimulatory activity which is the same, more than, or less than that of the wild-type cytokine, wherein the wild type cytokine is IL-12.
A polypeptide which comprises an antibody linked or fused to a modified cytokine which has a modified heparin binding region, wherein
- said antibody is specific for an antigen associated with a tumor;
- said modified heparin binding region comprises the following formula I:
- V-X1-X2-Q-X3-K*-X4-X5-X6-X7-K*-X8 (I)
- wherein X1 is R or Q,
- X2 is V, A, or I,
- X3 is G or R*,
- X4 is S, N, or K*,
- X5 is K*, N, or E,
- X6 is R or K,
- X7 is E, M, or T, and
- X8 is K* or E, and
- wherein one or more amino acid residues designated with an “*” are substituted with a non-polar amino acid residue selected from the group consisting of A, G, I, L, M, F, P, and V;
- and
- said modified cytokine having the modified heparin binding region exhibits a decrease in heparin binding as compared to the corresponding wild type cytokine which is IL-12.
Dependencies are inferred from the claim text.