Methods of treating cancer using interleukin-12p40 variants having improved stability

摘要

Modified interleukin-12 (IL-12) p40 polypeptides are disclosed. The modified polypeptides have alterations in the IL-12p40 subunit to eliminate the protease site between positions Lys260 and Arg261. The modified IL-12p40 polypeptides according to the invention have improved stability compared to wild-type mature human IL-12p40 polypeptides.

主权项

1. A method of treating a patient having cancer, the method comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a variant of an IL-12p40 subunit, the variant selected from the group consisting of:
(a) a variant being at least 90% identical to SEQ ID NO:2 and comprising an amino acid alteration at one or more positions corresponding to residues 258-266, wherein the amino acid alteration comprises an amino acid substitution selected from the group consisting of Lys260Asn, Lys260Gln, and Lys260Gly; (b) a variant being at least 90% identical to SEQ ID NO:2 and comprising an amino acid alteration at one or more positions corresponding to amino acids 258-266, wherein the amino acid alteration comprises an amino acid substitution at Lys260 and deletion of one or more of Lys258, Ser259, Lys263, Lys264, and Asp265; (c) a variant being at least 90% identical to SEQ ID NO:2 and comprising an amino acid alteration at one or more positions corresponding to amino acids 258-266, wherein the amino acid alteration comprises an amino acid substitution at Lys260 and one or more of amino acid substitutions Lys258Gln, Ser259Asp, and Lys260Gln; (d) a variant being at least 90% identical to SEQ ID NO:2 and comprising an amino acid alteration at one or more positions corresponding to amino acids 258-266, wherein the amino acid alteration comprises the amino acid substitution Ser259Asp; and (e) a variant being at least 90% identical to SEQ ID NO:2 and comprising an amino acid alteration at one or more positions corresponding to residues 258-266, wherein the amino acid alteration comprises an amino acid substitution selected from the group consisting of Arg261Asp and Arg261Thr.