US 2017/0204387 A1 · RIBOTOXIN MOLECULES DERIVED FROM SARCIN AND OTHER RELATED FUNGAL RIBOTOXINS

Abstract

The present application relates to modified T cell epitopes derived from fungal ribotoxins, including α-sarcin, clavin, gigantin, mitogillin, and restrictocin, as well as modified ribotoxin molecules comprising one or more of the modified epitopes. The modified ribotoxin molecules inhibit protein synthesis, like the wild type ribotoxins, but exhibit reduced immunogenicity as compared to the corresponding wild type ribotoxin. Another aspect relates to a fusion protein which comprises a modified ribotoxin fused or conjugated or otherwise linked to a targeting molecule that is effective for binding a target of interest. Another aspect relates to the use of the modified ribotoxin or fusion protein for treating or managing a disease or condition.

Claims18

Dependent claims

-25. (canceled)

An isolated nucleic acid encoding a modified sarcin polypeptide or a fusion protein comprising the modified sarcin polypeptide conjugated or fused to a targeting molecule, wherein the modified sarcin polypeptide comprises at least one mutation as compared to a wild type α-sarcin polypeptide having the amino acid sequence of SEQ ID NO:1, wherein the at least one mutation is within a first T cell epitope and/or a second T cell epitope of the wild type α-sarcin polypeptide, wherein the at least one mutation within the first T cell epitope is one or more of D9A, D9T, Q10K, Q10R, Q10A, P13I, T15G, T15Q, T15H, N16R, N16K, N16A, Y18H, Y18K, or Y18R and wherein the at least one mutation within the second T cell epitope is one or more of I134A, K139D, K139E, K139G, K139Q, K139H, K139N, E140D, Q142D, Q142N, Q142T, Q142E, Q142R, or Q142G, and wherein the first T cell epitope consists of the amino acid sequence of SEQ ID NO:6 and the second T cell epitope consists of the amino acid sequence of SEQ ID NO:4.

A modified mitogillin polypeptide comprising at least one mutation as compared to a wild type mitogillin polypeptide having the amino acid sequence of SEQ ID NO:26, wherein the at least one mutation is

a) at one or more of amino acids Q9, P12, T14, N15, or Y17 of the wild type mitogillin polypeptide and is within a first T cell epitope of the wild type mitogillin polypeptide consisting of the amino acid sequence of SEQ ID NO:36;
b) at one or more of amino acids I62, R65, I68, or F70 of the wild type mitogillin polypeptide and is within a second T cell epitope of the wild type mitogillin polypeptide consisting of the amino acid sequence of SEQ ID NO:33;
c) at one or more of amino acids V121, T124, P126, N127, or V129 of the wild type mitogillin polypeptide and is within a third T cell epitope of the wild type mitogillin polypeptide consisting of the amino acid sequence of SEQ ID NO:3;
d) at one or more of amino acids V129, G132, A135, or Q137 of the wild type mitogillin polypeptide and is within a fourth T cell epitope of the wild type mitogillin polypeptide consisting of the amino acid sequence of SEQ ID NO:34;
and/or
e) at one or more of amino acids I133, R138, G139, or Q141 of the wild type mitogillin polypeptide and is within a fifth T cell epitope of the wild type mitogillin polypeptide consisting of the amino acid sequence of SEQ ID NO:35, and
wherein the modified mitogillin polypeptide inhibits protein synthesis and elicits a reduced T cell response as compared to the wild type mitigillin polypeptide, wherein the inhibition of protein synthesis is measured using an in vitro transcription and translation assay (IVTT).

4 more elements

Dependencies are inferred from the claim text.

Facts

Application

15/430,906Filed 13 Feb 2017

Priority

14 Mar 2013

Published

20 Jul 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C12N 9/22
Acting on ester bonds: ribonucleases [RNase]; Deoxyribonucleases [DNase]
A61K 39/0002
Medicinal preparations containing antigens or antibodies: fungal antigens, e.g. Trichophyton, Aspergillus, Candida
A61P 35/00
Antineoplastic agents
C07K 14/38
From fungi: from Aspergillus

Family

Application61/783,589Us provisional application · filed 14 Mar 2013

Application61/902,972Us provisional application · filed 12 Nov 2013

Application14/774,445Continuation · filed 10 Sep 2015

Application15/430,906Continuation

US 2016/0106819 A1Published application

US 9,603,911 B2Related patent

US 9,976,131 B2Related patent

US 2017/0204387 A1This patent

From the US filing history. Foreign family members aren’t listed.

Ribotoxin molecules derived from sarcin and other related fungal ribotoxins

Life of this patent

Ribotoxin molecules derived from sarcin and other related fungal ribotoxins

Life of this patent

Abstract

Claims18