Mutant human and simian immunodeficiency virus ENV proteins with reduced immunosuppressive properties

Patent metadata

Field	Value
Publication number	US-9636396-B2
Application number	US-201213707885-A
Country	US
Kind code	B2
Filing date	Dec 7, 2012
Priority date	Dec 7, 2011
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

A pharmaceutical composition includes, as active substance a mutated lentiviral ENV protein, substantially devoid of immunosuppressive properties or a variant of the mutated lentiviral ENV protein or a fragment of the above proteins, in association with a pharmaceutically acceptable carrier.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising as active substance:
a) an isolated mutated human or simian lentiviral ENV protein having no or a reduced immunosuppressive activity as compared to a corresponding wild type non-mutated human or simian lentiviral ENV protein,
said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of the corresponding wild type non-mutated human or simian lentiviral ENV protein,
said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:

A-[I/V]-E-[K/R]-X a -X b -X-D-Q,
(SEQ ID NO: 416)

wherein,
X represents any amino acid,
and either

X a is A, F, G, L or R, and X b is any amino acid,
X a is any amino acid, and X b is R, or
X a is A, F, G, L, R, and X b is R,
or
b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having no or a reduced immunosuppressive activity as compared to the corresponding wild type non-mutated human or simian lentiviral ENV protein,
said fragment comprising at least 40 amino acids,
said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:

A-[I/V]-E-[K/R]-X a -X b -X-D-Q,
(SEQ ID NO: 416)

wherein,
X represents any amino acid,
and either

X a is A, F, G, L or R, and X b is any amino acid,
X a is any amino acid, and X b is R, or
X a is A, F, G, L, R, and X b is R,
in association with a pharmaceutically acceptable carrier, said absence or reduction of immunosuppressive activity of the above mentioned mutated human or simian lentiviral ENV protein or of the above defined fragment being liable to be assessed by the fact that in an in vivo assay involving engrafted tumor cells rejection,
said tumor cells being transduced either so as to express said mutated ENV protein or said fragment (mutated ENV tumor cells),
or said tumor cells being transduced so as to express the corresponding wild type non-mutated ENV protein or a fragment thereof (wild type ENV tumor cells),
or said tumor cells being not transduced (normal tumor cells),
the following ratio:
immunosuppression index of said mutated ENV protein or of said fragment (i mutated env )/immunosuppression index of wild type ENV protein (i wild type env ) is less than 0.5,
i mutated env being defined by: (maximum area reached by mutated ENV tumor cells−maximum area reached by normal tumor cells)/(maximum area reached by normal tumor cells), and
i wild type env being defined by: (maximum area reached by wild type ENV tumor cells−maximum area reached by normal tumor cells)/(maximum area reached by normal tumor cells).

2. The pharmaceutical composition according to claim 1 comprising as active substance:
a) an isolated mutated human or simian lentiviral ENV protein having no or a reduced immunosuppressive activity as compared to the corresponding wild type non-mutated human or simian lentiviral ENV protein,
said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of the corresponding wild type non-mutated human or simian lentiviral ENV protein,
said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:

A-[I/V]-E-[K/R]-X a -X b -X-D-Q,
(SEQ ID NO: 416)

wherein,
X represents any amino acid,
and either

X a is A, F, G, L or R, and X b is L, I, V, M or P,
X a is Y, I, H, C or T, and X b is R, or
X a is A, F, G, L or R, and X b is R,
or
b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having no or a reduced immunosuppressive activity as compared to the corresponding wild type non-mutated human or simian lentiviral ENV protein,
said fragment comprising at least 40 amino acids,
said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:

A-[I/V]-E-[K/R]-X a -X b -X-D-Q,
(SEQ ID NO: 416)

wherein,
X represents any amino acid,
and either

X a is A, F, G, L or R, and X b is L, I, V, M or P,
X a is Y, I, H, C or T, and X b is R, or
X a is A, F, G, L or R, and X b is R,
in association with a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 1 comprising as active substance:
a) an isolated mutated human or simian lentiviral ENV protein having no or a reduced immunosuppressive activity as compared to the corresponding wild type non-mutated human or simian lentiviral ENV protein,
said mutated human or simian lentiviral ENV protein resulting from mutation of the transmembrane (TM) subunit of the corresponding wild type non-mutated human or simian lentiviral ENV protein,
said mutated human or simian lentiviral ENV protein comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:

A-[I/V]-E-[K/R]-X a -X b -X-D-Q,
(SEQ ID NO: 416)

wherein
X represents any amino acid,
and either

X a is A, F, G, L or R, and X b is L,
X a is Y, and X b is R, or
X a is A, F, G, L, or R, and X b is R,
or
b) at least one fragment of said isolated mutated human or simian lentiviral ENV protein having no or a reduced immunosuppressive activity as compared to the corresponding wild type non-mutated human or simian lentiviral ENV protein,
said fragment comprising at least 40 amino acids,
said fragment comprising a mutated immunosuppressive domain (ISU) containing the following amino acid sequence:

A-[I/V]-E-[K/R]-X a -X b -X-D-Q,
(SEQ ID NO: 416)

wherein
X represents any amino acid,
and either

X a is A, F, G, L or R, and X b is L,
X a is Y, and X b is R, or
X a is A, F, G, L, or R, and X b is R,
in association with a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 1 compri

Assignees

• Centre Nat Rech Scient
• Univ Paris-Sud Xi
• Roussy Inst Gustave
• Viroxis S A S
• Insitut Gustave Roussy

Inventors

• Heidmann Thierry

Classifications

• C12N2740/16134

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• C12N2740/15033

  Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory · CPC title

• C12N2740/15034

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• C12N2740/16034

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• A61K39/21 Primary

  Retroviridae, e.g. equine infectious anemia virus · CPC title