REDUCTION OF THE NONSPECIFIC ANIMAL TOXICITY OF IMMUNOTOXINS BY MUTATING THE FRAMEWORK REGIONS OF THE FV TO LOWER THE ISOELECTRIC POINT

Title:

REDUCTION OF THE NONSPECIFIC ANIMAL TOXICITY OF IMMUNOTOXINS BY MUTATING THE FRAMEWORK REGIONS OF THE FV TO LOWER THE ISOELECTRIC POINT

Document Type and Number:

WIPO Patent Application WO2002040545

Kind Code:

A9

Abstract:

The invention provides recombinant immunotoxins that have been modified from a parental immunotoxin to lower liver toxicity. The immunotoxins are created by specifically mutating charged residues in the framework regions of the heavy chain, the light chain, or both, of the antibody portion or antigen-binding fragment thereof of the parental immunotoxin to reduce the pI of the antibody or fragment. In preferred forms, the antibody portion of the parental is an anti-Tac, anti-mesothelin, or anti-LewisY antigen antibody or antigen-binding fragment, and in particularly preferred forms the antibody portion is an M16 dsFv, a St6 dsFv or a Mt9 dsFv, or a sequence that has at least 90% sequence identity to one of these molecules but retain the particular mutations that lower pI without affecting antibody activity. The invention further provides nucleic acids encoding the recombinant immunotoxins of the invention, expression cassettes comprising the nucleic acids, and host cells comprising the expression cassettes. The invention also provides a method for killing a cell comprising an antigen on the surface of the cell, the method comprising contacting the cell with a recombinant immunotoxin of the invention that has an antibody or antigen-binding fragment thereof that binds specifically to the antigen on the surface of the cell, and uses of immunotoxins of the invention for the manufacture of medicaments.

Inventors:

PASTAN IRA H (US)
ONDA MASANORI (US)
NAGATA SATOSHI (US)
TSUTSUMI YASUO (US)
VINCENT JAMES J (US)
KREITMAN ROBERT J (US)
VASMATZIS GEORGE (US)
LEE BYUNGKOOK (US)

Application Number:

PCT/US2001/043602

Publication Date:

February 06, 2003

Filing Date:

November 16, 2001

Export Citation:

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Assignee:

US GOV HEALTH & HUMAN SERV (US)
PASTAN IRA H (US)
ONDA MASANORI (US)
NAGATA SATOSHI (US)
TSUTSUMI YASUO (US)
VINCENT JAMES J (US)
KREITMAN ROBERT J (US)
VASMATZIS GEORGE (US)
LEE BYUNGKOOK (US)

International Classes:

A61K47/48; A61P35/00; C07K14/21; C07K16/00; C07K16/18; C07K16/28; C07K16/30; C12N1/21; (IPC1-7): C07K19/00; A61K47/48; C12N15/62; C12N15/70; C12N1/21; A61P35/00

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