Patent ID: 6783960
Filing Date: 2004-08-31
Classification: A61K,A61P,C07K

Abstract:
A chimeric protein comprising:(a) a Kunitz-type domain 1 of Tissue Factor Pathway Inhibitor-2 (TFPI-2) or a mutein thereof, wherein the mutein is selected from the group consisting of: (i) a Kunitz-type domain 1 of TFPI-2 comprising 1-5 conservative amino acid substitutions that do not substantially change the conformation of TFPI-2; (ii) a Kunitz-type domain 1 of TFPI-2 comprising an amino acid substitution that eliminates an N-linked glycosylation site; (iii) a Kunitz-type domain 1 of TFPI-2 which has 1-5 anino acid substitutions that change a residue of TFPI-2 to a corresponding residue of TFPI; and (iv) a Kunitz-type domain 1 of TFPI-2 that comprises an amino acid substitution in the P1 reactive site and (b) a Kunitz-type domain 2 of Tissue Factor Pathway Inhibitor (TFPI) or a mutein thereof, wherein the mutein is selected from the group consisting of: (i) a Kunitz-type domain 2 of TFPI comprising 1-5 conservative amino acid substitutions that do not substantially change the conformation of TFPI-2; (ii) a Kunitz-type domain 2 of TFPI comprising an amino acid substitution that eliminates an N-linked glycosylation site; (iii) a Kunitz-type domain 2 of TFPI which has 1-5 amino acid substitutions that change a residue of TFPI to a corresponding residue of TFPI-2; and (iv) a Kunitz-type domain 2 of TFPI that comprises an amino acid substitution in the P1 reactive site; or (c) a Kunitz-type domain 2 of TFPI-2 or a mutein thereof, wherein the mutein is selected from the group consisting of: (i) a Kunitz-type domain 2 of TFPI-2 comprising 1-5 conservative amino acid substitutions that do not substantially change the conformation of TFPI-2; (ii) a Kunitz-type domain 2 of TFPI-2 comprising an amino acid substitution that eliminates an N-linked glycosylation site; (iii) a Kunitz-type domain 2 of TFPI-2 which has 1-5 amino acid substitutions that change a residue of TFPI-2 to a corresponding residue of TFPI; and (iv) a Kunitz-type domain 2 of TFPI-2 that comprises an amino acid substitution in the P1 reactive site; and (d) a Kunitz-type domain 1 of TFPI or a mutein thereof, wherein the mutein is selected from the group consisting of: (i) a Kunitz-type domain 1 of TFPI comprising 1-5 conservative amino acid substitutions that do not substantially change the conformation of TFPI; (ii) a Kunitz-type domain 1 of TFPI comprising an amino acid substitution that eliminates an N-linked glycosylation site; (iii) a Kunitz-type domain 1 of TFPI which has 1-5 amino acid substitutions that change a residue of TFPI to a corresponding residue of TFPI-2; and (iv) a Kunitz-type domain 1 of TFPI that comprises an amino acid substitution in the P1 reactive site, wherein the chimeric protein binds and inhibits factor VIIa/tissue factor complex and binds to and inhibits factor Xa.