Nucleic acid encoding modified membrane type serine protease 1 (MTSP-1) polypeptides and methods of use

A nucleic acid molecule, comprising a sequence of nucleotides encoding a modified membrane type serine protease 1 (MTSP-1) polypeptide, wherein the encoded modified MTSP-1 polypeptide comprises:

• a) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:
• 1 or 3, wherein the amino acid sequence comprises one or more substitution(s) selected from G759H or N, and/or Q802T with reference to numbering in SEQ ID NO:1 (equivalent to G151H or N, and Q192T, respectively, by chymotrypsin numbering);
• or
• b) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:
• 2 or 4, wherein the amino acid sequence comprises one or more substitution(s) selected from G145H or N, and/or Q188T with reference to numbering in SEQ ID NO:2 (equivalent to G151H or N, and Q192T, respectively, by chymotrypsin numbering), wherein:
• i) the modified MTSP-1 polypeptide has increased activity and/or specificity for complement protein C3 compared to the unmodified active form of the MTSP-1 polypeptide comprising the amino acid sequence set forth in any of SEQ ID NOs:
• 1-4 or a catalytically active fragment or form thereof;
• ii) amino acid modifications are selected from among replacements, insertions, and/or deletions in the unmodified MTSP-1 polypeptide;
• and
• iii) the modified MTSP-1 polypeptide cleaves a target site in C3 that inactivates C3 to thereby inhibit or reduce complement activation.