Psuedomonas exotoxins of low animal toxicity and high cytocidal activity
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsIra Pastan, David Fitzgerald, Vijay K. Chaudhary
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Abstract
Improved Pseudomonas exotoxins of low animal toxicity and high cytocidal activity are described. Substitution of positively charged amino acid residues with an amino acid residue without a positive charge provides markedly changed exotoxins. Conjugation of the new exotoxins with suitable targeting agents provides cytocidal specificity for killing desired cellular entities.
Claims13
A method of killing cells, said method comprising contacting said cells with a cytocidal amount of a modified Pseudomonas exotoxin (PE) attached to a targeting agent that binds to a specific site on said cells, said modified PE having at least one positively charged amino acid in domain 1a substituted by an amino acid without a positive charge so the modified PE has a lower animal toxicity compared to a PE lacking the substitution, said modified PE being selected from the group consisting of a PE in which each of the amino acids numbered 57, 246, 247 and 249 is glutamic acid (PE-Glu-57, 246, 247, 249), a PE in which amino acid 57 is a glutamic acid and amino acids 241-250 are deleted (PE-Glu-57.DELTA.241-250), and a PE in which amino acid 57 is a glutamic acid and each of the amino acids numbered 246, 247, and 249 is glycine (PE-Glu-57-Gly 246, 247, 249).
Dependencies are inferred from the claim text.