Mutated <i>Pseudomonas </i>exotoxins with reduced antigenicity

摘要

The invention provides mutated Pseudomonas exotoxins (PE) that have reduced immunogenicity compared to PEs containing the native sequence. The PEs of the invention have one or more individual mutations of positions of the native sequence of PE that reduce antibody binding to one or more PE epitopes. Nucleic acids encoding the mutated PEs, chimeric molecules comprising them, compositions comprising the chimeric molecules and methods of using them, are also provided.

主权项

1. An isolated Pseudomonas exotoxin A (“PE”) comprising a PE amino acid sequence, wherein one or more of amino acid residues N314, D324, Q332, D403, R412, R427, E431, R432, R458, D461, R467, R505, R538, E548, R576, K590, and L597 as defined by reference to SEQ ID NO: 1 are, independently, substituted, provided that
when amino acid residue Q332 is substituted, amino acid residue Q332 is substituted with a anine, glycine, or serine; when amino acid residue K590 is substituted, amino acid residue K590 is substituted with alanine, glycine, or serine; when amino acid residue L597 is substituted, amino acid residue L597 is substituted with glycine, serine or glutamine; and when one or more of amino acid residues N314, D324, D403, R412, R427, E431, R432, R458, D461, R467, R505, R538, E548, and R576 are substituted, the one or more of amino acid residues N314, D324, D403, R412, R427, E431, R432, R458, D461, R467, R505, R538, E548, and R576 are, independently, substituted with alanine, glycine, serine or glutamine; wherein the PE optionally has a further substitution of amino acid residue R490, as defined by reference to SEQ ID NO: 1, with alanine, valine, glycine, leucine, isoleucine or glutamine, and wherein the PE optionally has a further substitution of, independently, one or more of amino acid residues E282, E285, P290, R313, P319, E327, E331, R513, E522, and R551, as defined by reference to SEQ ID NO: 1, with alanine, glycine, serine or glutamine.