In the past few years we have focused on making improved immuntoxins that are less immunogenic and have fewer side effects in humans. Immunogenicity has been decreased by identifying residues in the toxin that are part of B cell or T cell epitopes and mutating them so they are no longer recognized by the human immune system. Side effects of immunotoxins have been reduced by deleting regions of the toxin not needed for cytotoxic activity. Based on these results we have engineered several new immunotoxins. One of these is RG7787 that targets mesothelin expressed on many human solid tumors. It has mutations that silence B cell epitopes, a deletion of amino acids in the toxin responsible for capillary leak syndrome and a humanized anti-mesothelin Fab to direct it to cancer cells. It was made in collaboration with our CRADA partner Roche. Clinical trials with this agent are in the planning stage and should begin late in 2014. In an animal model of mesothelin-expressing pancreatic cancer, RG7787 when combined with Taxol produces complete or near complete remissions suggesting such a combination should be tried in humans. LMB11 is a RIT similar to RG7787 but directed at CD22. It has a humanized anti-CD22 Fab instead of an anti-mesothelin Fab. Large amounts can be safely given to mice and completely remissions obtained of CA46 tumors growing subcutaneously in mice. LMB11 is a great improvement over HA22 since it can safely be given at much higher doses. Our next goal is to reengineer the Fv portion which we believe is responsible for producing hemolytic uremic syndrome in some patients. Other studies are focused on treating mice with immunosuppressive drugs to abolish antibody responses and remove preexisting antibodies; identifying drugs that can be used with immunotoxins to obtain better anti-tumor responses in mice and understanding more about the steps required for immunotoxins to kill cells or give toxin resistance.