Antibody fusion proteins: Anti-CD22 recombinant immunotoxin moxetumomab pasudotox

Abstract

Recombinant immunotoxins are fusion proteins that contain the cytotoxic portion of a protein toxin fused to the Fv portion of an antibody. The Fv binds to an antigen on a target cell and brings the toxin into the cell interior, where it arrests protein synthesis and initiates the apoptotic cascade. Moxetumomab pasudotox, previously calledHA22 orCAT-8015, is a recombinant immunotoxin composed of the Fv fragment of an anti- CD22 monoclonal antibody fused to a 38-kDa fragment of Pseudomonas exotoxin A, called PE38. Moxetumomab pasudotox is an improved, more active form of a predecessor recombinant immunotoxin, BL22 (also calledCAT-3888),whichproduced complete remissioninrelapsed/refractory hairy cell leukemia(HCL), but it had a <20% response rate in chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL), diseases inwhich the leukemic cells containmuch lower numbers ofCD22 target sites. Compared with BL22,moxetumomab pasudotox is up to 50-foldmore active on lymphoma cell lines and leukemic cells from patients with CLL and HCL. A phase I trial was recently completed in HCL patients, who achieved response rates similar to those obtained with BL22 but without dose-limiting toxicity. In addition to further testing in HCL, moxetumomab pasudotox is being evaluated in phase I trials in patients with CLL, B-cell lymphomas, and childhood ALL.Moreover, protein engineering is being used to increase its activity, decrease nonspecific side effects, and remove B-cell epitopes. ©2011 AACR.