title: Naptumomab estafenatox, an engineered antibody-superantigen fusion protein with low toxicity and reduced antigenicity.
abstract: Antibody-targeted superantigens have a potential to become useful drugs for tumor therapy. However, clinical practice has identified several issues that need to be addressed to optimize such molecules. On the basis of the experience from superantigen products in clinical trials, a novel tumor-targeted superantigen, naptumomab estafenatox (5T4FabV18-SEA/E-120 or ABR-217620) has been designed. Critical properties, such as tumor reactivity, therapeutic window, and seroreactivity were all improved. The engineered 5T4Fab moiety recognizes the 5T4 antigen expressed on a large number of solid tumor forms with an affinity in the order of 1 nM. The fusion protein induces T-cell mediated killing of tumor cells at concentrations around 10 pM. Compared with a construct with a wild-type superantigen, it is more potent in mediating killing of tumor cells but a 10,000-fold less active in mediating killing of MHC class II positive cells. The target epitopes for naturally occurring antibodies toward bacterial superantigens are reduced. Only large excesses of human anti-SEA antibodies neutralize the antitumor effects of the antibody-targeted superantigen. Naptumomab estafenatox induces dramatic reduction of established human tumors in Severe Combined Immunodeficient mice grafted with human lymphocytes. Thus, naptumomab estafenatox is a novel optimized tumor-targeted superantigen currently investigated in clinical trials.
authors.affiliation: Active Biotech Research AB, Sweden. goran.forsberg@activebiotech.com
authors.forename: Göran
authors.initials: G
authors.lastname: Forsberg
authors.forename: Niels-Jörgen
authors.initials: NJ
authors.lastname: Skartved
authors.forename: Marie
authors.initials: M
authors.lastname: Wallén-Ohman
authors.forename: Helen Carlsson
authors.initials: HC
authors.lastname: Nyhlén
authors.forename: Kristina
authors.initials: K
authors.lastname: Behm
authors.forename: Gunnar
authors.initials: G
authors.lastname: Hedlund
authors.forename: Thore
authors.initials: T
authors.lastname: Nederman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004768:Enterotoxins / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates; D000922:Immunotoxins / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D017354:Point Mutation / Q000235:genetics; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D018089:Superantigens / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D004768:Enterotoxins; D018796:Immunoconjugates; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C049463:enterotoxin E, Staphylococcal; C063709:trophoblastic glycoprotein 5T4, human; C543500:naptumomab estafenatox