Naptumomab estafenatox, an engineered antibody-superantigen fusion protein with low toxicity and reduced antigenicity.
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.
Forsberg
Göran
G
Active Biotech Research AB, Sweden. goran.forsberg@activebiotech.com
Skartved
Niels-Jörgen
NJ
Wallén-Ohman
Marie
M
Nyhlén
Helen Carlsson
HC
Behm
Kristina
K
Hedlund
Gunnar
G
Nederman
Thore
T
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
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