Death ligands designed to kill: development and application of targeted cancer therapeutics based on proapoptotic TNF family ligands.
The identification of molecular markers associated with cancer development or progression, opened a new era in the development of therapeutics. The successful introduction of a few low molecular weight chemicals and recombinant protein therapeutics with targeted actions into clinical practice have raised great expectations to broadly improve cancer therapy with respect to both overall clinical responses and tolerability. Targeting the apoptotic machinery of malignant cells is an attractive concept to combat cancer, which is currently exploited for the proapoptotic members of the TNF ligand family at various stages of preclinical and clinical development. This review summarizes recent progress in this rapidly progressing field of "biologic" therapies targeting the death receptors of TNF, CD95L, and TRAIL by means of its cognate protein ligands, receptor specific antibodies, and gene therapeutic approaches. Preclinical data on newly derived variants and fusion proteins based on these death ligands, designed to act in a tumor restricted manner, thereby preventing a systemic, potentially harmful action, will also be discussed.
Gerspach
Jeannette
J
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany. jeanette.gerspach@izi.uni-stuttgart.de
Wajant
Harald
H
Pfizenmaier
Klaus
K
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016503:Drug Delivery Systems; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053218:Receptors, Death Domain / Q000819:agonists* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D008024:Ligands; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha