title: An immunotoxin targeting the gH glycoprotein of KSHV for selective killing of cells in the lytic phase of infection.
abstract: Amongst the pathologies associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV), multicentric Castleman's disease is distinctive for involvement of the lytic phase of the virus replication cycle. This B cell lymphoproliferative disorder has shown clinical responsiveness not only to generalized immunotherapy and cytotoxic chemotherapy, but also to inhibitors of herpesvirus DNA replication, consistent with the involvement of lytic phase of replication. These findings suggest that selective killing of virus-producing cells might represent a novel therapeutic strategy. We designed an immunotoxin, YC15-PE38, containing a single chain variable region fragment of a monoclonal antibody against KSHV glycoprotein H (gH) linked to the effector domains of Pseudomonas aeruginosa exotoxin A. Purified YC15-PE38 displayed highly selective and potent killing of a gH-expressing transfectant cell line (subnanomolar IC(50)). The immunotoxin also strongly inhibited production of infectious KSHV virions from an induced chronically infected cell line, by virtue of selective killing of the virus-producing cells. Combination treatment studies indicated complementary activities between YC15-PE38 and the herpesviral DNA replication inhibitor ganciclovir. These results provide support for the development of anti-KSHV strategies based on targeted killing of infected cells expressing lytic phase genes.
authors: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
authors: Yingyun
authors: Y
authors: Cai
authors: Edward A
authors: EA
authors: Berger
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005098:Exotoxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D019288:Herpesvirus 8, Human / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D014779:Virus Replication; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D014759:Viral Envelope Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A