Bone marrow transplantation has become an important treatment modality for leukemia, congenital immunodeficiency states and aplastic anemia. However, formidible obstacles still remain to a predictably high success rate. The high incidence of serious opportunistic infections in the early post-transplant period when recipients are most vulnerable because of the absence of a functioning immune system, remains a major problem. Interstitial pneumonia frequently due to cytomegalovirus (CMV) is the major potentially fatal infectious complication in these patients. The current diagnostic methods and treatment of CMV infection has to date not proved adequate to alleviate this problem. We propose to generate a set of human monoclonal antibodies to CMV as both diagnostic, and for certain selected antibodies, as therapeutic agents. CMV-antibody producing cell lines will be made by Epstein-Barr virus transformation of B lymphocytes obtained from patients with recent CMV infection. These cell lines will subsequently be fused with human myeloma cells to convert them to high-secreting hybridomas. The basic technology has been tested and is well established as shown, by our development of human monoclonal antibody 312.A.91.4 to a major CMV structural protein. Antibodies will be rigorously tested for serological specificity, for virus neutralizing activity as well as for antibody dependent cell-mediated cytotoxicity. Sensitive diagnostic methods for CMV detection using currently available and newly produced antibodies will be developed, and retrospective and prospective studies undertaken to determine the cause-effect relationship for CMV in interstitial pneumonia in marrow transplant recipients. Prospective screening of both bone marrow and blood donors and marrow recipients for CMV specific antigens using these methods should lead to improved management or prevention of CMV infections in marrow transplant recipients. Finally selected human monoclonal antibodies will be used in both prophylactic and therapeutic immunotherapy trials in transplant patients at high risk of acquiring or having acquired CMV infection.
