LATEST PAPERS SEARCH for PAPERS Printer-friendly PDF Comment(s) >Abstract >Introduction >Results >Discussion >References >Materials & methods >Contact authors Cancer Immunity, Vol. 1, p. 2 (30 March 2001) Submitted: 22 December 2000. Accepted: 6 February 2001. Contributed by: JC Cerottini Redirecting anti-viral CTL against cancer cells by surface targeting of monomeric MHC class I-viral peptide conjugated to antibody fragments Bruno Robert 1* , Philippe Guillaume 2* , Immanuel Luescher 3 , Marie-Agnès Doucey 3 , Jean-Charles Cerottini 3 , Pedro Romero 4 , and Jean-Pierre Mach 1,5 1 Institute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland 2 Multidisciplinary Oncology Center, University Hospital (CHUV), CH-1011 Lausanne, Switzerland 3 Ludwig Institute for Cancer Research, Lausanne Branch, CH-1066 Epalinges, Switzerland 4 Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital (CHUV), CH-1011 Lausanne, Switzerland 5 Swiss Institute for Experimental Cancer Research, ISREC, CH-1066 Epalinges, Switzerland * These authors contributed equally to this work Keywords: tumor antibodies, Fab immunoglobulins, MHC class I, immunoconjugates, cultured tumor cells, cytotoxic T-lymphocytes, immunotherapy Abstract To combine the advantage of both the tumor targeting capacity of high affinity monoclonal antibodies (mAbs) and the potent killing properties of cytotoxic T lymphocytes (CTL), we investigated the activity of conjugates made by coupling single Fab' fragments, from mAbs specific for tumor cell surface antigens, to monomeric HLA-A2 complexes containing the immunodominant influenza-matrix peptide 58-66. In solution, the monovalent 95 kDa Fab-HLA-A2/Flu conjugates did not activate influenza-specific CTL. However, when targeted to tumor cells expressing the relevant tumor-associated antigen, the conjugates induced CTL activation and efficient tumor cell lysis, as a result of MHC/peptide surface oligomerization. The highly specific and sensitive in vitro cytotoxicity results presented suggest that injection of Fab-MHC/peptide conjugates could represent a new form of immunotherapy, bridging antibody and T lymphocyte attack on cancer cells. Introduction The efficiency of T cell-based active immunotherapy (1, 2, 3) may be limited by the absence or low expression of either MHC molecules (4, 5) or their associated antigenic peptides by tumor cells (6). In contrast, monoclonal antibodies binding with high affinity to cell surface molecules abundantly expressed on cancer cells have been shown in clinical studies to localize specifically to tumor tissues (see 7 for review). Furthermore, injections of large amounts of selected mAbs have proven to be useful in the treatment of B cell lymphoma and breast carcinoma (8, 9). However, the capacity of antibodies to kill carcinoma cells is much weaker than that of cytotoxic T lymphocytes and clinical trials based on the use of antibodies alone showed less than 10% of complete tumor remission (8, 9). Thus, the idea of using mAbs reacting with tumor cells to target CTL-defined antigens in the form of Fab' fragments coupled to a soluble MHC/peptide complex represents an attractive immunotherapeutic strategy. As a first step in that direction, we recently showed that MHC class I/peptide tetramers assembled on streptavidin molecules that were coupled to tumor-reactive antibody Fab' fragments induced a specific tumor cell killing by relevant CTL (10). Lysis was strictly dependent on expression of the target antigen by the tumor cells. In a three step strategy, it was also recently shown that the sequential coating of tumor cells with biotinylated anti-tumor antibodies, followed by streptavidin and biotinylated MHC/peptide complexes can also sensitize tumor cells for killing by CTL (11). Cancer Immunity 1:2 (2001) - ARTICLE http://www.cancerimmunity.org/v1p2/010101.htm (1 of 13)