Cancer Immunity 1:2 (2001)

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 Luescher³, Marie-Agnès Doucey³, Jean-Charles Cerottini³, Pedro Romero⁴, and Jean-Pierre Mach^1,5

¹Institute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland
²Multidisciplinary Oncology Center, University Hospital (CHUV), CH-1011 Lausanne, Switzerland
³Ludwig Institute for Cancer Research, Lausanne Branch, CH-1066 Epalinges, Switzerland
⁴Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, University Hospital (CHUV), CH-1011 Lausanne, Switzerland
⁵Swiss 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.