Selective antibody-mediated targeting of class I MHC to EGFR-expressing tumor cells induces potent antitumor CTL activity in vitro and in vivo.
Epidermal growth factor receptor (EGFR) is highly overexpressed in many tumor types. We present a new fusion molecule that can target solid tumors that express EGFR. The fusion molecule combines the advantage(s) of the well-established tumor targeting capabilities of high affinity recombinant fragments of antibodies with the known efficient, specific and potent killing ability of CD8 T lymphocytes directed against highly antigenic MHC/peptide complexes. A recombinant chimeric molecule was created by the genetic fusion of the scFv antibody fragment derived from the anti-EGFR monoclonal antibody C225, to monomeric single-chain HLA-A2 complexes containing immunodominant tumor or viral-specific peptides. The fusion protein can induce very efficiently CTL-dependent lysis of EGFR-expressing tumor cells regardless of the expression of self peptide-MHC complexes. Moreover, the molecule exhibited very potent antitumor activity in vivo in nude mice bearing preestablished human tumor xenografts. These in vitro and in vivo results indicate that recombinant scFv-MHC-peptide fusion molecules might represent a novel and powerful approach to immunotherapy of solid tumors, bridging antibody and T lymphocyte attack on cancer cells.
Novak
Hila
H
Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
Noy
Roy
R
Oved
Kfir
K
Segal
Dina
D
Wels
Winfried S
WS
Reiter
Yoram
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D066246:ErbB Receptors / Q000032:analysis / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use*; D057127:Single-Chain Antibodies; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C517216:scHLA-A2 scFv 225 fusion protein; D066246:ErbB Receptors