Recombinant antibody toxins specific for ErbB2 and EGF receptor inhibit the in vitro growth of human head and neck cancer cells and cause rapid tumor regression in vivo.
Overexpression of the ErbB2 and epidermal growth factor receptor (EGFR) tyrosine kinases is frequently observed in squamous cell carcinomas of the head and neck, and has been correlated with shorter overall survival. By immunoblot analysis, we have found EGFR and ErbB2 expression in 6 out of 6 established head and neck cancer cell lines. Elevated EGFR protein levels were noted in 3 and elevated ErbB2 levels in 5 of them. Significant expression of EGFR and ErbB2 was also detected in 17 of 47 and 26 of 45 primary tumor samples. Due to their enhanced expression on the tumor cell surface, these receptors can be regarded as suitable targets for directed cancer therapy. We have analyzed the antitumoral activity of recombinant single-chain antibody toxins specific for ErbB2 and EGFR against head and neck cancer cells in vitro and in vivo. The recombinant toxins consist of the variable domains of the heavy and light chains of monoclonal antibodies (MAbs) genetically fused to a truncated Pseudomonas exotoxin A (ETA). At low concentrations, the ErbB2-specific single-chain antibody (scFv) toxin scFv(FRP5)-ETA and the EGFR-specific toxins scFv(225)-ETA and scFv(14E1)-ETA inhibited the in vitro growth of established head and neck cancer cell lines and primary tumor cells. In a nude mouse tumor model, intratumoral injection of the antibody toxins resulted in the rapid regression of subcutaneously growing CAL 27 tumor xenografts, with scFv(FRP5)-ETA and scFv(14E1)-ETA treatment being most effective and leading to the cure of up to 50% of the animals. Our results suggest that EGFR and ErbB2-specific antibody toxins may become valuable therapeutic reagents for the treatment of squamous cell carcinomas of the head and neck.
Azemar
M
M
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Schmidt
M
M
Arlt
F
F
Kennel
P
P
Brandt
B
B
Papadimitriou
A
A
Groner
B
B
Wels
W
W
D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division; D066246:ErbB Receptors / Q000032:analysis / Q000276:immunology*; D005098:Exotoxins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D066246:ErbB Receptors; D005098:Exotoxins; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A