Engineered vascular-targeting antibody-interferon-gamma fusion protein for cancer therapy.
A number of cytokines are either approved drugs or are in advanced clinical trials, yet these biopharmaceuticals do not typically localize efficiently in solid tumors and manifest their therapeutic potential at the expense of severe side effects. The targeted delivery of cytokines to solid tumors is a promising avenue for increasing the therapeutic index of these biopharmaceuticals. We engineered a fusion protein between scFv(L19), a human antibody fragment specific to the EDB domain of fibronectin, and a cysteine-free mutant of murine interferon-gamma. The resulting fusion protein was capable of targeting new blood vessels in solid tumors, and the targeting efficiency was strikingly increased in tumor-bearing knockout mice lacking the interferon-gamma receptor. ScFv(L19)-interferon-gamma displayed a strong antitumor effect in both subcutaneous and metastatic murine F9 teratocarcinomas, but was not efficacious as single agent when used to treat C51 and CT26 tumors. The potency of this fusion protein could be substantially enhanced by combination with doxorubicin and other immunocytokines. These findings are of clinical relevance, as the EDB domain is a marker of angiogenesis, with identical sequence in mouse and man, which is abundantly expressed in a variety of aggressive solid tumors but is undetectable in most normal tissues.
Ebbinghaus
Christina
C
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Zürich, Switzerland.
Ronca
Roberto
R
Kaspar
Manuela
M
Grabulovski
Dragan
D
Berndt
Alexander
A
Kosmehl
Hartwig
H
Zardi
Luciano
L
Neri
Dario
D
D000230:Adenocarcinoma / Q000473:pathology* / Q000662:veterinary; D000818:Animals; D003110:Colonic Neoplasms / Q000473:pathology* / Q000662:veterinary; D005353:Fibronectins / Q000737:chemistry* / Q000494:pharmacology*; D007128:Immunoglobulin Fragments; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D057127:Single-Chain Antibodies; D018243:Teratocarcinoma / Q000473:pathology* / Q000662:veterinary; D013736:Testicular Neoplasms / Q000473:pathology* / Q000662:veterinary
D005353:Fibronectins; D007128:Immunoglobulin Fragments; D011993:Recombinant Fusion Proteins; C502475:ScFv(L19)-interferon-gamma; D057127:Single-Chain Antibodies; D007371:Interferon-gamma