Anti-tumor efficacy of an anti-epidermal-growth-factor-receptor monoclonal antibody and its F(ab')2 fragment against high- and low-EGFR-expressing carcinomas in nude mice.
Monoclonal antibody (MAb) MINT5 specifically detects the epidermal-growth-factor receptor (EGFR). In vitro analyses of intact MINT5 (IgG1) and its F(ab')2 fragment indicated that both forms of the MAb inhibited binding of 125I-mEGF to EGFR, induced receptor internalization and blocked EGF-induced EGFR tyrosine-kinase activation in A431 cells. Both forms of the MAb also inhibited to the same extent the proliferation of the carcinoma cell lines A431 and IGROVI, despite the difference in EGFR levels on the cells. The detection of TGF alpha mRNA and the inhibition of cell growth in EGF-free conditions by anti-EGFR MAb indicated the involvement of an EGFR/TGF alpha autocrine/paracrine pathway in the in vitro growth of both cell lines. Analysis of mice xenotransplanted s.c. with A431 cells and treated with MINT5 revealed a block in A431 tumor take in 6 of 10 animals when intact MAb was administered from day 0 to day 11. On a molar basis, F(ab')2 at the same dose was ineffective, although at a 7-fold higher dose F(ab')2 reduced s.c. tumor growth by 80%. At the same dose, intact MINT5 MAb reduced s.c. growth of the EGFR-negative MeWo cell line by 5%. Survival of mice bearing IGROVI i.p. xenotransplants and treated locally with either form of MAb was significantly prolonged even when treatment was initiated on day 3. Corrected doses of intact and F(ab')2 fragment, which accounted for the difference in serum half-lives of the MAb forms, resulted in similar survival rates in the tumor-bearing mice. These pre-clinical results suggest that MINT5 MAb might be safely used for systemic therapy of EGFR-over-expressing tumors. Loco-regional therapy might be contemplated in the case of tumors with moderate/low EGFR expression.
Tosi
E
E
Division of Experimental Oncology E, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Valota
O
O
Negri
D R
DR
Adobati
E
E
Mazzoni
A
A
Meazza
R
R
Ferrini
S
S
Colnaghi
M I
MI
Canevari
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D007140:Immunoglobulin Fab Fragments; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy*; D016019:Survival Analysis; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors