Monovalent immunotoxin containing truncated form of Pseudomonas exotoxin as potent antitumor agent.

摘要: Abstract Recombinant truncated forms of Pseudomonas exotoxin A that lack the cell binding domain were coupled to an F(ab′) fragment a monoclonal antibody HB21 directed against human transferrin receptor. One these was NlysPE40. The other, NlysPE38QQR, has two amino groups on residues near NH2-terminus and no COOH-terminus. proteins linked by stable thioether bond connected sulfhydryl group present in hinge region toxin. F(ab′)-PE40 immunotoxin, containing NlysPE40, exhibited potent cytotoxic activity carcinoma lines with concentration immunotoxin at which isotope incorporation falls 50% when compared nontreated cells (ID50) 5.3 pm (0.5 ng/ml) both epidermoid A431 colon Colo205. Immunotoxins madewith whole considerably less active, ID50 15.9 (3.1 lines. F(ab′)-PE38QQR, found be most active agent 1.05 (0.1 cells. greater cytotoxicity immunotoxins fragmented probably due higher affinity conjugates comparison increase made NlysPE38QQR than NlysPE40 may reflect selective coupling toxin through NH2-terminal groups. monovalent divalent had dose-dependent antitumor effects xenografts nude mice. tumors completely regressed all animals total dose 105 pmol (10 µg) F(ab′)-PE38QQR 154 (30 IgG-PE38QQR. Furthermore, toxic mice conjugate IgG (840 or 80 µg causing measurable adverse versus 208 40 µg, respectively). Thus, molecule is more antibody. Therefore, therapeutic index for about four times better immunotoxin.