Therapy of human cervical carcinoma with monoclonal antibody-Pseudomonas exotoxin conjugates.
Pseudomonas exotoxin A (PE) linked to the F(ab')2 fragment of 1H10, a murine monoclonal antibody recognizing a carbohydrate epitope of a glycoconjugate expressed on the surface of human cervical carcinoma tumor cells, was evaluated for in vitro and in vivo activity. PE can kill cells by ADP-ribosylating elongation factor 2 thus inhibiting protein synthesis. Disulfide- as well as thioether-linked immunotoxins (1H10-PE) killed cervical carcinoma cells in vitro and were 20-160 times more inhibitory to target than to control cells. Cell killing was antibody mediated as demonstrated by the reduction of 1H10-PE growth inhibition to target CaSki cells by free 1H10 F(ab')2. In addition, a control antibody immunotoxin was nontoxic to CaSki cells. Thioether-linked 1H10-PE administered either i.v. or i.p. suppressed the growth of established solid s.c. cervical carcinoma tumors xenografted in nude mice for over 30 days. Treatment with antibody alone or a control immunotoxin had no significant effect on tumor growth. Administration of immunotoxin i.p. was associated with less toxicity than administration i.v., but i.v. injections were more effective at suppressing the growth of established solid tumors.
Roffler
S R
SR
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
Yu
M H
MH
Chen
B M
BM
Tung
E
E
Yeh
M Y
MY
D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000918:Antibody Specificity; D001427:Bacterial Toxins; D004220:Disulfides / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D005098:Exotoxins / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013440:Sulfides / Q000737:chemistry / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000276:immunology; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D004220:Disulfides; D005098:Exotoxins; D000922:Immunotoxins; D013440:Sulfides; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A