Targeted therapy against human lung cancer in nude mice by high-affinity recombinant antimesothelin single-chain Fv immunotoxin.
Several tumors, including mesothelioma and ovarian cancer, can overexpress mesothelin, a glycosylphosphatidylinositol-linked differentiation glycoprotein. The membrane-bound type of mesothelin is found in the blood of cancer patients at a very low level, which makes mesothelin a good candidate for targeted therapy of certain cancers. An antimesothelin disulfide-linked Fv (SS1 Fv) was fused to a truncated mutant of Pseudomonas exotoxin A to produce the recombinant immunotoxin SS1(dsFv)-PE38, which has a high binding affinity to mesothelin (Kd = 0.7 nM). Our studies in vitro showed that SS1(dsFv)-PE38 is significantly more cytotoxic to the high-mesothelin-producing NCI-H226 human non-small cell lung cancer cells than to human lung adenocarcinoma PC14PE6 cells, which do not express mesothelin. When administered at a nontoxic dose of 500 microg/kg on days 7, 9, and 11 to nude mice injected i.v. with the two human lung cancer cell lines, SS1(dsFv)-PE38 selectively inhibited experimental lung metastases produced by the mesothelin-producing NCI-H226 cells. Our data indicate that mesothelin-producing squamous cell carcinoma of the lung may be a good target for this immunotoxin.
Fan
Dominic
D
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. dfan@mdanderson.org
Yano
Seiji
S
Shinohara
Hisashi
H
Solorzano
Carmen
C
Van Arsdall
Melissa
M
Bucana
Corazon D
CD
Pathak
Sen
S
Kruzel
Ewa
E
Herbst
Roy S
RS
Onn
Amir
A
Roach
Jennifer S
JS
Onda
Masanori
M
Wang
Qing-cheng
QC
Pastan
Ira
I
Fidler
Isaiah J
IJ
D036002:ADP Ribose Transferases / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007128:Immunoglobulin Fragments / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D007700:Kinetics; D008175:Lung Neoplasms / Q000628:therapy*; D000090204:Mesothelin; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009154:Mutation; D009368:Neoplasm Transplantation; D011549:Pseudomonas / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D037521:Virulence Factors / Q000378:metabolism; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D007128:Immunoglobulin Fragments; D000090204:Mesothelin; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C000715528:Msln protein, mouse; C055966:immunoglobulin Fv