title: Specific targeting and killing activities of anti-P-glycoprotein monoclonal antibody MRK16 directed against intrinsically multidrug-resistant human colorectal carcinoma cell lines in the nude mouse model.
abstract: Anti-P-glycoprotein (P-gp) monoclonal antibody, MRK16, and its F(ab')2 fragment were evaluated for its therapeutic efficacy to P-gp-mediated multidrug resistant human colorectal carcinoma cell lines in a nude mouse model. In a blood clearance experiment, 125I-labeled MRK16 had a half-life (16 h) 7 times longer than its F(ab')2 fragment (half-life of 1.8 h) in circulation in nude mice, and approximately 16 and 5% of MRK16 were retained on days 10 and 20 after injection, respectively. In biodistribution experiments using nude mice bearing HCT-15, an intrinsically resistant cell line, 125I-labeled MRK16 accumulated at the tumor site significantly higher than its F(ab')2 fragment as revealed by the percentage of injected dose/g of tissue values (7.4 versus 0.6%) on day 3 after injection. In contrast, the tissue to blood ratio at the tumor site of the MRK16 was significantly lower than that of its F(ab')2 fragment (1.2 versus 10.5). Specific targeting of the MRK16 F(ab')2 fragment to the P-gp-positive tumor (HCT-15) but not to the P-gp-negative tumor (COLO 205) was observed in the nude mice bearing both tumors. In the therapeutic efficacy tests, when administered i.v. 3 times on days 1, 4, and 7 after tumor s.c. inoculation, MRK16 alone showed the significant inhibition of tumor growth of P-gp-positive cell lines, HCT-15, DLD-1, SW480, and SW1417 in contrast to cases of P-gp-negative cell lines, COLO 205 and KM20L2. This inhibitory effect of MRK16 was enhanced in combination with Adriamycin, which alone hardly inhibited the tumor growth. However, MRK16 F(ab')2 fragment alone, even at 1 mg/mouse, had little inhibitory effect on the growth of HCT-15 in the same treatment schedule. When administered at early palpable stage, the degree of HCT-15 tumor growth suppression depended on the number of MRK16 injections. At more progressed stages, treatment with MRK16 alone showed little antitumor activity but when combined with Adriamycin resulted in significant suppression of tumor growth. The present results suggest that MRK16 may be useful for in vivo immunoscintigraphy and immunotherapy of multidrug-resistant colorectal carcinoma.
authors.affiliation: Pharma Research Laboratories, Hoechst Japan LTD., Saitama.
authors.forename: T
authors.initials: T
authors.lastname: Iwahashi
authors.forename: E
authors.initials: E
authors.lastname: Okochi
authors.forename: K
authors.initials: K
authors.lastname: Ariyoshi
authors.forename: H
authors.initials: H
authors.lastname: Watabe
authors.forename: E
authors.initials: E
authors.lastname: Amann
authors.forename: S
authors.initials: S
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
authors.forename: K
authors.initials: K
authors.lastname: Ono
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000628:therapy*; D004306:Dose-Response Relationship, Immunologic; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005260:Female; D006207:Half-Life; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D007140:Immunoglobulin Fab Fragments; D008562:Membrane Glycoproteins; D004317:Doxorubicin