Tumor localization and in vivo antitumor activity of the immunoconjugate composed of anti-human colon cancer monoclonal antibody and mitomycin C-dextran conjugate.
The tissue distribution and in vivo antitumor activity of a novel monoclonal antibody-mitomycin C conjugate (A7-MMCD) composed of anti-human MAb A7 and MMC-dextran conjugate were investigated using tumor-bearing mice. A7-MMCD was prepared via an anionic dextran intermediate for the purpose of keeping the non-specific uptake by the reticuloendothelial system to a minimum. 111In-labeled A7-MMCD showed about a 5-times-greater accumulation in SW1116 (targeted tumor) than in S180 (non-targeted tumor) 48 h after injection, and produced a tumor-to-blood ratio which was 3 times higher in SW1116-bearing mice than in S180-bearing mice 96 h after injection. Accumulations in the liver, spleen, and kidney were also observed to some extent. Pharmacokinetic analysis revealed that A7-MMCD had nearly the same properties in the body as MMCDan (MMCD with an anionic charge), i.e., those of a negatively charged macromolecule. Both A7-MMCD and MMCDan had relatively similar tissue uptake rate indices for the liver and spleen. The tumor uptake rate index for SW1116 was about 2.5 times greater than that for S180, and the total amount of 111In-A7-MMCD accumulated in SW1116 was calculated to be approximately 5 times greater than the amount in S180. These results indicated that A7-MMCD could achieve site-specific targeting in the body. Furthermore, in the therapeutic experiment using SW1116 implanted subcutaneously, A7-MMCD suppressed tumor growth significantly, compared to free MMC and MMCDan. These results suggest that in designing an monoclonal antibody-drug conjugate via an intermediary, the physicochemical properties of intermediate macromolecules must also be taken into consideration to obtain a high degree of efficacy in vivo.
Noguchi
A
A
Department of Surgery, Kyoto Prefectural University of Medicine.
Takahashi
T
T
Yamaguchi
T
T
Kitamura
K
K
Takakura
Y
Y
Hashida
M
M
Sezaki
H
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000276:immunology*; D003911:Dextrans / Q000627:therapeutic use*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008937:Mitomycins / Q000627:therapeutic use*; D009132:Muscles / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D003911:Dextrans; D008937:Mitomycins