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.