This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Trail, P. A. Articles by Hellström, I. Search for Related Content PubMed PubMed Citation Articles by Trail, P. A. Articles by Hellström, I.

Effect of Linker Variation on the Stability, Potency, and Efficacy of Carcinoma-reactive BR64-Doxorubicin Immunoconjugates

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543 [P. A. T., A. J. H., S. J. L., A. M. C., M. B. Y.]; Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492 [D. W., J. K., M. E. Z., H. D. K., S. J. H., R. A. F., K. M., K. F. K.]; and Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121 [K. E. H., I. H.]

The internalizing anti-Le^y monoclonal antibody (MAb) BR64 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to the DOX and either a disulfide or thioether bond to the MAb. The resulting disulfide (BR64-SS-DOX) and thioether (BR64-S-DOX) conjugates were evaluated for stability, potency, and antigen-specific antivity in both in vitro and in vivo model systems. The BR64-SS-DOX conjugates demonstrated antigen-specific activity both in vitro and when evaluated against antigen-expressing, DOX-sensitive human carcinoma xenografts. However, the stability and potency of disulfide conjugates were poor, and in vivo activity superior to unconjugated DOX was seen only at doses approaching the maximum tolerated dose. Furthermore, BR64-SS-DOX conjugates were not active against antigen-expressing, DOX-insensitive colon tumor xenografts. In contrast, the BR64-S-DOX conjugates demonstrated good stability both in vitro and in vivo. The increased stability of the BR64-S-DOX conjugates resulted in the delivery of more biologically active DOX to tumors with a concomitant increase in potency and efficacy over that which could be achieved with either unconjugated DOX or BR64-SS-DOX conjugates. Delivery of DOX by BR64-S-DOX conjugates resulted in complete regressions and cures of both DOX-sensitive lung xenografts and DOX-insensitive colon tumor xenografts. These results demonstrate the importance of linker stability when delivering drugs such as DOX to carcinomas via internalizing antibodies and are likely to have direct relevance to the clinical utility of MAb-directed delivery.

¹ To whom requests for reprints should be addressed, at Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, K22-01, Princeton, NJ 08543.

² Present address: Wyeth Ayerst Research, Radnor, PA 19087.

³ Present address: VION Pharmaceuticals, Inc., 4 Science Park, New Haven, CT 06511.

⁴ Present address: IDEC Corporation, 11011 Torreyana Dr., San Diego, CA 92121.

⁵ Present address: Sym Biotech, Inc., 8 Fairfield Boulevard, Wallingford, CT 06492.

Received 7/23/96. Accepted 11/ 1/96.

This article has been cited by other articles:

				D. E.H. Afar, V. Bhaskar, E. Ibsen, D. Breinberg, S. M. Henshall, J. G. Kench, M. Drobnjak, R. Powers, M. Wong, F. Evangelista, et al. Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer Mol. Cancer Ther., August 1, 2004; 3(8): 921 - 932. [Abstract] [Full Text] [PDF]