Synthesis and antitumor activity of the immunoconjugate BR96-Dox

• Published in: Journal of controlled release Vol. 39; no. 2; pp. 251 - 259
• Main Authors: Firestone, R.A., Willner, D., Hofstead, S.J., King, H.D., Kaneko, T., Braslawsky, G.R., Greenfield, R.S., Trail, P.A., Lasch, S.J., Henderson, A.J., Casazza, A.M., Hellström, I., Hellström, K.E.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier B.V 01-05-1996; Elsevier
• Subjects: Acid-labile hydrazone; Antibody-mediated targeting; Antineoplastic agents; Antitumor targeting; Biological and medical sciences; Doxorubicin; Endocytosis; General aspects; Hydrazone; Lysosome; Medical sciences; Pharmacology. Drug treatments; PBS; Antibody-mediated targeting; Ab; MR; Acid-labile hydrazone; Ag; Fab; Lysosome; ip; Dox; Doxorubicin; iv; MAb; SPDP; MST; CR; sc; Endocytosis; Le y; IC; Hydrazone; MTD; Fc; Antitumor targeting; Antineoplastic agent; Biological fixation; Anthracyclins; Monoclonal antibody; Immunoconjugate; Conjugated compound; Chemical synthesis; Biological activity; Tumor cell
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/0168-3659(95)00160-3

BR96-Dox is an immunoconjugate (IC) in which doxorubicin (8 equivalents) is linked via an acid-labile hydrazone to the chimeric MAb BR96. It binds to a modified Le
y Ag on tumor cells, which then internalize it via endocytosis into lysosomes. There, the acidic milieu hydrolyzes the hydrazone link, releasing free Dox. In vivo, it is more active and less toxic than untargeted Dox, producing complete remissions and many cures of subcutaneous human breast, lung and colon tumors, as well as disseminated lung tumors. In vivo, only BR96
+ and not BR96
− tumors respond, and ICs with nonbinding Abs are inactive.