Gary R. Braslawsky

Adriamycin(hydrazone)-antibody conjugates require internalization and intracellular acid hydrolysis for antitumor activity.

SummaryAdriamycin hydrazone (ADM-Hzn) immunoconjugates have previously been shown to exhibit antibody-directed antitumor activity in vitro and in vivo. In this report, the biological and biochemical properties of the mAb and linker were investigated. Conjugates prepared with two antibodies 5E9 [anti-(transferrin receptor)] and G28.1 (anti-CD37), (which internalize from the surface of target cells following binding) were more cytotoxic in vitro and had greater antitumor activity against Daudi B lymphoma tumor xenografts than a non-internalizing immunoconjugate prepared with mAb 2H7 (anti-CD20). In addition, the 13-acylhydrazone bond linking the drug to the mAb was labile at pH 5 and released unmodified ADM at a rapid rate (t1/2 = 2.5 h). Immunoconjugates prepared with an oxime linkage at the C-13 position were stable to acid and were not cytotoxic. These findings suggest that internalization of ADM-Hzn immunoconjugates and release of free ADM from the mAb in acidic intracellular compartments were important steps in the mechanism of action of ADM-Hzn immunoconjugates.

Future of monoclonal antibodies in the treatment of hematologic malignancies

BACKGROUND The approval of monoclonal antibodies (MAbs) as antibody-targeted therapy in the management of patients with hematologic malignancies has led to new treatment options for this group of patients. The ability to target antibodies to novel functional receptors can increase their therapeutic efficacy. METHODS The authors reviewed improvements in MAb design to enhance their effectiveness over the existing therapeutic MAb currently approved for treating hematologic malignancies. RESULTS Three classes of therapeutic MAbs showing promise in human clinical trials for treatment of hematologic malignancies include unconjugated MAb, drug conjugates in which the antibody preferentially delivers a potent cytotoxic drug to the tumor, and radioactive immunotherapy in which the antibody delivers a sterilizing dose of radiation to the tumor. CONCLUSIONS A better appreciation of how MAbs are metabolized in the body and localized to tumors is resulting in the development of new antibody constructs with improved biodistribution profiles.

Synthesis and antitumor activity of the immunoconjugate BR96-Dox

Abstract 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.