Adriamycin(hydrazone)-antibody conjugates require internalization and intracellular acid hydrolysis for antitumor activity |
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Authors: | Gary R Braslawsky Kathleen Kadow Jay Knipe Kerry McGoff Mary Edson Takushi Kaneko Robert S Greenfield |
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Institution: | (1) Bristol-Myers Squibb, 5 Research Parkway, P. O. Box 5100, 06492-7600 Wallingford, CT, USA;(2) Central Chemistry, Pfizer Inc., 06340 Groton, CT, USA |
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Abstract: | Summary Adriamycin 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. |
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Keywords: | Monoclonal antibodies Immunoconjugates Adriamycin |
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