ArticleProceedings of the National Academy of Sciences of the United States of America2001
In vivo activity in a catalytic antibody-prodrug system: Antibody catalyzed etoposide prodrug activation for selective chemotherapy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 98 citations in OpenAlex.
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- Dual-Drug Nanosystem: Etoposide Prodrug and Cisplatin Coloaded Nanostructured Lipid Carriers for Lung Cancer Therapy.Drug design, development and therapy · 2022Article
- Chemical Modification of Linkers Provides Stable Linker-Payloads for the Generation of Antibody-Drug Conjugates.ACS medicinal chemistry letters · 2020Article
- Dual turn-on fluorescence signal-based controlled release system for real-time monitoring of drug release dynamics in living cells and tumor tissues.Theranostics · 2018Article
- Expanding the concept of chemically programmable antibodies to RNA aptamers: chemically programmed biotherapeutics.Angewandte Chemie (International ed. in English) · 2010Article
- Direct observation of an enamine intermediate in amine catalysis.Journal of the American Chemical Society · 2009Article
- Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation.Proceedings of the National Academy of Sciences of the United States of America · 2007Article
- Breaking the one antibody-one target axiom.Proceedings of the National Academy of Sciences of the United States of America · 2006Article
- Prodrugs of dynemicin analogs for selective chemotherapy mediated by an aldolase catalytic Ab.Proceedings of the National Academy of Sciences of the United States of America · 2004Article
- Chemically programmed monoclonal antibodies for cancer therapy: adaptor immunotherapy based on a covalent antibody catalyst.Proceedings of the National Academy of Sciences of the United States of America · 2003Article
- Alternative splicing as a novel of means of regulating the expression of therapeutic genes.Cancer gene therapy · 2002Article
- Synthesis of an organoinsulin molecule that can be activated by antibody catalysis.Proceedings of the National Academy of Sciences of the United States of America · 2001Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Effective chemotherapy remains a key issue for successful cancer treatment in general and neuroblastoma in particular. Here we report a chemotherapeutic strategy based on catalytic antibody-mediated prodrug activation. To study this approach in an animal model of neuroblastoma, we have synthesized prodrugs of etoposide, a drug widely used to treat this cancer in humans. The prodrug incorporates a trigger portion designed to be released by sequential retro-aldol/retro-Michael reactions catalyzed by aldolase antibody 38C2. This unique prodrug was greater than 10(2)-fold less toxic than etoposide itself in in vitro assays against the NXS2 neuroblastoma cell line. Drug activity was restored after activation by antibody 38C2. Proof of principle for local antibody-catalyzed prodrug activation in vivo was established in a syngeneic model of murine neuroblastoma. Mice with established 100-mm3 s.c. tumors who received one intratumoral injection of antibody 38C2 followed by systemic i.p. injections with the etoposide prodrug showed a 75% reduction in s.c. tumor growth. In contrast, injection of either antibody or prodrug alone had no antitumor effect. Systemic injections of etoposide at the maximum tolerated dose were significantly less effective than the intratumoral antibody 38C2 and systemic etoposide prodrug combination. Significantly, mice treated with the prodrug at 30-fold the maximum tolerated dose of etoposide showed no signs of prodrug toxicity, indicating that the prodrug is not activated by endogenous enzymes. These results suggest that this strategy may provide a new and potentially nonimmunogenic approach for targeted cancer chemotherapy.
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