Abstract | PURPOSE: Linking a cytotoxic anticancer drug to an antibody that recognizes a tumor-associated antigen can improve the therapeutic index of the drug. We asked whether a conjugate of the cytotoxic antibiotic N-acetyl gamma calicheamicin dimethyl hydrazide (CalichDMH) and an antibody recognizing Lewis(y) ( Le(y)) antigen could eliminate carcinomas that express Le(y). Because Le(y) is highly expressed on carcinomas of colon, breast, lung, ovary, and prostate, a CalichDMH conjugate targeting Le(y) could provide a treatment option for various cancers. EXPERIMENTAL DESIGN: The humanized anti-Le(y) antibody hu3S193 was conjugated to CalichDMH via the bifunctional AcBut linker. Selectivity and avidity of the conjugate (hu3S193-CalichDMH) for Le(y)-BSA or Le(y+) cells was tested by BIAcore or flow cytometry. Cytotoxicity of hu3S193-CalichDMH was compared with toxicity of a control conjugate on monolayers of Le(y+) and Le(y-) carcinoma cells. Inhibition of tumor growth by hu3S193-CalichDMH was assessed on three types of s.c. xenografts. RESULTS:
Hu3S193-CalichDMH had similar selectivity as hu3S193. The conjugate had lower affinity for Le(y)-BSA but not for Le(y+) cells. When tested on monolayers of human Le(y+) carcinoma cells, hu3S193-CalichDMH was more cytotoxic than a control conjugate. This difference in efficacy was not noted on Le(y-) cells. Efficacy of hu3S193-CalichDMH depended on the expression of Le(y) and on the sensitivity of the cells to CalichDMH. In vivo, hu3S193-CalichDMH inhibited growth of xenografted human gastric (N87), colon (LOVO), and prostate carcinomas (LNCaP). When used against N87 xenografts, hu3S193-CalichDMH arrested tumor growth for at least 100 days. CONCLUSION:
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Authors | Erwin R Boghaert, Latha Sridharan, Douglas C Armellino, Kiran M Khandke, John F DiJoseph, Arthur Kunz, Maureen M Dougher, Fan Jiang, Lyka B Kalyandrug, Philip R Hamann, Philip Frost, Nitin K Damle |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 10
Issue 13
Pg. 4538-49
(Jul 01 2004)
ISSN: 1078-0432 [Print] United States |
PMID | 15240546
(Publication Type: Journal Article)
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Chemical References |
- Aminoglycosides
- Antibodies, Monoclonal
- Antigens
- Drug Combinations
- Enediynes
- Hydrazines
- Laminin
- Lewis Blood Group Antigens
- Lewis Y antigen
- Proteoglycans
- hu3S193-N-acetyl gamma calicheamicin dimethyl hydrazide
- calicheamicin gamma(1)I
- matrigel
- Collagen
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Topics |
- Aminoglycosides
(chemistry, pharmacology)
- Animals
- Antibodies, Monoclonal
(chemistry, pharmacology)
- Antigens
(chemistry)
- Carcinoma
(metabolism)
- Cell Line, Tumor
- Cell Separation
- Collagen
(chemistry)
- Dose-Response Relationship, Drug
- Dose-Response Relationship, Immunologic
- Drug Combinations
- Enediynes
- Female
- Flow Cytometry
- Humans
- Hydrazines
(pharmacology)
- Hydrolysis
- Immunotherapy
(methods)
- Kinetics
- Laminin
(chemistry)
- Lewis Blood Group Antigens
(chemistry)
- Male
- Mice
- Mice, Nude
- Models, Chemical
- Neoplasm Transplantation
- Protein Binding
- Proteoglycans
(chemistry)
- Sensitivity and Specificity
- Surface Plasmon Resonance
- Tissue Distribution
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