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Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193-N-Acetyl Calicheamicin Dimethyl Hydrazide Targets Lewis^y and Eliminates Lewis^y-Positive Human Carcinoma Cells and Xenografts

¹ Wyeth Discovery Oncology and ² Wyeth Discovery Chemical and Screening Sciences, Pearl River, New York

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 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: Hu3S193-CalichDMH can specifically eliminate Le^y+ tumors. These results support development of this conjugate for treatment of carcinomas.

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