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Identification and immunotherapeutic targeting of antigens induced by chemotherapy


Cancer cells differ from normal cells in their response to chemotherapy. We exploited this dissimilarity by identifying and targeting tumor-specific, cell-surface proteins whose expression is induced by the chemotherapeutic irinotecan (CPT-11; Camptosar). A cytotoxin-armed antibody reactive with one of these drug-induced surface proteins, the LY6D/E48 antigen, originally identified as the target of a monoclonal antibody reactive with squamous cell carcinomas, caused complete regression of colorectal tumor xenografts in mice treated with CPT-11, whereas either agent alone was less effective. These results suggest that a positive therapeutic index may be generated for other drug combinations by immunotherapeutic targeting of chemotherapy-induced antigens.

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Figure 1: mRNA transcripts coding for cell-surface proteins induced by CPT-11.
Figure 2: Expression of mouse intestinal transcripts homologous to those induced in human tumor xenografts.
Figure 3: Induction of cell-surface reactive LY6D/E48 protein in vitro by CPT-11 and SN-38.
Figure 4: Anti-tumor activity of CPT-11 combined with anti-LY6D/E48-drug conjugate.

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We thank Peter Senter and Damon Meyer for preparation of drug-conjugated antibodies, Tracey McKenna, Angela Lamb, JoAnne Hongo and Kurt Schroeder for generation and purification of monoclonal antibodies to LY6D/E48 and technical assistance.

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Correspondence to Paul Polakis.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Transcripts induced in Colo205 tumor xenografts exposed to CPT-11. (PDF 51 kb)

Supplementary Table 2

Transcripts induced in the intestine of mice exposed to CPT-11. (PDF 46 kb)

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Rubinfeld, B., Upadhyay, A., Clark, S. et al. Identification and immunotherapeutic targeting of antigens induced by chemotherapy. Nat Biotechnol 24, 205–209 (2006).

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