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Copper-67 Radioimmunotherapy and Growth Inhibition by Anti–L1-Cell Adhesion Molecule Monoclonal Antibodies in a Therapy Model of Ovarian Cancer Metastasis

Authors' Affiliations: ¹ Center for Radiopharmaceutical Science, ETH-PSI-USZ, Paul Scherrer Institute, Villigen, Switzerland; ² Federal Institute of Technology, Zürich, Switzerland; ³ German Cancer Research Center, Heidelberg, Germany; and ⁴ Department of Pathology, Kaplan Medical Center, Rehovot, Israel

Requests for reprints: Ilse Novak-Hofer, Center for Radiopharmaceutical Science, ETH-PSI-USZ, Paul Scherrer Institute, CH-5232 Villigen, Switzerland. Phone: 41-56-310-4067; Fax: 41-56-310-2849; E-mail: ilse.novak{at}psi.ch.

Purpose: We examined the tumor-targeting and therapeutic effects of ⁶⁷Cu-labeled single amino acid mutant forms of anti-L1 monoclonal antibody chCE7 in nude mice with orthotopically implanted SKOV3ip human ovarian carcinoma cells.

Experimental Design: For radioimmunotherapy, chCE7 antibodies with a mutation of histidine 310 to alanine (chCE7H310A) and a mutation of asparagine 297 to glutamine (chCE7agl) were generated to achieve more rapid blood clearance. Biodistributions of ⁶⁷Cu-4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl benzoic acid tetrachloride (CPTA)–labeled mutant antibodies were measured in nude mice bearing SKOV3ip human ovarian cancer metastases. The effects of single i.v. injections of ⁶⁷Cu-chCE7agl alone on tumor reduction and survival were investigated. In addition, a combination of low-dose ⁶⁷Cu-radioimmunotherapy with unlabeled anti-L1 antibody L1-11A on survival was investigated.

Results: ⁶⁷Cu-CPTA-chCE7agl showed high (up to 49% ID/g) and persistent (up to 168 h) uptake in SKOV3ip metastases, with low levels in normal tissues. ⁶⁷Cu-CPTA-chCE7H310A revealed a shorter half-life in the blood and a lower tumor uptake and retention. A single low dose of 4 MBq of ⁶⁷Cu-chCE7agl reduced tumor growth but did not prolong survival significantly, whereas a single 10.5 MBq dose of ⁶⁷Cu-chCE7agl reduced tumor growth and prolonged survival significantly. The combination of unlabeled monoclonal antibody L1-11A with a subtherapeutic dose of ⁶⁷Cu-radioimmunotherapy also prolonged survival significantly.

Conclusion: The results show improved pharmacokinetics and biodistributions as well as the therapeutic effect of the ⁶⁷Cu-labeled single amino acid mutant chCE7agl. Therapeutic data indicate, for the first time, the feasibility of combining anti–L1-directed growth inhibition and ⁶⁷Cu-radioimmunotherapy, thereby increasing the efficiency of antibody treatment of metastatic ovarian carcinoma.