Copper-67 radioimmunotherapy and growth inhibition by anti-L1-cell adhesion molecule monoclonal antibodies in a therapy model of ovarian cancer metastasis

Purpose: We examined the tumor-targeting and therapeutic effects of Cu-67-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 Cu-67-4-(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 Cu-67-chCE7agl alone on tumor reduction and survival were investigated. In addition, a combination of low-dose Cu-67-radioimmunotherapy with unlabeled anti-L1 antibody L1-11A on survival was investigated. Results : Cu-67-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. Cu-67-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 Cu-67-chCE7agl reduced tumor growth but did not prolong survival significantly, whereas a single 10.5 MBq dose of Cu-67-chCE7agl reduced tumor growth and prolonged survival significantly. The combination of unlabeled monoclonal antibody L1-11A with a subtherapeutic dose of Cu-67-radioimmunotherapy also prolonged survival significantly. Conclusion: The results show improved pharmacokinetics and biodistributions as well as the therapeutic effect of the Cu-67-labeled single amino acid mutant chCE7agl. Therapeutic data indicate, for the first time, the feasibility of combining anti-L1-directed growth inhibition and Cu-67-radioimmunotherapy, thereby increasing the efficiency of antibody treatment of metastatic ovarian carcinoma.