Antigenic heterogeneity in human ovarian cancer.

Primary and metastatic tumor tissues from 21 patients with ovarian epithelial cancer were studied with a panel of 8 monoclonal antibodies. Primary tumors reacted with 1 to 7 antibodies (mean, 3.5). Heterogeneity was observed even within histologic subtypes. Comparison of metastases (including ascites) with their respective primaries revealed differences in antigen profile in each of 10 cases studied. In one patient variable antigen expression was observed in five ascites samples collected over a 12-month period. These observations of antigenic heterogeneity and modulation with respect to site and time suggest that single monoclonal antibody immunotherapy would not be appropriate for all patients or even for a single patient over time.

Distribution and pharmacokinetics of radiolabeled monoclonal antibody OC 125 after intravenous and intraperitoneal administration in gynecologic tumors.

Radiolabeled monoclonal antibodies may be useful for radioimmunotherapy of gynecologic tumors. Iodine 131-labeled F(ab')2 fragments of a monoclonal antibody, OC 125, with specificity for ovarian carcinoma, were used to study the distribution and pharmacokinetics of this antibody in patients with gynecologic tumors. The radiolabeled antibody was injected intravenously or intraperitoneally into 10 patients suspected of having ovarian cancer. Blood and urine samples were used for pharmacokinetic studies, and biopsy specimens were examined for the uptake of antibody. The serum half-life of the labeled antibody was 30 hours after intravenous administration, with 20% of the injected dose per liter detected at 24 hours. After intraperitoneal injection, the appearance of antibody in serum was slow, with a maximum level of 1.4% of the injected dose per liter at 24 hours. Urinary excretion of the radiolabeled antibody was similar for intravenous and intraperitoneal administration, with approximately 50% of the injected dose excreted after 48 hours. Intraperitoneal administration of the radiolabeled antibody resulted in a higher uptake of antibody in the tumor and a lower uptake of antibody in normal tissues. On the basis of this limited study, intraperitoneal administration of radiolabeled antibody is preferred over intravenous administration for radioimmunotherapy of ovarian cancer.

Localization of radiolabelled F(ab')2 fragments of monoclonal antibodies in nude mice bearing intraperitoneally growing human ovarian cancer xenografts.

The biodistribution and pharmacokinetics of 2 monoclonal antibodies (MAbs) specific for ovarian carcinoma, OC125 and OV-TL3, were studied in nude mice bearing intraperitoneally (i.p.) growing human ovarian carcinoma xenografts of NIH:OVCAR-3. The ovarian carcinoma xenografts grew as non-adherent cells in ascites and as solid implants in the peritoneal cavity of injected mice. The biodistribution and pharmacokinetics were determined by measurement of radioactivity in tumor masses, ascites, blood and other tissues after intravenous (i.v.) and i.p. injection of radioiodinated F(ab')2 fragments of MAbs. The specificity of the observed tumor localization was then evaluated by comparing the uptake of the anti-ovarian carcinoma antibodies OC125 and OV-TL3 with the uptake of a radioiodinated non-ovarian carcinoma-specific MAb A2C6. The results of the study indicate that uptake of the anti-ovarian carcinoma antibodies was highest in the non-adherent tumor cells in the ascites after i.p. injection. The observed uptake was 85% injected dose/g for OV-TL3 and 22% injected dose/g for OC125. This compares to the observed antibody uptake of 9% injected dose/g for OV-TL3 and less than 1% injected dose/g for OC125 in solid tumor masses after i.p. injection. After i.v. injection, uptake of OC125 and OV-TL3 was less than 3% injected dose/g, both for nonadherent tumor cells and for solid tumor masses. The data support the conclusion that OV-TL3 is superior to OC125 and that i.p. administration of radiolabelled MAb F(ab')2 fragments is superior to their i.v. administration for immunotherapy of ovarian carcinoma.

Biodistribution, pharmacokinetics and imaging of 131I-labelled OC125 in ovarian cancer.

Fifteen patients with or suspected of having ovarian carcinoma were injected intravenously (i.v.) or intraperitoneally (i.p.) with 131I-labelled OC125 F(ab')2. Radioimmunoscintigraphy after i.v. injection revealed 50% of the tumor sites. After i.p. injection all tumor sites were visualized, except in one case in which the antibody remained loculated because of adhesions. One patient with endometrial cancer showed no specific uptake of the antibody after i.p. injection. The serum half-life of the radiolabelled antibody after i.v. injection was 30 hr. After i.p. injection there was a slow appearance of radiolabelled antibody in the blood with a maximum level of 1.4% dose per liter at 24 hr after injection. Urinary excretion of the radiolabel was the same for both routes of administration, with 50% of the dose excreted in approximately 48 hr. Tumor uptake was slightly higher after i.p. injection. Liver and bone marrow uptake after i.p. injection were one-half of the uptake after i.v. injection.

Antibody-antigen complex formation following injection of OC125 monoclonal antibody in patients with ovarian cancer.

Monoclonal antibody (MAb) OC125 binds to approximately 80% of epithelial ovarian cancers. Serum antigen, CA125, can be detected in these patients. 131I-OC125-F(ab')2 was injected into 5 ovarian carcinoma patients with preinjection serum levels of 150 to 9,000 CA125 U/ml. Patients received the antibody intravenously in doses ranging from 0.46 to 0.94 mg with a specific activity of approximately 2.5 mCi/mg 131I. The half-life in the circulation was approximately 30 hr and was independent of serum CA125 levels. Clearance of 131I from the circulation fitted an open, one-compartment mathematical model. Gel filtration chromatography revealed antibody-antigen complexes in sera 15 min after injection of the radiolabelled antibody. By 5 days after injection, the free form of OC125 antibody could not be detected in the serum. The rate of complex formation correlated well with the observed preinjection serum CA125 levels. This direct correlation was verified in vitro using purified CA125 antigen and radiolabelled OC125 F(ab')2 fragments. The specific effects of complex formation on tumor localization remains unclear. However, the presence of complexes should not be ignored, when planning for diagnostic imaging or immunotherapy with OC125 or other MAbs reacting with circulating antigen.