Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment. See The biology behind: K. A. Foon and M. Bhattacharya-Chatterjee, Are solid tumor anti-idiotype vaccines ready for prime time? Clin. Cancer Res., 7:1112-1115, 2001.

The aim of the present study was to assess whether the induction of specific immune responses by vaccination with the murine monoclonal anti-idiotypic antibody ACA125, which imitates the tumor-associated antigen CA125, has a positive influence on the survival of patients with recurrent ovarian carcinoma. Forty-two patients with platinum-pretreated recurrences were included in a clinical Phase I/II trial of consolidation in third-line therapy. Patients initially received four immunizations with 2 mg of alum-precipitated anti-idiotype ACA125 every 2 weeks and then monthly applications. No serious allergic reactions could be detected within a maximal control period of 56 months. Hyperimmune sera of 27 of 42 patients (64.2%) showed increased concentrations of human antimouse antibodies. Specific anti-anti-idiotypic antibodies as a marker for induced immunity were detected in 28 of 42 patients (66.7%). The survival of the whole ACA125-treated collective of patients after a mean of 12.6 antibody applications was 14.9 +/- 12.9 months. The survival of patients with a positive immune response was 19.9 +/- 13.1 months in contrast with 5.3 +/- 4.3 months in those patients without detectable anti-CA125 immunity (P < 0.0001). According to these results, vaccination with a suitable anti-idiotypic antibody offers an effective way to induce specific immunity against a primarily nonimmunogenic tumor antigen such as CA125 and is associated with a positive impact on the survival of patients with recurrent ovarian cancer with few side effects, which warrants a Phase III trial for ovarian cancer patients after primary therapy.

Immunological properties of a single-chain fragment of the anti-idiotypic antibody ACA125.

Vaccination with anti-idiotypic antibodies has been described as a promising concept for treatment of several malignant diseases. The murine monoclonal anti-idiotypic antibody ACA125 imitates a specific epitope of the tumor-associated antigen CA125 expressed by 80% of ovarian carcinomas. In the first clinical trial it could be shown that mAb ACA125 is able to elicit anti-anti-idiotypic antibodies (Ab3) with anti-CA125 specificity in patients with advanced ovarian cancer. In order to improve the capabilities of anti-idiotype vaccines we generated a genetically engineered single-chain fragment (scFv) ACA125 composed of heavy- and light-chain variable regions connected by a flexible linker. The antigenicity of scFv ACA125 was demonstrated by immunizing rats i.p. with scFv or complete mAb in complete/incomplete Freund's adjuvants (CFA/IFA) or precipitated by aluminium hydroxide. Negative control groups included applications of irrelevant mouse IgG or adjuvants alone. Anti-anti-idiotypic antibodies (Ab3) directed against the mAb ACA125 as well as specific anti-CA125 antibodies (Ab1') could be detected in all animals treated with scFv in CFA/IFA. Nevertheless, antibody titers were lower than when the complete mAb ACA 125 was used. Suprisingly, an increase of specificity could not be observed in scFv-immunized animals, which had been expected because of the lack of heavy- and light-chain constant regions that could raise rather unspecific anti-isotypic and anti-allotypic rat anti-(mouse Ig) antibodies (RAMA). In contrast, the RAMA responses detected in these rats were even stronger than those following immunization with complete mAb ACA125. In conclusion, the anti-idiotypic scFv ACA125 alone cannot improve the immunogenic features of the corresponding mAb, but provides a useful tool for the further development of genetic vaccines.

[Monoclonal anti-idiotype antibodies in immunotherapy of ovarian carcinoma (MAb ACA125) and breast carcinoma (MAb ACA14C5)]. / Monoklonale Anti-Idiotypen Antikörper zur Immuntherapie des Ovarialkarzinoms (MAk ACA125) und des Mammakarzinoms (MAk ACA14C5).

Anti-idiotypic antibodies, which imitate a tumor-associated antigen by their variable region, offer an elegant method for the induction of a specific immune response, when used as a surrogate antigen for immunization. We generated anti-idiotypic antibodies imitating 2 different tumor-associated antigens. I. CA125 for ovarian carcinomas and II. 14C5, a tumor-associated cell substrate adhesion molecule on breast cancer cells, whereas the first approach could be introduced in a first clinical trial and the second was evaluated in an immunocompetent animal model. For the induction of an immune response against CA125, 18 patients with advanced ovarian cancer (n = 6) or heavily pretreated recurrences (n = 12) were immunized with the anti-idiotypic antibody MAb ACA125. Patients were treated with 2 mg anti-idiotype antibody every two weeks for 4 injections i.m. and then monthly. 12 of 18 patients demonstrated an anti-anti-idiotypic (Ab3) response, which was to a lower extent also directed against CA125 and 9 of 18 patients developed a CA125 specific cellular immune response by their peripheral blood lymphocytes. Based on this data a follow-up clinical trial in advanced ovarian cancer patients with minimal residual disease in an adjuvant approach after primary therapy was started to evaluate the effect of the immune response on the progression free survival. For immunotherapy of breast cancer, we generated a murine monoclonal anti-idiotypic antibody (MAb ACA14C5), which imitates a cell substrate adhesion molecule on breast cancer cells. The anti-idiotype was introduced in an immunocompetent animal to prove his capability on induction of an immune and tumor response. The results showed a highly significant difference in the tumor growth of the ACA14C5 treated group in contrast to the controls starting the immunization on day 6 after tumor cell application with 10 of 12 animals being cured from their tumor burden. Prophylactic immunization against the invasion antigen of breast cancer by anti-idiotypic antibodies showed protection against increasing tumor burden. However, in the situation of established tumors only minor responses could be detected. Vaccination with anti-idiotypic antibodies comprises an effective method for induction of a specific immune response against non-immunogenic tumor-associated antigens and should be therefore considered in immunological approaches to tumor therapy, where the primary structure and sequence of the antigen, e.g. CA125, is up to now not available.