The murine monoclonal anti-CA125 antibody MAb-B43.13 has previously been administered as an immunoscintigraphic agent in order to monitor recurrence of ovarian cancer in patients, and a long-term follow-up demonstrated a survival benefit for these patients. The clinical benefit was initially attributed to the activation of the idiotypic network. The objective of this study was to investigate the role of CA125-MAb-B43.13 immune complex formation on the induction of CA125-specific immune responses. Analysis of patient serum samples from pharmacokinetic studies demonstrated that the antibody forms immune complexes with CA125 in circulation within 30 minutes of injection. Induction of humoral and cellular anti-CA125 responses correlated with the amount of circulating CA125 antigen present at time of antibody injection. Subsequent to the injection of MAb-B43.13, the patients generated anti-CA125 antibodies that were directed against various epitopes on the antigen and were not restricted to the specific epitope recognized by MAb-B43.13. The generation of CA125-specific B and T cell responses after MAb-B43.13 injection correlated with improved survival. The influence of circulating CA125 for the induction of CA125-specific immune responses and the multi-epitopic nature of the human anti-CA125 antibodies suggest that the majority of these antibodies were not induced via the idiotypic network but by the autologous antigen itself. Since antibody and T cell responses to CA125 were not present before injection of MAb-B43.13, it is hypothesized that complex formation of MAb-B43.13 with circulating antigen triggers the induction of CA125-specific immune responses.
Intravenous injection of the murine monoclonal anti-CA125 antibody B43.13 (Ovarex: Ab1) into ovarian cancer patients led to the induction of an idiotypic network. Of the 75 patients who received one to ten injections of a 2-mg dose of the antibody, 48 developed anti-(mAb B43.13) antibodies (Ab2); 18 of these patients also had elevated levels of anti-[anti-(mAb B43.13)] antibodies (Ab3; = anti-CA125 antibodies) compared to pre-injection values. Characterization of these antibodies revealed that the binding to CA125 could be inhibited by mAb B43.13 in most samples. Human anti-CA125 antibodies or Ab3 purified from patient serum samples specifically recognized human ovarian tumor cells and tissues expressing CA125. In addition, these anti-CA125 antibodies were able to conduct Fc-mediated tumor cell killing (antibody-dependent cell-mediated cytotoxicity). This raises the possibility of using an Ab1 for anti-idiotype induction immunotherapy of cancer.
Human anti‐mouse antibodies (HAMA) are observed frequently after immunoscintigraphy with monoclonal antibodies (MoAb) directed against CA‐125.1 As the authors have shown previously,2–5 HAMA can cause false‐positive CA‐125 values in routine CA‐125 immunoradiometric assay (IRMA) tumor‐marker assays (in one case, up to 900 days after immunoscintigraphy). In 32 patients, the authors found a HAMA frequency of 34% (11/32: 3/7 after the first administration, 6/13 after the second, and 2/2 after the third). Ten patients developed extremely high CA‐125 levels after undergoing the CIS IRMA assay (up to 80,000 U/ml) in parallel to a significant HAMA increase. The use of different assays, or HAMA removal before in vitro testing, can solve this problem. After a new CA‐125 assay containing antibodies that recognize different epitopes on the CA‐125 antigen (Biomira Tru‐Quant OV) was applied, only mildly increased assay results or normal levels were measured. Most of HAMA‐positive patients demonstrated a predominantly anti‐idiotypic response, determined with two different HAMA assays.
Seven patients with anti‐idiotypic HAMA responses after OC‐125 immunoscintigraphy remained free of tumor or had stable disease (2–42 or more months), contrary to their poor prognoses that had been made based on the underlying stages of their tumors. All of these patients are currently doing well (Karnofsky Index > 70%) and show no significant tumor progression. In light of their extremely poor prognoses (5‐year survival rates of 3–5% in recurrent International Federation of Gynecology and Obstetrics III/IV stages), without further chemotherapy, these courses are extremely unusual.
Preliminary in vitro experiments lead to the postulatation that anti‐idiotypic HAMA may trigger an antitumor effect either by suppressing the growth of CA‐125‐expressing cancer cells directly, or by activating the patient's immune response via induction of Ab3. Similar results are observed after immunoscintigraphy with a technetium‐99m‐labeled anti‐CA‐125 monoclonal antibody (B43.13), which the authors now also use for immunotherapy of ovarian cancer patients by repeated injections, hoping that induction of anti‐idiotypic HAMA will be beneficial for prolonged survival of patients with ovarian carcinoma. Cancer 1994; 73:1121–5.
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