Anti-idiotypic monoclonal antibody AB3, reacting with the primary antigen (CEA), can localize in human colon-carcinoma xenografts as efficiently as AB1 (original) (raw)
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Journal of Cellular Biochemistry, 1992
Anti-idiotype antibodies can mimic the conformational epitopes of the original antigen and act as antigen substitutes for vaccination and/or serological purposes. To investigate this possibility concerning the tumor marker carcinoembryonic antigen (CEA), BALB/c mice were immunized with the previously described anti-CEA monoclonal antibody (MAb) 5.D11 (A61). After cell fusion, 15 stable cloned cell lines secreting anti-Ids (A62) were obtained. Selected MAbs gave various degrees of inhibition (up to 100%) of the binding of 1251-labeled CEA to MAb 5.D11. Absence of reactivity of anti-Id MAbs with normal mouse IgG was first demonstrated by the fact that anti-Id MAbs were not absorbed by passage through a mouse IgG column, and second because they bound specifically to non-reduced MAb 5.D11 on Western blots. Anti-5.Dl1 MAbs did not inhibit binding to CEA of MAb 10.69, another anti-CEA antibody obtained in the same fusion as 5.D11, or that of several anti-CEA MAbs reported in an international workshop, with the exception of two other anti-CEA MAbs, both directed against the GOLD IV epitope. When applied to an Id-anti-Id competitive radioimmunoassay, a sensitivity of 2 ng/ml of CEA was obtained, which is sufficient for monitoring circulating CEA in carcinoma patients. To verify that the anti-Id MAbs have the potential to be used as CE4 vaccines, syngeneic BALB/c mice were immunized with these MAbs (A62). Sera from immunized mice were demonstrated to contain A63 antibodies recognizing the original antigen, CEA, both in enzyme immunoassay and by immunoperoxidase staining of human colon carcinoma. These results open the perspective of vaccination against colorectal carcinoma through the use of anti-idiotype antibodies as antigen substitutes.
Proceedings of the National Academy of Sciences, 1995
Induction of immunity against antigens expressed on tumor cells might prevent or delay recurrence of the disease. Six patients operated on for colorectal carcinoma were immunized with human monoclonal anti-idiotypic antibodies (h-Ab2) against the mouse 17-4A anti-colon carcinoma antibody, mimicking a nominal antigen (GA733-2). All patients developed a long-lasting T-cell immunity against the extracellular domain of GA733-2 (GA733-2E) (produced in a baculovirus system) and h-Ab2. This was shown in vitro by specific cell proliferation (DNA-synthesis) assay as well as by interleukin 2 and interferon y production and in vivo by the delayed-type hypersensitivity reaction. Five patients mounted a specific humoral response (IgG) against the tumor antigen GA733-2E (ELISA) and tumor cells expressing GA733-2. Epitope mapping using 23 overlapping peptides of GA733-2E revealed that the B-cell epitope was localized close to the N terminus of GA733-2. Binding of the antibodies to the tumor antigen and to one 18-aa peptide was inhibited by h-Ab2, indicating that the antibodies were able to bind to the antigen as well as to h-Ab2. The results suggest that our h-Ab2 might be able to induce an anti-tumor immunity which may control the growth of tumor cells in vivo.
International Journal of Cancer, 1996
Anti-idiotypic antibodies (Ab2) that bind to the antigencombining region of anti-tumor antibodies (Ab I) may functionally, and even structurally, mimic tumor antigen. We have previously demonstrated that polyclonal goat Ab2 directed against anti-human gastrointestinal carcinoma Ab I GA733 induces anti-anti-idiotypic antibodies (Ab3) in animals that are Ab I -like in their binding specificity and idiotope expression. To obtain more defined Ab2 vaccines with potentially increased specificity and efficacy, a monoclonal Ab2 (FG I) was produced against Ab I GA733 in rats. The monoclonal Ab2 FG I, similar to the polyclonal Ab2 described previously, induced Ab3 in rabbits that were Ab I -like in their idiotope expression and binding specificity to tumor cells and antigen. Antigen-specific Ab3 induced by Ab2 FG I were easily detected in unprocessed rabbit sera, whereas the demonstration of such Ab3 after polyclonal Ab2 immunization required purification of the Ab3 from the rabbit sera. In addition, Ab2 FG I induced antigen-specific humoral and cellular immunity in mice. Murine Ab3 bound specifically to antigen-positive tumor cells. Ab2-immunized mice showed antigen-specific delayed-type hypersensitivity (DTH) reaction, and cultured splenocytes from the immune mice demonstrated specific proliferation and cytokine (interferon-y and interleukin-4) secretion upon stimulation with GA733 antigen. However, immune mice were not protected against a challenge with syngeneic GA733 antigen-expressing colon carcinoma cells.
Nuclear Medicine and Biology, 1993
The therapeutic effects of '251-labelled (18-97 MBq) monoclonal antibodies (MAb) C-242, C-2 15 and S-S. 1 were studied in nude mice with human colorectal adenocarcinoma tumours. The antibodies were administered 2 or lo-16 days after implantation of the tumour cells. The monoclonal antibody C-242 was internalized into the tumour cells, C-21 5 was internalized to a lower degree while S-S. 1 (unspecific MAb) was not internalized at all. No enhanced therapeutic effect of '2s1-C-242 was observed, as a result of Auger electrons, compared with '25I-C-215 and "'1-S-S. 1
Cancer Research
The pharmacokinetics of the '"I-labeled murine anti-rat colon carci noma monoclonal antibody, E4, and its F(ab'>2 fragments were compared in normal Sprague-Dawley rats as well as in syngeneic BDIX rats and nude mice bearing the tumor to which the monoclonal antibodies had been generated. '"I-labeled irrelevant antibody of the same IgG2a sub class or its labeled 1(a!>')..fragments were used as controls. Results of labeled antibody uptake after i.v. administration were analyzed in terms of accumulation and localization indices for normal tissues and tumor. Whole E4, which is tumor specific by immunoperoxidase staining, bound to a variety of normal tissues, in addition to the tumor. These tissues included liver, stomach, colon, and lung of rats bearing s.c. tumors. Targeting to the tumor was better in rats bearing i.p. tumors, but targeting to other organs was also high. The use of 1(ali')., fragments in rats bearing s.c. tumors showed results similar to those found with the whole antibody and did not improve tumor localization. These observations demonstrate a lack of correlation between in vivo tissue uptake of injected murine monoclonals, or their fragments, and in vitro histochemical studies. In contrast to observations in rats, tumor alone was specifically targeted with whole E4 or F(ab')2 fragments in tumor-bearing nude mice.
Cancer research, 1990
One of the problems of in vivo diagnosis and therapy of tumors with monoclonal antibodies is their heterogeneity with respect to antigen expression, with some cells expressing no antigen and others being weakly or strongly positive. Selected mixtures of antibodies to different antigens are therefore likely to react with more cells than single antibodies and be more effective for imaging and therapy. With this in mind, we have examined a new human colon cancer cell line (LIM1899) which has a heterogeneous expression of several cell surface molecules: by flow cytometry 38% were carcinoembryonic antigen positive; 64%, human milk fat globule positive, and 73%, CD46 positive; 87% of tumor cells bound a mixture of all three antibodies in vitro. Some blocking of the binding of anti-human milk fat globule antibody by the anti-CD46 antibody was noted. LIM1899 was established as a xenograft in nude mice and in vivo biodistribution studies performed using antibodies alone or in combination. Mi...
Acta Oncologica, 1991
The biokinetics of seven '3'I-labelled monoclonal antibodies (MAbs), directed against human colon carcinoma and one lzsIlabelled unspecific MAb have been examined. The study in nude mice, carrying human colon carcinoma, was intended to be a step in the selection of the most suitable antibody for clinical scintigraphy. The biological half-life in blood was found to be between 1.3 and 7.4 days for the different MAbs. Chromatography of plasma samples showed that the radioiodine was mainly bound to IgGsized molecules. The (normal tissue)/blood ratios were similar for all the MAbs. The tumour/blood ratio was 0.41 for the unspecific MAb and 0.49-1.1 for the specific MAbs, and the tumour/muscle ratio was between 3.2 and 6.8 for the specific MAbs 6 days after injection. For one MAb tumour/blood and tumour/muscle ratios were 3.9 and 9.8 respectively 9 days after injection. Localization indices were at their highest 2.6 6 days after injection. For at least two of the monoclonal antibodies the tumour/blood and turnour/ muscle ratios found are high enough to justify clinical trials regarding their usefulness for scintigraphy of colon cancer in man.