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.o 1996 Wiley-Liss, Inc.

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Polyclonal goat anti-idiotypic Abs directed against anti-human gastrointestinal carcinoma mAb GA733 were administered to 13 colon cancer patients who had their primary tumor and lymph node metastases removed before immunotherapy. Patients received four s.c. doses (0.5 to 8 mg each) of alum-precipitated anti-idiotypic Ab. Seven of the 13 patients produced anti-anti-Ids that bound specifically to the GA733 epitope on tumor cells and shared idiotopes with mAb GA733. In four of the seven responding patients, anti-Id therapy specifically modulated T cell responses. In two patients who did not demonstrate GA733 Ag/anti-Id-reactive T cells before therapy, anti-Id administration induced CD4+, MHC class II-dependent T cells that specifically proliferated in culture in response to stimulation with either anti-Id or GA733 Ag. In two other patients who did demonstrate Ag/anti-Id-reactive T cells before therapy, anti-Id administration transiently induced lymphocytes that suppressed the proliferative responses of cultured pretherapy lymphocytes to stimulation with anti-Id or GA733 Ag. Nine of the 13 treated patients showed no evidence of disease after 39 to 86 mo of observation. Five of these patients developed Ag-specific Ab3 and one had, in addition, a T cell response.

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