Immunity to p53 Induced by an Idiotypic Network of Anti-p53 Antibodies: Generation of Sequence-specific Anti-DNA Antibodies and Protection from Tumor Metastasis1

The general overexpression of p53 by different types of tumor cells suggests that p53 immunity might be generally useful for tumor ininiunotherapy. We describe here the induction of immunity to p53 and resistance to tumor metastasis using an idiotypic network. Mice were immunized with domain-specific anti-p53 monoclonal antibodies (Abl): PAb-248 directed to the N-terminus; PAb-246 directed to the specific DNA-binding region; or PAb-240 directed to a mutant p53 that does not bind specific DNA. Immunized mice responded by making anti-idiotypic antibodies (Ab2) specific for the Abl inducer. Abl PAb-246 induced Ab2 that, like p53 itself, could bind the specific DNA oligonucleotide sequence of the p53 responsive element. Mice immunized with Abl PAb-240 or PAb-246 spontaneously made Ab3 anti-p53 antibodies that reflected the specificity of their Abl inducers: Abl PAb-246 induced Ab3 specific for wild-type p53; PAb-240 induced Ab3 specific for mutant p53. Abl PAb248 induced only Ab2. The spontaneously arising Ab3 were of T celldependent IgG isotypes. Peptides from the complementarity determining regions of the Abl antibodies PAb-240 and PAb-246 could also induce Ab3 anti-p53. Finally, mice that produced Ab3 anti-p53 acquired resist ance to tumor métastases. Therefore, an anti-idiotypic network built around certain domains of p53 seems to be programmed within the immune system, specific Ab2 antibodies can mimic the DNA binding domain of p53, and Ab3 network immunity to p53 can be associated with resistance to tumor cells.