Immunity to p53 induced by an idiotypic network of anti-p53 antibodies: Generation of sequence-specific anti-DNA antibodies and protection from tumormetastasis

The general overexpression of p53 by different types of tumor cells suggest s that p53 immunity might be generally useful for tumor immunotherapy, We d escribe here the induction of immunity to p53 and resistance to tumor metas tasis using an idiotypic network. Mice were immunized with domain-specific anti-p53 monoclonal antibodies (Ab1): PAb-248 directed to the N-terminus; P Ab-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 m aking anti-idiotypic antibodies (Ab2) specific for the Ab1 inducer. Ab1 PAb -246 induced Ab2 that, like p53 itself, could bind the specific DNA oligonu cleotide sequence of the p53 responsive element, Mice immunized with Ab1 PA b-240 or PAb-246 spontaneously made Ab3 anti-p53 antibodies that reflected the specificity of their Ab1 inducers: Ab1 PAb-246 induced Ab3 specific for wild-type p53; PAb-240 induced Ab3 specific for mutant p53. Ab1 PAb-248 in duced only Ab2, The spontaneously arising Ab3 were of T cell-dependent IgG isotypes, Peptides from the complementarity determining regions of the Ab1 antibodies PAb-240 and PAb-246 could also induce Ab3 anti-p53, Finally, mic e that produced Ab3 anti-p53 acquired resistance to tumor metastases, There fore, an anti-idiotypic network built around certain domains of p53 seems t o 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 asso ciated with resistance to tumor cells.