Cancer vaccines: single-epitope anti-idiotype vaccine versus multiple-epitope antigen vaccine

In this study, we compared the immunogenicity and tumor-protective activity of anti-idiotypic antibodies mimicking a single tumor-associated epitope a nd tumor-associated antigen expressing multiple potentially immunogenic epi topes. We focused our study on the colorectal-carcinoma(CRC)-associated ant igen GA733 (also known as CO17-1A/KS1-4/KSA/EpCAM). Monoclonal anti-idiotyp ic antibody (Ab2) BR3E4 was produced against murine anti-CRC mAb CO17-1A (A bl) in rats. Full-length native GA733 protein was isolated from human tumor cells, and the extracellular domain protein (GA733-2E) was isolated from s upernatants of recombinant baculovirus-infected insect cells by immunoaffin ity chromatography. The immunomodulatory activity of the Ab2 was compared w ith that of the antigen, both in rabbits and ill mice. Mice, like humans bu t not rabbits, express a GA733 antigen homologue on some of their normal ti ssues. Thus, these in vivo models allow the comparison of the immunogenicit y of Ab2 and antigen in the presence (mice) and absence (rabbits) of normal tissue expression and immunological tolerance of the GA733 antigen homolog ue. In rabbits, aluminum-hydroxide(alum)-precipitated native GA733 antigen was superior to alum-precipitated Ab2 in inducing specific humoral immunity . In mice, alum-precipitated recombinant GA733-2E antigen, but not alum-pre cipitated Ab2, induced specific humoral immunity. However, when the Ab2 was administered to mice in Freund's complete adjuvant, specific humoral immun e responses were elicited. Ab2 in complete Freund's adjuvant and GA733-2E i n alum were compared for their capacity to induce antigen-specific cellular immunity in mice. Whereas lymphoproliferative responses were obtained with the recombinant antigen only, delayed-type hypersensitivity responses were obtained with both recombinant antigen and Ab2, although these responses w ere lower than after antigen immunization. The recombinant antigen in alum did not protect mice against challenge with antigen-positive syngeneic muri ne CRC cells. Similar studies with Ab2 BR3E4 mimicking the CO17-1A epitope were not possible because the tumor cells do not express this epitope after transfection with the human GA733-2 cDNA. However, similar studies with Ab 2 mimicking the epitope defined by mAb GA733, which is expressed by the tra nsfected tumor cells, indicated a lack of tumor-protective activity of this Ab2. In contrast, the full-length antigen expressed by recombinant adenovi rus inhibited the growth of established tumors in mice. In conclusion, solu ble antigen is a more potent modulator of humoral and cellular immune respo nses than Ab2, both administered in adjuvant. However, for induction of pro tective immunity, the immunogenicity of the antigen must be further enhance d, e.g., by expression of the antigen in a viral vector.