Cancer vaccines: single-epitope anti-idiotype vaccine versus multiple-epitope antigen vaccine |
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Authors: | Haruhiko Maruyama Jan Zaloudik Weiping Li Melinda Sperlagh Takashi Koido Rajasekharan Somasundaram Stacey Scheck Marie Prewett Dorothee Herlyn |
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Institution: | (1) The Wistar Institute of Anatomy and Biology, 36th Street at Spruce, Philadelphia, PA 19104, USA e-mail: dherlyn@wistar.upenn.edu Tel.: +1-215-898-3962 Fax: +1-215-898-0980, US |
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Abstract: | In this study, we compared the immunogenicity and tumor-protective activity of anti-idiotypic antibodies mimicking a single
tumor-associated epitope and tumor-associated antigen expressing multiple potentially immunogenic epitopes. We focused our
study on the colorectal-carcinoma(CRC)-associated antigen GA733 (also known as CO17-1A/KS1-4/KSA/EpCAM). Monoclonal anti-idiotypic
antibody (Ab2) BR3E4 was produced against murine anti-CRC mAb CO17-1A (Ab1) in rats. Full-length native GA733 protein was
isolated from human tumor cells, and the extracellular domain protein (GA733-2E) was isolated from supernatants of recombinant
baculovirus-infected insect cells by immunoafffinity chromatography. The immunomodulatory activity of the Ab2 was compared
with that of the antigen, both in rabbits and in mice. Mice, like humans but not rabbits, express a GA733 antigen homologue
on some of their normal tissues. Thus, these in vivo models allow the comparison of the immunogenicity of Ab2 and antigen
in the presence (mice) and absence (rabbits) of normal tissue expression and immunological tolerance of the GA733 antigen
homologue. 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-precipitated Ab2,
induced specific humoral immunity. However, when the Ab2 was administered to mice in Freund's complete adjuvant, specific
humoral immune responses were elicited. Ab2 in complete Freund's adjuvant and GA733-2E in 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 were lower than after antigen immunization. The recombinant antigen in alum did not protect mice against challenge
with antigen-positive syngeneic murine 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 Ab2 mimicking the epitope defined by mAb GA733, which is expressed by the transfected tumor cells, indicated a lack of
tumor-protective activity of this Ab2. In contrast, the full-length antigen expressed by recombinant adenovirus inhibited
the growth of established tumors in mice. In conclusion, soluble antigen is a more potent modulator of humoral and cellular
immune responses than Ab2, both administered in adjuvant. However, for induction of protective immunity, the immunogenicity
of the antigen must be further enhanced, e.g., by expression of the antigen in a viral vector.
Received: 27 December 1999 / Accepted: 27 January 2000 |
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Keywords: | Anti-idiotypic antibodies Colorectal carcinoma CO17-1A/GA733/KSI-4/KSA/EpCAM Humoral immunity Cellular immunity |
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