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A Novel Hydrophobized Polysaccharide/Oncoprotein Complex Vaccine Induces in Vitro and in Vivo Cellular and Humoral Immune Responses against HER2-expressing Murine Sarcomas¹

Second Department of Internal Medicine [X-G. G., M. S., A. H., H. I., H. S.], and Department of Bioregulation [K. K.], Mie University School of Medicine, Tsu 514-8507; Second Department of Surgery, Nagasaki University School of Medicine, Nagaski 852-8102 [Y. N.]; Department of Synthetic Chemistry & Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 606-5801 [Y. S., K. A., J. S.]; and Mitsubishi Chemical Corporation, Yokohama Research Center, Yokohama 227 [H. N.], Japan

To elicit specific cellular immune responses against cancer, the development of efficient devices to deliver tumor antigen peptides to the MHC class I pathway constitutes a central issue. We report here a novel formula of hydrophobized polysaccharide nanoparticles, which can deliver a HER2 oncoprotein containing an epitope peptide to the MHC class I pathway.

A protein consisting of the 147 amino-terminal amino acids of oncogene erbB-2/neu/HER2 (HER2) was complexed with two kinds of hydrophobized polysaccharides, cholesteryl group-bearing mannan (CHM) and cholesteryl group-bearing pullulan (CHP), to form nanoparticles (CHM-HER2 and CHP-HER2). CHM-HER2 and CHP-HER2 were able to induce CD3⁺/CD8⁺ CTLs against HER2-transfected syngeneic fibrosarcoma cell lines. In contrast, the oncoprotein alone failed to do so. These CTLs were K^d-restricted and specifically recognized a peptide (position 63–71) that was a part of a truncated HER2 protein used as an immunogen. In addition, vaccination by CHM-HER2 complexes led to a strongly enhanced production of IgG antibodies against HER2, whereas vaccination with HER2 proteins alone resulted in a production of antibodies at a marginal level. Mice immunized with CHM-HER2 or CHP-HER2 before tumor challenge successfully rejected HER2-transfected tumors. The complete rejection of tumors also occurred when CHM-HER2 was applied not later than 3 days after tumor implantation. In the effector phase of in vivo tumor rejection, CD8⁺ T cells played a major role.

The results suggest that a sort of hydrophobized polysaccharide may help soluble proteins to induce cellular immunity as well enhance humoral immunity; hence, such a novel vaccine may be of potential benefit to cancer prevention and cancer therapy.

¹ Supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan, X-G. G. was granted an Educational Award by the Yoneyama Foundation of Rotary Japan, and M. S. was awarded a Science and Technology Fellowship (STF10) by the European Commission.

² Present address: Microbiology and Tumorbiology Center, Karolinska Institute, S-171 77 Stockholm, Sweden, E-mail: Xiaogang.Gu@mtc.ki.se.

³ Present address: University of Ulm, Third Department of Internal Medicine, Robert-Koch-Strasse 8, 89081 Ulm, Germany. E-mail: michael.schmitt@medizin.uni-ulm.de.

⁴ To whom requests for reprints should be addressed, at Second Department of Internal Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu 514-8507, Japan. Phone: 81-59-231-5016; Fax: 81-59-231-5200; E-mail: shiku@clin.medic.mie-u.ac.jp.

Received 2/27/98. Accepted 6/ 3/98.

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