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Cancer Immunol Res. 2018 May 23. doi: 10.1158/2326-6066.CIR-17-0661. [Epub ahead of print]

Nanobody-Antigen Conjugates Elicit HPV-Specific Antitumor Immune Responses.

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts. andrew.woodham@childrens.harvard.edu hidde.ploegh@childrens.harvard.edu.
2
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
3
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.
4
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
5
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
6
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California.
7
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
8
Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.

Abstract

High-risk human papillomavirus-associated cancers express viral oncoproteins (e.g., E6 and E7) that induce and maintain the malignant phenotype. The viral origin of these proteins makes them attractive targets for development of a therapeutic vaccine. Camelid-derived single-domain antibody fragments (nanobodies or VHHs) that recognize cell surface proteins on antigen-presenting cells (APC) can serve as targeted delivery vehicles for antigens attached to them. Such VHHs were shown to induce CD4+ and CD8+ T-cell responses against model antigens conjugated to them via sortase, but antitumor responses had not yet been investigated. Here, we tested the ability of an anti-CD11b VHH (VHHCD11b) to target APCs and serve as the basis for a therapeutic vaccine to induce CD8+ T-cell responses against HPV+ tumors. Mice immunized with VHHCD11b conjugated to an H-2Db-restricted immunodominant E7 epitope (E749-57) had more E7-specific CD8+ T cells compared with those immunized with E749-57 peptide alone. These CD8+ T cells acted prophylactically and conferred protection against a subsequent challenge with HPV E7-expressing tumor cells. In a therapeutic setting, VHHCD11b-E749-57 vaccination resulted in greater numbers of CD8+ tumor-infiltrating lymphocytes compared with mice receiving E749-57 peptide alone in HPV+ tumor-bearing mice, as measured by in vivo noninvasive VHH-based immune-positron emission tomography (immunoPET), which correlated with tumor regression and survival outcome. Together, these results demonstrate that VHHs can serve as a therapeutic cancer vaccine platform for HPV-induced cancers. Cancer Immunol Res; 6(7); 1-11. ©2018 AACR.

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