Targeted delivery of antigens to CD11b+ cells via nanobodies induces strong antigen-specific T cell and anti-tumor responses

• Published in: The Journal of immunology (1950) Vol. 200; no. 1_Supplement; pp. 181 - 181.6
• Main Authors: Woodham, Andrew W., Cheloha, Ross W., Ling, Jingjing, Rashidian, Mohammad, Kolifrath, Stephen C., Mesyngier, Maia, Duarte, Joao N., Bader, Justin M., Skeate, Joseph G., Da Silva, Diane M., Kast, W. Martin, Ploegh, Hidde L.
• Format: Journal Article
• Language: English
• Published: 01.05.2018
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.200.Supp.181.6

Abstract The variable regions of camelid heavy chain-only antibodies (nanobodies or VHHs) are the smallest antibody fragments that retain full antigen binding. Owing to their small size, ease of expression, and high tissue penetration, VHHs that recognize cell surface proteins on antigen-presenting cells (APCs) can serve as targeted delivery vehicles for antigens conjugated to them. We site-specifically attached antigens to the C-terminus of an anti-CD11b VHH (VHHCD11b), and then investigated the ability of the VHH-antigen conjugates to elicit antigen-specific T cell and anti-tumor responses in a mouse model of human papillomavirus (HPV)-induced cancer. This VHH had high affinity for CD11b+ dendritic cells (apparent KD = 204 ± 90 pM), and enhanced cross-presentation of a conjugated antigen (OVA257–264) in vitro. Mice immunized with the VHH conjugated to an immunodominant HPV16 E7 epitope (E749–57) had more E7-specific cytotoxic T cells compared to mice immunized with E7 peptide alone, conferring protection against HPV16 E7+ tumor cell challenge. Therapeutically, VHHCD11b-E7 vaccination resulted in greater numbers of CD8+ tumor infiltrating lymphocytes compared to mice receiving E7 peptide alone in HPV16+ tumor-bearing mice, as measured by in vivo non-invasive VHH-based positron emission tomography (PET), which correlated with tumor regression and increased survival. Thus, targeting CD11b for the delivery of antigens via VHHs may be a promising cancer immunotherapeutic strategy.