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Protective Epitope Discovery and the Design of MUC1 Based Vaccine for Effective Tumor Protections in Immunotolerant Mice
Umeå University, Faculty of Science and Technology, Department of Chemistry. Leibniz-Institut für Analytische Wissenschaften−ISAS, Dortmund, Germany.
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2018 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 48, p. 16596-16609Article in journal (Refereed) Published
Abstract [en]

Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUC1 antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qβ carrier with MUC1 glycopeptides containing 20-22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qβ-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qβ-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018. Vol. 140, no 48, p. 16596-16609
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-153256DOI: 10.1021/jacs.8b08473ISI: 000452693800032PubMedID: 30398345Scopus ID: 2-s2.0-85057781219OAI: oai:DiVA.org:umu-153256DiVA, id: diva2:1262833
Funder
NIH (National Institute of Health), R01 CA225105German Research Foundation (DFG), WE 4751/2-1Available from: 2018-11-13 Created: 2018-11-13 Last updated: 2019-02-28Bibliographically approved

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Pett, ChristianSchorlemer, ManuelWesterlind, Ulrika

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