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Vaccine Detail
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MUC1-Tn-Pam3CysSK4 glycopeptide tripartite vaccine |
| Vaccine Information |
- Vaccine Name: MUC1-Tn-Pam3CysSK4 glycopeptide tripartite vaccine
- Target Pathogen: Cancer
- Target Disease: Cancer
- Type: Conjugate vaccine
- Status: Research
- Host Species for Licensed Use: Mouse
- Antigen: 9-mer MUC1 (SAPDTRPAP), Tn at T5(Ingale et al., 2007, Ref6924:Lakshminarayanan et al., 2012, Ref6926:Abdel-Aal et al., 2014)
- Immunization Route: Intradermal injection (i.d.)
- Description: A fully synthetic tripartite glycolipopeptide conjugate vaccine composed of the antigenic-dominant MUC1 B-cell epitope SAPDT(αGalNAc)RPAP bearing the Tn antigen (αGalNAc-Thr), the T-helper epitope KLFAVWKITYKDT from poliovirus, and the TLR2 agonist Pam3CysSK4, formulated as SUVs. Pam3CysSK4 mediates TLR2-dependent APC internalization, upregulation of CD80, CD83, and CD86, and induction of TNF-α, RANTES, IL-6, IL-1β, and IL-12/23p40 without immunosuppressant IL-10; sparse Tn permits APC antigen processing (Lakshminarayanan et al., 2012). Evaluated in BALB/c mice [Ref6925:Ingale et al., 2007, with QS-21 as additional adjuvant in that study only) and MUC1.Tg mice (Lakshminarayanan et al., 2012, Ref6926:Abdel-Aal et al., 2014). Vaccination elicited total IgG titers of 169,600 in BALB/c (Ingale et al., 2007) and 30,200–31,900 in MUC1.Tg mice (Lakshminarayanan et al., 2012), with 59,100 in MUC1.Tg mice (Abdel-Aal et al., 2014), IgG3 confirming anti-carbohydrate responses, mixed Th1/Th2, absence of epitope suppression, MUC1-positive MCF7 but not SK-MEL-28 binding (Ingale et al., 2007), MHC-I H-2Kb responses (Lakshminarayanan et al., 2012), and antisera recognizing both glycosylated and unglycosylated epitopes with higher affinity for glycosylated form. Significant ADCC lysis against Yac-1.MUC1 and C57mg.MUC1 cells, with significant tumor burden reduction in MMT and MT.MUC1 models through specific and nonspecific Pam3CysSK4 adjuvant effects, with tolerance reversal (Lakshminarayanan et al., 2012, Ref6926:Abdel-Aal et al., 2014). Glycosylation was critical: CTLs recognized both glycosylated and unglycosylated epitopes versus unglycosylated only for the non-glycosylated vaccine, with IFN-γ CD8+ T cells confirmed by ELISPOT (Lakshminarayanan et al., 2012). Covalent attachment was essential, yielding significantly higher responses over non-covalent mixtures. Pam3CysSK4 outperformed Pam2CysSK4 (Ingale et al., 2007) and CpG-ODN 1826 (Abdel-Aal et al., 2014) by uniquely reducing Foxp3+ Treg suppression and enhancing CTL cytotoxicity (Abdel-Aal et al., 2014).
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| Host Response |
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| References |
Abdel-Aal et al., 2014: Abdel-Aal AB, Lakshminarayanan V, Thompson P, Supekar N, Bradley JM, Wolfert MA, Cohen PA, Gendler SJ, Boons GJ. Immune and anticancer responses elicited by fully synthetic aberrantly glycosylated MUC1 tripartite vaccines modified by a TLR2 or TLR9 agonist. Chembiochem : a European journal of chemical biology. 2014; 15(10); 1508-1513. [PubMed: 24890740].
Ingale et al., 2007: Ingale S, Wolfert MA, Gaekwad J, Buskas T, Boons GJ. Robust immune responses elicited by a fully synthetic three-component vaccine. Nature chemical biology. 2007; 3(10); 663-667. [PubMed: 17767155].
Lakshminarayanan et al., 2012: Lakshminarayanan V, Thompson P, Wolfert MA, Buskas T, Bradley JM, Pathangey LB, Madsen CS, Cohen PA, Gendler SJ, Boons GJ. Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(1); 261-266. [PubMed: 22171012].
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