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Vaccine Detail
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Oxidized Mannan-MUC1 Fusion Protein (M-FP) vaccine |
| Vaccine Information |
- Vaccine Name: Oxidized Mannan-MUC1 Fusion Protein (M-FP) vaccine
- Target Pathogen: Cancer
- Target Disease: Cancer
- Type: Conjugate vaccine
- Status: Clinical trial
- Host Species for Licensed Use: Human
- Antigen: 5VNTRs (5×PAHGVTSAPDTRPAPGSTAP) (Karanikas et al., 1997); 5VNTRs (20 aa) (Lees et al., 2000); 2006: 3VNTRs (3×PDTRPAPGSTAPPAHGVTSA) (Apostolopoulos et al., 2006)
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Adjuvant:
Oxidized mannan (Karanikas et al., 1997; Lees et al., 2000; Apostolopoulos et al., 2006)
- Immunization Route: subcutaneous injection
- Description: A recombinant MUC1 fusion protein conjugated to oxidized mannan via periodate chemistry, targeting the macrophage mannose receptor and directing antigen into the MHC class I presentation pathway. The construct used five VNTR repeats (PAHGVTSAPDTRPAPGSTAP) of MUC1 expressed in E. coli in preclinical and Phase I studies, and three VNTR repeats (PDTRPAPGSTAPPAHGVTSA) plus two flanking homologous sequences in the Phase III study. In MUC1 transgenic mice, three injections of M-FP generated CTLp frequencies of 1/55,000, which increased to 1/19,000 with IL-12 co-administration (VVIL-12); M-FP+IL-12 achieved complete tumor protection (0% palpable tumors) versus 62.5% with M-FP+VV control (p=0.025) against subcutaneous P815-MUC1 challenge. In HLA-A*0201×MUC1 double transgenic mice, M-FP+IL-12 generated HLA-A2-restricted CTLp (1/35,000) lysing human MCF-7 mammary carcinoma cells (Lees et al., 2000). In Phase I trials of 25 patients with metastatic adenocarcinoma of the breast, colon, rectum, and stomach, M-FP generated high-titer IgG1 anti-MUC1 antibody responses in 13/25 patients (titers 1/320–1/20,480), with dominant epitopes STAPPAHG and PAPGSTAP; T cell proliferation was detected in 4/15 patients (all HLA-A1, B8, DR3) and MHC-restricted CTL responses in 2/10 patients (both HLA-A2) (Karanikas et al., 1997). In a randomized double-blind pilot Phase III trial in 31 early-stage breast cancer patients, 0/16 M-FP vaccinated patients had recurrence versus 4/15 placebo patients (27%) after follow-up ranging from 60 to 99 months (8.5 years from start of first patient treatment; p=0.0292), with anti-MUC1 antibodies induced in 9/13 and MUC1-specific IFN-γ T cell responses in 4/10 evaluable vaccinated patients, persisting up to 3 years post-immunization; efficacy was observed only in early-stage disease (Apostolopoulos et al., 2006). No significant toxicity or autoimmunity was observed, with mild skin redness at the injection site reported in some patients.
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| Host Response |
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| References |
Apostolopoulos et al., 2006: Apostolopoulos V, Pietersz GA, Tsibanis A, Tsikkinis A, Drakaki H, Loveland BE, Piddlesden SJ, Plebanski M, Pouniotis DS, Alexis MN, McKenzie IF, Vassilaros S. Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835]. Breast cancer research : BCR. 2006; 8(3); R27. [PubMed: 16776849].
Karanikas et al., 1997: Karanikas V, Hwang LA, Pearson J, Ong CS, Apostolopoulos V, Vaughan H, Xing PX, Jamieson G, Pietersz G, Tait B, Broadbent R, Thynne G, McKenzie IF. Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein. The Journal of clinical investigation. 1997; 100(11); 2783-2792. [PubMed: 9389743].
Lees et al., 2000: Lees CJ, Apostolopoulos V, Acres B, Ramshaw I, Ramsay A, Ong CS, McKenzie IF. Immunotherapy with mannan-MUC1 and IL-12 in MUC1 transgenic mice. Vaccine. 2000; 19(2-3); 158-162. [PubMed: 10930667].
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