DPP-4-targeting vaccine for treating diabetes
A technology for DPP-4 and diabetes, which is applied in the fields of vaccines for preventing or treating diabetes, DPP-4 neutralizing antibodies, and preventive or therapeutic agents for diabetes. Achieve the effect of reducing the frequency of dosing and improving insulin secretion
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Embodiment 1
[0154] Example 1 Selection and Screening of Suitable Antigen Sequences for DPP-4 Vaccine
[0155] Based on the three-dimensional structure, three peptides were designed: a part of the N-terminal sequence of DPP-4 (E1; SEQ ID NO:5), and two other sequences (E2; SEQ ID NO:6, E3; SEQ ID NO:4). Because the induced antibody can overlap the active pore of DPP-4, it is expected to function as a DPP-4 neutralizing antibody. Three candidate peptides (E1, E2, E3) were conjugated to KLH and injected into male C57BL / 6J mice (8 weeks old, n=6 / group) 3 times ( figure 1A). Antibody titers against DPP-4 (shown as half maximum) did not increase 14 days after the first immunization. However, in mice immunized with E1 or E3 vaccines (hereinafter sometimes described as E1 vaccine group, E3 vaccine group, respectively), antibody titers increased significantly in a dose-dependent manner at day 28, and at day 42 and 56 days further increased and gradually decreased on the 70th day. In mice immu...
Embodiment 2
[0158] Example 2 Improvement of Insulin Resistance by E3 Vaccine in High Fat Diet Mice
[0159] Since it has been reported that the secretion of GLP-1 can also be by complex nutrients, which is similar to the secretion by glucose (YamazakiK et al., JPharmacolSci. 2007 May;104(1):29-38), so by performing a dietary tolerance test Evaluation of the role of the E3 vaccine in glucose metabolism. As a result, E3 vaccine immunized male mice (8 weeks old, n=6 / group) did not show the reduction of blood glucose level or insulin level compared with KLH vaccine immunized control mice under normal diet conditions ( Figure 4 A, B). These results suggest that the E3 vaccine did not induce hypoglycemia in mice under normal chow conditions.
[0160] To further evaluate the effect of the E3 vaccine, C57BL / 6J mice (8 weeks old, n=6 / group) were fed a high-fat diet (60% fat) from the beginning of immunization ( Figure 4 C) An oral meal tolerance test (MTT) was performed on day 105, and the im...
Embodiment 3
[0163] Example 3 Evaluation of the initial type 2 diabetes model mice induced by high-fat diet
[0164] To further study the effectiveness of the E3 vaccine in the diabetes model, the previously reported high-fat diet-induced naïve type 2 diabetes model mice (GuimK et al., Diabetes, 2004 Dec. 53:S225-S232) were used. Mice (8 weeks old, n=6 / group) were fed with high-fat diet for 5 weeks before initial E3 vaccine (20 μg / mouse) administration ( Figure 7 A). The DPP-4 activity inhibition rate in the E3 vaccine group was increased compared to the KLH vaccine group (22%, p Figure 7 B, C). These results suggest that E3 vaccine not only improves insulin resistance, but also improves the initial symptoms of type 2 diabetes.
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