Application of anti-PD-1 antibody in type 2 diabetes mellitus
A type 2 diabetes, PD-1 technology, applied in the direction of antibody medical ingredients, antibodies, medical preparations containing active ingredients, etc., can solve the problems of substandard blood sugar control and unsatisfactory diabetes control status.
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Embodiment 1
[0124] Example 1: Hypoglycemic effect after continuous anti-PD-1 antibody treatment in T2DM primate model.
[0125] 1. Model building
[0126] According to the definition of T2DM by the World Health Organization, the inventor screened 239 male rhesus monkeys who maintained a normal standard diet (for the purpose of preventing mating, no experiments were conducted on female rhesus monkeys), and 20 rhesus monkeys Elevated fasting plasma levels (fasting plasma lipid (FPL) >6.5mmol / L). Through the glucose tolerance test (2 hours after oral administration of 75g glucose), the venous blood glucose level was ≥11.1mmol / L.
[0127] In order to rule out the possibility of T1DM, the inventors measured insulin antibody (IAA), islet cell antibody (ICA), glutamic acid decarboxylase antibody ( GADA) were all negative. Therefore, it was determined that all hyperglycemic rhesus monkeys suffer from T2DM.
[0128] 2. Hypoglycemic effect of anti-PD-1 antibody treatment on rhesus monkeys with ...
Embodiment 2
[0135] Example 2: NLRP6 as a biomarker for anti-PD-1 antibody treatment in rhesus monkeys with T2DM
[0136] To assess inflammation in rhesus monkeys with T2DM, the inventors measured NLRP (nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein, nucleotide-binding and oligomerization domain-like receptor pyrin domain protein) in peripheral blood containing) and pro-inflammatory cytokine levels. The inventors found that the levels of pro-inflammatory cytokines (including TNF-α, IL-1β, IL-18 and IL-10) were significantly increased in the whole blood of rhesus monkeys with T2DM compared with healthy rhesus monkeys ,like Figure 3a shown.
[0137] Since NLRP is mainly expressed in the cytoplasm, the inventors further measured the NLRP level of PBMC. like Figure 3b As shown, among the immune-related NLRP1, AIM2, NLRP3, NLNC4, and NLRP6, the level of NLRP3 was significantly increased in rhesus monkeys with T2DM, while the level of NLRP6 was sign...
Embodiment 3
[0141] Example 3: Anti-PD-1 Antibody Treatment Attenuates MDM Inflammatory Response in Rhesus Monkeys with T2DM
[0142] Previous studies have shown that monocyte TLR expression and its downstream inflammatory cytokine production are upregulated in T2DM patients. Concurrently, NLRP3 inflammatory cell activation was elevated in monocyte-derived macrophages (MDM) from T2DM patients. The inventors first demonstrated changes in the inflammasome NLRP3, NLRP6 and related genes in healthy rhesus monkeys and T2DM model rhesus monkeys in sorted MDM under lipopolysaccharide (LPS) stimulation in a high glucose environment Consistent with results in human MDM (see Figure 4 ).
[0143] The inventors assessed the expression of NLRP3, NLRP6, IL1-β, IL-18 in MDM induced with LPS in a high glucose (15mmol / L) environment (see Figure 5 ).
[0144] Rhesus monkeys with T2DM had significantly higher mRNA levels of NLRP3, IL1-β, IL-18 and significantly lower mRNA levels of NLRP6 in normal envi...
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