A method of treating cachexia with the removal or inactivation of macrophage inhibitory cytokine-1
A macrophage and cachexia technology, applied in the field of cachexia, can solve the problems of complex weight control and incomplete understanding
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Embodiment 1
[0045] Example 1 Regulation of Serum MIC-1 Levels
[0046] MIC-1, like other members of the TGF-β superfamily, is synthesized as a precursor with an N-terminal propeptide and a C-terminal mature MIC-1 domain. The precursor undergoes disulfide-linked dimerization in the endoplasmic reticulum (ER) and, once dimerized, exits the ER into the Golgi apparatus, where it is cleaved by a protein-like convertase at the conserved RXXR site (amino acid 196) (SEQ ID NO: 1). This cleavage removes the propeptide from the mature C-terminal domain, thus, MIC-1 releases a 24.5 kD disulfide polymerized mature 112 amino acid polypeptide 1 ( figure 1 ).
[0047] It was previously found that large amounts of MIC-1 are secreted in unprocessed form. For example, the endogenous unprocessed protein MIC-1 was derived from the trophoblast cell line BeWo 4 , prostate cancer cell lines LnCAP and PC3, pancreatic cell line Pane 1, and monocyte-like cell line U937. The unprocessed protein MIC-1 was foun...
Embodiment 2
[0056] Example 2 Regulation of appetite by MIC-1
[0057] During the study in Example 1, it was noticed that the tumor xenograft model mice bearing overexpression of MIC-1 either lost weight or did not gain so much weight compared with the control mice. This therefore led to research into the extent and cause of the effect on mouse weight.
[0058] Materials and methods
[0059] The mice were weighed before sacrifice, and the weight loss (weight / %) was compared with the determined serum MIC-1 level (ie, determined by ELISA as in Example 1).
[0060] To assess whether serum MIC-1 levels were associated with the observed weight loss, a second study was performed in which nude mice were injected subcutaneously with the DU145 clone overexpressing mature human MIC-1 (previously associated with highest serum MIC-1 levels) , on the 27th day, after the mice lost a lot of body weight, they were injected with 1 mg or 10 mg of control purified sheep IgG or serum purified from sheep (pr...
Embodiment 3
[0067] Example 3 Weight loss associated with secreting tumor MIC-1 is reversed by application of anti-MIC-1 monoclonal antibody
[0068] Results and discussion
[0069] A xenograft mouse model was established using nude mice (as previously described), which were laterally injected with DU145 cells overexpressing mature MIC-1. Mice injected with DU145 cells overexpressing mature MIC-1 began to lose weight rapidly. Only 0.1-1 mg of MIC-1 monoclonal antibody (MAb26) was applied, on the 11th day, the body weight began to increase, and the amount and duration increased with the increase of MAb26 ( Figure 8A -C). At the highest dose of about 1 mg, body weight rose to pre-xenograft levels and then fell back to the body weight when the antibody was first administered after 17 days. Effect of MAb26 on tumor growth ( Figure 8D -F), untreated mice ( Figure 8G ) and mice treated with phosphate buffered saline (PBS) only ( Figure 8F ) had no effect, rapid and continuous weight lo...
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