Anti-cd40 antibodies for use in treatment of sj gren's syndrome
A technology for Sjogren's syndrome and antibodies, applied in the direction of antibodies, antibody medical components, anti-receptors/cell surface antigens/cell surface determinant immunoglobulins, etc., can solve problems such as lack of appropriateness
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example 1
[0155] Example 1. Anti-CD40 Antibodies
[0156] Anti-CD40 mAbs with silent ADCC activity have been disclosed in patents US8828396 and US9221913, which are hereby incorporated by reference in their entirety. Anti-CD40 mAbs predicted to have silent ADCC activity have an improved safety profile relative to other anti-CD40 antibodies, and in particular may be more suitable for non-neoplastic indications such as Sjogren's syndrome (SS), especially primary Sjogren's syndrome (pSS).
[0157] Based on the non-binding hypothesis of the inventors, two mAbs from patents US8828396 and US9221913, called mAb1 and mAb2, were considered suitable compounds for the treatment of SS. Antibody mAbl (also known as CFZ533) is particularly preferred.
[0158] mAb1 inhibits CD154-induced activation in vitro as well as T cell-dependent antibody formation and germinal center formation in vivo. In patients with pSS, CD40 blockade with mAbl has been shown to provide a new therapeutic modality (Exampl...
example 2
[0233] Example 2. Pharmacology
[0234] 1. Main pharmacology
[0235] mAb1 with high affinity (K d 0.3nM) binds to human CD40. However, it does not bind Fc gamma receptors (including CD16) or mediate antibody-dependent or complement-dependent cytotoxicity. mAb1 inhibits recombinant CD154 (rCD154)-induced activation of human leukocytes, but does not induce PBMC proliferation or cytokine production by monocyte-derived dendritic cells (DCs). mAb1 binds human and nonhuman primate CD40 with very similar affinity.
[0236] In vivo, mAb1 blocks primary and secondary T cell-dependent antibody responses (TDARs) and can prolong renal allograft survival in nonhuman primates (Cordoba et al. 2015). Additionally, mAb1 can disrupt established germinal centers (GCs) in vivo.
[0237] CD40 receptor occupancy and functional activity were simultaneously assessed in vitro using human whole blood cultures. Functional activity was quantified by CD154-induced expression of CD69 (activation m...
example 3
[0240] Example 3. Nonclinical Toxicology and Safety Pharmacology
[0241] Toxicology studies with mAbl did not reveal any significant organ toxicity, including no evidence of thromboembolic events, as reported in a clinical trial with anti-CD154 mAb (Kawai et al. 2000). In a 13-week GLP rhesus study (administered weekly at 10, 50 and 150 mg / kg), lymphocytic increases (which were thought to be due to persistent infection) were noted in 5 / 22 animals, which The observations are consistent with the pharmacology of mAb1. Inflammatory lesions were noted in the kidneys and lungs of 2 animals at 50 mg / kg, and in one of the two animals, lesions were also noted in the eyes and trachea. While a direct effect of mAb1 on the kidneys and lungs cannot be ruled out, the weight of the evidence, including demonstration of opportunistic pathogens, suggests that these findings may be secondary to mAb1-mediated immunosuppression and an infectious source. Given these inflammatory findings, the ...
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