Although natural killer (NK) cells have been implicated in regulating immune responses, their ability to modulate disease development in autoimmune arthritis has not been analyzed. Here we investigate the contribution of NK cells to regulating collagen-induced arthritis, a well-characterized preclinical model of human rheumatoid arthritis. We find that the disease is induced by the combined action of two CD4
+
T helper (T
H
) subsets: follicular T
H
cells and T
H
17 cells. Both CD4
+
T
H
subsets are highly susceptible to lysis by NK cells after activation. Administration of antibody that activates NK cells through blockade of its inhibitory CD94/NKG2A receptor allows enhanced elimination of pathogenic follicular T
H
and T
H
17 cells and arrest of disease progression. These results suggest that antibody-dependent enhancement of NK activity may yield effective, previously undescribed therapeutic approaches to this autoimmune disorder.
SummaryPreclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (antimC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of antimC5aR treatment in single-dose treatment studies. We found that 48 h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.
Endogenous peptide hormones, such as glucagon used for treatment of severe hypoglycemia events in patients with diabetes, are commonly unstable in aqueous solution making development of ready-to-use injection solutions a challenge. Analogs of endogenous peptide hormones can be designed to increase the stability of the molecules. Another approach to enable easy administration of unstable peptides is to formulate them in non-aqueous formulations, such as DMSO (dimethyl sulfoxide).
The current study was conducted to compare the PK/PD of glucagon following SC administration in rats when formulated in DMSO or an aqueous formulation (Phosphate buffered solution (PBS)). The PD data were compared to data generated for the stable glucagon analog dasiglucagon in rats.
Four to six male Sprague-Dawley rats received 3 nmol/kg of glucagon in DMSO or in a PBS formulation or dasiglucagon at 2 nmol/kg in a PBS formulation. Blood samples for bioanalysis (glucagon groups only) and blood glucose measurement were taken at pre-dose (0) and 15, 30, 45, 60, 75, 90, 105 and 120 min post dose.
Glucagon in PBS demonstrated a faster absorption, a higher Cmax (98.3 versus 39.9 pmol/L) and faster Tmax (15 versus 45 minutes) compared to glucagon in DMSO. The increase in blood glucose was similar for glucagon and dasiglucagon in PBS and faster compared to glucagon in DMSO.
Disclosure
C. Wenander: Employee; Self; Zealand Pharma A/S. A.H. Valeur: Employee; Self; Zealand Pharma A/S. M. Elander: Employee; Self; Zealand Pharma A/S.
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