Journal: Blood Advances

Article Title: The preclinical profile of SerpinPC: a potential new treatment for hemophilia

doi: 10.1182/bloodadvances.2024015201

Figure Lengend Snippet: Blood loss volume in a mouse tail clip model is reduced by SerpinPC treatment in a dose- and time-dependent manner. (A) Blood loss volume over a 20-minute observation period is plotted for background strain B6;129S mice (magenta), and fVIII-deficient (HA) mice treated with vehicle (red), human fVIII at doses of 100 and 400 U/kg (green), or SerpinPC at 0.3, 1, 10, and 100 mg/kg (blue). Tails were transected 15 minutes after the injection of vehicle, fVIII, or SerpinPC. Blood loss values for vehicle-treated mice are taken from multiple experiments, and those for HA mice treated with 100 U/kg are taken from 2 separate experiments. For all other conditions, 3 mice were used per group, with median indicated by a line. (B) The effect of time of pre-exposure to SerpinPC on blood loss volume was assessed at a dose of 0.3 mg/kg. SerpinPC was injected 15, 60, and 120 minutes before tail transection, and blood loss was measured over a 20-minute period similar to that in panel A. Vehicle-treated HA and background control blood loss levels are indicated by a dashed line, with a gray area representing 1 standard deviation, calculated from panel A. Three mice were used per group, with average and standard deviation plotted. The line represents a nonlinear fit, forced through the average untreated value at t = 0. (C) To determine the lowest single dose of SerpinPC capable of reducing blood loss volume in the HA mouse, doses of 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg were given 12 hours before tail transection. The average blood loss volume of untreated HA and control mice are indicated similar to that in panel B. Dose dependency of blood loss is nonlinear, plateauing in the WT blood loss range at a dose of ∼1 mg/kg SerpinPC. Three mice were used per group with average and standard deviation plotted.

Article Snippet: SerpinPC and the control parent molecule human α 1 AT were produced in Chinese hamster ovary cells by Lonza (Cambridge, United Kingdom).

Techniques: Injection, Control, Standard Deviation

Journal: Blood Advances

Article Title: The preclinical profile of SerpinPC: a potential new treatment for hemophilia

doi: 10.1182/bloodadvances.2024015201

Figure Lengend Snippet: Effect of SerpinPC on spontaneous bleeding in HA mice. (A) A Kaplan-Meier survival curve is plotted for HA mice treated with either vehicle or 0.01, 0.1, or 1 mg/kg SerpinPC by subcutaneous injection 3 times per week for a maximum of 8 weeks (56 days). The vehicle and 0.01 mg/kg groups were euthanized early after reaching the humane end point. Only 2 mice from the 0.1 mg/kg group died, and none died in the 1 mg/kg group. (B) Surviving mice at the end of the treatment periods were examined to detect overt internal bleeding. Vehicle-treated mice experienced bleeding into many tissues, whereas those treated with 0.1 or 1 mg/kg SerpinPC did not exhibit any signs of internal bleeding.

Article Snippet: SerpinPC and the control parent molecule human α 1 AT were produced in Chinese hamster ovary cells by Lonza (Cambridge, United Kingdom).

Techniques: Injection

Journal: Blood Advances

Article Title: The preclinical profile of SerpinPC: a potential new treatment for hemophilia

doi: 10.1182/bloodadvances.2024015201

Figure Lengend Snippet: Use of SerpinPC to treat an ongoing bleed in HA mice and in WT mice treated with apixaban. (A) Mice were cannulated via the jugular vein to allow for the administration of agent 1 minute after tail transection. Vehicle-treated background control (B6;129S) mice (magenta) and HA mice (red) gave blood loss values similar to those observed in the pretreatment model. Human fVIII at 100 and 400 U/kg (green) and NovoSeven at 90 and 270 μg/kg (orange) reduced blood loss volume in a dose-dependent manner. SerpinPC reduced blood loss volume at doses of 1, 10, and 100 mg/kg (blue), with maximal effect observed for the 2 higher doses. Four mice were used per group, with median indicated. (B) To assess the ability of SerpinPC to reduce excessive bleeding caused by overanticoagulation, WT B6;129S mice were treated with either vehicle (magenta) or 10 mg/kg apixaban via jugular vein cannulas 5 minutes before tail transection. One minute after tail transection, either vehicle (red), 100 IU/kg Factor Eight Inhibitor Bypassing Agent (FEIBA; yellow), or 10 mg/kg SerpinPC (blue) was administered via the jugular vein, and bleeding volume was assessed over 20 minutes (n = 6 per group with averages indicated).

Article Snippet: SerpinPC and the control parent molecule human α 1 AT were produced in Chinese hamster ovary cells by Lonza (Cambridge, United Kingdom).

Techniques: Control

Journal: Blood Advances

Article Title: The preclinical profile of SerpinPC: a potential new treatment for hemophilia

doi: 10.1182/bloodadvances.2024015201

Figure Lengend Snippet: The effect of SerpinPC and anti-PC/APC antibodies in a sublethal LPS model. Serum IL-6 (A) and BUN levels (B) 13 hours after WT mice were given a sublethal dose of LPS and either vehicle (PBS), 10 mg/kg SerpinPC, or 10 mg/kg control antibodies MAPC1591 or MPC1609. MPC1609 conferred lethality in this model and increased serum IL-6 and BUN levels relative to PBS-treated mice. MAPC1591 did not cause lethality but did significantly increase both markers relative to the vehicle control (IL-6, P = .0431; BUN, P = .0309). In contrast, SerpinPC reduced IL-6 relative to vehicle ( P = .0309), and had no effect on serum BUN levels relative to PBS controls. Controls from mice treated with PBS and saline, instead of LPS, are included.

Article Snippet: SerpinPC and the control parent molecule human α 1 AT were produced in Chinese hamster ovary cells by Lonza (Cambridge, United Kingdom).

Techniques: Control, Saline