Exploration ofα1-Antitrypsin Treatment Protocol for Islet Transplantation: Dosing Plan and Route of Administration

Abstract

Lifelong weekly infusions of human α1-antitrypsin (hAAT) are currently administered as augmentation therapy for patients with genetic AAT deficiency (AATD). Several recent clinical trials attempt to extend hAAT therapy to conditions outside AATD, including type 1 diabetes. Because the endpoint for AATD is primarily the reduction of risk for pulmonary emphysema, the present study explores hAAT dose protocols and routes of administration in attempt to optimize hAAT therapy for islet-related injury. Islet-grafted mice were treated with hAAT (Glassia; intraperitoneally or subcutaneously) under an array of clinically relevant dosing plans. Serum hAAT and immunocyte cell membrane association were examined, as well as parameters of islet survival. Results indicate that dividing the commonly prescribed 60 mg/kg i.p. dose to three 20 mg/kg injections is superior in affording islet graft survival; in addition, a short dynamic descending dose protocol (240→120→60→60 mg/kg i.p.) is comparable in outcomes to indefinite 60 mg/kg injections. Although pharmacokinetics after intraperitoneal administration in mice resembles exogenous hAAT treatment in humans, subcutaneous administration better imitated the physiologic progressive rise of hAAT during acute phase responses; nonetheless, only the 60 mg/kg dose depicted an advantage using the subcutaneous route. Taken together, this study provides a platform for extrapolating an islet-relevant clinical protocol from animal models that use hAAT to protect islets. In addition, the study places emphasis on outcome-oriented analyses of drug efficacy, particularly important when considering that hAAT is presently at an era of drug-repurposing toward an extended list of clinical indications outside genetic AATD.

Point Mutation of a Non-Elastase-Binding Site in Human α1-Antitrypsin Alters Its Anti-Inflammatory Properties

“…In regard to CP increased distribution volume and half-life, since these distinctions appear to accompany this variant’s enhanced anti-inflammatory capacity, it is suggested that its physical properties render it functionally unique. It has been shown that exogenously administered hAAT is readily detected on the surface of activated immune cells ( 78 ), coinciding with observations by Subramaniyam et al, in which hAAT localizes on membrane lipid rafts ( 29 ). This property is in agreement with evidence for direct binding of oxidized cholesterol ( 31 ) and fatty acids ( 79 ) by hAAT, and suggests that hAAT membranal presence might serve as a platform for several of its functional attributes ( 80 – 82 ).…”

Alpha-1 antitrypsin suppresses macrophage activation and promotes islet graft survival after intrahepatic islet transplantation

“…Recent studies show that human AAT dose protocols and routes of administration impact the protective effects of AAT therapy for islet-related injuries. 42 We found that infusion of 4 mg/mouse of AAT achieved better protection to human islet grafts compared to the lower dose of 2 mg/mouse. Our experience shows that the dose of human AAT needs to be optimized in different transplantation situations.…”

A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Alpha-1 Antitrypsin (AAT) (Glassia®) in the Treatment of Recent-Onset Type 1 Diabetes

“…Previous reports with AAT in recent-onset type 1 diabetes included smaller study populations with a wide age variability, doses up to 90 mg/kg/dose, and no placebo group [17,18,19,20]. Higher doses of AAT (>120 mg/kg per dose) have been explored both in preclinical and clinical studies [23], with no evidence for dose-dependency beyond 120 mg/kg per dose. In 2018, we reported on periodic AAT treatment (up to 36 infusions) in a cohort as being safe and well tolerated during a surveillance period of 5 years [20].…”