Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 – 2015)

Lior, Yotam; Geyra, A.; Lewis, Eli C.

doi:10.1517/13543776.2016.1165210

Cited by 12 publications

(10 citation statements)

References 55 publications

(82 reference statements)

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“…Recent years have witnessed an expansion of potential clinical applications for hAAT treatment beyond that of straightforward augmentation therapy for genetic hAAT deficiency; these include type 1 diabetes ( 37 , 50 – 52 ), allogeneic and xenogeneic transplants ( 44 – 46 , 53 , 54 ), graft-versus-host disease ( 53 , 55 , 56 ), acute myocardial infarction ( 57 – 59 ), inflammatory bowel disease ( 52 , 60 ), rheumatoid arthritis ( 61 – 63 ), multiple sclerosis ( 41 ), and osteoporosis ( 64 , 65 ). Collectively, these represent an extension of earlier preclinical studies that portray hAAT as possessing anti-inflammatory and immunoregulatory properties ( 3 , 4 , 26 , 35 ).…”

Section: Discussionmentioning

confidence: 54%

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

et al. 2018

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IntroductionHuman α1-antitrypsin (hAAT) is a 394-amino acid long anti-inflammatory, neutrophil elastase inhibitor, which binds elastase via a sequence-specific molecular protrusion (reactive center loop, RCL; positions 357–366). hAAT formulations that lack protease inhibition were shown to maintain their anti-inflammatory activities, suggesting that some attributes of the molecule may reside in extra-RCL segments. Here, we compare the protease-inhibitory and anti-inflammatory profiles of an extra-RCL mutation (cys232pro) and two intra-RCL mutations (pro357cys, pro357ala), to naïve [wild-type (WT)] recombinant hAAT, in vitro, and in vivo.MethodsHis-tag recombinant point-mutated hAAT constructs were expressed in HEK-293F cells. Purified proteins were evaluated for elastase inhibition, and their anti-inflammatory activities were assessed using several cell-types: RAW264.7 cells, mouse bone marrow-derived macrophages, and primary peritoneal macrophages. The pharmacokinetics of the recombinant variants and their effect on LPS-induced peritonitis were determined in vivo.ResultsCompared to WT and to RCL-mutated hAAT variants, cys232pro exhibited superior anti-inflammatory activities, as well as a longer circulating half-life, despite all three mutated forms of hAAT lacking anti-elastase activity. TNFα expression and its proteolytic membranal shedding were differently affected by the variants; specifically, cys232pro and pro357cys altered supernatant and serum TNFα dynamics without suppressing transcription or shedding.ConclusionOur data suggest that the anti-inflammatory profile of hAAT extends beyond direct RCL regions. Such regions might be relevant for the elaboration of hAAT formulations, as well as hAAT-based drugs, with enhanced anti-inflammatory attributes.

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Section: Discussionmentioning

confidence: 54%

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

et al. 2018

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“…The study places emphasis on function- and outcome-oriented analyses of treatment, a particularly important entity when considering that hAAT is entering an era of drug-repurposing toward an extended list of clinical indications (Lewis, 2012; Lior et al, 2016). More studies are to be undertaken to optimize treatment protocols relevant to diseases other than AATD.…”

Section: Discussionmentioning

confidence: 99%

“…Several clinical trials presently address the potential benefit of AAT therapy to individuals without AATD, including islet and lung transplantation, type 1 diabetes (T1D), graft-versus-host disease, acute myocardial infarction, and cystic fibrosis (Lior et al, 2016). In the case of T1D clinical trials, the initial dosing plan for assessing islet protection by AAT was directly borrowed from the long-standing protocols of AAT augmentation therapy for AATD patients, e.g., weekly infusions of 60–80 mg/kg plasma-derived affinity-purified human AAT (Balbi et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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

Baranovski

Ozeri

Shahaf

et al. 2016

J Pharmacol Exp Ther

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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.

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“… 121 There is a theoretical basis and some supporting data for the potential benefit of AAT in other conditions characterized by excessive neutrophilic inflammation such as inflammatory bowel disease, rheumatoid arthritis and postoperative systemic inflammatory response syndrome (SIRS). 122 For example, Daemen et al have demonstrated that AAT mitigates renal reperfusion injury in mice via reduced TNF-α and neutrophil influx. 123 Kaner et al have shown that transgenic mice expressing the human AAT gene have reduced levels of liver and pancreatic dysfunction compared to wild-type mice in an SIRS model, as well as improved survival at 24 hours.…”

Section: Positive Effects Of Aat As Treatment In Other Lung Diseasesmentioning

confidence: 99%

The impact of alpha-1 antitrypsin augmentation therapy on neutrophil-driven respiratory disease in deficient individuals

Dunlea

Fee

McEnery

et al. 2018

JIR

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Alpha-1 antitrypsin (AAT) is the most abundant serine protease inhibitor circulating in the blood. AAT deficiency (AATD) is an autosomal codominant condition affecting an estimated 3.4 million individuals worldwide. The clinical disease associated with AATD can present in a number of ways including COPD, liver disease, panniculitis and antineutrophil cytoplasmic antibody vasculitis. AATD is the only proven genetic risk factor for the development of COPD, and deficient individuals who smoke are disposed to more aggressive disease. Principally, AAT is a serine protease inhibitor; however, over the past number of years, the assessment of AAT as simply an antiprotease has evolved, and it is now recognized that AAT has significant anti-inflammatory properties affecting a wide range of cells, including the circulating neutrophil.

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Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 – 2015)

Cited by 12 publications

References 55 publications

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

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

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

The impact of alpha-1 antitrypsin augmentation therapy on neutrophil-driven respiratory disease in deficient individuals

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