Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis <scp>B</scp> infection

Tanwandee, Tawesak; Piratvisuth, Teerha; Thongsawat, Satawat; Hui, Aric Josun; Zhang, Hongfei; Ren, Hong; Chen, Pei‐Jer; Chuang, Wan‐Long; Sobhonslidsuk, Abhasnee; Li, Ruobing; Yin, Qin; Præstgaard, Jens; Han, Yamei; Xu, Jing; Stein, Daniel S.

doi:10.1111/jgh.12671

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…In the phase IIb study of a combination therapy of ribavirin and albinterferon to treat hepatitis C virus, patients given albinterferon of 900 μg and 1200 μg every 2 weeks showed the same sustained virologic response as the standard treatment of PEGylated interferon α-2a (Pegasys®) 180 μg every week [ 105 ]. In the phase III studies albinterferon was equal to standard treatment of PEGylated interferon α-2a though treatment discontinuation due to adverse effects which were 4.1 %, 10.4 % and 10.0 % for PEGylated interferon α-2a, albinterferon 1200 μg and albinterferon 900 μg respectively [ 106 , 107 ]. As of October 2010 FDA issued a complete response letter and Novartis and Human Genome Sciences, Inc. decided to stop further development of the drug [ 108 ].…”

Section: Introductionmentioning

confidence: 99%

Albumin-based drug delivery: harnessing nature to cure disease

et al. 2016

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The effectiveness of a drug is dependent on accumulation at the site of action at therapeutic levels, however, challenges such as rapid renal clearance, degradation or non-specific accumulation requires drug delivery enabling technologies. Albumin is a natural transport protein with multiple ligand binding sites, cellular receptor engagement, and a long circulatory half-life due to interaction with the recycling neonatal Fc receptor. Exploitation of these properties promotes albumin as an attractive candidate for half-life extension and targeted intracellular delivery of drugs attached by covalent conjugation, genetic fusions, association or ligand-mediated association. This review will give an overview of albumin-based products with focus on the natural biological properties and molecular interactions that can be harnessed for the design of a next-generation drug delivery platform.

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Section: Introductionmentioning

confidence: 99%

Albumin-based drug delivery: harnessing nature to cure disease

et al. 2016

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“…Due to its long t 1/2 , albumin has been harnessed for the pharmacokinetic (PK) extension of low molecular weight proteins, peptides, and small molecules. Notable Food and Drug Administration-approved examples include an interferon alpha-albumin fusion protein (albinterferon Alfa-2B, for chronic hepatitis C); 12 the glucagon-like peptide-1 agonist semaglutide, which contains an albumin-binding fatty acid moiety, 13 (Rybelsus®, for diabetes); 14 and the albumin-binding small molecule paclitaxel (Abraxane®, for pancreatic cancer). 15 When engineering albumin fusion proteins, the C-terminus has been shown to be required for FcRn binding 16 and in this study we present routes to engineer antigen specificity into albumin, independently of the termini.…”

Section: Introductionmentioning

confidence: 99%

The proximity of the N- and C- termini of bovine knob domains enable engineering of target specificity into polypeptide chains

Hawkins¹,

Joyce

Brady³

et al. 2022

mAbs

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Cysteine-rich knob domains can be isolated from the ultralong heavy-chain complementarity-determining region (CDR) 3, which are unique to a subset of bovine antibodies, to create antibody fragments of ~4 kDa. Advantageously, the N- and C- termini of these small binding domains are in close proximity, and we propose that this may offer a practical route to engineer extrinsic binding specificity into proteins. To test this, we transplanted knob domains into various loops of rat serum albumin, targeting sites that were distal to the interface with the neonatal Fc receptor. Using knob domains raised against the clinically validated drug target complement component C5, we produced potent inhibitors, which exhibit an extended plasma half-life in vivo via attenuated renal clearance and neonatal Fc receptor-mediated avoidance of lysosomal catabolism. The same approach was also used to modify a Camelid V HH , targeting a framework loop situated at the opposing end of the domain to the CDRs, to produce a small, single-chain bispecific antibody and a dual inhibitor of Complement C3 and C5. This study presents new protein inhibitors of the complement cascade and demonstrates a broadly applicable method to engineer target specificity within polypeptide chains, using bovine knob domains.

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“…Approximately 250 million people worldwide are chronically infected with hepatitis B virus (HBV) and are at high risk of developing liver steatosis, cirrhosis, end-stage liver failure or hepatocellular carcinoma [ 1 , 2 ]. Currently approved therapeutic strategies, including interferon-alpha (IFN-α), nucleoside and nucleotide analogs only provide limited efficacy in sustaining long-term HBV “eradication” [ 1 , 3 , 4 ], and the occurrence of adverse events leads to treatment termination or poor adherence [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

et al. 2021

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Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

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Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis B infection

Abstract: Albinterferon doses with similar anti-HBV efficacy to pegylated-interferon-α2a had higher rates of certain adverse events, particularly changes in lung diffusion capacity (http://www.clinicaltrials.gov number NCT00964665).

Cited by 7 publications

References 26 publications

Albumin-based drug delivery: harnessing nature to cure disease

Albumin-based drug delivery: harnessing nature to cure disease

The proximity of the N- and C- termini of bovine knob domains enable engineering of target specificity into polypeptide chains

CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

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