Hepatitis C New Drugs Review
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Continuing Medical Education: Sofosbuvir for He... [N Engl J Med. 2013] - PubMed - NCBI

PubMed comprises more than 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
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Hepatitis C New Drugs Review
FDA approved Incivek(telaprevir, Vertex) on Monday 23 May by its PDUFA deadline.A paradigm shift in the treatment of Hepatitis C virus infection. http://knol.google.com/k/krishan-maggon/boceprevir-merck-telaprevir-vertex/3fy5eowy8suq3/151#
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Created public version #121 of the knol: "Boceprevir (Merck) & Telaprevir (Vertex) Hepatitis C : FDA Review & Approval"

Created public version #121 of the knol: "Boceprevir (Merck) & Telaprevir (Vertex) Hepatitis C : FDA Review & Approval" | Hepatitis C New Drugs Review | Scoop.it
Krishan Maggon published version 121 of a knol titled: "Boceprevir (Merck) & Telaprevir (Vertex) Hepatitis C : FDA Review & Approval"...
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Cost-Utility of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Genotype 1 Infection

Cost-Utility of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Genotype 1 Infection | Hepatitis C New Drugs Review | Scoop.it
Abstract Objective To evaluate the cost-utility of treatment with elbasvir/grazoprevir (EBR/GZR) regimens compared with ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3D ± RBV), and sofosbuvir/velpatasvir (SOF/VEL) in patients with chronic hepatitis C...
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Tailored Ahp‐cyclodepsipeptides as Potent Non‐covalent Serine Protease Inhibitors

Tailored Ahp‐cyclodepsipeptides as Potent Non‐covalent Serine Protease Inhibitors | Hepatitis C New Drugs Review | Scoop.it
The S1 serine protease family is one of the largest and most biologically important protease families. Despite their biomedical significance, generic approaches to generate potent, class‐specific
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Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants - Journal of Medicinal Chemistry (ACS Publications)

Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants - Journal of Medicinal Chemistry (ACS Publications) | Hepatitis C New Drugs Review | Scoop.it
A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure–activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156, and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC50 values ≤5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance.
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J. Med. Chem., Article ASAP 
DOI: 10.1021/acs.jmedchem.7b00426 
Publication Date (Web): June 8, 2017 


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Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase

Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase | Hepatitis C New Drugs Review | Scoop.it
Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real-time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a.
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Viruses 2017, 9(6), 151; doi:10.3390/v9060151 (registering DOI)
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Changes in risk behaviours during and following treatment for hepatitis C virus infection among people who inject drugs: The ACTIVATE study

Changes in risk behaviours during and following treatment for hepatitis C virus infection among people who inject drugs: The ACTIVATE study | Hepatitis C New Drugs Review | Scoop.it
The risk of hepatitis C virus (HCV) reinfection due to continued injecting risk behaviours
might remain a barrier to HCV treatment among people who inject drugs. We aimed to
evaluate changes in risk behaviours during and following HCV treatment among people
with ongoing injecting drug use or receiving opioid substitution treatment (OST).
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Complementary and alternative medications in hepatitis C infection

Complementary and alternative medications in hepatitis C infection | Hepatitis C New Drugs Review | Scoop.it
Chronic hepatitis C (CHC) infection affects almost 3% of the global population and can lead to cirrhosis, liver failure, and hepatocellular carcinoma in a significant number of those infected. Until recently, the only treatments available were pegylate
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Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus Three Direct-Acting Antiviral Regimen: Paritaprevir/Ritonavir, Ombitasvir, and Dasabuvir

Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus Three Direct-Acting Antiviral Regimen: Paritaprevir/Ritonavir, Ombitasvir, and Dasabuvir | Hepatitis C New Drugs Review | Scoop.it
To assess drug-drug interaction (DDI) potential for the three direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir, and paritaprevir, in vitro studies profiled drug-metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, organic anion-transporting polypeptide (OATP) 1B1/1B3, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp). Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations, but additional physiologically based pharmacokinetic modeling was necessary to achieve the same for drug transporters. When perpetrator interactions were assessed, ritonavir was responsible for the strong increase in exposure of sensitive CYP3A substrates, whereas paritaprevir (an OATP1B1/1B3 inhibitor) greatly increased the exposure of sensitive OATP1B1/1B3 substrates. The 3D regimen drugs are UGT1A1 inhibitors and are predicted to moderately increase plasma exposure of sensitive UGT1A1 substrates. Paritaprevir, ritonavir, and dasabuvir are BCRP inhibitors. Victim DDI predictions were qualitatively in line with the clinical observations. Plasma exposures of the 3D regimen were reduced by strong CYP3A inducers (paritaprevir and ritonavir; major CYP3A substrates) but were not affected by strong CYP3A4 inhibitors, since ritonavir (a CYP3A inhibitor) is already present in the regimen. Strong CYP2C8 inhibitors increased plasma exposure of dasabuvir (a major CYP2C8 substrate), OATP1B1/1B3 inhibitors increased plasma exposure of paritaprevir (an OATP1B1/1B3 substrate), and P-gp or BCRP inhibitors (all compounds are substrates of P-gp and/or BCRP) increased plasma exposure of the 3D regimen. Overall, the comprehensive mechanistic assessment of compound disposition along with mechanistic and PBPK approaches to predict victim and perpetrator DDI liability may enable better clinical management of nonstudied drug combinations with the 3D regimen.
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Increased warfarin requirements in a patient with chronic hepatitis C infection receiving sofosbuvir and ribavirin

Increased warfarin requirements in a patient with chronic hepatitis C infection receiving sofosbuvir and ribavirin | Hepatitis C New Drugs Review | Scoop.it
Purpose A case of increased warfarin requirements during treatment with sofosbuvir and ribavirin for chronic hepatitis C virus (HCV) infection is reported.

Summary A 63-year-old white man receiving long-term anticoagulation with warfarin for atrial fibrillation and a history of cardioembolic stroke was initiated in September 2014 on a 12-week course of sofosbuvir 400 mg orally daily and weight-based ribavirin 600 mg orally twice daily for HCV genotype 2 infection. Before starting this treatment regimen, the patient had been stable on warfarin 52.5 mg weekly, with therapeutic International Normalized Ratio (INR) values. During the 12-week course of sofosbuvir and ribavirin, the patient’s dose of warfarin progressively increased from 52.5 to 77.5 mg weekly due to subtherapeutic INRs, with the first adjustment in the warfarin dose occurring 9 days after initiation of HCV treatment. Three weeks after completion of the sofosbuvir and ribavirin regimen, the patient’s INR was 3.06, and his warfarin dose was then decreased to 70 mg weekly. The patient continued with this warfarin dosage until 18 weeks after completion of his HCV regimen. The dosage was then decreased to 65 mg weekly after an INR of 3.86. Three weeks later, his INR was 2.19, and warfarin 65 mg weekly was continued. As of June 2016, the patient has continued to require warfarin 62.5–65 mg weekly to maintain a therapeutic INR.

Conclusion A 63-year-old man on a stable dose of warfarin experienced a decrease in INR values after the initiation of a 12-week course of sofosbuvir and ribavirin for the treatment of chronic HCV infection.
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Is There a Relationship Between Treatment With Direct Antiviral Agents for HCV Infection and the Development of Malignancies? - PubMed - NCBI

Is There a Relationship Between Treatment With Direct Antiviral Agents for HCV Infection and the Development of Malignancies? - PubMed - NCBI | Hepatitis C New Drugs Review | Scoop.it
J Clin Gastroenterol. 2017 Jun 5. doi: 10.1097/MCG.0000000000000853. [Epub ahead of print]
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NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains

NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains | Hepatitis C New Drugs Review | Scoop.it
Author summary Inhibitors targeting the HCV NS5A protein are a key component of highly effective interferon-free combination therapies for chronic hepatitis C. Despite their high potency against HCV, the precise details of their mode of action are poorly understood. They are known to block assembly and release of virus particles from infected hepatocytes, resulting in a rapid drop in viral RNA in the blood. Additionally they block formation of intracellular membrane structures that are the site of viral RNA synthesis in infected hepatocytes. By preventing membrane remodeling, NS5A inhibitors effectively block formation of new RCs within the cell. Following addition of NS5A inhibitors to infected cell cultures, the kinetics of antiviral suppression were found to vary between different HCV strains, independent of specific differences in NS5A sequence. Using an integrated experimental and mathematical modeling approach, we provide evidence that the rate of decline of viral RNA abundance in infected cells treated with NS5A inhibitors is determined by the stability or half-life of the functional HCV RC.
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Citation: Benzine T, Brandt R, Lovell WC, Yamane D, Neddermann P, De Francesco R, et al. (2017) NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains. PLoS Pathog 13(6): e1006343. https://doi.org/10.1371/journal.ppat.1006343
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'Miracle' hepatitis C drugs costing £30k per patient 'may have no clinical effect'

'Miracle' hepatitis C drugs costing £30k per patient 'may have no clinical effect' | Hepatitis C New Drugs Review | Scoop.it
Review concludes drugs hailed as cure for potentially fatal liver disease may clear virus from blood, but there is no evidence they prevent harm or save lives
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Renal failure in HCV cirrhosis

Renal failure in HCV cirrhosis | Hepatitis C New Drugs Review | Scoop.it
The patient was diagnosed with hepatitis C 15 years ago; now, his kidneys are failing.
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Funding the war on hepatitis – deploying innovative finance mechanisms to eliminate hepatitis C in Europe

Funding the war on hepatitis – deploying innovative finance mechanisms to eliminate hepatitis C in Europe | Hepatitis C New Drugs Review | Scoop.it
This website links to patient friendly commentary making it easier ​to navigate key HCV data.
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Successful Treatment for Chronic Hepatitis C-Autoimmune Hepatitis Overlap Syndrome due to Daclatasvir and Asunaprevir. - PubMed - NCBI

Successful Treatment for Chronic Hepatitis C-Autoimmune Hepatitis Overlap Syndrome due to Daclatasvir and Asunaprevir. - PubMed - NCBI | Hepatitis C New Drugs Review | Scoop.it

Case Rep Gastroenterol. 2017 May 17;11(2):305-311. doi: 10.1159/000475752. eCollection 2017 May-Aug.


Abstract Persistent hepatitis C virus (HCV) infection may induce autoimmune diseases and chronic hepatitis C is sometimes accompanied by autoimmune hepatitis (AIH). However, we are worried about the treatment for chronic hepatitis C-AIH overlap syndrome because interferon-based antiviral therapies may enhance autoimmunity and immunosuppressive corticosteroid administration may promote viral replication. Here, we report a patient having chronic hepatitis C-AIH overlap syndrome treated with the direct-acting antivirals (DAA), daclatasvir and asunaprevir. A 50-year-old man was referred to our hospital because of positive anti-HCV antibody and liver dysfunction at a health checkup. Blood tests showed increased immunoglobulin G (IgG) and a high titer of antinuclear antibody (ANA) in addition to elevated serum alanine aminotransferase (ALT) and HCV-RNA. Infiltration of lymphocytes and plasma cells in Glisson’s capsule and severe interface hepatitis were observed in biopsied specimen, which fulfilled the criteria of AIH. We first started oral corticosteroid administration, and serum ALT levels decreased once but elevated again. We commenced daclatasvir and asunaprevir (60 and 200 mg/day, respectively) and serum HCV-RNA became negative after 6 weeks. Adverse effects were not found during the DAA treatment, and serum ALT, IgG, and ANA were significantly decreased. Corticosteroid could be tapered and stopped, but no recurrence occurred. DAA treatment appears to be effective and safe for the patients with chronic hepatitis C-AIH overlap syndrome.

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Case Rep Gastroenterol 2017;11:305–311 https://doi.org/10.1159/000475752
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Review article: hepatitis E—a concise review of virology, epidemiology, clinical presentation and therapy

Review article: hepatitis E—a concise review of virology, epidemiology, clinical presentation and therapy | Hepatitis C New Drugs Review | Scoop.it
Hepatitis E virus (HEV) is a leading cause of acute icteric hepatitis and acute liver failure in the developing world. During the last decade, there has been increasing recognition of autochthonou
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Nucleoside analogue 2’-C-methylcytidine inhibits hepatitis E virus replication but antagonizes ribavirin

Nucleoside analogue 2’-C-methylcytidine inhibits hepatitis E virus replication but antagonizes ribavirin | Hepatitis C New Drugs Review | Scoop.it
Hepatitis E virus (HEV) infection has emerged as a global health issue, but no approved medication is available. The nucleoside analogue 2’-C-methylcytidine (2CMC), a viral polymerase inhibitor, has b
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Demystifying Medicine 2014 - HAV and HCV RNA Viruses: Clinical and Basic Advances and Challenges - Virology

Demystifying Medicine 2014 - HAV and HCV RNA Viruses: Clinical and Basic Advances and Challenges - Virology | Hepatitis C New Drugs Review | Scoop.it
Demystifying Medicine 2014 – HAV and HCV RNA Viruses: Clinical and Basic Advances and Challenges Air date: Tuesday, April 15, 2014, 4:00:00 PM … source
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Prevention of HCV infection using a broad cross-neutralizing monoclonal antibody (AR4A) and Epigallocatechin-Gallate

Prevention of HCV infection using a broad cross-neutralizing monoclonal antibody (AR4A) and Epigallocatechin-Gallate | Hepatitis C New Drugs Review | Scoop.it

The anti-HCV activity of a novel monoclonal antibody (mAb; AR4A) and Epigallocatechin-gallate (EGCG) were studied in-vitro using an HCV cell culture system and in-vivo using a humanized liver mouse model capable of supporting HCV replication. Alone, bot


Abstract 


The anti-HCV activity of a novel monoclonal antibody (mAb; AR4A) and Epigallocatechin-gallate (EGCG) were studied in-vitro using an HCV cell culture system and in-vivo using a humanized liver mouse model capable of supporting HCV replication. Alone, both exhibit reliable cross-genotype HCV inhibition in-vitro, and combination therapy completely prevented HCV infection. In-vivo AR4A mAb (alone and combined with EGCG) robustly protects against the establishment of HCV genotype 1a infection. EGCG alone fails to reliably protect against HCV challenge. 


 Conclusion AR4A mAb represents a safe and efficacious broadly neutralising antibody against HCV applicable to strategies to safely prevent HCV re-infection following liver transplantation, and lends further support to the concept of HCV vaccine development. The poor bioavailability of EGCG limits HCV anti-viral activity in-vivo. 


Keywords: Liver transplantation, HCV prevention, anti-HCV monoclonal antibody, Epigallocatechin-gallate

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Liver Transpl. Author manuscript; available in PMC 2017 Mar 1. Published in final edited form as: Liver Transpl. 2016 Mar; 22(3): 324–332. Published online 2016 Jan 29. doi: 10.1002/lt.2434
PMCID: PMC4769112 NIHMSID: NIHMS725009
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Evaluation of three Techniques for detection of IL28B SNP: a prognostic tool for HCV treatment outcome

Evaluation of three Techniques for detection of IL28B SNP: a prognostic tool for HCV treatment outcome | Hepatitis C New Drugs Review | Scoop.it
The study was accompanied to evaluate the specificity, cost and turn‐around time of three different types of techniques that can be used for analysis of single nucleotide polymorphism o
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HIV and hepatitis C treatment uptake among people who use drugs participating in the Amsterdam Cohort Studies, 1985–2015

HIV and hepatitis C treatment uptake among people who use drugs participating in the Amsterdam Cohort Studies, 1985–2015 | Hepatitis C New Drugs Review | Scoop.it
HIV-positive people who use drugs (PWUD) start antiretroviral therapy (ART) later
than other risk groups, and among HCV-positive PWUD, HCV treatment uptake is low.
Nowadays, HCV direct-acting antivirals (DAAs) are available and reimbursed in the
Netherlands (since 2014). The Amsterdam Cohort Studies (ACS), initiated in 1985, provides
us the opportunity to describe temporal trends in ART and HCV-treatment uptake among
PWUD through 2015.
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Costs for generic hepatitis C drugs available in India would be paid back in 5 to 10 years

Costs for generic hepatitis C drugs available in India would be paid back in 5 to 10 years | Hepatitis C New Drugs Review | Scoop.it
A research team led by a Massachusetts General Hospital investigator has found that use of the generic versions of directly-acting antiviral drugs that are available in India to treat hepatitis C virus infection is not only cost effective but actually saves lifetime treatment costs for patients in that country.
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Direct-Acting Antiviral Agents for Patients With Hepatitis C Virus Genotype 1 Infection Are Cost-Saving

Direct-Acting Antiviral Agents for Patients With Hepatitis C Virus Genotype 1 Infection Are Cost-Saving | Hepatitis C New Drugs Review | Scoop.it
Direct-acting antivirals (DAAs) are effective in treatment of hepatitis C virus (HCV)
genotype 1 infection, but their cost and value have been debated. We performed a systematic
review of published cost-effectiveness analyses of DAAs, synthesized their results
with updated drug prices, and calculated the maximum price at which DAA therapy for
HCV genotype 1 infection is cost-effective (increased quality-adjusted life-years
[QALYs] and increased cost that the society is willing to pay) and cost-saving (increased
QALYs and decreased costs).
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Researchers identify how class of drugs blocks Hepatitis C virus replication

Researchers identify how class of drugs blocks Hepatitis C virus replication | Hepatitis C New Drugs Review | Scoop.it
Globally, an estimated 71 million people are living with chronic hepatitis C virus (HCV). Over decades of infection, chronic HCV infection results in progressive damage to the liver and an increased risk for end stage live
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Your Body Can Lead the Battle against HCV Infection - Selig Health

Your Body Can Lead the Battle against HCV Infection - Selig Health | Hepatitis C New Drugs Review | Scoop.it
The transmission of the virus that causes hepatitis C has been well-documented, but this disease sti
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HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer

HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer | Hepatitis C New Drugs Review | Scoop.it
T cell receptor (TCR)-gene-modified T cells for adoptive cell transfer can mediate
objective clinical responses in melanoma and other malignancies. When introducing
a second TCR, mispairing between the endogenous and introduced α and β TCR chains
limits expression of the introduced TCR, which can result in impaired efficacy or
off-target reactivity and autoimmunity. One approach to promote proper TCR chain pairing
involves modifications of the introduced TCR genes: introducing a disulfide bridge,
substituting murine for human constant regions, codon optimization, TCR chain leucine
zipper fusions, and a single-chain TCR.
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