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1.
J Infect Dis ; 226(11): 1985-1991, 2022 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-36082606

RESUMEN

BACKGROUND: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. METHODS: CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure. RESULTS: At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. CONCLUSIONS: LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Farmacorresistencia Viral/genética , Cápside , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , VIH-1/genética , Antirretrovirales/uso terapéutico
2.
J Antimicrob Chemother ; 77(4): 989-995, 2022 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-35028668

RESUMEN

BACKGROUND: Lenacapavir in vitro resistance selections identified seven mutations in HIV-1 capsid protein (CA) associated with reduced susceptibility. OBJECTIVES: To analyse lenacapavir activity against lenacapavir-associated resistance mutations in multiple assays. We also report Day 10 resistance analyses conducted in a Phase 1b study of lenacapavir (Study 4072) in people with HIV (PWH). METHODS: Mutations were inserted in a proviral DNA clone by site-directed mutagenesis, and viruses (n = 12) were generated by transfection. Sequences were used to generate single-cycle (SC) test vectors that were evaluated in a Gag-Pro assay, and replicative viruses were tested in a multicycle (MC) MT-2 assay to determine lenacapavir susceptibility. Study 4072 was a Phase 1b, double-blinded, placebo-controlled, dose-ranging, randomized study of lenacapavir in untreated PWH. Participants received a single dose of lenacapavir (up to 750 mg) or placebo (10 day monotherapy). CA resistance was characterized using genotypic and/or phenotypic assays. RESULTS: Lenacapavir susceptibility in the SC assay showed an inverse relationship between replication capacity and resistance. In Study 4072, all 29 participants receiving lenacapavir showed a robust virological response with no rebound. At baseline, no participant had resistance mutations to lenacapavir, and all had WT susceptibility to lenacapavir. Post-monotherapy analyses revealed the emergence of CA mutation Q67H at Day 10 in two participants. CONCLUSIONS: In vitro assays confirmed that increased resistance to lenacapavir was associated with decreased replication capacity of mutant viruses. In the clinical study no pre-existing lenacapavir resistance was detected. Emergence of Q67H occurred at exposures below the dose used in current Phase 2/3 studies. These results support development of lenacapavir as an antiretroviral agent.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Mutación
3.
Cell Mol Neurobiol ; 41(5): 949-960, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32107752

RESUMEN

OBJECTIVE: Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models. METHODS: Graded noxious stimulus intensities were used in rats to establish the antinociceptive potency and efficacy of NKTR-181 relative to morphine, fentanyl, and oxycodone. Characteristics of MOR agonist actions, as measured by antinociceptive tolerance and cross-tolerance, as well as opioid-induced hyperalgesia (OIH) and naloxone-precipitated withdrawal in NKTR-181- and morphine-dependent in mice, were compared. RESULTS: NKTR-181 showed dose- and time-related antinociception with similar maximal effects to morphine in the rat and mouse hot-water tail-flick test. No sex or species differences were observed in NKTR-181 or morphine antinociception. Rats treated with NKTR-181 and morphine exhibited decreases in both potency and maximal efficacy as nociceptive stimulus intensity was increased from a water temperature of 50 °C to 54 °C. Evaluation of antinociception at a high stimulus intensity revealed that oxycodone and fentanyl exhibited greater efficacy than either NKTR-181 or morphine. The relative potency difference between NKTR-181 and morphine across all tail-flick studies was determined to be 7.6-fold (90% confidence interval, 2.6, 21.5). The peak antinociceptive effect of NKTR-181 was delayed compared to that of the other opioids and cumulative drug effects were not observed. Repeated treatment with escalating, approximately equi-analgesic doses of NKTR-181 or morphine, produced antinociceptive tolerance and cross-tolerance. Under these pharmacological conditions, OIH and naloxone-precipitated physical dependence were similar for NKTR-181 and morphine. CONCLUSIONS: NKTR-181 had a slower onset, but similar efficacy, to morphine in the models studied supporting reduced abuse potential while maintaining analgesic effect in comparison with current opioids.


Asunto(s)
Analgésicos Opioides/farmacología , Morfinanos/farmacología , Morfina/farmacología , Dimensión del Dolor/efectos de los fármacos , Receptores Opioides mu/agonistas , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Masculino , Ratones , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Receptores Opioides mu/fisiología , Roedores
4.
Artículo en Inglés | MEDLINE | ID: mdl-39298557

RESUMEN

BACKGROUND: HIV envelope (env) diversity may result in resistance to broadly neutralizing antibodies (bNAbs). Assessment of genotypic or phenotypic susceptibility to antiretroviral treatment is often performed in people with HIV-1 (PWH) and used for clinical trial screening for HIV-1 bNAb susceptibility. Optimal bNAb susceptibility screening methods are not yet clear. METHODS: Phenotypic and genotypic analyses were conducted on 124 screening samples from a Phase 1b study of bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS) administered with lenacapavir in virally suppressed PWH. Phenotypic analysis was conducted on integrated HIV-1 provirus and stimulated outgrowth virus, with susceptibility to bNAbs defined as 90% inhibitory concentration ≤2 µg/mL. The proviral DNA HIV env gene was genotyped using deep sequencing, and bNAb susceptibility predicted using published env amino acid signatures. RESULTS: Proviral phenotypic results were reported for 109 of 124 samples; 75% (82/109) were susceptible to teropavimab, 65% (71/109) to zinlirvimab, and 50% (55/109) to both bNAbs. Phenotypic susceptibility of outgrowth viruses was available for 39 samples; 56% (22/39) were susceptible to teropavimab, and 64% (25/39) to zinlirvimab. Phenotypic susceptibilities correlated between these methods: teropavimab r = 0.82 (P<0.0001); zinlirvimab r = 0.77 (P<0.0001). Sixty-seven samples had genotypic and phenotypic data. Proviral genotypic signatures predicted proviral phenotypic susceptibility with high positive predictive value (68-86% teropavimab; 63-90% zinlirvimab). CONCLUSIONS: bNAb susceptibility was correlated among all three in-vitro assays used to determine teropavimab and zinlirvimab susceptibility in virally suppressed PWH. These findings may help refine PWH selection criteria for eligibility for future studies.

5.
AIDS ; 38(4): 607-610, 2024 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-38416554

RESUMEN

We studied the relationship between viral diversity and susceptibility to broadly neutralizing antibodies (bNAbs) in longitudinal plasma and peripheral blood mononuclear cells from 89 people with HIV who initiated antiretroviral therapy (ART) during acute and early HIV-1 infection (AEHI). HIV-1 diversity and predicted bNAb susceptibility were comparable across AEHI. Diversity evolution was not observed during ART, suggesting (pro)viruses at initiation or during treatment may identify individuals with susceptible virus for bNAb interventional trials.


Asunto(s)
Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , Infecciones por VIH/tratamiento farmacológico , Anticuerpos ampliamente neutralizantes , Leucocitos Mononucleares
6.
Lancet HIV ; 11(3): e146-e155, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38307098

RESUMEN

BACKGROUND: Long-acting treatment for HIV has potential to improve adherence, provide durable viral suppression, and have long-term individual and public health benefits. We evaluated treatment with two antibodies that broadly and potently neutralise HIV (broadly neutralising antibodies; bNAbs), combined with lenacapavir, a long-acting capsid inhibitor, as a long-acting regimen. METHODS: This ongoing, randomised, blind, phase 1b proof-of-concept study conducted at 11 HIV treatment centres in the USA included adults with a plasma HIV-1 RNA concentration below 50 copies per mL who had at least 18 months on oral antiretroviral therapy (ART), CD4 counts of at least 500 cells per µL, and protocol-defined susceptibility to bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS). Participants stopped oral ART and were randomly assigned (1:1) to one dose of 927 mg subcutaneous lenacapavir plus an oral loading dose, 30 mg/kg intravenous teropavimab, and 10 mg/kg or 30 mg/kg intravenous zinlirvimab on day 1. Investigational site personnel and participants were masked to treatment assignment throughout the randomised period. The primary endpoint was incidence of serious adverse events until week 26 in all randomly assigned participants who received one dose or more of any study drug. This study is registered with ClinicalTrials.gov, NCT04811040. FINDINGS: Between June 29 and Dec 8, 2021, 21 participants were randomly assigned, ten in each group received the complete study regimen and one withdrew before completing the regimen on day 1. 18 (86%) of 21 participants were male; participants ranged in age from 25 years to 61 years and had a median CD4 cell count of 909 (IQR 687-1270) cells per µL at study entry. No serious adverse events occurred. Two grade 3 adverse events occurred (lenacapavir injection-site erythaema and injection-site cellulitis), which had both resolved. The most common adverse events were symptoms of injection-site reactions, reported in 17 (85%) of 20 participants who received subcutaneous lenacapavir; 12 (60%) of 20 were grade 1. One (10%; 95% CI 0-45) participant had viral rebound (confirmed HIV-1 RNA concentration of ≥50 copies per mL) in the zinlirvimab 10 mg/kg group, which was resuppressed on ART, and one participant in the zinlirvimab 30 mg/kg group withdrew at week 12 with HIV RNA <50 copies per mL. INTERPRETATION: Lenacapavir with teropavimab and zinlirvimab 10 mg/kg or 30 mg/kg was generally well tolerated with no serious adverse events. HIV-1 suppression for at least 26 weeks is feasible with this regimen at either zinlirvimab dose in selected people with HIV-1. FUNDING: Gilead Sciences.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Humanos , Masculino , Femenino , Infecciones por VIH/diagnóstico , Anticuerpos ampliamente neutralizantes/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Anticuerpos Anti-VIH/uso terapéutico , ARN/uso terapéutico , Carga Viral
7.
J Clin Invest ; 133(16)2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37384413

RESUMEN

Long-acting antiretroviral agents for preexposure prophylaxis (PrEP) represent a promising new alternative to daily oral regimens for HIV prevention. Lenacapavir (LEN) is a first-in-class long-acting capsid inhibitor approved for the treatment of HIV-1 infection. Here, we assessed the efficacy of LEN for PrEP using a single high-dose simian-human immunodeficiency virus (SHIV) rectal challenge macaque model. In vitro, LEN showed potent antiviral activity against SHIV, as it did for HIV-1. In macaques, a single subcutaneous administration of LEN demonstrated dose proportional increases in and durability of drug plasma levels. A high-dose SHIV inoculum for the PrEP efficacy evaluation was identified via virus titration in untreated macaques. LEN-treated macaques were challenged with high-dose SHIV 7 weeks after drug administration, and the majority remained protected from infection, as confirmed by plasma PCR, cell-associated proviral DNA, and serology testing. Complete protection and superiority to the untreated group was observed among animals whose LEN plasma exposure exceeded its model-adjusted clinical efficacy target at the time of challenge. All infected animals had subprotective LEN concentrations and showed no emergent resistance. These data demonstrate effective SHIV prophylaxis in a stringent macaque model at clinically relevant LEN exposures and support the clinical evaluation of LEN for HIV PrEP in humans.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Humanos , Macaca , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética
8.
Lancet HIV ; 10(1): e15-e23, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36566079

RESUMEN

BACKGROUND: Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV. METHODS: In a phase 2, randomised, open-label, ongoing study at 41 investigational sites in the USA and Dominican Republic, we randomly assigned adults with HIV who had not previously received antiretrovirals to four groups (2:2:2:1). Randomisation was stratified by plasma HIV-1 RNA load (≤100 000 or >100 000 copies per mL) at screening. Groups 1 and 2 both received lenacapavir (927 mg) subcutaneously every 26 weeks (after 2 weeks of oral loading [600 mg on days 1 and 2, followed by 300 mg on day 8]) with oral daily emtricitabine (200 mg) and tenofovir alafenamide (25 mg) for 28 weeks followed by subcutaneous lenacapavir (927 mg) plus oral daily tenofovir alafenamide (25 mg, group 1) or bictegravir (75 mg, group 2). Group 3 received oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) with emtricitabine (200 mg) and tenofovir alafenamide (25 mg). Group 4 received oral daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants and investigators were not masked to group assignment. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 54, analysed in the full analysis set (all randomly assigned participants who received at least one dose of study drug) using only on-treatment data. The safety outcome measures were incidences of treatment-emergent adverse events and graded laboratory abnormalities, analysed in the full analysis set. This study is registered at ClinicalTrials.gov, NCT04143594. FINDINGS: Between Nov 22, 2019, and Aug 27, 2020, 249 people with HIV were screened, 183 participants were randomly assigned and 182 received a dose of antiretroviral drugs (52 in group 1, 53 in group 2, 52 in group 3, and 25 in group 4). 22 participants did not complete the full study course (five in group 1, 12 in group 2, four in group 3, and one in group 4). At week 54, virological suppression was 90% (47 of 52 patients) for group 1 (difference vs group 4: -2·6%, 95% CI -18·4 to 13·2), 85% (45 of 53) for group 2 (-7·1%, -23·4 to 9·3), 85% (44 of 52) for group 3 (-7·2%, -23·5 to 9·1), and 92% (23 of 25) for group 4. The most frequent non-injection-site adverse events with lenacapavir (subcutaneous or oral) were headache (13%, 21 of 157) and nausea (13%, 21 of 157). The most common lenacapavir-related injection-site reactions were erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105), which were generally mild or moderate. No serious adverse event related to study treatment occurred. Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions (two for induration and one for erythema or swelling). INTERPRETATION: Lenacapavir warrants further investigation as a potential antiretroviral used orally and as injection in combination with other antiretroviral drugs. FUNDING: Gilead Sciences.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/diagnóstico , Tenofovir/uso terapéutico , Resultado del Tratamiento , Oxazinas/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Emtricitabina/uso terapéutico , Antirretrovirales/uso terapéutico , Adenina/uso terapéutico , ARN/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos , Carga Viral
9.
Front Pain Res (Lausanne) ; 2: 695962, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35295409

RESUMEN

Mu opioid receptor (MOPr) agonists are well-known and frequently used clinical analgesics but are also rewarding due to their highly addictive and often abusive properties. This may lead to opioid use disorder (OUD) a disorder that effects millions of people worldwide. Therefore, novel compounds are urgently needed to treat OUD. As opioids are effective analgesics and OUD often occurs in conjunction with chronic pain, these novel compounds may be opioids, but they must have a low abuse liability. This could be mediated by diminishing or slowing blood-brain barrier transport, slowing target receptor binding kinetics, and showing a long half-life. NKTR-181 is a PEGylated oxycodol and a MOPr agonist that has slowed blood-brain barrier transport, a long half-life, and diminished likeability in clinical trials. In this study, we examined the signaling and behavioral profile of NKTR-181 in comparison with oxycodone to determine whether further therapeutic development of this compound may be warranted. For this preclinical study, we used a number of in vitro and in vivo assays. The signaling profile of NKTR-181 was determined by the electrophysiological assessment of MOPr-Ca2+ channel inhibition in the nociceptive neurons of rodent dorsal root ganglia. Heterologous cell-based assays were used to assess biased agonism and receptor trafficking. Different rodent behavioral models were used to define the NKTR-181-induced relief of effective and reflexive nociception and drug-seeking behavior as assessed by an intravenous self-administration (IVSA) of NKTR-181. We found that NKTR-181 and oxycodone are partial agonists in G-protein signaling and Ca2+ channel inhibition assays and promote limited MOPr desensitization. However, NKTR-181 inhibits Ca2+ channels by a different mechanism than oxycodone and induces a different pattern of arrestin recruitment. In addition, NKTR-181 has a slower receptor on-rate and a slower rate of Ca2+ channel coupling than oxycodone. This signaling profile is coupled with a slower onset of antinociception and limited drug-seeking behavior in comparison with oxycodone. Together with its known long half-life and slow blood-brain barrier transport, these data suggest that NKTR-181 could be further studied as a pharmacotherapeutic treatment modality for OUD.

10.
J Transl Autoimmun ; 4: 100103, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34041473

RESUMEN

Impaired interleukin-2 (IL-2) production and regulatory T-cell dysfunction have been implicated as immunological mechanisms central to the pathogenesis of multiple autoimmune and inflammatory diseases. NKTR-358, a novel regulatory T-cell stimulator, is an investigational therapeutic that selectively restores regulatory T-cell homeostasis in these diseases. We investigated NKTR-358's selectivity for regulatory T-cells, receptor-binding properties, ex vivo and in vivo pharmacodynamics, ability to suppress conventional T-cell proliferation in mice and non-human primates, and functional activity in a murine model of systemic lupus erythematosus. In vitro, NKTR-358 demonstrated decreased affinity for IL-2Rα, IL-2Rß, and IL-2Rαß compared with recombinant human IL-2 (rhIL-2). A single dose of NKTR-358 in cynomolgus monkeys produced a greater than 15-fold increase in regulatory T-cells, and the increase lasted until day 14, while daily rhIL-2 administration for 5 days only elicited a 3-fold increase, which lasted until day 7. Repeated dosing of NKTR-358 over 6 months in cynomolgus monkeys elicited cyclical, robust increases in regulatory T-cells with no loss in drug activity over the course of treatment. Regulatory T-cells isolated from NKTR-358-treated mice displayed a sustained, higher suppression of conventional T-cell proliferation than regulatory T-cells isolated from vehicle-treated mice. NKTR-358 treatment in a mouse model (MRL/MpJ-Faslpr) of systemic lupus erythematosus for 12 weeks maintained elevated regulatory T-cells for the treatment duration and ameliorated disease progression. Together, these results suggest that NKTR-358 has the ability to elicit sustained and preferential proliferation and activation of regulatory T-cells without corresponding effects on conventional T-cells, with improved pharmacokinetics compared with rhIL-2.

11.
Chem Res Toxicol ; 21(9): 1733-8, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18690724

RESUMEN

The toxicity of acrolein, an alpha,beta-unsaturated aldehyde produced during lipid peroxidation, is attributable to its high reactivity toward DNA and cellular proteins. The major acrolein-DNA adduct, gamma-hydroxypropano-2'-deoxyguanosine (gamma-HOPdG), ring opens to form a reactive N(2)-oxopropyl moiety that cross-links to DNA and proteins. We demonstrate the ability of gamma-HOPdG in a duplex oligonucleotide to cross-link to a protein (EcoRI) that specifically interacts with DNA at a unique sequence. The formation of a cross-link to EcoRI was dependent on the intimate binding of the enzyme to its gamma-HOPdG-modified recognition site. Interestingly, the cross-link did not restrict the ability of EcoRI to cleave DNA substrates. However, stabilization of the cross-link by reduction of the Schiff base linkage resulted in loss of enzyme activity. This work indicates that the gamma-HOPdG-EcoRI cross-link is in equilibrium with free oligonucleotide and enzyme. Reversal of cross-link formation allows EcoRI to effect enzymatic cleavage of competitor oligonucleotides.


Asunto(s)
ADN/química , Desoxiguanosina/análogos & derivados , Desoxirribonucleasa EcoRI/química , Desoxiguanosina/química , Estructura Molecular , Relación Estructura-Actividad , Factores de Tiempo
12.
Clin Cancer Res ; 22(3): 680-90, 2016 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-26832745

RESUMEN

PURPOSE: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates. EXPERIMENTAL DESIGN: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates. RESULTS: In a murine melanoma tumor model, the ratio of tumor-killing CD8(+) T cells to Foxp3(+) regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti-CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates. CONCLUSIONS: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies.


Asunto(s)
Antineoplásicos/farmacología , Interleucina-2/análogos & derivados , Neoplasias/metabolismo , Neoplasias/patología , Polietilenglicoles/farmacología , Profármacos , Receptores de Interleucina-2/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Animales , Antineoplásicos/química , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Femenino , Humanos , Memoria Inmunológica , Interleucina-2/química , Interleucina-2/farmacología , Linfocitos Infiltrantes de Tumor , Masculino , Melanoma Experimental , Ratones , Modelos Moleculares , Conformación Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Polietilenglicoles/química , Unión Proteica , Receptores de Interleucina-2/química , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Carga Tumoral/efectos de los fármacos
13.
Biochemistry ; 44(13): 5024-33, 2005 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-15794640

RESUMEN

DNA damage may alter the outcome of protein-nucleic acid interactions. The malondialdehyde-deoxyguanosine adduct, 3-(2'-deoxy-beta-d-erythro-pentofuranosyl)pyrimido[1,2-alpha]purin-10-(3H)-one (M(1)dG), miscodes in vivo and in vitro. M(1)dG is an exocyclic adduct that undergoes ring-opening in duplex DNA to form the acyclic adduct, N(2)-(3-oxo-1-propenyl)-deoxyguanosine (N(2)-OPdG). These two adducts have different effects on DNA polymerase bypass and may affect other DNA processing enzymes. We employed the EcoRI restriction endonuclease as a model for the interaction of DNA binding proteins with adducted DNA substrates. The presence of M(1)dG in the EcoRI recognition sequence impaired the ability of the enzyme to cleave DNA, resulting in only 60% cleavage of the adducted strand and 75% cleavage of the complementary strand. Three adducts of similar structure to M(1)dG that are unable to ring-open were cleaved poorly, or not at all, by EcoRI. None of the adducts appeared to inactivate or sequester EcoRI. Additional studies with BssHII and PauI confirmed these results and demonstrated a positional effect of M(1)dG on cleavage efficiency. These data suggest dissimilar modes of protein-nucleic acid interactions based on differences in adduct structure. Comparison of the solution structures of DNA adducts and the crystal structure of EcoRI complexed to substrate suggest a model to explain the functional differences.


Asunto(s)
Aductos de ADN/química , Aductos de ADN/metabolismo , ADN/química , ADN/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/química , Desoxiguanosina/metabolismo , Desoxirribonucleasa EcoRI/metabolismo , Secuencia de Bases , Dominio Catalítico , Daño del ADN , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Desoxirribonucleasa EcoRI/química , Técnicas In Vitro , Cinética , Modelos Moleculares , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/metabolismo , Especificidad por Sustrato
14.
Proc Natl Acad Sci U S A ; 100(24): 14247-52, 2003 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-14603032

RESUMEN

Instability of repetitive sequences is a hallmark of human cancer, and its enhancement has been linked to oxidative stress. Malondialdehyde is an endogenous product of oxidative stress that reacts with guanine to form the exocyclic adduct, pyrimido[1,2- alpha]purin-10(3H)-one (M1G). We used site-specifically modified single- and double-stranded vectors to investigate the mutagenic potential of M1G in bacteria and mammalian cells. M1G induced frameshift mutations (-1 and -2) when positioned in a reiterated (CpG)4 sequence but not when positioned in a nonreiterated sequence in Escherichia coli and in COS-7 cells. The frequency of frameshift mutations was highest when M1G was placed at the third G in the sequence. M1G induced base pair substitutions at comparable frequencies in both sequence contexts in COS-7 cells. These studies indicate that M1G, an endogenously generated product of oxidative stress, induces sequence-dependent frameshift mutations and base pair substitutions in bacteria and in mammalian cells. This finding suggests a potential role for the M1G lesion in the induction of mutations commonly associated with human diseases.


Asunto(s)
Carcinógenos/toxicidad , Aductos de ADN/toxicidad , Mutación del Sistema de Lectura , Mutágenos/toxicidad , Purinas/toxicidad , Pirimidinas/toxicidad , Animales , Secuencia de Bases , Células COS , Chlorocebus aethiops , ADN/genética , ADN Bacteriano/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Mutación Puntual
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