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1.
PLoS One ; 16(12): e0256885, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34972105

RESUMO

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein co-administered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06-1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.


Assuntos
Vacinas contra a AIDS/sangue , Vacinas contra a AIDS/imunologia , Adjuvantes Imunológicos/farmacologia , Formação de Anticorpos/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Criança , Regiões Determinantes de Complementaridade , Epitopos/imunologia , Humanos , Imunização , Cadeias Pesadas de Imunoglobulinas/metabolismo , Memória Imunológica/efeitos dos fármacos , Macaca mulatta , Hipermutação Somática de Imunoglobulina , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo
2.
NPJ Vaccines ; 6(1): 137, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34795290

RESUMO

We developed a SARS-CoV-2 spike subunit vaccine formulation containing dual TLR ligand liposome adjuvant. The vaccine-induced robust systemic neutralizing antibodies and completely protected mice from a lethal challenge. Two immunizations protected against lung injury and cleared the virus from lungs upon challenge. The adjuvanted vaccine also elicited systemic and local anti-Spike IgA which can be an important feature for a COVID-19 vaccine.

3.
Front Immunol ; 12: 683157, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248966

RESUMO

Amebiasis is a neglected tropical disease caused by Entamoeba histolytica. Although the disease burden varies geographically, amebiasis is estimated to account for some 55,000 deaths and millions of infections globally per year. Children and travelers are among the groups with the greatest risk of infection. There are currently no licensed vaccines for prevention of amebiasis, although key immune correlates for protection have been proposed from observational studies in humans. We previously described the development of a liposomal adjuvant formulation containing two synthetic TLR ligands (GLA and 3M-052) that enhanced antigen-specific fecal IgA, serum IgG2a, a mixed IFNγ and IL-17A cytokine profile from splenocytes, and protective efficacy following intranasal administration with the LecA antigen. By applying a statistical design of experiments (DOE) and desirability function approach, we now describe the optimization of the dose of each vaccine formulation component (LecA, GLA, 3M-052, and liposome) as well as the excipient composition (acyl chain length and saturation; PEGylated lipid:phospholipid ratio; and presence of antioxidant, tonicity, or viscosity agents) to maximize desired immunogenicity characteristics while maintaining physicochemical stability. This DOE/desirability index approach led to the identification of a lead candidate composition that demonstrated immune response durability and protective efficacy in the mouse model, as well as an assessment of the impact of each active vaccine formulation component on protection. Thus, we demonstrate that both GLA and 3M-052 are required for statistically significant protective efficacy. We also show that immunogenicity and efficacy results differ in female vs male mice, and the differences appear to be at least partly associated with adjuvant formulation composition.


Assuntos
Antígenos de Protozoários/imunologia , Entamoeba histolytica/imunologia , Entamebíase/imunologia , Entamebíase/prevenção & controle , Vacinas Protozoárias/imunologia , Adjuvantes Imunológicos/química , Administração Intranasal , Animais , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Fenômenos Químicos , Citocinas/metabolismo , Composição de Medicamentos , Entamebíase/parasitologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imunogenicidade da Vacina , Imunoglobulina G/imunologia , Lipossomos , Camundongos , Vacinas Protozoárias/administração & dosagem , Vacinas Protozoárias/química , Vacinação
4.
Sci Immunol ; 6(61)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266981

RESUMO

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Vacinas contra COVID-19 , COVID-19/prevenção & controle , SARS-CoV-2 , Saccharomycetales/genética , Glicoproteína da Espícula de Coronavírus/genética , Administração por Inalação , Administração Intranasal , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Linhagem Celular , Citocinas/imunologia , Humanos , Imunoglobulina G/imunologia , Pulmão/patologia , Macaca mulatta , Masculino , Ligação Proteica , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral
5.
Nature ; 594(7864): 553-559, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33971664

RESUMO

Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)1-4. Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID50) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.


Assuntos
Anticorpos Neutralizantes/imunologia , Betacoronavirus/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Resfriado Comum/prevenção & controle , Reações Cruzadas/imunologia , Pandemias , Vacinas Virais/imunologia , Adjuvantes Imunológicos , Administração Intranasal , Animais , COVID-19/epidemiologia , Vacinas contra COVID-19/imunologia , Resfriado Comum/imunologia , Resfriado Comum/virologia , Modelos Animais de Doenças , Feminino , Humanos , Macaca/imunologia , Masculino , Modelos Moleculares , Nanopartículas/química , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Traqueia , Vacinação
6.
bioRxiv ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33619494

RESUMO

Betacoronaviruses (betaCoVs) caused the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, and now the SARS-CoV-2 pandemic. Vaccines that elicit protective immune responses against SARS-CoV-2 and betaCoVs circulating in animals have the potential to prevent future betaCoV pandemics. Here, we show that immunization of macaques with a multimeric SARS-CoV-2 receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052-Alum elicited cross-neutralizing antibody responses against SARS-CoV-1, SARS-CoV-2, batCoVs and the UK B.1.1.7 SARS-CoV-2 mutant virus. Nanoparticle vaccination resulted in a SARS-CoV-2 reciprocal geometric mean neutralization titer of 47,216, and robust protection against SARS-CoV-2 in macaque upper and lower respiratory tracts. Importantly, nucleoside-modified mRNA encoding a stabilized transmembrane spike or monomeric RBD protein also induced SARS-CoV-1 and batCoV cross-neutralizing antibodies, albeit at lower titers. These results demonstrate current mRNA vaccines may provide some protection from future zoonotic betaCoV outbreaks, and provide a platform for further development of pan-betaCoV nanoparticle vaccines.

7.
J Immunother Cancer ; 7(1): 244, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511088

RESUMO

BACKGROUND: Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically "cold" tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated. METHODS: The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models. RESULTS: Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models. CONCLUSION: Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.


Assuntos
Células Dendríticas/imunologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Células Matadoras Naturais/imunologia , Melanoma Experimental/tratamento farmacológico , Ácidos Esteáricos/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Microambiente Tumoral/imunologia , Imunidade Adaptativa , Adjuvantes Imunológicos/farmacologia , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Imunoterapia , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Ratos Sprague-Dawley , Células Tumorais Cultivadas
8.
NPJ Vaccines ; 3: 22, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900011

RESUMO

Amebiasis caused by Entamoeba histolytica is the third leading cause of parasitic mortality globally, with some 100,000 deaths annually, primarily among young children. Protective immunity to amebiasis is associated with fecal IgA and IFN-γ in humans; however, no vaccine exists. We have previously identified recombinant LecA as a potential protective vaccine antigen. Here we describe the development of a stable, manufacturable PEGylated liposomal adjuvant formulation containing two synthetic Toll-like receptor (TLR) ligands: GLA (TLR4) and 3M-052 (TLR7/8). The liposomes stimulated production of monocyte/macrophage chemoattractants MCP-1 and Mip-1ß, and Th1-associated cytokines IL-12p70 and IFN-γ from human whole blood dependent on TLR ligand composition and dose. The liposomes also demonstrated acceptable physicochemical compatibility with the recombinant LecA antigen. Whereas mice immunized with LecA and GLA-liposomes demonstrated enhanced antigen-specific fecal IgA titers, mice immunized with LecA and 3M-052-liposomes showed a stronger Th1 immune profile. Liposomes containing GLA and 3M-052 together elicited both LecA-specific fecal IgA and Th1 immune responses. Furthermore, the quality of the immune response could be modulated with modifications to the liposomal formulation based on PEG length. Compared to subcutaneous administration, the optimized liposome adjuvant composition with LecA antigen administered intranasally resulted in significantly enhanced fecal IgA, serum IgG2a, as well as systemic IFN-γ and IL-17A levels in mice. The optimized intranasal regimen provided greater than 80% protection from disease as measured by parasite antigen in the colon. This work demonstrates the physicochemical and immunological characterization of an optimized mucosal adjuvant system containing a combination of TLR ligands with complementary activities and illustrates the importance of adjuvant composition and route of delivery to enhance a multifaceted and protective immune response to amebiasis.

9.
JCI Insight ; 2(6): e91020, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28352660

RESUMO

Infection is the most common cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, newborns fail to respond optimally to most vaccines. Adjuvantation is a key approach to enhancing vaccine immunogenicity, but responses of human newborn leukocytes to most candidate adjuvants, including most TLR agonists, are functionally distinct. Herein, we demonstrate that 3M-052 is a locally acting lipidated imidazoquinoline TLR7/8 agonist adjuvant in mice, which, when properly formulated, can induce robust Th1 cytokine production by human newborn leukocytes in vitro, both alone and in synergy with the alum-adjuvanted pneumococcal conjugate vaccine 13 (PCV13). When admixed with PCV13 and administered i.m. on the first day of life to rhesus macaques, 3M-052 dramatically enhanced generation of Th1 CRM-197-specific neonatal CD4+ cells, activation of newborn and infant Streptococcus pneumoniae polysaccharide-specific (PnPS-specific) B cells as well as serotype-specific antibody titers, and opsonophagocytic killing. Remarkably, a single dose at birth of PCV13 plus 0.1 mg/kg 3M-052 induced PnPS-specific IgG responses that were approximately 10-100 times greater than a single birth dose of PCV13 alone, rapidly exceeding the serologic correlate of protection, as early as 28 days of life. This potent immunization strategy, potentially effective with one birth dose, could represent a new paradigm in early life vaccine development.


Assuntos
Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia , Adjuvantes Imunológicos/farmacologia , Adulto , Animais , Linfócitos B/imunologia , Células Cultivadas , Humanos , Recém-Nascido , Macaca mulatta , Linfócitos T/imunologia
10.
Vaccine ; 35(6): 916-922, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28089548

RESUMO

Diarrheal infectious diseases represent a major cause of global morbidity and mortality. There is an urgent need for vaccines against diarrheal pathogens, especially parasites. Modern subunit vaccines rely on combining a highly purified antigen with an adjuvant to increase their efficacy. In the present study, we evaluated the ability of a nanoliposome adjuvant system to trigger a strong mucosal immune response to the Entamoeba histolytica Gal/GalNAc lectin LecA antigen. CBA/J mice were immunized with alum, emulsion or liposome based formulations containing synthetic TLR agonists. A liposome formulation containing TLR4 and TLR7/8 agonists was selected based on its ability to generate intestinal IgA, plasma IgG2a/IgG1, IFN-γ and IL-17A. Immunization with a mucosal prime followed by a parenteral boost generated a high mucosal IgA response that inhibited adherence of parasites to mammalian cells. Inclusion of the immune potentiator all-trans retinoic acid in the regimen further improved the mucosal IgA response. Immunization protected from infection with up to 55% efficacy. Our results show that a nanoliposome delivery system containing TLR agonists is a promising prospect for the development of vaccines against enteric pathogens, especially when a multifaceted immune response is desired.


Assuntos
Anticorpos Antiprotozoários/biossíntese , Entamoeba histolytica/efeitos dos fármacos , Entamebíase/prevenção & controle , Imunidade nas Mucosas/efeitos dos fármacos , Lipossomos/imunologia , Vacinas Protozoárias/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Compostos de Alúmen/administração & dosagem , Animais , Antígenos de Protozoários/química , Antígenos de Protozoários/imunologia , Entamoeba histolytica/crescimento & desenvolvimento , Entamoeba histolytica/imunologia , Entamebíase/imunologia , Entamebíase/parasitologia , Imunização , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Lectinas/química , Lectinas/imunologia , Lipopolissacarídeos/administração & dosagem , Lipossomos/administração & dosagem , Lipossomos/química , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos CBA , Oligodesoxirribonucleotídeos/administração & dosagem , Polissorbatos/administração & dosagem , Vacinas Protozoárias/química , Vacinas Protozoárias/imunologia , RNA/administração & dosagem , Esqualeno/administração & dosagem , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/imunologia , Tretinoína/administração & dosagem , Vacinas de Subunidades
11.
J Control Release ; 244(Pt A): 98-107, 2016 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-27847326

RESUMO

For nearly a century, aluminum salts have been the most widely used vaccine adjuvant formulation, and have thus established a history of safety and efficacy. Nevertheless, for extremely challenging disease targets such as tuberculosis or HIV, the adjuvant activity of aluminum salts may not be potent enough to achieve protective efficacy. Adsorption of TLR ligands to aluminum salts facilitates enhanced adjuvant activity, such as in the human papilloma virus vaccine Cervarix®. However, some TLR ligands such as TLR7/8 agonist imidazoquinolines do not efficiently adsorb to aluminum salts. The present report describes a formulation approach to solving this challenge by developing a lipid-based nanosuspension of a synthetic TLR7/8 ligand (3M-052) that facilitates adsorption to aluminum oxyhydroxide via the structural properties of the helper lipid employed. In immunized mice, the aluminum oxyhydroxide-adsorbed formulation of 3M-052 enhanced antibody and TH1-type cellular immune responses to vaccine antigens for tuberculosis and HIV.


Assuntos
Adjuvantes Imunológicos/química , Hidróxido de Alumínio/química , Óxido de Alumínio/química , Imidazóis/química , Nanopartículas/química , Quinolinas/química , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Vacinas contra a AIDS/imunologia , Adsorção , Animais , Estabilidade de Medicamentos , Humanos , Imidazóis/imunologia , Imunidade Celular , Imunidade Humoral , Ligantes , Lipídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Quinolinas/imunologia , Propriedades de Superfície , Vacinas contra a Tuberculose/imunologia
12.
Oncotarget ; 6(7): 4663-76, 2015 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-25609199

RESUMO

In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Radiação Ionizante , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Neoplasias Colorretais/metabolismo , Terapia Combinada , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/efeitos da radiação , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Imidazóis/farmacologia , Técnicas Imunoenzimáticas , Imunoterapia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/metabolismo , Quinolinas/farmacologia , Linfócitos T Citotóxicos/imunologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Expert Rev Vaccines ; 12(7): 809-19, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23885825

RESUMO

Small molecule Toll-like receptor (TLR) 7/8 agonists have demonstrated potential as vaccine adjuvants, since they directly activate APCs and can enhance both humoral and cellular immune responses, especially Th1 responses. Although the natural ligands for TLR7 and TLR8 are ssRNA, the vast majority of vaccine studies performed thus far have been performed with synthetic small molecule imidazoquinolines, such as imiquimod and resiquimod. Despite the approved clinical use of the topical TLR7 agonist, imiquimod (Aldara(®) Imiquimod 5% cream; 3M, MN, USA), for external genital warts, superficial basal cell carcinoma and actinic keratosis, no vaccines using TLR7, TLR8 or TLR7/8 agonists have progressed beyond early-phase clinical studies thus far. This review will highlight the nonclinical and clinical studies that indicate promise for TLR7/8 ligands as vaccine adjuvants, reasons for inconsistent results thus far, problems with current technology and potential paths forward for TLR7/8 agonists as vaccine adjuvants.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Vacinas/imunologia , Aminoquinolinas/administração & dosagem , Aminoquinolinas/farmacologia , Ensaios Clínicos como Assunto , Descoberta de Drogas/tendências , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Imiquimode , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia
15.
Cancer Biol Ther ; 10(2): 155-65, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20519933

RESUMO

The aim of the current study was to evaluate the influence of chemotherapeutic drugs on immunotherapy with Imidazoquinoline Toll-like Receptor (TLR) agonists in cancer. First, the previously described antitumor efficacy of TLR agonists [i.e. a TLR7 agonist (852A) and a dual TLR7/8 agonist (3M-011)] was confirmed in additional cancer models, and second the therapeutic potential of TLR agonists in combination with cyclophosphamide was investigated. The antitumor potential was evaluated against a panel of syngeneic tumor models; namely B16-F10 melanoma, M3 melanoma and MC-26 colon carcinoma. Systemic administration of either 3M-011 or 852A in these various syngeneic models induced significant antitumor activity as evidenced by delays in tumor growth curves. Combination of cyclophosphamide with either 3M-011 or 852A demonstrated that cyclophosphamide does not negatively interfere with the TLR agonist's antitumor effects, but may, depending on the dosing schedule, to actually potentiate the effect. These findings suggest that the immunomodulatory TLR agonists may be used in combination with cytotoxic agents in the treatment of cancer.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Quinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Carga Tumoral , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Células HEK293 , Humanos , Interferon Tipo I/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Modelos Animais , NF-kappa B/imunologia , Quinolinas/administração & dosagem , Estatísticas não Paramétricas , Sulfonamidas/administração & dosagem , Células Tumorais Cultivadas
16.
Cancer Immunol Immunother ; 58(4): 575-87, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18791716

RESUMO

Innate immune stimulation with Toll-like receptor (TLR) agonists is a proposed modality for immunotherapy of melanoma. Here, a TLR7/8 agonist, 3M-011, was used effectively as a single systemic agent against disseminated mouse B16-F10 melanoma. The investigation of the mechanism of antitumor action revealed that the agonist had no direct cytotoxic effects on tumor cells tested in vitro. In addition, 3M-011 retained its effectiveness in scid/B6 mice and scid/NOD mice, eliminating the requirement for T and B cells, but lost its activity in beige (bg/bg) and NK1.1-immunodepleted mice, suggesting a critical role for natural killer (NK) cells in the antitumor response. NK cytotoxicity was enhanced in vivo by the TLR7/8 agonist; this activation was long lasting, as determined by sustained expression of the activation marker CD69. Also, in human in vitro studies, 3M-011 potentiated NK cytotoxicity. TLR7/8-mediated NK-dependent antitumor activity was retained in IFN-alpha/beta receptor-deficient as well as perforin-deficient mice, while depletion of IFN-gamma significantly decreased the ability of 3M-011 to delay tumor growth. Thus, IFN-gamma-dependent functions of NK cell populations appear essential for cancer immunotherapy with TLR7/8 agonists.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Células Matadoras Naturais/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Quinolinas/uso terapêutico , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Animais , Feminino , Humanos , Interferon gama/imunologia , Camundongos , NF-kappa B/imunologia
17.
Drug News Perspect ; 21(2): 69-87, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18389099

RESUMO

Imiquimod 5% cream is approved for the topical treatment of external anogenital warts caused by human papillomavirus (HPV) and for the skin cancer conditions superficial basal cell carcinoma and actinic keratosis. This drug is the first approved topically active Toll-like receptor (TLR) 7 agonist. Imiquimod activates innate immune cells to produce interferon-a and other cytokines. The induced cytokine cascade, in combination with effects in enhancing antigen presentation, also promotes an antigen-specific T helper type 1 cell-mediated immune response. This immune-based mechanism provides activity against a number of viruses and other intracellular pathogens. Imiquimod was effective topically in clinical studies for HPV but caused mixed results for Molluscum contagiosum, and herpes simplex virus (HSV). Activity against several other viruses were reported in case reports or patient series involving "off-label" usage of imiquimod, while others were evaluated only in preclinical models. Resiquimod, a more potent investigational analogue of imiquimod with mixed TLR7/8 agonist activity, was evaluated in clinical studies topically for the treatment of HSV and systemically for hepatitis C virus also with mixed success. This review focuses on the mechanism of action and antiviral usage reported for the TLR7 agonist imiquimod, the TLR7/8 agonist resiquimod and related imidazoquinoline analogues.


Assuntos
Antivirais/farmacologia , Viroses/tratamento farmacológico , Aminoquinolinas/farmacologia , Animais , Ensaios Clínicos como Assunto , Farmacorresistência Viral , Humanos , Imidazóis/farmacologia , Imiquimode , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas
18.
J Interferon Cytokine Res ; 28(4): 253-63, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18439103

RESUMO

Antitumor effects of the toll-like receptor 7 (TLR7) agonist, 852A, were evaluated. Supernatants from human peripheral blood mononuclear cells (PBMC) stimulated with 852A inhibited the proliferation of tumor cell lines Hs294T and 769-P but had no effect on others (786-O and Caki-1). Because addition of 852A directly to the Hs294T cells did not inhibit their proliferation, the mechanism(s) of inhibition of tumor cell proliferation was investigated. Low nanomolar concentrations of 852A stimulated the production of interferon-alpha (IFN-alpha), IFN-inducible protein-10 (IP-10), interleukin-1 receptor antagonist (IL-1Ra), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from human PBMCs. Cytokines stimulated by submicromolar concentrations of 852A were sufficient to inhibit Hs294T proliferation. At higher concentrations (3-30 microM), 852A induced the production of IL-12p70, IL-18, and IFN-gamma. PBMC cultures depleted of plasmacytoid dendritic cells (pDC) did not produce IFN-alpha, and their conditioned medium did not inhibit Hs294T proliferation. Anti-IFN-alpha/beta receptor (IFNAR) and anti-IFN-alpha antibodies partially abrogated Hs294T proliferation inhibition by 852A-stimulated PBMC supernatants, whereas separate neutralization of TRAIL, tumor necrosis factor-alpha (TNF-alpha, IFN-gamma, IFN-beta, or IFN-omega had no effect. In vivo, six doses of 852A administration significantly delayed the onset of lung colonies in a B16 melanoma model. Thus, the results demonstrate that the TLR7 agonist 852A inhibits in vitro proliferation of some tumor cells in a pDC-dependent and IFN-alpha-dependent manner and can delay tumor growth in vivo.


Assuntos
Células Dendríticas/imunologia , Interferon Tipo I/imunologia , Neoplasias/patologia , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Receptor 7 Toll-Like/agonistas , Aminoquinolinas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Humanos , Imiquimode , Leucócitos Mononucleares/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Melanoma/patologia , Camundongos , Oligodesoxirribonucleotídeos/farmacologia , Frações Subcelulares/efeitos dos fármacos , Receptor Toll-Like 9/agonistas
19.
Expert Rev Vaccines ; 6(5): 835-47, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17931162

RESUMO

Synthetic immune response modifiers, such as resiquimod, are Toll-like receptor 7 and 8 agonists that act as vaccine adjuvants, enhancing antigen-specific antibody production and skewing immunity towards a Th1 response. These compounds stimulate dendritic cells to secrete cytokines, upregulate costimulatory molecule expression and enhance antigen presentation to T cells. The compounds have demonstrated vaccine adjuvant properties in a number of animal models. The adjuvant effects can be enhanced by measures that allow the drug to stay localized with the vaccine without quickly entering the systemic circulation. Clinical studies demonstrate that topical application of resiquimod and analogs is safe and effective at activating the local immune response. For injection, resiquimod or a similar compound may need to be formulated to allow for local immune activation without induction of systemic cytokines.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Imidazóis/administração & dosagem , Fatores Imunológicos/administração & dosagem , Vacinas/administração & dosagem , Animais , Humanos , Imidazóis/imunologia , Fatores Imunológicos/imunologia , Vacinas/imunologia
20.
Int Immunol ; 18(7): 1115-26, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16728430

RESUMO

NK cells limit the emergence of cancers and viral infections by surveillance of 'missing-self' and 'induced-self' ligands, and by direct recognition of pathogen-associated molecules. We examined individual roles for Toll-like receptors (TLRs)-7 and -8 in human NK-cell activation using synthetic, small molecule agonists of either TLR-7 (imiquimod and 3M-001), TLR-8 (3M-002) or both TLR-7/8 (3M-003 and R-848) for comparison with known ligands of TLR-2 to -9. Tracking cytokine production in PBMC initially revealed that a subset of TLR agonists including polyinosinic-polycytidylic acid (poly I:C), 3M-002, 3M-003, R-848 and single-stranded RNA trigger relatively high levels of IFN-gamma expression by NK cells. Isolated NK cells did not express TLR-7 or TLR-8. Unlike MALP-2 and poly I:C, 3M-001-3 did not induce expression of either CD69 or IFN-gamma by purified NK cells suggesting indirect activation. IL-18 and IL-12p70 were primarily required for induction of IFN-gamma by both synthetic and natural TLR-8 ligands, while type I IFN was required for induction of CD69 on NK cells by the TLR-7 agonist 3M-001. In addition to expression of IFN-gamma and CD69, relative induction of NK-cell cytotoxicity by TLR-7 and TLR-8 agonists was compared. Immune response modifiers (IRMs) with a TLR-8 agonist component (3M-002 and 3M-003) stimulated greater levels of K562 cytolysis than achieved with 3M-001 or IL-2 (1000 units ml(-1)). In vivo NK-cell cytotoxicity was also enhanced by R-848, but not in type I IFNR-deficient mice. We conclude that IRMs can modulate NK-cell function both in vitro and in vivo and that distinct indirect pathways control human NK-cell activation by TLR-7 and TLR-8 agonists.


Assuntos
Indutores de Interferon/farmacologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Citocinas/imunologia , Humanos , Imidazóis/farmacologia , Células K562 , Lectinas Tipo C , Ligantes , Ativação Linfocitária/imunologia , Camundongos , Camundongos Mutantes , Quinolinas/farmacologia , Receptores de Interferon/imunologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia
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