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In silico immunogenicity risk assessment has been an important step in the development path for many biologic therapeutics, including monoclonal antibodies. Even if the source of a given biologic is 'fully human', T cell epitopes that are contained in the sequences of the biologic may activate the immune system, enabling the development of anti-drug antibodies that can reduce drug efficacy and may contribute to adverse events. Computational tools that identify T cell epitopes from primary amino acid sequences have been used to assess the immunogenic potential of therapeutic candidates for several decades. To facilitate larger scale analyses and accelerate preclinical immunogenicity risk assessment, our group developed an integrated web-based platform called ISPRI, (Immunogenicity Screening and Protein Re-engineering Interface) that provides hands-on access through a secure web-based interface for scientists working in large and mid-sized biotech companies in the US, Europe, and Japan. This toolkit has evolved and now contains an array of algorithms that can be used individually and/or consecutively for immunogenicity assessment and protein engineering. Most analyses start with the advanced epitope mapping tool (EpiMatrix), then proceed to identify epitope clusters using ClustiMer, and then use a tool called JanusMatrix to define whether any of the T cell epitope clusters may generate a regulatory T cell response which may diminish or eliminate anti-drug antibody formation. Candidates can be compared to similar products on a normalized immunogenicity scale. Should modifications to the biologic sequence be an option, a tool for moderating putative immunogenicity by editing T cell epitopes out of the sequence is available (OptiMatrix). Although this perspective discusses the in-silico immunogenicity risk assessment for monoclonal antibodies, bi-specifics, multi-specifics, and antibody-drug conjugates, the analysis of additional therapeutic modalities such as enzyme replacement proteins, blood factor proteins, CAR-T, gene therapy products, and peptide drugs is also made available on the ISPRI platform.
ISPRI (Interactive Screening and Protein Reengineering Interface): Integrated, cloud-based, comprehensive toolkit for Immunogenicity Risk Assessment.EpiMatrix Immunogenicity Score: Combined T effector and Treg Epitope Content per unit protein.Tregitopes: Treg Epitopes found in IgG Framework that have been shown to modulate antigen-specific effector T cell responses.ClustiMer: Tool for identifying epitope rich polypeptides from within a given protein sequence.JanusMatrix: Tool for Predicting Tolerance, Putative Treg Epitopes, and Anti-self-immune responses.OptiMatrix: Tool for modifying T cell epitope sequences to reduce (or enhance) MHC binding.
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Productos Biológicos , Epítopos de Linfocito T , Humanos , Péptidos , Secuencia de Aminoácidos , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
The identification and removal of host cell proteins (HCPs) from biologic products is a critical step in drug development. Despite recent improvements to purification processes, biologics such as monoclonal antibodies, enzyme replacement therapies, and vaccines that are manufactured in a range of cell lines and purified using diverse processes may contain HCP impurities, making it necessary for developers to identify and quantify impurities during process development for each drug product. HCPs that contain sequences that are less conserved with human homologs may be more immunogenic than those that are more conserved. We have developed a computational tool, ISPRI-HCP, that estimates the immunogenic potential of HCP sequences by evaluating and quantifying T cell epitope density and relative conservation with similar T cell epitopes in the human proteome. Here we describe several case studies that support the use of this method for classifying candidate HCP impurities according to their immunogenicity risk.
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Anticuerpos Monoclonales , Productos Biológicos , Humanos , Línea Celular , Desarrollo de Medicamentos , Epítopos de Linfocito T , Medición de RiesgoRESUMEN
BACKGROUND: A major challenge to adeno-associated virus (AAV)-mediated gene therapy is the presence of anti-AAV capsid neutralizing antibodies (NAbs), which can block viral vector transduction even at very low titers. In the present study, we examined the ability of a combination immunosuppression (IS) treatment with bortezomib and a mouse-specific CD20 monoclonal antibody to suppress anti-AAV NAbs and enable readministration of AAV vectors of the same capsid in mice. METHODS: An AAV8 vector (AAV8-CB-hGAA) that ubiquitously expresses human α-glucosidase was used for initial gene therapy and a second AAV8 vector (AAV8-LSP-hSEAP) that contains a liver-specific promoter to express human secreted embryonic alkaline phosphatase (hSEAP) was used for AAV readministration. Plasma samples were used for determination of anti-AAV8 NAb titers. Cells isolated from whole blood, spleen, and bone marrow were analyzed for B-cell depletion by flow cytometry. The efficiency of AAV readministration was determined by the secretion of hSEAP in blood. RESULTS: In näive mice, an 8-week IS treatment along with AAV8-CB-hGAA injection effectively depleted CD19+ B220+ B cells from blood, spleen, and bone marrow and prevented the formation of anti-AAV8 NAbs. Following administration of AAV8-LSP-hSEAP, increasing levels of hSEAP were detected in blood for up to 6 weeks, indicating successful AAV readministration. In mice pre-immunized with AAV8-CB-hGAA, comparison of IS treatment for 8, 12, 16, and 20 weeks revealed that the 16-week IS treatment demonstrated the highest plasma hSEAP level following AAV8-LSP-hSEAP readministration. CONCLUSIONS: Our data suggest that this combination treatment is an effective IS approach that will allow retreatment of patients with AAV-mediated gene therapy. A combination IS treatment with bortezomib and a mouse-specific CD20 monoclonal antibody effectively suppressed anti-AAV NAbs in naïve mice and in mice with pre-existing antibodies, allowing successful readministration of the same AAV capsid vector.
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Anticuerpos Neutralizantes , Enfermedad del Almacenamiento de Glucógeno Tipo II , Humanos , Ratones , Animales , Bortezomib/farmacología , Bortezomib/uso terapéutico , Cápside , Anticuerpos Antivirales , Vectores Genéticos/genética , Retratamiento , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Dependovirus/genéticaRESUMEN
Introduction: The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800). Methods: We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800). Results: Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1ß) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers. Discussion: The immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Inmunofenotipificación , Terapia de Reemplazo Enzimático , Citocinas , Linfocitos BRESUMEN
Polyethylene glycol (PEG) is present in a variety of products. Little is known regarding the accumulation of high-molecular-weight PEGs or the long-term effects resulting from PEG accumulation in certain tissues, especially the choroid plexus. We evaluated the toxicity of high-molecular-weight PEGs administered to Sprague Dawley rats. Groups of 12 rats per sex were administered subcutaneous injections of 20, 40, or 60 kDa PEG or intravenous injections of 60 kDa PEG at 100 mg PEG/kg body weight/injection once a week for 24 weeks. A significant decrease in triglycerides occurred in the 60 kDa PEG groups. PEG treatment led to a molecular-weight-related increase in PEG in plasma and a low level of PEG in cerebrospinal fluid. PEG was excreted in urine and feces, with a molecular-weight-related decrease in the urinary excretion. A higher prevalence of anti-PEG IgM was observed in PEG groups; anti-PEG IgG was not detected. PEG treatment produced a molecular-weight-related increase in vacuolation in the spleen, lymph nodes, lungs, and ovaries/testes, without an inflammatory response. Mast cell infiltration at the application site was noted in all PEG-treated groups. These data indicate that subcutaneous and intravenous exposure to high-molecular-weight PEGs produces anti-PEG IgM antibody responses and tissue vacuolation without inflammation.
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Anticuerpos/sangre , Formación de Anticuerpos/efectos de los fármacos , Plexo Coroideo/efectos de los fármacos , Polietilenglicoles/toxicidad , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Peso Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
The in silico prediction of T cell epitopes within any peptide or biologic drug candidate serves as an important first step for assessing immunogenicity. T cell epitopes bind human leukocyte antigen (HLA) by a well-characterized interaction of amino acid side chains and pockets in the HLA molecule binding groove. Immunoinformatics tools, such as the EpiMatrix algorithm, have been developed to screen natural amino acid sequences for peptides that will bind HLA. In addition to commonly occurring in synthetic peptide impurities, unnatural amino acids (UAA) are also often incorporated into novel peptide therapeutics to improve properties of the drug product. To date, the HLA binding properties of peptides containing UAA are not accurately estimated by most algorithms. Both scenarios warrant the need for enhanced predictive tools. The authors developed an in silico method for modeling the impact of a given UAA on a peptide's likelihood of binding to HLA and, by extension, its immunogenic potential. In silico assessment of immunogenic potential allows for risk-based selection of best candidate peptides in further confirmatory in vitro, ex vivo and in vivo assays, thereby reducing the overall cost of immunogenicity evaluation. Examples demonstrating in silico immunogenicity prediction for product impurities that are commonly found in formulations of the generic peptides teriparatide and semaglutide are provided. Next, this article discusses how HLA binding studies can be used to estimate the binding potentials of commonly encountered UAA and "correct" in silico estimates of binding based on their naturally occurring counterparts. As demonstrated here, these in vitro binding studies are usually performed with known ligands which have been modified to contain UAA in HLA anchor positions. An example using D-amino acids in relative binding position 1 (P1) of the PADRE peptide is presented. As more HLA binding data become available, new predictive models allowing for the direct estimation of HLA binding for peptides containing UAA can be established.
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Investigación Biomédica , COVID-19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/inmunología , Sistema Inmunológico/inmunología , SARS-CoV-2/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Factores de Edad , Animales , Autoinmunidad , COVID-19/metabolismo , COVID-19/terapia , COVID-19/virología , Síndrome de Liberación de Citoquinas/metabolismo , Síndrome de Liberación de Citoquinas/virología , Citocinas/metabolismo , Interacciones Huésped-Patógeno , Humanos , Sistema Inmunológico/metabolismo , Sistema Inmunológico/virología , Pronóstico , Factores de Riesgo , SARS-CoV-2/patogenicidad , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/terapia , Síndrome de Respuesta Inflamatoria Sistémica/virologíaRESUMEN
PURPOSE: To assess the magnitude of benefit to early treatment initiation, enabled by newborn screening or prenatal diagnosis, in patients with cross-reactive immunological material (CRIM)-negative infantile Pompe disease (IPD), treated with enzyme replacement therapy (ERT) and prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and intravenous immunoglobulin (IVIG). METHODS: A total of 41 CRIM-negative IPD patients were evaluated. Among patients who were treated with ERT + ITI (n = 30), those who were invasive ventilator-free at baseline and had ≥6 months of follow-up were stratified based on age at treatment initiation: (1) early (≤4 weeks), (2) intermediate (>4 and ≤15 weeks), and (3) late (>15 weeks). A historical cohort of 11 CRIM-negative patients with IPD treated with ERT monotherapy served as an additional comparator group. RESULTS: Twenty patients were included; five, seven, and eight in early, intermediate, and late treatment groups, respectively. Genotypes were similar across the three groups. Early-treated patients showed significant improvements in left ventricular mass index, motor and pulmonary outcomes, as well as biomarkers creatine kinase and urinary glucose tetrasaccharide, compared with those treated later. CONCLUSION: Our preliminary data suggest that early treatment with ERT + ITI can transform the long-term CRIM-negative IPD phenotype, which represents the most severe end of the Pompe disease spectrum.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Terapia de Reemplazo Enzimático , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Humanos , Tolerancia Inmunológica , Recién Nacido , Tamizaje Neonatal , Embarazo , Resultado del Tratamiento , alfa-Glucosidasas/genética , alfa-Glucosidasas/uso terapéuticoRESUMEN
Identification of T cell epitopes that are recognized by Tregs may elucidate the relative contributions of thymic Tregs and induced Tregs to control of autoimmune diseases and allergy. One such T regulatory cell epitope or 'Tregitope', derived from blood Factor V, is described here. Tregs responding to Tregitope FV621 are potent suppressors of CD4+ T effector responses to Tetanus Toxoid in an in vitro bystander suppression assay, strongly inhibit proliferation of effector CD8+ T cells, down-modulate CD86 and HLA DR on antigen-presenting cells, and enhance expression of granzyme B in Tregs. Tregitope FV621 also suppresses anti-OVA immune responses in vivo. The immunomodulatory effect of Tregitope FV621 is enhanced when conjugated to albumin, suggesting that the short half-life of Tregitope peptides can be prolonged. The in silico tools used to prospectively identify the FV Tregitope described here, when combined with in vitro /in vivo validating assays, may facilitate future Tregitope discoveries.
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Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Epítopos de Linfocito T/metabolismo , Factor V/metabolismo , Linfocitos T Reguladores/metabolismo , Secuencia de Aminoácidos , Animales , Biomarcadores/metabolismo , Efecto Espectador , Epítopos de Linfocito T/química , Factor V/química , Humanos , Inmunoglobulina G , Proteínas de la Membrana , Ratones , Ovalbúmina/inmunología , Péptidos/química , Toxoide TetánicoAsunto(s)
Anticuerpos/inmunología , Anticuerpos/uso terapéutico , Enfermedades Autoinmunes/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Proteínas/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Niño , Terapia de Reemplazo Enzimático/efectos adversos , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Proteínas/uso terapéuticoRESUMEN
Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26-39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1-11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11-55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.
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Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Tolerancia Inmunológica/efectos de los fármacos , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunosupresores/administración & dosificación , Metotrexato/administración & dosificación , Rituximab/administración & dosificación , alfa-Glucosidasas/uso terapéutico , Anticuerpos/sangre , Niño , Preescolar , Quimioterapia Combinada , Terapia de Reemplazo Enzimático/efectos adversos , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Enfermedad del Almacenamiento de Glucógeno Tipo II/inmunología , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Inmunosupresores/efectos adversos , Lactante , Masculino , Metotrexato/efectos adversos , Estudios Retrospectivos , Rituximab/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , alfa-Glucosidasas/efectos adversos , alfa-Glucosidasas/inmunologíaAsunto(s)
Angioedema/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/metabolismo , Neumonía Viral/inmunología , Angioedema/sangre , Angioedema/patología , Angioedema/virología , Enzima Convertidora de Angiotensina 2 , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antivirales/uso terapéutico , Biomarcadores/sangre , COVID-19 , Prueba de COVID-19 , Técnicas de Laboratorio Clínico/métodos , Congresos como Asunto , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/virología , Citocinas/antagonistas & inhibidores , Citocinas/sangre , Citocinas/inmunología , Humanos , Internet , Sistema Calicreína-Quinina/efectos de los fármacos , Sistema Calicreína-Quinina/inmunología , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Alveolos Pulmonares/inmunología , Alveolos Pulmonares/patología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Factores de Tiempo , Tiempo de Tratamiento , Tratamiento Farmacológico de COVID-19RESUMEN
Immune modulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) has shown great success in inducing immune tolerance in a large cohort of enzyme replacement therapy (ERT)-naïve infantile Pompe disease patients. Antibody-dependent cellular cytotoxicity, the principal mechanism by which rituximab depletes B-cells, requires CD20 binding by Fab'2 of rituximab on B-cells and the concomitant binding of its Fc region to Fc receptors on effector cells or to complement. To protect patients against microbial infections when using rituximab, IVIG was added to the immunomodulation regimen used in Pompe disease. Administration of IVIG can saturate neonatal Fc receptors (FcRn), which recycle endogenous as well as administered polyclonal/monoclonal antibodies via the binding of the Fc moiety to FcRn. As such, the administration of IVIG prior to rituximab, a chimeric mouse-human monoclonal antibody, may sharply reduce the half-life of rituximab and in turn, its efficacy. Based on this understanding, it is vital to understand the optimal timing of IVIG administration in relation to rituximab administration for the purposes of inducing immune tolerance.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Inmunoglobulinas Intravenosas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Rituximab/administración & dosificación , Enfermedad del Almacenamiento de Glucógeno Tipo II/inmunología , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Resultado del TratamientoRESUMEN
The first case of human transmission of SARS-CoV-2 was reported in China in December 2019. A few months later, this viral infection had spread worldwide and became a pandemic. The disease caused by SARS-CoV-2, termed COVID-19, is multifactorial and associated with both specific antiviral as well as inflammatory responses, the extent of which may determine why some individuals are asymptomatic while others develop serious complications. Here we review possible life-threating immune events that can occur during disease progression to uncover key factors behind COVID-19 severity and provide suggestions for interventions with repurposed drugs in well-controlled and randomized clinical trials. These drugs include therapeutics with potential to inhibit SARS-CoV-2 entry into host cells such as serine protease inhibitors of the cellular protease TMPS2 and drugs targeting the renin-angiotensin system; antivirals with potential to block SARS-CoV-2 replication or factors that could boost the antiviral response; monoclonal antibodies targeting pro-inflammatory cytokines that drive the hyperinflammatory response during COVID-19 progression toward the severe stage and therapeutics that could ameliorate the function of the lungs. Furthermore, in order to help make more informed decisions on the timing of the intervention with the drugs listed in this review, we have grouped these therapeutics according to the stage of COVID-19 progression that we considered most appropriate for their mechanism of action.
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Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Antivirales/uso terapéutico , COVID-19 , Progresión de la Enfermedad , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Pandemias , Tratamiento Farmacológico de COVID-19RESUMEN
To evaluate the expression of immune checkpoint genes, their concordance with expression of IFNγ, and to identify potential novel ICP related genes (ICPRG) in colorectal cancer (CRC), the biological connectivity of six well documented ("classical") ICPs (CTLA4, PD1, PDL1, Tim3, IDO1, and LAG3) with IFNγ and its co-expressed genes was examined by NGS in 79 CRC/healthy colon tissue pairs. Identification of novel IFNγ- induced molecules with potential ICP activity was also sought. In our study, the six classical ICPs were statistically upregulated and correlated with IFNγ, CD8A, CD8B, CD4, and 180 additional immunologically related genes in IFNγ positive (FPKM > 1) tumors. By ICP co-expression analysis, we also identified three IFNγ-induced genes [(IFNγ-inducible lysosomal thiol reductase (IFI30), guanylate binding protein1 (GBP1), and guanylate binding protein 4 (GBP4)] as potential novel ICPRGs. These three genes were upregulated in tumor compared to normal tissues in IFNγ positive tumors, co-expressed with CD8A and had relatively high abundance (average FPKM = 362, 51, and 25, respectively), compared to the abundance of the 5 well-defined ICPs (Tim3, LAG3, PDL1, CTLA4, PD1; average FPKM = 10, 9, 6, 6, and 2, respectively), although IDO1 is expressed at comparably high levels (FPKM = 39). We extended our evaluation by querying the TCGA database which revealed the commonality of IFNγ dependent expression of the three potential ICPRGs in 638 CRCs, 103 skin cutaneous melanomas (SKCM), 1105 breast cancers (BC), 184 esophageal cancers (ESC), 416 stomach cancers (STC), and 501 lung squamous carcinomas (LUSC). In terms of prognosis, based on Pathology Atlas data, correlation of GBP1 and GBP4, but not IFI30, with 5-year survival rate was favorable in CRC, BC, SKCM, and STC. Thus, further studies defining the role of IFI30, GBP1, and GBP4 in CRC are warranted.
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Neoplasias de la Mama/genética , Colon/fisiología , Neoplasias Colorrectales/genética , Interferón gamma/metabolismo , Melanoma/genética , Neoplasias Cutáneas/genética , Neoplasias Gástricas/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Femenino , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteínas de Punto de Control Inmunitario/genética , Masculino , Melanoma/inmunología , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/genética , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Pronóstico , Neoplasias Cutáneas/inmunología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/mortalidad , Análisis de Supervivencia , Melanoma Cutáneo MalignoAsunto(s)
Inmunidad Adaptativa/efectos de los fármacos , Productos Biológicos/inmunología , Desarrollo de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inmunología , Modelos Inmunológicos , Productos Biológicos/administración & dosificación , Desarrollo de Medicamentos/normas , Monitoreo de Drogas/métodos , Monitoreo de Drogas/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/terapia , Humanos , Monitorización Inmunológica/métodos , Monitorización Inmunológica/normas , Medición de Riesgo/métodos , Medición de Riesgo/normas , Sociedades Científicas/normas , Estados Unidos , United States Food and Drug Administration/normasRESUMEN
Pompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase resulting in intralysosomal glycogen accumulation in multiple tissue types, especially cardiac, skeletal, and smooth muscle. Enzyme replacement therapy (ERT) with alglucosidase alfa has led to improved clinical outcomes and prolonged survival in patients with Pompe disease. While ERT has changed the natural course of Pompe disease, with many long-term survivors, several factors affect the response to ERT. Previous studies in Pompe disease have shown that IgG antibodies to ERT can lead to a decline in muscle strength, pulmonary function, and overall and ventilator-free survival. Additionally, antibody responses to ERT can also cause hypersensitivity reactions. Various strategies to prevent or eliminate the IgG antibody response have been attempted in patients with Pompe disease. A detailed literature search was performed to compile data regarding the consequences of IgG antibodies, clinical approaches to prevent or eliminate IgG antibodies in patients with Pompe disease, and to expand our understanding of new modalities being developed in non-clinical settings. All qualifying articles describing the impact of IgG antibodies on the response to ERT, immunomodulation in patients with Pompe disease, and non-clinical settings identified via a PubMed database search were included in the review. Here, we provide a comprehensive review of combination- and single-agent therapies that have been investigated in the context of immune tolerance induction to ERT in Pompe disease to date. Immunomodulation strategies that successfully induce immune tolerance to ERT have improved overall survival, especially reflected in the decreased number of ventilator-dependent or deceased cross-reactive immunologic material (CRIM)-negative infantile Pompe disease (IPD) patients due to development of IgG antibodies when treated with ERT alone. Immunomodulation in CRIM-positive patients at the time they receive ERT also results in a decrease in the development of IgG antibodies compared to cases treated with ERT alone. Lessons learned from current approaches, alongside results from trials of novel immunomodulation strategies, may provide important insights into the development of next-generation therapies.