RESUMEN
T-cell dependent antibody responses to biotherapeutics remain a challenge to the optimal clinical application of biotherapeutics because of their capacity to impair drug efficacy and their potential to cause safety issues. To minimize this clinical immunogenicity risk, preclinical assays measuring the capacity of biotherapeutics to elicit CD4 T cell response in vitro are commonly used. However, there is considerable variability in assay formats and a general poor understanding of their respective predictive value. In this study, we evaluated the performance of three different CD4 T cell proliferation assays in their capacity to predict clinical immunogenicity: a CD8 T cell depleted peripheral blood mononuclear cells (PBMC) assay and two co-culture-based assays between dendritic cells (DCs) and autologous CD4 T cells with or without restimulation with monocytes. A panel of 10 antibodies with a wide range of clinical immunogenicity was selected. The CD8 T cell depleted PBMC assay predicted the clinical immunogenicity in four of the eight highly immunogenic antibodies included in the panel. Similarly, five antibodies with high clinical immunogenicity triggered a response in the DC: CD4 T cell assay but the responses were of lower magnitude than the ones observed in the PBMC assay. Remarkably, three antibodies with high clinical immunogenicity did not trigger any response in either platform. The addition of a monocyte restimulation step to the DC: CD4 T cell assay did not further improve its predictive value. Overall, these results indicate that there are no CD4 T cell assay formats that can predict the clinical immunogenicity of all biotherapeutics and reinforce the need to combine results from various preclinical assays assessing antigen uptake and presentation to fully mitigate the immunogenicity risk of biotherapeutics.
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Linfocitos T CD4-Positivos , Células Dendríticas , Humanos , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Medición de Riesgo , Técnicas de Cocultivo , Activación de Linfocitos/inmunología , Leucocitos Mononucleares/inmunología , Proliferación Celular , Linfocitos T CD8-positivos/inmunología , Evaluación Preclínica de Medicamentos , Productos Biológicos/inmunología , Productos Biológicos/efectos adversos , Anticuerpos/inmunología , Células CultivadasRESUMEN
The naïve human antibody repertoire has theoretical access to an estimated > 1015 antibodies. Identifying subsets of this prohibitively large space where therapeutically relevant antibodies may be found is useful for development of these agents. It was previously demonstrated that, despite the immense sequence space, different individuals can produce the same antibodies. It was also shown that therapeutic antibodies, which typically follow seemingly unnatural development processes, can arise independently naturally. To check for biases in how the sequence space is explored, we data mined public repositories to identify 220 bioprojects with a combined seven billion reads. Of these, we created a subset of human bioprojects that we make available as the AbNGS database (https://naturalantibody.com/ngs/). AbNGS contains 135 bioprojects with four billion productive human heavy variable region sequences and 385 million unique complementarity-determining region (CDR)-H3s. We find that 270,000 (0.07% of 385 million) unique CDR-H3s are highly public in that they occur in at least five of 135 bioprojects. Of 700 unique therapeutic CDR-H3, a total of 6% has direct matches in the small set of 270,000. This observation extends to a match between CDR-H3 and V-gene call as well. Thus, the subspace of shared ('public') CDR-H3s shows utility for serving as a starting point for therapeutic antibody design.
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Productos Biológicos , Regiones Determinantes de Complementariedad , Minería de Datos , Descubrimiento de Drogas , Humanos , Minería de Datos/métodos , Descubrimiento de Drogas/métodos , Productos Biológicos/inmunología , Regiones Determinantes de Complementariedad/genética , Regiones Determinantes de Complementariedad/inmunología , Región Variable de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/genéticaRESUMEN
BACKGROUND: Formation of anti-drug antibodies (ADAs) against biologics is an important cause of psoriasis treatment failure. OBJECTIVE: This study aimed to summarize the characteristics of ADAs formation under different biological therapies and the influence of ADAs on the clinical effects and safety of biologics in patients with psoriasis. METHODS: PubMed, Embase, and Web of Science databases were searched from their inception to August 2022. Studies on biologics that assessed ADA levels in patients with psoriasis were included. The Cochrane risk-of-bias tool was used to assess the quality of randomized controlled trials (RCTs), the Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control and cohort studies, and the Joanna Briggs Institute (JBI) critical appraisal checklist for single-arm studies. We calculated the pooled incidence with a random-effects model using R software. Subgroup analyses revealed that differences in patient characteristics, disease conditions, study design, and immunoassays may influence ADA generation and detection. RESULTS: The analysis included 86 studies, with a total population of 42,280 individuals. The pooled ADA rates were 0.49%, 2.20%, 2.38%, 4.08%, 7.38%, 7.94%, 14.29%, 21.93%, 29.70%, 31.76%, and 39.58% for secukinumab, etanercept, brodalumab, ustekinumab, tildrakizumab, guselkumab, ixekizumab, risankizumab, infliximab, adalimumab, and bimekizumab, respectively. >70% (95% CI, 0.71-0.81) of ADAs against adalimumab were neutralizing antibodies, and over 70% of ADAs against secukinumab and brodalumab were transient. Concomitant methotrexate therapy with tumor necrosis factor-α (TNF-α) inhibitors decreased ADA levels. Lower infliximab doses and intermittent therapy with interleukin (IL)-23 p19 inhibitors increased ADA formation. Additionally, ADA formation under treatment using TNF-α inhibitors and IL-12/23 p40 inhibitors was associated with lower response rates or serum drug levels, but only high ADA titers reduced the clinical effects of IL-17 inhibitors. The occurrence of IL-23 p19 and TNF-α inhibitors has been linked to injection-site reactions. CONCLUSIONS: Among the 11 biologics, secukinumab, etanercept, and brodalumab resulted in the lowest ADA formation rates. Immunogenicity contributes to lower biological efficacy and a higher likelihood of injection-site reactions. Low doses, intermittent treatment may increase ADA formation. An appropriate biologic should be selected based on the ADA formation rate and course of treatment.
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Productos Biológicos , Psoriasis , Psoriasis/inmunología , Psoriasis/tratamiento farmacológico , Humanos , Productos Biológicos/uso terapéutico , Productos Biológicos/inmunología , Productos Biológicos/efectos adversos , Anticuerpos/inmunología , Anticuerpos/sangreRESUMEN
Viruses have been widely used to treat cancer for many years and they achieved tremendous success in clinical trials with outstanding results, which has led to the foundation of companies that develop recombinant viruses for a better tumor treatment. Even though there has been a great progress in the field of viral tumor immunotherapy, until now only one virus, the oncolytic virus talimogene laherparepvec (TVEC), a genetically modified herpes simplex virus type 1 (T-VEC), has been approved by the FDA for cancer treatment. Although oncolytic viruses showed progress in certain cancer types and patient populations but they have yet shown limited efficacy when it comes to solid tumors. Only recently it was demonstrated that the immune stimulatory aspect of oncolytic viruses can strongly contribute to their anti-tumoral activity. One specific example in this context are arenaviruses, which have been shown to be non-cytopathic in nature lead to the massive immune activation within the tumor resulting in strong anti-tumoral activity. This strong immune activation might be also linked to their noncytopathic features, as their immune stimulatory potential is not self-limiting as is the case for oncolytic viruses due to their fast eradication by anti-viral immune effects. Because of this strong immune activation, arenaviruses appear superior to oncolytic viruses when it comes to potent and long-lasting anti-tumor effects in a broad variety of tumor types. Currently one of the most promising therapeutics which has turned to be very much beneficial for the treatment of different cancer types is represented by antibodies targeting checkpoint inhibitors such as PD-1/PD-L-1. In this review, we will summarize anti-tumoral effects of arenaviruses, and will discuss their potential to be combined with checkpoint inhibitors for a more efficient tumor treatment, which further emphasizes that arenavirus therapy as a viroimmunotherapy can be an efficient tool for the better clearance of tumors.
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Arenavirus/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos/inmunología , Productos Biológicos/inmunología , Productos Biológicos/uso terapéutico , Herpesvirus Humano 1/inmunología , Humanos , Neoplasias/inmunología , Neoplasias/terapiaRESUMEN
Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-based intralesional oncolytic immunotherapy approved for the treatment of unresectable melanoma. The present, ongoing study aimed to estimate the treatment effect of neoadjuvant T-VEC on recurrence-free survival (RFS) of patients with advanced resectable melanoma. An open-label, phase 2 trial (NCT02211131) was conducted in 150 patients with resectable stage IIIB-IVM1a melanoma who were randomized to receive T-VEC followed by surgery (arm 1, n = 76) or surgery alone (arm 2, n = 74). The primary endpoint was a 2-year RFS in the intention-to-treat population. Secondary and exploratory endpoints included overall survival (OS), pathological complete response (pCR), safety and biomarker analyses. The 2-year RFS was 29.5% in arm 1 and 16.5% in arm 2 (overall hazard ratio (HR) = 0.75, 80% confidence interval (CI) = 0.58-0.96). The 2-year OS was 88.9% for arm 1 and 77.4% for arm 2 (overall HR = 0.49, 80% CI = 0.30-0.79). The RFS and OS differences between arms persisted at 3 years. In arm 1, 17.1% achieved a pCR. Increased CD8+ density correlated with clinical outcomes in an exploratory analysis. Arm 1 adverse events were consistent with previous reports for T-VEC. The present study met its primary endpoint and estimated a 25% reduction in the risk of disease recurrence for neoadjuvant T-VEC plus surgery versus upfront surgery for patients with resectable stage IIIB-IVM1a melanoma.
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Productos Biológicos/administración & dosificación , Inmunoterapia , Melanoma/terapia , Terapia Neoadyuvante , Adulto , Anciano , Productos Biológicos/inmunología , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/inmunología , Humanos , Masculino , Melanoma/genética , Melanoma/patología , Melanoma/virología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Recurrencia Local de Neoplasia/virología , Estadificación de Neoplasias , Viroterapia Oncolítica/tendencias , Virus Oncolíticos/genética , Virus Oncolíticos/inmunologíaRESUMEN
On murine T cells, mono-ADP ribosyltransferase ARTC2.2 catalyzes ADP-ribosylation of various surface proteins when nicotinamide adenine dinucleotide (NAD+) is released into the extracellular compartment. Covalent ADP-ribosylation of the P2X7 receptor by ARTC2.2 thereby represents an additional mechanism of activation, complementary to its triggering by extracellular ATP. P2X7 is a multifaceted receptor that may represents a potential target in inflammatory, and neurodegenerative diseases, as well as in cancer. We present herein an experimental approach using intramuscular injection of recombinant AAV vectors (rAAV) encoding nanobody-based biologics targeting ARTC2.2 or P2X7. We demonstrate the ability of these in vivo generated biologics to potently and durably block P2X7 or ARTC2.2 activities in vivo, or in contrast, to potentiate NAD+- or ATP-induced activation of P2X7. We additionally demonstrate the ability of rAAV-encoded functional heavy chain antibodies to elicit long-term depletion of T cells expressing high levels of ARTC2.2 or P2X7. Our approach of using rAAV to generate functional nanobody-based biologics in vivo appears promising to evaluate the role of ARTC2.2 and P2X7 in murine acute as well as chronic disease models.
Asunto(s)
ADP Ribosa Transferasas , Productos Biológicos/inmunología , Dependovirus , Vectores Genéticos , Depleción Linfocítica , Receptores Purinérgicos P2X7/inmunología , Anticuerpos de Dominio Único , ADP Ribosa Transferasas/antagonistas & inhibidores , ADP Ribosa Transferasas/inmunología , Animales , Ratones , Anticuerpos de Dominio Único/genética , Anticuerpos de Dominio Único/inmunologíaRESUMEN
The immune response to exogenous proteins can overcome the therapeutic benefits of immunotherapies and hamper the treatment of protein replacement therapies. One clear example of this is haemophilia A resulting from deleterious mutations in the FVIII gene. Replacement with serum derived or recombinant FVIII protein can cause anti-drug antibodies in 20-50% of individuals treated. The resulting inhibitor antibodies override the benefit of treatment and, at best, make life unpredictable for those treated. The only way to overcome the inhibitor issue is to reinstate immunological tolerance to the administered protein. Here we compare the various approaches that have been tested and focus on the use of antigen-processing independent T cell epitopes (apitopes) for tolerance induction. Apitopes are readily designed from any protein whether this is derived from a clotting factor, enzyme replacement therapy, gene therapy or therapeutic antibody.
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Presentación de Antígeno/inmunología , Productos Biológicos/inmunología , Epítopos de Linfocito T/inmunología , Tolerancia Inmunológica/inmunología , Humanos , Inmunoterapia/efectos adversosRESUMEN
Immunogenicity, the potential to elicit an antidrug immune response, is a critical concern in developing biological products, but its consequences are difficult to predict with animal studies. The aims of the present study are to investigate the evolution of immunogenicity information in labeling and to identify attributes associated with immunogenicity labeling updates. Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research, US Food and Drug Administration between 2008 and 2017 were studied. A majority of BLAs described the incidence/prevalence of antidrug antibodies (ADAs) (94.9%) and neutralizing antibodies (NAbs) (68.4%) in their original labeling documents. However, less than one third of the BLAs mentioned the impact of ADAs/NAbs in the original (20.3%) and most recent (29.1%) labeling documents. BLAs with a priority review status (57.4% vs. 33.3%), orphan designation (61.5% vs. 34.2%), or a mention of ADA impact in the latest label (69.6% vs. 38.9%) had higher percentages of applications with postmarketing requirements (PMRs) directly related to immunogenicity concerns in comparison with applications without those characteristics. Among the BLAs with updated immunogenicity information, the mean time to the first update was 1,077 days, while that for BLAs with accelerated approval was shorter (709.1 ± 492.2 days vs. 1173.8 ± 661.8 days). The results suggest that there is a substantial amount of critical information lacking in the original labeling documents and an overdependence on PMRs for more evidence. Additional efforts should be made to investigate the impact of ADAs to provide timely information for improved patient care.
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Productos Biológicos/inmunología , Aprobación de Drogas/métodos , Etiquetado de Medicamentos/métodos , Fenómenos Inmunogenéticos , Licencia en Farmacia , United States Food and Drug Administration , Aprobación de Drogas/legislación & jurisprudencia , Etiquetado de Medicamentos/legislación & jurisprudencia , Humanos , Licencia en Farmacia/legislación & jurisprudencia , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudenciaRESUMEN
The testing of protein drug candidates for inducing the generation of anti-drug antibodies (ADA) plays a fundamental role in drug development. The basis of the testing strategy includes a screening assay followed by a confirmatory test. Screening assay cut points (CP) are calculated mainly based on two approaches, either non-parametric, when the data set does not appear normally distributed, or parametric, in the case of a normal distribution. A normal distribution of data is preferred and may be achieved after outlier exclusion and, if necessary, transformation of the data. The authors present a Weibull transformation and a comparison with a decision tree-based approach that was tested on 10 data sets (healthy human volunteer matrix, different projects). Emphasis is placed on a transformation calculation that can be easily reproduced to make it accessible to non-mathematicians. The cut point value and the effect on the false positive rate as well as the number of excluded samples of both methods are compared.
Asunto(s)
Anticuerpos Neutralizantes/sangre , Productos Biológicos/inmunología , Desarrollo de Medicamentos/métodos , Anticuerpos Neutralizantes/inmunología , Productos Biológicos/administración & dosificación , Productos Biológicos/efectos adversos , Interpretación Estadística de Datos , Conjuntos de Datos como Asunto , Árboles de Decisión , Voluntarios Sanos , Humanos , Distribución Normal , Valores de ReferenciaRESUMEN
Aim: To investigate the feasibility of singlicate analysis in anti-drug antibody (ADA) assay by comparing performance characteristics for assays qualified in duplicate and singlicate formats. Materials & methods: We employed modeling to assess and quantify the impact of singlicate to cut point factor (CPF) in scenarios with the duplicate precision from 1-20% and the proportion of well-to-well variance to overall assay variance from 0.01-0.90. The impact to CPF by singlicate is marginal if the well-to-well coefficient of variation is <10% and represents <25% of the overall variability. Results & conclusion: The assay parameters including sensitivity, precision, selectivity, drug and target tolerance were comparable between singlicate and duplicate based assays. Our results suggested the minimal impact of singlicate analysis on ADA assay with good duplicate precision. The study provided additional supportive evidence that the singlicate-based analysis is feasible in ADA ligand binding assays.
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Productos Biológicos/inmunología , Mediciones Luminiscentes/métodos , Estudios de Factibilidad , Humanos , Modelos Estadísticos , Sensibilidad y Especificidad , SueroRESUMEN
Spinal muscular atrophy (SMA) is an inherited lower motor neuron disease. SMA occurs secondary to alterations in the survival motor neuron 1 gene (SMN1), which is the main driver of SMN protein production. The severity of the disease is determined by the number of copies of the SMN2 gene, which is a homolog to SMN1 but not as efficient in protein production. Three medications have recently been approved for the treatment of SMA. Nusinersen is an intrathecal antisense oligonucleotide that alters SMN2 pre-mRNA, onasemnogene abeparvovec-xioi is an intravenous SMN1 gene replacement therapy, and risdiplam is an oral small molecule splicing modifier of SMN2. No head-to-head studies have been conducted comparing these medications, so selection of one of these medications for an individual with SMA can be challenging. In this article we outline the efficacy, safety, and other pertinent factors to consider when selecting a therapy for an individual with SMA. The age of the individual and comorbidities, such as liver or kidney disease, help guide treatment choices. All three of these medications are efficacious, and early initiation is critical for obtaining the best outcomes.
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Atrofia Muscular Espinal/tratamiento farmacológico , Fármacos Neuromusculares/administración & dosificación , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos/administración & dosificación , Animales , Compuestos Azo/administración & dosificación , Compuestos Azo/inmunología , Productos Biológicos/administración & dosificación , Productos Biológicos/inmunología , Humanos , Atrofia Muscular Espinal/epidemiología , Atrofia Muscular Espinal/inmunología , Fármacos Neuromusculares/inmunología , Oligonucleótidos/inmunología , Oligonucleótidos Antisentido/inmunología , Pirimidinas/administración & dosificación , Pirimidinas/inmunología , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/inmunología , Resultado del TratamientoRESUMEN
The pandemic coronavirus disease 2019 (COVID-19) is instigated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is mainly transmitted via the inhalation route and characterized by fever, coughing and shortness of breath. COVID-19 affects all age groups with no single cure. The drug discovery, manufacturing, and safety studies require extensive time and sources and, therefore, struggled to match the exponential spread of COVID-19. Yet, various repurposed drugs (antivirals, immune-modulators, nucleotide analogues), and convalescent plasma therapy have been authorized for emergency use against COVID-19 by Food and Drug Administration under certain limits and conditions. The discovery of vaccine is the biggest milestone achieved during the current pandemic era. About nine vaccines were developed for human use with varying claims of efficacy. The rapid emergence of mutations in SARS-CoV-2, suspected adverse drug reactions of current therapies in special population groups and limited availability of drugs in developing countries necessitate the development of more efficacious, safe and cheap drugs/vaccines for treatment and prevention of COVID-19. Keeping in view these limitations, the current review provides an update on the efficacy and safety of the repurposed, and natural drugs to treat COVID-19 as well as the vaccines used for its prophylaxis.
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Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/uso terapéutico , COVID-19/inmunología , COVID-19/terapia , Reposicionamiento de Medicamentos/tendencias , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Enzima Convertidora de Angiotensina 2/inmunología , Animales , Antivirales/inmunología , Antivirales/uso terapéutico , Productos Biológicos/inmunología , Productos Biológicos/uso terapéutico , COVID-19/epidemiología , Reposicionamiento de Medicamentos/métodos , Humanos , Inmunización Pasiva , Factores Inmunológicos/inmunología , Factores Inmunológicos/uso terapéutico , Sueroterapia para COVID-19RESUMEN
Development of antidrug antibodies (ADAs) is an undesirable potential outcome of administration of biotherapeutics and involves the innate and adaptive immune systems. ADAs can have detrimental clinical consequences: they can reduce biotherapeutic efficacy or produce adverse events. Because animal models are considered poor predictors of immunogenicity in humans, in vitro assays with human innate and adaptive immune cells are commonly used alternatives that can reveal cell-mediated unwanted immune responses. Multiple methods have been developed to assess the immune cell response following exposure to biotherapeutics and estimate the potential immunogenicity of biotherapeutics. This review highlights the role of innate and adaptive immune cells as the drivers of immunogenicity and summarizes the use of these cells in assays to predict clinical ADA.
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Inmunidad Adaptativa/inmunología , Productos Biológicos/inmunología , Inmunidad Innata/inmunología , Anticuerpos Monoclonales/inmunología , Productos Biológicos/análisis , Linfocitos T CD4-Positivos/metabolismo , Antígenos HLA-D/inmunología , Humanos , Receptores de Antígenos de Linfocitos B/análisis , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos T/análisis , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
The pathogen Mycobacterium tuberculosis (Mtb), causing tuberculosis disease, features an extraordinary thick cell envelope, rich in Mtb-specific lipids, glycolipids, and glycans. These cell wall components are often directly involved in host-pathogen interaction and recognition, intracellular survival, and virulence. For decades, these mycobacterial natural products have been of great interest for immunology and synthetic chemistry alike, due to their complex molecular structure and the biological functions arising from it. The synthesis of many of these constituents has been achieved and aided the elucidation of their function by utilizing the synthetic material to study Mtb immunology. This review summarizes the synthetic efforts of a quarter century of total synthesis and highlights how the synthesis layed the foundation for immunological studies as well as drove the field of organic synthesis and catalysis to efficiently access these complex natural products.
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Productos Biológicos/síntesis química , Pared Celular/química , Mycobacterium tuberculosis/citología , Productos Biológicos/química , Productos Biológicos/inmunología , Interacciones Huésped-Patógeno , Humanos , Tuberculosis/microbiologíaAsunto(s)
Productos Biológicos/administración & dosificación , Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , SARS-CoV-2/efectos de los fármacos , Productos Biológicos/inmunología , COVID-19/epidemiología , COVID-19/inmunología , Vacunas contra la COVID-19/inmunología , Humanos , SARS-CoV-2/inmunología , Resultado del TratamientoRESUMEN
Natural Killer (NK) cells are components of innate immune surveillance against transformed cells. NK cell immunotherapy has attracted attention as a promising strategy for cancer treatment, whose antitumor effects, however, require further improvement. The use of small molecules with immunomodulatory potentials and selective tumor-killing possesses the potential to complement immunotherapy. This study demonstrated that Piperlongumine (PL), a natural alkaloid obtained from long pepper fruit, alone has antitumor and anti-proliferative potential on all the tested tumors in vitro. PL pretreatment of tumor cells also potentiates their susceptibility to NK cell cytolysis at the doses where NK cell functions were preserved. Importantly, PL suppresses both NK -sensitive MHC-I -deficient and MHC-I -sufficient tumor growth in vivo. Mechanistically, PL induces misfolded proteins, impedes autophagy, increases ROS and tumor conjugation with NK cells. Furthermore, PL enhances the expression of NK cell-activating receptors on NK cells and its ligands on tumor cells, possibly leading to increased susceptibility to NK cell killing. Our findings showed the antitumor and immunomodulatory potential of PL, which could be explored to complement NK cell immunotherapy for cancer treatment.
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Antineoplásicos Fitogénicos/farmacología , Productos Biológicos/farmacología , Dioxolanos/farmacología , Células Asesinas Naturales/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Animales , Antineoplásicos Fitogénicos/inmunología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Productos Biológicos/inmunología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Dioxolanos/inmunología , Humanos , Células Asesinas Naturales/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Receptores de Células Asesinas Naturales/efectos de los fármacos , Receptores de Células Asesinas Naturales/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Biotherapeutics, which are biologic medications that are natural or bioengineered products of living cells, have revolutionized the treatment of many diseases. However, unwanted immune responses still present a major challenge to their widespread adoption. Many patients treated with biotherapeutics develop antigen-specific anti-drug antibodies (ADAs) that may reduce the efficacy of the therapy or cross-react with the endogenous counterpart of a protein therapeutic, or both. Here, we describe an in vitro method for assessing the immunogenic risk of a biotherapeutic. We found a correlation between clinical immunogenicity and the frequency with which a biotherapeutic stimulated an increase in CD134, CD137, or both cell surface markers on CD4+ T cells. Using high-throughput flow cytometry, we examined the effects of 14 biotherapeutics with diverse rates of clinical immunogenicity on peripheral blood mononuclear cells from 120 donors with diverse human leukocyte antigen class II-encoding alleles. Biotherapeutics with high rates of ADA development in the clinic had higher proportions of CD4+ T cells positive for CD134 or CD137 than biotherapeutics with low clinical immunogenicity. This method provides a rapid and simple preclinical test of the immunogenic potential of a new candidate biotherapeutic or biosimilar. Implementation of this approach during biotherapeutic research and development enables rapid elimination of candidates that are likely to cause ADA-related adverse events and detrimental consequences.
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Anticuerpos Monoclonales/toxicidad , Productos Biológicos/toxicidad , Activación de Linfocitos/efectos de los fármacos , Receptores OX40/metabolismo , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Pruebas de Toxicidad , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Anticuerpos Monoclonales/inmunología , Formación de Anticuerpos , Productos Biológicos/inmunología , Biomarcadores/metabolismo , Células Cultivadas , Reacciones Cruzadas , Citometría de Flujo , Ensayos Analíticos de Alto Rendimiento , Humanos , Medición de Riesgo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Regulación hacia ArribaRESUMEN
To examine whether patients with inflammatory arthritis (IA) treated with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) and/or biologic (b) DMARDs, could be affected from SARS-CoV-2 infection and to explore the COVID-19 disease course and outcome in this population. This is a prospective observational study. During the period February-December 2020, 443 patients with IA who were followed-up in the outpatient arthritis clinic were investigated. All patients were receiving cs and/or bDMARDs. During follow-up, the clinical, laboratory findings, comorbidities and drug side effects were all recorded and the treatment was adjusted or changed according to clinical manifestations and patient's needs. There were 251 patients with rheumatoid arthritis (RA), 101 with psoriatic arthritis (PsA) and 91 with ankylosing spondylitis (AS). We identified 32 patients who contracted COVID-19 (17 RA, 8 PsA, 7 AS). All were in remission and all drugs were discontinued. They presented mild COVID-19 symptoms, expressed mainly with systemic manifestations and sore throat, while six presented olfactory dysfunction and gastrointestinal disturbances, and all of them had a favorable disease course. However, three patients were admitted to the hospital, two of them with respiratory symptoms and pneumonia and were treated appropriately with excellent clinical response and outcome. Patients with IA treated with cs and/or bDMARDs have almost the same disease course with the general population when contract COVID-19.
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Artritis Reumatoide/complicaciones , COVID-19/complicaciones , Adulto , Antirreumáticos/inmunología , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Productos Biológicos/inmunología , Productos Biológicos/uso terapéutico , COVID-19/diagnóstico , COVID-19/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19RESUMEN
T-cell engaging biologics is a class of novel and promising immune-oncology compounds that leverage the immune system to eradicate cancer. Here, we compared and contrasted a bispecific diabody-Fc format, which displays a relatively short antigen-binding arm distance, with our bispecific IgG platform. By generating diverse panels of antigen-expressing cells where B cell maturation antigen is either tethered to the cell membrane or located to the juxtamembrane region and masked by elongated structural spacer units, we presented a systematic approach to investigate the role of antigen epitope location and molecular formats in immunological synapse formation and cytotoxicity. We demonstrated that diabody-Fc is more potent for antigen epitopes located in the membrane distal region, while bispecific IgG is more efficient for membrane-proximal epitopes. Additionally, we explored other parameters, including receptor density, antigen-binding affinity, and kinetics. Our results show that molecular format and antigen epitope location, which jointly determine the intermembrane distance between target cells and T cells, allow decoupling of cytotoxicity and cytokine release, while antigen-binding affinities appear to be positively correlated with both readouts. Our work offers new insight that could potentially lead to a wider therapeutic window for T-cell engaging biologics in general.