RESUMO
Common gamma receptor-dependent cytokines and their JAK/STAT pathways play pivotal roles in T cell immunity. Abnormal activation of this system was pervasive in diverse T cell malignancies assessed by pSTAT3/pSTAT5 phosphorylation. Activating mutations were described in some but not all cases. JAK1 and STAT3 were required for proliferation and survival of these T cell lines whether or not JAKs or STATs were mutated. Activating JAK and STAT mutations were not sufficient to initiate leukemic cell proliferation but rather only augmented signals from upstream in the cytokine pathway. Activation required the full pathway, including cytokine receptors acting as scaffolds and docking sites for required downstream JAK/STAT proteins. JAK kinase inhibitors have depressed leukemic T cell line proliferation. The insight that JAK/STAT system activation is pervasive in T cell malignancies suggests novel therapeutic approaches that include antibodies to common gamma cytokines, inhibitors of cytokine-receptor interactions, and JAK kinase inhibitors that may revolutionize therapy for T cell malignancies.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Imunoterapia/métodos , Janus Quinases/metabolismo , Linfoma de Células T/imunologia , Fatores de Transcrição STAT/metabolismo , Animais , Antineoplásicos/uso terapêutico , Carcinogênese , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Linfoma de Células T/terapia , Receptores de Citocinas/antagonistas & inibidores , Transdução de SinaisRESUMO
The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/imunologia , Animais , Humanos , Imunoterapia/tendências , Ativação Linfocitária/efeitos dos fármacos , Neoplasias/imunologia , Evasão Tumoral , Microambiente TumoralRESUMO
Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aß antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as was selection of patients at relatively early stages of disease. Biomarkers of the target pathologies, including amyloid and tau PET, and insights from past trials were also critical to the recent successes. Moving forward, the challenge will be to develop more efficacious therapies with greater efficiency. Novel trial designs, including combination therapies and umbrella and basket protocols, will accelerate clinical development. Better diversity and inclusivity of trial participants are needed, and blood-based biomarkers may help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms, and the creation of new career paths will be critical to build momentum in these exciting times.
Assuntos
Doença de Alzheimer , Desenvolvimento de Medicamentos , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Proteínas Amiloidogênicas , Anticorpos Monoclonais/uso terapêutico , Biomarcadores , Ensaios Clínicos como AssuntoRESUMO
Monoclonal antibodies (mAbs) have revolutionized the treatment of several human diseases, including cancer and autoimmunity and inflammatory conditions, and represent a new frontier for the treatment of infectious diseases. In the last 20 years, innovative methods have allowed the rapid isolation of mAbs from convalescent subjects, humanized mice, or libraries assembled in vitro and have proven that mAbs can be effective countermeasures against emerging pathogens. During the past year, an unprecedentedly large number of mAbs have been developed to fight coronavirus disease 2019 (COVID-19). Lessons learned from this pandemic will pave the way for the development of more mAb-based therapeutics for other infectious diseases. Here, we provide an overview of SARS-CoV-2-neutralizing mAbs, including their origin, specificity, structure, antiviral and immunological mechanisms of action, and resistance to circulating variants, as well as a snapshot of the clinical trials of approved or late-stage mAb therapeutics.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , COVID-19/patologia , COVID-19/virologia , Humanos , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/imunologia , Tratamento Farmacológico da COVID-19RESUMO
SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8+ T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.
Assuntos
Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Antivirais , Linfócitos T CD8-Positivos , COVID-19 , Fragmentos Fc das Imunoglobulinas/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Células CHO , COVID-19/imunologia , COVID-19/terapia , Chlorocebus aethiops , Cricetulus , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , SARS-CoV-2/imunologia , Células Vero , Carga ViralRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Modelos Animais de Doenças , Pneumonia Viral/terapia , Enzima de Conversão de Angiotensina 2 , Animais , COVID-19 , Chlorocebus aethiops , Infecções por Coronavirus/virologia , Feminino , Células HEK293 , Humanos , Imunização Passiva/métodos , Pulmão/metabolismo , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , SARS-CoV-2 , Transdução Genética , Células Vero , Carga Viral/imunologiaRESUMO
Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2-/- mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.
Assuntos
Imunoterapia , Glicoproteínas de Membrana/metabolismo , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Receptor 1 de Quimiocina CX3C/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/metabolismo , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Metilcolantreno/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/induzido quimicamente , Neoplasias/patologia , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Microambiente TumoralRESUMO
The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Betacoronavirus/metabolismo , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Enzima de Conversão de Angiotensina 2 , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/uso terapêutico , Reações Antígeno-Anticorpo , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Sítios de Ligação , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cricetinae , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Cinética , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches.
Assuntos
Antígeno B7-H1/metabolismo , Antígeno B7-H1/fisiologia , Microambiente Tumoral/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Exossomos/metabolismo , Humanos , Imunoterapia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Microambiente Tumoral/fisiologiaRESUMO
Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
Assuntos
Colite Ulcerativa/patologia , Colo/metabolismo , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Bestrofinas/metabolismo , Antígenos CD8/metabolismo , Estudos de Casos e Controles , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Colo/patologia , Enterócitos/citologia , Enterócitos/metabolismo , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Linfócitos T/citologia , Linfócitos T/metabolismo , Trombospondinas/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (CLR + RAMP1) offer considerable improvements over existing drugs in migraine prophylaxis and are the first designed to act on the trigeminal pain system. Erenumab is approved by the FDA and EMA and has reached the market since May 2018. Two antibodies, fremanezumab and galcanezumab, directed towards the CGRP ligand, were approved by the FDA in September 2018. To view this Bench to Bedside, open or download the PDF.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/tratamento farmacológico , HumanosRESUMO
Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2+ breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.
Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Citofagocitose/imunologia , Macrófagos/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/fisiologia , Antígeno B7-H1/genética , Antígeno B7-H1/fisiologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Citofagocitose/fisiologia , Proteínas de Ligação a DNA/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia , Células Matadoras Naturais/fisiologia , Linfoma/imunologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fagocitose/imunologia , Fagocitose/fisiologia , Fagossomos/fisiologia , Receptores de IgG/imunologiaRESUMO
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.
Assuntos
Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Epigênese Genética , Mutação em Linhagem Germinativa , Neoplasias/genética , Neoplasias/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Autofagia , Linhagem Celular Tumoral , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Imunoterapia , Ipilimumab/farmacologia , Masculino , Melanoma/genética , Melanoma/imunologia , Antígenos Específicos de Melanoma/genética , Antígenos Específicos de Melanoma/imunologia , Camundongos , Camundongos Transgênicos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologiaRESUMO
Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.
Assuntos
Quinases Ciclina-Dependentes/metabolismo , Neoplasias da Próstata/patologia , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Reparo do DNA , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Humanos , Masculino , Mutação de Sentido Incorreto , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/imunologia , Próstata/diagnóstico por imagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologia , Tomografia Computadorizada por Raios XRESUMO
Dupilumab is a fully human IgG4 monoclonal antibody directed against the IL-4Rα subunit of IL-4 and IL-13 receptors. It blocks the signaling pathways of IL-4 and IL-13, key cytokines that drive type 2 inflammatory response. In March 2017, dupilumab was approved for use in the treatment of atopic dermatitis (eczema). To view this Bench to Bedside, open or download the PDF.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Ensaios Clínicos como Assunto , Aprovação de Drogas , Humanos , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Terapia de Alvo MolecularRESUMO
Lartruvo (olaratumab) is a monoclonal antibody against the extracellular domain of PDGFRA. Olaratumab blocks ligand binding and thereby inhibits activation of PDGFRA kinase activity. Pre-clinically, this antibody inhibited PDGFRA-dependent tumor growth. In a randomized Phase II study, adding olaratumab to doxorubicin chemotherapy significantly improved overall survival, leading to FDA approval.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Aprovação de Drogas , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Imunoterapia , Melanoma/terapia , Microambiente Tumoral , Estudo de Associação Genômica Ampla , Humanos , Melanoma/genética , Melanoma/imunologia , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T , TranscriptomaRESUMO
Clostridium difficile infection (CDI) is facilitated by alteration of the microbiome following antibiotic administration. Antimicrobial therapy directed against the pathogen can treat CDI. Unfortunately, â¼20% of successfully treated patients will suffer recurrence. Bezlotoxumab, a human monoclonal antibody, binds to C. difficile toxin B (TcdB), reducing recurrence presumably by limiting epithelial damage and facilitating microbiome recovery.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Clostridioides difficile/fisiologia , Enterocolite Pseudomembranosa/tratamento farmacológico , Anticorpos Amplamente Neutralizantes , Microbioma Gastrointestinal , Humanos , Intestinos/efeitos dos fármacos , Prevenção SecundáriaRESUMO
Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature. However, ZIKV escape mutants emerged in vitro and in vivo in the presence of ZKA190, as well as of other neutralizing mAbs. To counter this problem, we developed a bispecific antibody (FIT-1) comprising ZKA190 and a second mAb specific for DII of E protein. In addition to retaining high in vitro and in vivo potencies, FIT-1 robustly prevented viral escape, warranting its development as a ZIKV immunotherapy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Infecção por Zika virus/terapia , Zika virus/química , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/química , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/química , Microscopia Crioeletrônica , Epitopos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Moleculares , Alinhamento de Sequência , Proteínas do Envelope Viral/química , Zika virus/imunologiaRESUMO
Alirocumab and evolocumab are monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a circulating protein that degrades low-density lipoprotein (LDL) receptors. These therapies increase LDL receptors on the cell surface and reduce plasma LDL cholesterol. Both therapies are approved to lower LDL cholesterol, a causative agent for atherosclerotic cardiovascular disease.