RESUMO
Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.
Assuntos
Anticorpos Biespecíficos , Neoplasias Hematológicas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Antígeno CD47 , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Citotoxicidade Celular Dependente de AnticorposRESUMO
Multiple myeloma (MM) invariably develops in the bone marrow (BM), indicating the strong requirement of this tumor for the peculiar BM microenvironment, rich in cytokine and hematopoietic precursor cells. Interleukin-6 (IL-6) and a proliferation inducing ligand (APRIL) are key cytokines implicated in MM development. Here, we show that MM cells changed the hematopoietic microenvironment early upon BM infiltration by strongly downregulating hematopoietic precursor cells from all lineages except myeloid precursor cells. Myeloid precursor cells constituted a major source of APRIL in MM-infiltrated BM, and their proliferative response to IL-6 upregulation explained their relative resistance to MM infiltration. The osteolytic molecule receptor activator of NF-kB ligand (RANK-L) expressed by MM cells started this myeloid proliferation by inducing in a contact-dependent manner IL-6 production by myeloid precursor cells themselves. Taken together, our data demonstrate that MM cells do not simply displace hematopoietic cells upon BM infiltration, but rather selectively modulate the BM microenvironment to preserve a pool of high APRIL-producing myeloid precursor cells. Our data also identify a positive regulation of APRIL by IL-6 in myeloid precursor cells.
Assuntos
Comunicação Autócrina , Medula Óssea/patologia , Interleucina-6/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Imunofenotipagem , Interleucina-6/farmacologia , Camundongos , Modelos Biológicos , Células Mieloides/efeitos dos fármacos , Células Progenitoras Mieloides/efeitos dos fármacos , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/patologia , Ligante RANK/metabolismo , Transdução de Sinais , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
Multiple myeloma (MM) is a non-curable tumor developing in the bone marrow (BM). The BM microenvironment rich in hematopoietic precursors is suspected to have a role in MM development. Here we show that a proliferation-inducing ligand (APRIL) mediated in vivo MM promotion. In MM-infiltrated BM, APRIL originated from differentiating myeloid cells with an expression peak in precursor cells. Notably, APRIL expression stayed stable in BM despite MM infiltration. The pool of APRIL-producing cells changed upon MM infiltration. Although CD16(+) mature myeloid cells constituted about half of the APRIL-producing cells in healthy BM, CD16(-) Elastase(+) myeloid precursor cells were predominant in MM-infiltrated BM. Myeloid precursor cells secreted all the APRIL they produced, and binding of secreted APRIL to MM cells, strictly dependent of heparan sulfate carried by CD138, resulted in an in situ internalization by tumor cells. This indicated APRIL consumption by MM in BM. Taken together, our data show that myelopoiesis dysregulation characterized by an increased proportion of precursor cells occurs in MM patients. Such dysregulation correlates with a stable expression of the MM-promoting factor APRIL in infiltrated BM.
Assuntos
Medula Óssea/metabolismo , Medula Óssea/patologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mielopoese , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Humanos , Imunofenotipagem , Camundongos Knockout , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Células Mieloides/metabolismo , Células Mieloides/patologia , Mielopoese/genética , Comunicação Parácrina , Ligação Proteica , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
The treatment of multiple myeloma has undergone significant changes in the recent past. The arrival of novel agents, especially thalidomide, bortezomib and lenalidomide, has expanded treatment options and patient outcomes are improving significantly. This article summarises the discussions of an expert meeting which was held to debate current treatment practices for multiple myeloma in Switzerland concerning the role of the novel agents and to provide recommendations for their use in different treatment stages based on currently available clinical data. Novel agent combinations for the treatment of newly diagnosed, as well as relapsed multiple myeloma are examined. In addition, the role of novel agents in patients with cytogenetic abnormalities and renal impairment, as well as the management of the most frequent side effects of the novel agents are discussed. The aim of this article is to assist in treatment decisions in daily clinical practice to achieve the best possible outcome for patients with multiple myeloma.
Assuntos
Antineoplásicos/uso terapêutico , Medicina Baseada em Evidências , Mieloma Múltiplo/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Biópsia por Agulha , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Transplante de Medula Óssea , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/uso terapêutico , Bortezomib , Terapia Combinada , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Humanos , Lenalidomida , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/patologia , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Retratamento , Suíça , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêuticoRESUMO
A proliferation inducing ligand (APRIL) is one of the most recently cloned members of the tumor necrosis factor (TNF) family. Early experiments implicated a pathophysiological role for APRIL in the promotion of solid tumors. Later, identification of APRIL receptors on B lymphocytes indicated a physiological role for APRIL in humoral responses. We have been able to generate antibodies that detect APRIL protein in human tissues. The study of in situ APRIL expression showed that APRIL mainly regulates late stages of B-cell humoral responses. It also provided evidence that APRIL may modulate tumor development in patients, but only for specific B-cell malignancies. Here, we will review to what extent fine characterization of in situ expression adds valuable information on APRIL (patho) physiological functions.
Assuntos
Linfoma de Células B/imunologia , Plasmócitos/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Sobrevivência Celular , Humanos , Ligantes , Linfoma de Células B/patologia , Modelos ImunológicosRESUMO
Inflammatory cells produce a proliferation inducing ligand (APRIL), one of the most recently cloned members of the tumor necrosis factor (TNF) family. Early experiments implicated APRIL as a promoting factor in the natural course of various cancers, reinforcing the concept that host inflammatory reactions are part of a tumor development. Recent studies have further analyzed the tumor-promoting role of APRIL in patients with solid tumors or with hematological malignancies. Here, we will review the recent literature, and provide evidence that APRIL may be a useful prognostic tool and a potential target in the treatment of some cancers.
Assuntos
Neoplasias/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/fisiologia , Animais , HumanosAssuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Prognóstico , Fatores de RiscoRESUMO
Differentiation of naïve B cells into plasma cells or memory cells occurs in the germinal centers (GCs) of lymph follicles or alternatively via a GC- and T-cell-independent pathway. It is currently assumed that B-cell lymphomas correlate to normal B-cell differentiation stages, but the precise correlation of several B-cell lymphomas to these two pathways remains controversial. In the present report, we describe the junctional adhesion molecule C (JAM-C), currently identified at the cell-cell border of endothelial cells, as a new B-cell marker with a tightly regulated expression during B-cell differentiation. Expression of JAM-C in tonsils allows distinction between two CD27+ B-cell subpopulations: JAM-C- GC B cells and JAM-C+ non-germinal B cells. The expression of JAM-C in different B-cell lymphomas reveals a disease-specific pattern and allows a clear distinction between JAM-C- lymphoproliferative syndromes (chronic lymphocytic leukemia, mantle cell lymphoma and follicular lymphoma) and JAM-C+ ones (hairy cell leukemia, marginal zone B-cell lymphoma). Therefore, we propose JAM-C as a new identification tool in B-cell lymphoma diagnosis.
Assuntos
Linfócitos B/citologia , Moléculas de Adesão Celular/análise , Centro Germinativo/citologia , Leucemia de Células B/diagnóstico , Linfoma de Células B/diagnóstico , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Biomarcadores Tumorais , Humanos , Leucemia de Células B/patologia , Linfoma de Células B/patologiaRESUMO
PU.1, a transcription factor of the ETS family, plays a pivotal role in normal hematopoiesis, and particularly in myeloid differentiation. Altered PU.1 function is possibly implicated in leukemogenesis, as PU.1 gene mutations were identified in some patients with acute myeloid leukemia (AML) and as several oncogenic products (AML1-ETO, promyelocytic leukemia-retinoic acid receptor alpha, FMS-like receptor tyrosine kinase 3 internal tandem duplication) are associated with PU.1 downregulation. To demonstrate directly a role of PU.1 in the blocked differentiation of leukemic blasts, we transduced cells from myeloid cell lines and primary blasts from AML patients with a lentivector encoding PU.1. In NB4 cells we obtained increases in PU.1 mRNA and protein, comparable to increases obtained with all-trans retinoic acid-stimulation. Transduced cells showed increased myelomonocytic surface antigen expression, decreased proliferation rates and increased apoptosis. Similar results were obtained in primary AML blasts from 12 patients. These phenotypic changes are characteristic of restored blast differentiation. PU.1 should therefore constitute an interesting target for therapeutic intervention in AML.
Assuntos
Crise Blástica/patologia , Lentivirus/genética , Leucemia Mieloide/patologia , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Adulto , Idoso , Apoptose , Antígenos CD13/genética , Diferenciação Celular , Feminino , Vetores Genéticos , Humanos , Leucemia Mieloide/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Transativadores/antagonistas & inibidores , Transativadores/genética , Tretinoína/farmacologiaAssuntos
Dermatite Alérgica de Contato/diagnóstico , Doenças Palpebrais/diagnóstico , Leucemia Prolinfocítica/diagnóstico , Leucemia de Células T/diagnóstico , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Infiltração Leucêmica/diagnóstico , Pseudolinfoma/diagnóstico , Pele/patologiaRESUMO
Sideroblastic anemias are a heterogenous group of disorders characterized by the presence of sideroblasts in the bone marrow aspirate. Current classification schemes distinguish between diseases of the heme synthesis pathway and diseases of other mitochondrial pathways which can either be of primary origin (defects in mitochondrial DNA) or of secondary origin (defects in nuclear DNA). Although several distinct hereditary forms exist, sideroblastic anemias are most frequently acquired diseases and belong to the group of myelodysplastic syndromes with the propensity to develop into overt leukemia. Treatment is mainly supportive (vitamins, blood transfusions, cytokines) and only rarely are bone marrow transplantations performed. The molecular defects of a few hereditary forms have already been elucidated, but the genes involved in the acquired forms are still largely unknown.
Assuntos
Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/terapia , Anemia Sideroblástica/classificação , Anemia Sideroblástica/genética , Humanos , Guias de Prática Clínica como Assunto , Padrões de Prática MédicaAssuntos
População Negra , Emigração e Imigração , Doenças do Pé/diagnóstico , Úlcera do Pé/diagnóstico , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Úlcera Varicosa/diagnóstico , Biópsia , Diagnóstico Diferencial , Doenças do Pé/patologia , Úlcera do Pé/patologia , Alemanha , Gana/etnologia , Humanos , Linfonodos/patologia , Metástase Linfática , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Úlcera Varicosa/patologiaRESUMO
We report on a patient with terbinafine-induced SCLE covering clinical, histopathological and serological findings. Positive serological results included ANA, SS-A (Ro)-antibodies and anti-histone-antibodies with specificity for H1 and H3. The literature on terbinafine-induced SCLE is reviewed. We discuss H1- and H3-specific anti-histone antibodies as a possible diagnostic criterion of drug-induced SCLE.
Assuntos
Antifúngicos/efeitos adversos , Toxidermias/diagnóstico , Lúpus Eritematoso Cutâneo/induzido quimicamente , Naftalenos/efeitos adversos , Onicomicose/tratamento farmacológico , Idoso , Antifúngicos/uso terapêutico , Toxidermias/patologia , Feminino , Humanos , Lúpus Eritematoso Cutâneo/diagnóstico , Naftalenos/uso terapêutico , Pele/patologia , TerbinafinaRESUMO
Lentivectors, derived from human immunodeficiency virus-1 (HIV-1), represent a novel investigational and therapeutic tool for targeting hematopoietic progenitor cells. We describe a new protocol whereby we achieved a highly efficient lentiviral transduction of erythroid precursor cells originating from the bone marrow of healthy adults and patients with myelodysplastic syndromes (MDS). CD34(+) stem cells from healthy subjects were cultured with erythropoietin, IL-3 and stem cell factor, and thereby expanded approximately 300-fold. When these cultures were transduced with a lentiviral vector expressing GFP as a reporter gene, 70% glycophorin(+) cells were GFP(+). Although proliferation and levels of transduction were reduced in cultures of CD34(+) stem cells from patients with myelodysplastic syndromes, 50% of glycophorin(+) cells became GFP(+), amongst which 30% were sideroblastic erythroid precursors. This study demonstrates that lentiviral vectors are capable of efficiently transducing MDS precursors and offers new perspectives to investigate the influence of specific genes on normal erythroid differentiation. This may eventually help to correct defects in patients suffering from myelodysplastic syndromes.
Assuntos
Células Precursoras Eritroides/fisiologia , Vetores Genéticos , HIV-1 , Síndromes Mielodisplásicas/genética , Transdução Genética , Adulto , Antígenos CD34 , Terapia Genética , Proteínas de Fluorescência Verde , Células-Tronco Hematopoéticas/fisiologia , Humanos , Proteínas Luminescentes , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Transdução Genética/métodosRESUMO
Idiopathic acquired sideroblastic anaemias (IASAs) form a subgroup of the myelodysplastic syndromes and are characterized by mitochondrial iron accumulation, bone marrow erythroid hyperplasia and decreased peripheral red blood cell counts. Increased intramedullary apoptosis of erythroid precursors is presumed to constitute the pathophysiological mechanism explaining this ineffective erythropoiesis, but if and how mitochondrial dysfunction is implicated in this process is currently unknown. We therefore studied bone marrow precursor cells obtained from nine patients with IASA for (i) caspase 3 activity, (ii) numbers of Annexin V- and 7-amino-actinomycin-positive cells, (iii) numbers of cells with diminished mitochondrial membrane potential, Delta Psi(m), and (iv) numbers of cells producing reactive oxygen species (ROS), and we compared the results with those of five normal bone marrow samples. Compared with controls, we found increased caspase 3 activity in all IASA samples, which correlated with increased numbers of Annexin-V-positive cells (r = 0.7). Analysis of different subpopulations showed increased apoptosis in erythroid populations compared with myeloid and/or lymphoid populations in five out of nine cases, and increased apoptosis in the last two populations in four out of nine cases. As evidence of mitochondrial dysfunction, Delta Psi(m) was found to be diminished in the erythroid subpopulations of all cases of IASA (66.6 +/- 17% vs. 34.6 +/- 12% in normals). Delta Psi(m) decrease was correlated to Annexin V positivity (r = 0.7). Astonishingly, no difference was found between IASA and normal bone marrows with regard to the number of ROS-producing cells. In fact, both groups exhibited a similar low proportion of ROS production (10.3 +/- 7% in normals vs. 6.8 +/- 5% in IASA). Taken together, our results show that mitochondria are clearly implicated in the apoptotic process in IASA patients. Whether this is a result of an intramitochondrial defect (e.g. Fe accumulation, secondary to mitochondrial or nuclear DNA mutations) or is secondary to an extracellular stimulus [e.g. tumour necrosis factor (TNF), Fas ligand (FasL)] remains to be determined.
Assuntos
Anemia Sideroblástica/patologia , Apoptose , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Sideroblástica/metabolismo , Anexina A5/análise , Células da Medula Óssea/enzimologia , Estudos de Casos e Controles , Catalase/metabolismo , Dactinomicina/análogos & derivados , Dactinomicina/análise , Eritroblastos/enzimologia , Eritroblastos/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismoAssuntos
Leucemia Mieloide/patologia , Neoplasias Uterinas/secundário , Doença Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Terapia Combinada , Feminino , Humanos , Leucemia Mieloide/fisiopatologia , Leucemia Mieloide/terapia , Indução de Remissão , Neoplasias Uterinas/fisiopatologia , Neoplasias Uterinas/terapiaRESUMO
Acute normovolaemic haemodilution (ANH) is used to avoid perioperative blood loss and consists of the withdrawal of whole blood just before or just after anaesthesia induction and its simultaneous replacement by synthetic colloids and crystalloid solutions. In an attempt to improve the efficiency of this technique while at the same time avoiding cardiovascular complications, we set up a pilot study to test the association of rHuEpo/ANH during elective surgery for total hip replacement. Five patients (3 males, 2 females) were included in this study. The amount of whole blood drawn was 3 x 450 ml from the men and 2 x 450 ml from the women. Before blood was taken, the mean increase in haemoglobin was 1.2 +/- 0.9 g/dl and mean increase in reticulocytes 106 +/- 34 G/l. No patient received homologous transfusion during the perioperative period; 3 patients received the totality of predonated blood and one patient 2 of the 3 units taken. The mean fall in haemoglobin at day 1 post-surgery was 3.6 g/dl. In conclusion, the stimulation of erythropoiesis by rHuEpo in the pre-surgery phase led on average to a 1 g/dl gain in haemoglobin, permitting an isovolaemic withdrawal of 900 to 1350 ml of blood depending on body weight without the development of severe anaemia. It was thus possible to perform total hip replacement in all the patients without homologous blood support and with a post-surgery haemoglobin value of > 10 g/dl. This protocol should be further tested in a prospective randomised study (rHuEpo versus placebo) in order to assess the real benefit of rHuEpo.
Assuntos
Artroplastia de Quadril , Transfusão de Sangue , Eritropoetina/administração & dosagem , Hemodiluição , Complicações Pós-Operatórias/sangue , Adulto , Idoso , Perda Sanguínea Cirúrgica/fisiopatologia , Feminino , Hemoglobinometria , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Proteínas Recombinantes , Resultado do TratamentoRESUMO
SEQ DATA who developed polyclonal hypergammaglobulinaemia: 38.3 milligrams polyclonal IgG, 0.97 milligram IgA and 0.33 milligram IgM. Immunophenotyping showed a monoclonal lymphocytic population CD19+ CD5+ CD40+ CD23+, low sIg+ (95%), kappa type in the great majority (96%). RT-PCR of immunoglobulin genes gave evidence of monoclonal rearrangement of the IgM type. Our tests showed that IL-2 was produced when leukaemic B cells were stimulated with phorbol myristate acetate, ionomycin and lipopolysaccharide. In addition, transfections with the full IL-2 promoter or elements thereof revealed that IL-2 expression is inducible and mediated through the NF-kB-promoter element. Finally, the amount of IL-2 secreted by these cells is about 39 ng/ml/10(6) cells, which is remarkably high for non-T cells. These results suggest that the large amounts of polyclonal IgG seen in this case of B-CLL are secreted by normal B cells which are in turn stimulated by IL-2 produced by proliferating monoclonal (leukaemic) B cells. Under cyclosporin A treatment, immunoglobulin secretion and B cell count remained low.