Advances and challenges in therapeutic monoclonal antibodies drug development

The use of serum containing polyclonal antibodies from animals immunized with toxins marked the beginning of the application of antibody-based therapy in late nineteenth century. Advances in basic research led to the development of the hybridoma technology in 1975. Eleven years later, the first therapeutic monoclonal antibody (mAb) was approved, and since then, driven by technological advances, the development of mAbs has played a prominent role in the pharmaceutical industry. In this review, we present the developments to circumvent problems of safety and efficacy arising from the murine origin of the first mAbs and generate structures more similar to human antibodies. As of October 2017, there are 61 mAbs and 11 Fc-fusion proteins in clinical use. An overview of all mAbs currently approved is provided, showing the development of sophisticated mAbs formats that were engineered based on the challenges posed by therapeutic indications, including antibody-drug conjugates (ADC) and glycoengineered mAbs. In the field of immunotherapy, the use of immunomodulators, bispecific mAbs and CAR-T cells are highlighted. As an example of promising therapy to treat infectious diseases, we discuss the generation of neutralizing monoclonal-oligoclonal antibodies obtained from human B cells. Scientific and technological advances represent mAbs successful translation to the clinic

A novel 3-base deletion (IVS3+2_4delTGG) of the hydroxymethylbilane synthase gene in a Brazilian patient with acute intermittent porphyria

Acute intermittent porphyria (AIP, OMIM 176000) is an autosomal dominant metabolic disease caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS; EC 4.3.1.8; formely named porphobilinogen deaminase, PBGD), mapped to chromosome 11q23.3. We describe a novel mutation of the HMBS gene, a de novo 3-base deletion in the splicing donor site of intron 3 (IVS3+2_4delTGG) in a woman affected by AIP. RT-PCR analysis revealed an abnormal HMBS mRNA, compatible with exon 3 skipping.

Análise de expressão gênica diferencial em linhagens celulares de mama com diferentes perfis de expressão de ERBB2 na presença e ausência de docetaxel / Analysis of differentially expressed genes in normal mammary cell lines expressing different levels of ERBB2 with or without docetaxel

O câncer de mama é o de maior ocorrência na população feminina e a segunda causa de óbitos por câncer em mulheres. A expressão aumentada do gene ERBB2 é encontrada em 15-30% dos tumores de mama, e está associada a um pior prognóstico e a quimioresistência a diversas drogas anti-tumorais, incluindo os taxanos, paclitaxel e docetaxel. O docetaxel é, no momento, a droga mais efetiva no tratamento de tumores de mama avançados. Utilizando-se a técnica de SAGE, foi determinado o perfil de expressão gênica de duas linhagens de células de mama normal, HB4a e C5.2, que apresentam diferentes níveis de expressão de ERBB2, na ausência e na presença do tratamento intensivo com docetaxel, visando identificar genes associados a quimioresistência... A comparação do transcriptoma das linhagens celulares HB4a e C5.2 antes e após o tratamento com docetaxel revelou diferenças substanciais no padrão de expressão gênica. Vinte e um genes encontrados diferencialmente expressos nas células HB4a e C5.2, na ausência e na presença do tratamento com docetaxel, foram analisados por qPCR... O uso da técnica de SAGE nos permitiu a identificação de um grande número de genes potencialmente regulados por ERBB2, que atuam em diversos processos celulares, como proliferação celular, apoptose, adesão celular e organização de citoesqueleto, e podem estar envolvidos na resistência ao docetaxel. Entretanto, um maior número de estudos experimentais e clínicos deve ser realizado para que seja confirmado o potencial destes genes como marcadores de resposta à quimioterapia em câncer de mama (AU)

Breast cancer is the most commonly diagnosed malignancy and the second leading cause of mortality related to cancer in women. Over-expression of ERBB2 gene occurs in 15-30% of breast tumors and is associated with poor prognosis and chemoresistance to a variety of anticancer drugs, including the taxanes, paclitaxel and docetaxel. Docetaxel is currently the most effective chemotherapeutic drug for the treatment of advanced breast cancer. Using SAGE technique, we obtained the gene expression profiles from two normal mammary cell lines, HB4a and C5.2, expressing different levels of ERBB2, before and after intensive exposure to docetaxel, aiming to identify genes involved in chemoresistance. The parental cell line HB4a expresses basal levels of ERBB2, and its clone C5.2 expresses high levels of ERBB2. A total of 307,506 tags were generated from HB4a (81,684 tags; 30,854 unique tags), HB4a treated with docetaxel (70,715; 31,546 unique tags), C5.2 (79,948 tags; 30,568 unique tags) and C5.2 treated with docetaxel (75,159; 31,293 unique tags). Comparisons of the transcriptome of the cell lines before and after docetaxel exposure revealed substantially different expression patterns. Twenty-one differentially expressed genes between HB4a and C5.2 cell lines, before and after docetaxel treatment, were further analyzed by qPCR. The alterations in the expression patterns in HB4a and C5.2 cell lines in response to docetaxel treatment observed by SAGE analysis were confirmed by qPCR in the majority of genes analyzed, including TPM1, SPARC, RUVBL1, LGALS1 and MGC11242. The use of SAGE technique allowed us to identify a large number of potential ERBB2 target genes implicated with a variety of cellular processes including cell proliferation, cell adhesion, apoptosis and cytoskeleton organization. However, additional experimental and clinical studies are needed to confirm the predictive value of these genes in chemotherapy response in breast cancer (AU)