Class Of Biological Agents Research Articles

Ustekinumab. Neoplasias y otros aspectos de seguridad

The recent introduction of a new class of biologic agents in psoriasis has led to important advances in the management of this disease. IL-12 and IL-23 play a key role in the control of malignancies and infections. The development of novel molecules capable of blocking the action of these cytokines has rekindled the debate on whether biologic agents increase the risk of malignancy in patients with psoriasis.In this chapter, we review the safety data for patients who have been treated for 3 or 4 years and the literature on the use of ustekinumab.Based on the available evidence, it can be concluded that patients treated with stekinumab do not have a higher risk of malignancy than the general population.

Clinical efficacy of abatacept in Japanese rheumatoid arthritis patients

The purpose of this study was to examine the treatment retention and efficacy of abatacept, the first member of a new class of biologic agents, in Japanese rheumatoid arthritis (RA) patients during clinical practice. A retrospective multicenter study was conducted with patients who underwent abatacept therapy for 24weeks (n=143). Patients at baseline had a mean age of 63.5years, a mean disease duration of 11.3years, and a mean disease activity score in 28 joints (DAS28) of 4.5. Overall retention of abatacept treatment was 83.2% at 24weeks, when 46.2% of patients achieved DAS28-defined low disease activity (LDA; DAS28 <3.2) and 26.6% achieved DAS28-defined remission (DAS28 <2.6). LDA was achieved in a significantly higher proportion of patients without prior biologics therapy compared to those with prior biologics (60.9 vs. 34.2%, p=0.001). There was no significant difference between patients with or without concomitant methotrexate (MTX) therapy (45.2 vs. 47.5%). Abatacept therapy appears to be highly effective and well tolerated during clinical treatment of RA. Abatacept was particularly effective in patients with no history of biologics use, and did not appear to be dependent on concomitant MTX therapy.

Biological Prognostic Markers in Diffuse Large B-Cell Lymphoma

Multiple novel therapeutic options have emerged in the treatment of non-Hodgkin lymphoma, including monoclonal antibodies and different classes of biological agents. With this increased diagnostic sophistication, novel prognostic markers are needed to stratify patients according to risk factors, particularly those with a mechanistic underpinning, to provide the basis for individually tailored treatment. Numerous prognostic markers have been proposed in patients with diffuse large B-cell lymphoma (DLBCL), and this review discusses the more studied and the most widely used prognostic markers in DLBCL in the rituximab era. Prognostic markers in DLBCL include a range of biomarkers assessed by morphology, immunohistochemistry, and relatively novel molecular methods including gene expression profiling, high-resolution array comparative genomic hybridization, and next-generation sequencing. Most of these methods are not routinely used due to substantial cost, technical complexity, and the requirement for fresh or frozen tissue. Efforts are underway to translate previous microarray findings to platforms that can be readily used in routine clinical practice with high reproducibility, precise measurements, and minimal loss of information. At the present time, there is no consensus on which biological prognostic markers should be routinely assessed in patients with DLBCL, and practices vary widely among different institutions. With more global approaches, the ability to assess biomarkers in the cellular or tumor context may be possible, resulting in a better understanding of their biological and prognostic significance.

A review and expert opinion of the use of certolizumab for Crohn's disease

Introduction: Crohn's disease (CD) is a chronic, idiopathic, inflammatory bowel disease with no known cure. In those patients with moderate to severe disease, the result is often a clinically debilitating condition. In the last decade, one of the most significant developments in therapy has been a class of biological agents that neutralize TNFα. Certolizumab pegol (CZP) is the most recently FDA approved anti-TNF agent for the induction and maintenance of moderate to severely active Crohn's disease.Areas covered: The currently available evidence regarding the use of CZP in CD, the expected efficacy and possible adverse events associated with this population.Expert opinion: CZP is a TNFα inhibitor that is a safe and effective agent for treatment of CD. It has several unique features which make it useful in patients with moderate to severe disease.

MiR-34a Replacement As a Novel Therapeutic Approach for Multiple Myeloma: Preclinical In Vitro and In Vivo Evidence

Abstract 2910Multiple myeloma (MM) remains an incurable disease despite important therapeutic advances in the last few years. Small non-coding RNAs (miRNAs) synthetic mimics are a new class of biological agents which have recently demonstrated preclinical activity against a variety of human neoplasms. miRNA antitumor activity has been related to their capacity to interfere with mRNA stability and protein transducing activity. miR-34a has tumor suppressor activity and is transcriptionally regulated by p53. We investigated the in vitro and in vivo therapeutic potential of pre-miR-34a mimics against human MM cells. Transient expression of pre-miR-34a mimics, after electroporation of SKMM1 and RPMI-8226 MM cell lines which display low constitutive miR-34a levels, triggered antiproliferative effects, as demonstrated by MTT and long-term soft-agar colony assays. 48 hours after cell transfection, apoptotic events were detected in both cell lines exposed to miR-34a mimics. In parallel experiments, MM cells stably transduced with miR-34a gene cloned in a lentiviral vector showed significant growth reduction as compared to empty vector-transduced cell colonies, providing additional evidence of miR-34a tumor suppressor activity in MM cells. qRT-PCR analysis of treated MM cells showed that pre-miR-34a mimics induced down-regulation of mRNAs coding for Notch1 and the cell-cycle dependent kinase 6 (CDK6), validated miR-34a targets. Furthermore, decreased anti-apoptotic Bcl-2 and CDK6 proteins was detected after pre-miR-34a mimic expression, evidence by western blotting analysis. The anti-MM activity of pre-miR-34a mimics was also evaluated in vivo using xenografted SCID models of human MM. Intra-tumor delivery of pre-miR-34a was performed by a novel formulation with Neutral Lipid Emulsion (NLE). Following 4 injections (3 days apart) of pre-miR34a formulated in NLE particles, a highly significant inhibition of tumor growth was detected in SKMM1 xenografted SCID mice. At day 13 after the first treatment, tumors in mice treated with formulated pre-miR-34a were significantly smaller than tumors in mice treated with the formulated scrambled sequence (P=0.0002) or vehicle (P=0.0002) or PBS (P=0.0001). Interestingly, at day 21a three mice enrolled in the miR-34a treated group showed complete regression of tumors. Formulated synthetic pre-miR-34a also produced a significant increase of mice survival (P=0.01 versus formulated scrambled sequence). A similar in vivo tumor growth inhibition was observed in mice xenografted with SKMM1 MM cells stably transduced with a miR-34a lentiviral construct, as compared to cells transduced with the empty vector. We here provide the first proof-of-principle demonstrating that replacement of miR-34a produces therapeutic activity against MM cells with low constitutive miR-34a expression. Our findings provide a framework for development of miR-34a-based therapeutic strategies in MM.Supported by AIRC 5 per mille, Molecular Clinical Oncology Program No. 9980 Disclosures:Anderson:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Actelion: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Efficacy of biologic agents (BA) in metastatic, triple-negative breast cancer (TNBC): A systematic review.

e11587 Background: TNBC accounts for about 15% of all invasive breast cancers, usually with an aggressive behavior and poor prognosis also because of lack of standard-of-care therapy. In this setting, BA in combination with chemotherapy (CT) may have a role, also based on TNBC cellular specific targets. Methods: To assess the role of BA in metastatic TNBC, a systematic review of randomized controlled trials published from January 2006 to January 2011 and of communications presented at ESMO, ASCO and SABCS congresses in 2009 and 2010 was performed. Only studies comparing BA+CT versus CT alone in TNBC, or in unspecified advanced breast cancer but presenting data on TNBC subgroup, were considered. The relevant statistical variables for the pooled analysis were the log of hazard ratio (HR) and relative variance for progression-free survival (PFS) and overall survival (OS). Results: Out of 346 Pubmed publications and 126 studies registered on http://clinicaltrial.gov, 8 trials were selected for analysis. A total of 3463 patients were analyzed: 1286 of them were TNBC patients. BA studied were: bevacizumab (Miles 2010, Brufsky 2010 and Gray 2009), lapatinib (Finn 2009), iniparib (O'Shaughnessy 2011), sunitinib (Curigliano 2010), sorafenib (Gomez 2010) and cetuximab (Baselga 2010). A PFS improvement was detected in the group of pts receiving BA, with a relative risk reduction of 27% (95% CI: 18%-35%). I2 statistic for quantifying heterogeneity among class of BA [1) anti-angiogenic, 2) EGFR inhibitors 3) Parp Inhibitors] was 43.8%; only class 1 and 3 showed a statistically significant improvement in PFS. No effect on OS was observed. Conclusions: In our systematic review we detected: 1. Improvement of PFS in TNBC pts treated with BA+CT vs CT alone. 2. No single BA class showed a statistically significant superiority over others, however for EGFR inhibitors no statistically significant difference was reached. 3. The effect of BA on OS hasn't been demonstrated, similarly in the general population with non-TNBC advanced breast cancer.

Transcriptional Gene Silencing as a Genetic Therapy for HIV-1

The discovery of RNA interference (RNAi) has resulted in a new class of biological agents that can specifically downmodulate HIV-1 gene expression. Delivery of these RNAi-based agents and the emergence of viral resistance present pressing issues in the use of RNAi in a genetic-based therapy for HIV-1. Here, we discuss a potential avenue around viral resistance and a targeted delivery scheme for treating HIV-1-infected individuals involving transcriptional gene silencing. Specifically, the use of small antisense RNAs targeted to the viral promoter regions and delivery by lentiviral-based mobilization-competent vectors expressing these promoter targeted RNAs may prove therapeutically relevant in a genetic therapy-based approach to treating HIV-1 infection.

Monoclonal antibodies: Pharmacological relevance

Monoclonal antibodies (MAbs), a new class of biological agents, are used these days in therapeutics and diagnosis. MAbs also labeled as 'magic bullets', are highly specific antibodies produced by a clone of single hybrid cells formed in the laboratory by fusion of B cell with the tumor cell. The hybridoma formed yields higher amount of MAbs. MAbs can be produced in vitro and in vivo . Animals are utilized to produce MAbs, but these antibodies are associated with immunogenic and ethical problems. Of late, recombinant DNA technology, genetic engineering,phage display and transgenic animals are used to produce humanized MAbs or pure human MAbs, which have fewer adverse effects. MAbs alone or conjugated with drugs, toxins, or radioactive atoms are used for treatment of cancer, autoimmune disorders, graft rejections, infectious diseases, asthma, and various cardiovascular disorders. New MAbs are being developed which are more specific and less toxic.

Development of a recombinant growth factor and fusion protein: lessons from GM-CSF.

Several colony stimulating factors (CSFs) and cytokines have been successfully used to mobilize hematopoietic cells during myeloablative therapy, bone marrow failure, and transplantation and to provide supportive treatment during sepsis. The use of yeast-derived recombinant human granulocyte-macrophage CSF (rhuGM-CSF) and its interleukin-3 fusion protein, PIXY321, provides an example of issues associated with development programs for recombinant hematopoietic growth factors. Species specificity of rhuGM-CSF, different bioactivity of homologous molecules in mice, and production in laboratory animals of antibodies to human proteins limit preclinical evaluation of such molecules. In clinical trials, rhuGM-CSF was efficacious and well tolerated. The derivation of the recombinant molecule, optimal dosing, scheduling, and confounding effects of concurrent disease and treatments are factors that influence efficacy, adverse responses, and immunogenicity reported in patients treated with CSFs. In comparisons of yeast-derived with Escherichia coli-derived rhuGM-CS, the reduced severity and frequency of all adverse events, preponderance of low-grade adverse events, and similarity of positive clinical response versus adverse events reported for granulocyte CSF support safety and efficacy of yeast-derived rhuGM-CSE Enhanced pharmacoeconomic evaluations are beginning to limit and redirect clinical applications in this class of biological agents.

A phase I trial of intraperitoneal recombinant gamma-interferon in advanced ovarian carcinoma.

The interferons are a class of biological agents that have demonstrated antineoplastic activity in a variety of tumors both in vitro and in vivo. Previous reports have suggested that interferons can be safely administered by the intraperitoneal (IP) route with a pharmacokinetic advantage for peritoneal cavity exposure compared with the systemic circulation and with objective antitumor activity being demonstrated. On the basis of these reports and laboratory data suggesting activity for recombinant gamma-interferon (r-GIFN) against several malignant cell lines, we treated 27 refractory ovarian carcinoma patients, including six with very-small-volume residual disease, with this agent delivered by the IP route. While r-GIFN was found to be remarkably well tolerated, with a 150- to 200-fold pharmacokinetic advantage for peak levels achieved in the peritoneal cavity compared with the plasma, no objective responses were observed. Despite the lack of demonstrated activity for single-agent IP-administered r-GIFN in this clinical setting, there remains considerable interest in this agent when delivered by the IP route because of in vitro data suggesting concentration-dependent synergy between r-GIFN and other biological agents.