Safety Of Monoclonal Antibodies Research Articles

Reporting, Visualization, and Modeling of Immunogenicity Data to Assess Its Impact on Pharmacokinetics, Efficacy, and Safety of Monoclonal Antibodies.

The rapidly increasing number of therapeutic biologics in development has led to a growing recognition of the need for improvements in immunogenicity assessment. Published data are often inadequate to assess the impact of an antidrug antibody (ADA) on pharmacokinetics, safety, and efficacy, and enable a fully informed decision about patient management in the event of ADA development. The recent introduction of detailed regulatory guidance for industry should help address many past inadequacies in immunogenicity assessment. Nonetheless, careful analysis of gathered data and clear reporting of results are critical to a full understanding of the clinical relevance of ADAs, but have not been widely considered in published literature to date. Here, we review visualization and modeling of immunogenicity data. We present several relatively simple visualization techniques that can provide preliminary information about the kinetics and magnitude of ADA responses, and their impact on pharmacokinetics and clinical endpoints for a given therapeutic protein. We focus on individual sample- and patient-level data, which can be used to build a picture of any trends, thereby guiding analysis of the overall study population. We also discuss methods for modeling ADA data to investigate the impact of immunogenicity on pharmacokinetics, efficacy, and safety.

Preclinical Safety Considerations for Biosimilars

It is now a foregone conclusion that the new frontier of biomedical research lies in biologics, which hold the potential to yield, over time, effective treatments for conditions or diseases hitherto considered incurable or untreatable. On the scale of medical development, biologics are a fairly recent innovation and the majority of them are still under patent protection. The global outlook for biologics is positive and it is estimated that approximately two-dozen biological products with global sales of more than $67 billion will come off patent by 2020. Advances in biotechnology and the end of patent exclusivity have resulted in burgeoning opportunities for cost-effective followon biologics, commonly known as ‘biosimilars’, to enter the market. Unlike generic chemical drugs, biosimilars are similar but not identical to their respective reference innovator products. Even minor changes to the original manufacturing process may result in alterations to the secondary, tertiary, and quaternary structure of the molecule, which may have an impact on the efficacy and safety of the drug in various therapeutic indications and its safety profile in diverse risk populations may be different from that of the innovator product. The assessment of toxicity and safety of monoclonal antibodies (mAbs) becomes more challenging because of the higher complexity and size of these products, giving rise to higher variability. The manufacturing of biosimilar mAbs can lead to differences in glycosylation pattern, resulting in a high level of micro-heterogeneity. In addition, mAbs often have a complex mode of action as they comprise multifunctional molecules with biological properties involving both their Fab and Fc fragments. Many challenges are associated with the approval process of biosimilar mAbs. Read More...

Comparative effectiveness and safety of monoclonal antibodies (bevacizumab, cetuximab and panitumumab) in the treatment of metastatic colorectal cancer: Systematic review and metanalysis.

e15008 Background: Biological agents have presented variable results in the treatment of metastatic colorectal cancer. This study aim to evaluate the effectiveness and safety of the monoclonal antibodies bevacizumab, cetuximab and panitumumab associated or not to chemotherapy in this scenario. Methods: A systematic review and metanaysis was performed based on observational cohort studies published in the following databases: MEDLINE/ Pubmed, LILACS, COCHRANE Library and EMBASE, up to march 2016. The effectiveness outcomes assessed in this trial were overall survival (OS), progression free survival (PFS), pos-progression survival (PPS), response rate based on RECIST criteria and metastasectomy rate. The safety outcome assessed was adverse events. Review Manager 5.3 software was used to perform the data metanalysis and the Newcastle-Ottawa scale evaluated the methodological quality of the observational trials included. Results: 16 trials were included in this metanalysis, 11 evaluating effectiveness and 8 assessing safety. Their methodological quality were considered moderate according to the Newcastle-Ottawa Scale. Basically, this study compared bevacizumab based therapies with no bevacizumab based therapies, once there was no enough data regarding cetuximab and panitumumab. Overall, the group treated with bevacizumab based therapies did better than those in the no bevacizumab group, with OS mean difference (MD) of 4,41 (95% CI 1.75 to 7.07; p = 0.001; I² = 86%) and PFS MD of 3.19 (95% CI 0.42 to 5.96; p = 0,02 I² = 96%). The PPS MD was also statistically significant (MD = 5.90; 95% CI 2.59 to 9.21; p = 0,0005; I² = 82%). When safety was the outcome concerned, the group treated with bevacizumab had more hypertension and gastrointestinal perforation. There was no statistical difference between the groups regarding others side effects. Conclusions: This study showed a potential benefit in using bevacizumab as a part of the treatment of mCRC. Bevacizumab improved PFS, OS and PPS and these differences were statistically significant. However, the drug also increased treatment related toxicities.

The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis

BackgroundMigraine has been recognized as one of the leading causes of disability in the 2013 Global Burden of Disease Study and seriously affects the quality of patients’ life, current treatment options are not ideal. Monoclonal antibodies to calcitonin gene-related peptide and its receptor (CGRP-mAbs) appear more promising for migraine because of considerably better effect and safety profiles. The objective of this study is to systematically assess the clinical efficacy and safety of CGRP-mAbs for migraine therapy.MethodsA systematic literature search in PubMed, Cochrane Library and Baidu Scholar was performed to identify randomized controlled trials (RCTs), which compared the effect and safety of CGRP-mAbs with placebo on migraine. Regarding the efficacy, the reduction of monthly migraine days from baseline to weeks 1–4, 5–8, and 9–12; responder rates were extracted as the outcome measures of the effects of CGRP-mAbs. Regarding the safety, total adverse events, the main adverse events, and other adverse events were evaluated.ResultsWe found significant reduction of monthly migraine days in CGRP-mAbs vs. placebo (weeks 1–4: SMD −0.49, 95% CI −0.61 to −0.36; weeks 5–8: SMD −0.43, 95% CI −0.56 to −0.30; weeks 9–12: SMD −0.37, 95% CI −0.49 to −0.24). 50% and 75% responder rates (OR 2.59, 95% CI 1.99 to 3.37; and OR 2.91, 95% CI 2.06 to 4.10) were significantly increased compared with placebo. There was no significant difference in total adverse events (OR 1.17, 95% CI 0.91 to 1.51), and the main adverse events including upper respiratory tract infection (OR 1.44, 95% CI 0.82 to 2.55), nasopharyngitis (OR 0.59, 95% CI 0.30 to 1.16), nausea (OR 0.61, 95% CI 0.29 to 1.32), injection-site pain (OR 1.73, 95% CI 0.95 to 3.16) and back pain (OR 0.97, 95% CI 0.49 to 1.90) were not obviously changed compared with placebo control, but the results showed significant increase of dizziness in CGRP-mAbs vs. placebo (OR 3.22, 95% CI 1.09 to 9.45).ConclusionsThis meta-analysis suggests that CGRP-mAbs are effective in anti-migraine therapy with few adverse reactions, but more and larger sample-size RCTs are required to verify the current findings.

An overview on safety of monoclonal antibodies.

Biological agents have been a treatment option for many chronic immune-mediated diseases as well as oncological conditions. The issue of infusion reactions is of particular importance and at least in some cases related to the immunogenicity of these drugs with the production of antidrug antibodies. Infectious diseases are a well described side-effect of certain biological agents, even if, at least regarding the biological agents used for the treatment of allergic diseases and immune-mediated diseases, the risk has been reduced. Biological agents clearly impact the physiological functions of the immune system also those connected to immunosurveillance against cancers. This review discusses the safety profile to the main biological agents currently in use in allergic and chronic immune-mediated diseases. By reducing chronic inflammation in immune-mediated diseases, biological agents decrease mortality, cardiovascular events without increasing significantly the risk of cancer. In addition, specific clinical procedure enables the identification of potentially reactive patients and the prevention of acute severe reactions. Overall, the ratio between therapeutic and side-effects is clearly in favor of the former. The safety profile of biological agents is, just as much as their efficacy, one of the fundamental criteria justifying their clinical broad use.

Controlling the time evolution of mAb N-linked glycosylation - Part II: Model-based predictions.

N-linked glycosylation is known to be a crucial factor for the therapeutic efficacy and safety of monoclonal antibodies (mAbs) and many other glycoproteins. The nontemplate process of glycosylation is influenced by external factors which have to be tightly controlled during the manufacturing process. In order to describe and predict mAb N-linked glycosylation patterns in a CHO-S cell fed-batch process, an existing dynamic mathematical model has been refined and coupled to an unstructured metabolic model. High-throughput cell culture experiments carried out in miniaturized bioreactors in combination with intracellular measurements of nucleotide sugars were used to tune the parameter configuration of the coupled models as a function of extracellular pH, manganese and galactose addition. The proposed modeling framework is able to predict the time evolution of N-linked glycosylation patterns during a fed-batch process as a function of time as well as the manipulated variables. A constant and varying mAb N-linked glycosylation pattern throughout the culture were chosen to demonstrate the predictive capability of the modeling framework, which is able to quantify the interconnected influence of media components and cell culture conditions. Such a model-based evaluation of feeding regimes using high-throughput tools and mathematical models gives rise to a more rational way to control and design cell culture processes with defined glycosylation patterns. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1135-1148, 2016.

Effectiveness and safety of monoclonal antibodies for metastatic colorectal cancer treatment: systematic review and meta-analysis.

BackgroundThe effectiveness of chemotherapy (CT) for select cases of metastatic colorectal cancer (MCRC) has been well established in the literature, however, it provides limited benefits and in many cases constitutes a treatment with high toxicity. The use of specific molecular biological treatments with monoclonal antibodies (MA) has been shown to be relevant, particularly for its potential for increasing the response rate of the host to the tumour, as these have molecular targets present in the cancerous cells and their microenvironment thereby blocking their development. The combination of MA and CT can bring a significant increase in the rate of resectability of metastases, the progression-free survival (PFS), and the global survival (GS) in MCRC patients.ObjectiveTo assess the effectiveness and safety of MA in the treatment of MCRC.MethodsA systematic review was carried out with a meta-analysis of randomised clinical trials comparing the use of cetuximab, bevacizumab, and panitumumab in the treatment of MCRC.ResultsSixteen randomised clinical trials were selected. The quality of the evidence on the question was considered moderate and data from eight randomised clinical trials were included in this meta-analysis. The GS and PFS were greater in the groups which received the MA associated with CT, however, the differences were not statistically significant between the groups (mean of 17.7 months versus 17.1 months; mean difference of 1.09 (CI: 0.10–2.07); p = 0.84; and 7.4 versus 6.9 months. mean difference of 0.76 (CI: 0.08–1.44); p = 0.14 respectively). The meta-analysis was not done for any of the secondary outcomes.ConclusionThe addition of MA to CT for patients with metastatic colorectal cancer does not prolong GS and PFS.

Fluorescence dye-based detection of mAb aggregates in CHO culture supernatants

Product yields, efficacy, and safety of monoclonal antibodies (mAbs) are reduced by the formation of higher molecular weight aggregates during upstream processing. In-process characterization of mAb aggregate formation is a challenge since there is a lack of a fast detection method to identify mAb aggregates in cell culture. In this work, we present a rapid method to characterize mAb aggregate-containing Chinese hamster ovary (CHO) cell culture supernatants. The fluorescence dyes thioflavin T (ThT) and 4-4-bis-1-phenylamino-8-naphthalene sulfonate (Bis-ANS) enabled the detection of soluble as well as large mAb aggregates. Partial least square (PLS) regression models were used to evaluate the linearity of the dye-based mAb aggregate detection in buffer down to a mAb aggregate concentration of 2.4μgmL(-1). Furthermore, mAb aggregates were detected in bioprocess medium using Bis-ANS and ThT. Dye binding to aggregates was stable for 60min, making the method robust and reliable. Finally, the developed method using 10μmolL(-1) Bis-ANS enabled discrimination between CHO cell culture supernatants containing different levels of mAb aggregates. The method can be adapted for high-throughput screening, e.g., to screen for cell culture conditions influencing mAb product quality, and hence can contribute to the improvement of production processes of biopharmaceuticals in mammalian cell culture.

Monoclonal Antibodies: A Target Therapy for Multiple Sclerosis

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. It is characterized by a proinflammatory and neurodegenerative process that results in neuroaxonal damage. Over the last two decades, a wide range of immunomodulatory and immunosuppressive treatments have been used for the management of MS. Several treatments have been developed or are under evaluation for reducing relapses, disease progression and long-term MS-related disability. Recently, a growing interest has emerged for therapeutics with very selective actions, particularly monoclonal antibodies, to target several biological pathways involved in MS. To date, only Natalizumab (Tysabri(®)) has been approved for the treatment of active MS forms. Its therapeutic mechanism is the blockade of the a4-integrin molecule of many leukocytes, which leads to a decrease of immune cells migration, in particular of lymphocytes, across the blood-brain barrier. Furthermore, other promising molecules are under study in clinical trials. In this review, we summarize and discuss the history, pharmacodynamics and safety of monoclonal antibodies that have been approved or are under evaluation for the selective treatment of MS.

Monoclonal Antibodies in the Treatment of Multiple Sclerosis

Multiple sclerosis (MS), a chronic demyelinating disorder, is characterized by recurrent neurological deficits or progressive impairment with a high risk of permanent disability. Since the exact pathophysiology and etiology remains still unclear, no curing therapy is currently available. However, several treatments with beneficial effect on relapse rate such as the first line therapies interferon-beta and glatiramer acetate were approved for relapsing-remitting MS. One new important tool in the therapy of MS is the use of monoclonal antibodies. Natalizumab is the first and so far only monoclonal antibody that is approved for MS treatment by the US Food and Drug Administration and the European Medicines Agency. In addition to natalizumab other monoclonal antibodies previously used in cancer and other autoimmune disorders or even newly developed for MS are now being tested in clinical trials. With their high target specificity and efficacy monoclonal antibodies are a promising treatment approach in MS. This review summarizes the present knowledge on the use, effectiveness and safety of monoclonal antibodies in MS treatment.

Les complications « toxiques » liées à l’utilisation des anticorps monoclonaux

The extensive use of therapeutic monoclonal antibodies in clinic has shown that toxic effects may occur in patients. Examples such as muromonab (anti-CD3) and recently TGN1412 (anti-CD28) clearly establish that prediction of toxic effects for these targeted therapies is still complex. These undesirable effects can be classified in four categories: cytokine release syndrome, auto-immune diseases, organ toxicity and opportunistic infections. Immunogenicity, which is highly variable depending on the degree of humanization, could also potentially lead to adverse effects due to immune-complexes formation. The recent accident observed with the anti-CD28 TGN1412 has led to the conclusion that the relative confidence in the safety of monoclonal antibodies should be revised. In addition, the prediction of non-clinical models is rather limited and extrapolation of animal results to the human situation should be performed with caution. A better knowledge of the cellular target of the antibodies and of their mechanisms of action and the identification of risk factors (immune cell activation, wide expression of the target...) should improve the clinical safety of these products. .

Monoclonal antibodies as a strategy for pulmonary diseases.

Monoclonal antibodies have been used successfully to elucidate the roles of putative mediators of pulmonary disease. In particular, clinical trials with monoclonal antibodies directed against interleukin-5, IgE or CD4 yielded results that were critical in dissecting the pathophysiology of asthma; but, more importantly, fundamental changes in the discovery, manufacture and safety of monoclonal antibodies have reinforced the enormous potential of these agents in treating pulmonary diseases. An unprecedented number of monoclonal antibodies are in development for a variety of acute and chronic conditions. Moreover, whereas only two monoclonal antibodies had received regulatory approval from the United States Food and Drug Administration between 1986 and 1997, seven more have received approval since then. Indeed, monoclonal antibody therapy has come of age.

Efficacy and safety of monoclonal antibody purified factor IX concentrate in haemophilia B patients undergoing surgical procedures.

The present study summarizes results of the efficacy and safety of monoclonal antibody (MAb) purified factor IX concentrate [Mononine® Coagulation Factor IX (Human), Centeon L.L.C., King of Prussia, PA, USA] for surgical prophylaxis in 74 patients with mild, moderate or severe haemophilia B who underwent a total of 81 different operative interventions. Surgical procedures included joint replacement/arthroplasty (n= 12), gastrointestinal (GI) or rectal surgery (n= 6), synovectomy/osteotomy (n= 8), hernia repair (n= 4), central catheter insertion (n= 3), ENT surgery (n= 4), dental procedures (n= 14), biopsies (n= 2), gynaecological procedures (n= 4), ophthalmological surgery (n= 4), spinal surgery (n= 4), urogenital surgery (n= 2), other orthopaedic surgery (n= 4) or other miscellaneous procedures (n= 10). All patients demonstrated haemostasis rated as 'excellent' by the investigators. No patients experienced clinically evident thromboembolic complications during treatment with MAb factor IX. These results, from a large and varied random group of patients, demonstrate that this highly purified factor IX concentrate is safe and effective for surgical prophylaxis in patients with haemophilia B, including those patients who have experienced thromboembolic complications during prior treatment with prothrombin complex concentrates.