Atemonate and Imuteran: novel Russian monoclonal antibody-based therapeutic agents

The N. Blokhin National Cancer Research Center is one of the few Russian scientific institutions in which hybridoma technology of monoclonal antibody (mAb) production has been successfully established. Using this technology, several dozens of mAbs to various antigens of human leukocytes have been elaborated. These mAbs are widely used for immune status evaluation and for differential diagnostics of leukemias. Two mAbs were used to develop therapeutic drugs. Imuteran is a pharmaceutical form of mAb ICO-25 against a mucin-like antigen of human milk fat globules and proposed for treatment of epithelial cell-originating cancers (breast, intestinal, ovarian, lung cancer, etc.). ThePhase II clinical study of this agent is now nearly completed, and preliminary results suggest Imuteran to be a promising anticancer agent with tumor-stabilizing activity, but patients should be carefully monitored for signs of allergic reactions. mAb ICO-90 against the CD3 antigen of human T lymphocytes was used to develop the therapeutic agent Atemonate proposed for treatment of acute transplant rejection. At present, the Phase II clinical study of this agent is over, and the results confirm the drug safety and efficacy for this indication. The drug is being registered at the Ministry of Healthcare and Social Development, and transfer to serial production is expected shortly.     

Isotope tracing in health and disease

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Opinion: antibody-based therapies for malaria

Antibodies are multifunctional glycoproteins that are found in blood and tissue fluids, and can protect against malaria by binding and neutralizing malaria parasites and preparing them for destruction by immune cells. Important technical advances mean that it is now possible to synthesize antibodies against important Plasmodium antigens that could be used for therapeutic purposes. These reagents could be designed to act like a drug and kill parasites directly, or could be used in vaccine strategies to protect individuals from infection. In this article, we discuss the possible therapeutic uses of antibodies in the treatment and prevention of malaria.     

Transgenic plants for animal health: plant-made vaccine antigens for animal infectious disease control

A variety of plant species have been genetically modified to accumulate vaccine antigens for human and animal health and the first vaccine candidates are approaching the market. The regulatory burden for animal vaccines is less than that for human use and this has attracted the attention of researchers and companies, and investment in plant-made vaccines for animal infectious disease control is increasing. The dosage cost of vaccines for animal infectious diseases must be kept to a minimum, especially for non-lethal diseases that diminish animal welfare and growth, so efficient and economic production, storage and delivery are critical for commercialization. It has become clear that transgenic plants are an economic and efficient alternative to fermentation for large-scale production of vaccine antigens. The oral delivery of plant-made vaccines is particularly attractive since the expensive purification step can be avoided further reducing the cost per dose. This review covers the current status of plant-produced vaccines for the prevention of disease in animals and focuses on barriers to the development of such products and methods to overcome them.     

A novel antibody-based biomarker for chronic algal toxin exposure and sub-acute neurotoxicity

The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins.     

Food technology: challenge for health promotion

The food technology has brought countless benefits to today's food supply. Despite its many positive contributions, it has also brought unintended negative consequences. It is the time to mobilize the food technology to help the food supply more secure, safer and healthier, and here three possible approaches are foreseeable: First, we should continue to improve the conventional technologies. Many wholesome foods have been prepared and preserved using natural materials simply by fermentation. Second, we have to enhance the minimal processing as much as applicable. Third, new ingredients, intelligent packaging and functional foods should be explored to improve food supply and health. Today, consumer interest in the functional foods has been increased tremendously, and the future of food lies in the functional foods. However, the situations in the developing world are different from this. As food resource is limited in this region, food technology has to be emphasized to increase food supply. To help solve such complex problems, not only new technologies, but also conventional technologies have to be mobilized. Simultaneously, even higher technical capabilities have to be built up by applying new findings from the related disciplines to allow the food technology to play its vital role.     

ABAP: antibody-based assay for peptidylarginine deiminase activity

Members of the family of peptidylarginine deiminases (PADs, EC 3.5.3.15) catalyze the posttranslational modification of peptidylarginine into peptidylcitrulline. Citrulline-containing epitopes have been shown to be major and specific targets of autoantibodies produced by rheumatoid arthritis patients. Recently, the citrullination of histone proteins by PAD enzyme was reported to influence gene expression levels. These findings greatly increase the interest in the PAD enzymes and their activities. A few procedures to monitor PAD activity in biological samples have been described previously. However, these assays either have low sensitivity or are rather laborious. Here we describe a reliable and reproducible method for the determination of PAD activity in both purified and crude samples. The method is based on the quantification of PAD-dependent citrullination of peptides, immobilized in microtiter plates, using antibodies that are exclusively reactive with the reaction product(s). Our results demonstrate that this antibody-based assay for PAD activity, called ABAP, is very sensitive and can be applied to monitor PAD activity in biological samples.     

Standardization in animal cell technology

Continuous cell lines offer a level of reproducibility, and thus standardization, which cannot normally be achieved using primary cells. However, even with continuous cell lines adoption of correct cell banking and appropriate quality control procedures are critical to the provision of reliable, reproducible and safe cell stocks. These procedures enable establishment of cryopreserved stocks of pure cultures of correct identity and phenotype which are free from adventitious agents. In addition to quality control techniques, culture conditions and growth medium used often require standardization. In particular different sources of serum, growth factors and cell attachment substrates may lead to significant variation in the ‘performance’ of cell lines. To ensure a high degree of reliability it is essential to obtain cells from authenticated and quality controlled sources. In culture collections, the principles of correct cell banking should be applied with appropriate quality control for which the minimum standard should be confirmation of viability and mycoplasma testing. Such approaches will afford increased confidence in research data and avoid the waste of time and resources which result from the use of cross-contaminated or infected cells. Presented at the FEMS Symposium “Novel Methods and Standardization in Microbiology”, Košice (Slovakia) 1996.     

Impact of genomics on animal agriculture and opportunities for animal health

Livestock production is an important source of animal protein worldwide. In the developed world meat consumption will remain steady but demand is forecast to grow enormously in developing countries. The use of genomics will speed genetic improvement and increase levels of production quickly in the developed world but might face problems in the developing world, including scientific, economic and political challenges. Considerable increases in public and private research funding will be required to develop and utilize novel tools and collections of detailed trait information on appropriate animals. The development of policies protecting the environment and managing all genetic resources will also be needed. Advances in livestock genomics have major implications for increasing food output as well as improving human health.     

Scale-up engineering in animal cell technology: Part I

‘Scale-up’ is sometimes loosely used to describe an increase in production capacity. The purpose of any scale-up procedure is to reproduce a given process on a larger scale and to achieve a predictable process result. Scale-up may, therefore, be defined as the ‘predictable’ (engineered) increase in production capacity. Ideally, what the scale-up engineer would like to do is simulate and predict the performance of a large-scale reactor (e.g. 5000 l reactor volume) using only data from a bench-top vessel (e.g. 5 l volume). In order to do this equations are required that correlate the performance of a reactor with its size.In this review we will address some of the current trends and approaches currently being pursued to establish the basis for such calculations. Most of the correlations in animal cell culture processes are based on laboratory models alone, and still await confirmation of their utility as practical industrial tools. Although development work of this kind is under way within the industry, commercial constraints impede publication.Neither the validity of the theoretical concepts underlying these models nor the various possible reactor designs will be reviewed. Rather we will address the approaches to establishing the numerical tools needed to determine the required reactor design, its subsequent optimization, scale-up and scale-down procedures.     

Scale-up engineering in animal cell technology: Part II

In the first part of this article we defined what is meant by scale-up. We also introduced the idea that engineers, in seeking to scale up bioprocesses, look at parameters that limit that process. If the parameters are independent of scale or reactor configuration they may enable the calculation of engineering data to predict behavior at large scales. In this exercise, dimensional analysis is one of the engineer's most important tools.In Part II, we will examine the application of the approach outlined in Part I to the analysis of scale-up in situations where shear or mass transfer may be limiting factors, situations which are particularly likely to arise in animal cell culture.     

Transgenic animal technology: alternatives in genotyping and phenotyping

Over the past decade, breakthrough technologies in transgenic animal technology and functional genomics have played a central role in the explosive growth of rodent modeling and in scientific innovation. Various noninvasive alternatives to routine surgical biopsy have been described for genotypic and phenotypic analyses of laboratory animals. A number of options are available to refine or replace potentially painful and invasive procedures ranging from tissue biopsies (including tail biopsies and toe docking) to several blood sampling techniques. Unfortunately, adoption of many non- or minimally invasive alternatives has proven difficult on a number of fronts ranging from historical reservations to procedural expectations and actual experimental productivity. Similarly, a variety of phenotyping considerations have addressed throughput efficiencies and the health and well being of research animals. From an animal welfare perspective, marked increases in laboratory animal populations have accompanied rapid advancements spanning the life sciences. As described for rodent modeling, but with applications across many laboratory animal species, diverse procedural refinements are available that will readily aid in the analysis of whole animal models. Ultimately, non-invasive technologies and complementary refinements have bearing on the quality and reproducibility of data that are reported, as well as of critical importance to the well being and ethical management of animals at all developmental stages: from fetal existence, to the neonatal period, and on through adulthood.     

Optimization of vaccine production for animal health

Vaccines on the basis of mammalian cell cultures are of major importance for human and animal health. Therefore efforts are undertaken for the improved production of more effective vaccines. Of course, the main purpose of all these approaches is to save lives and improve the quality of life for human beings. However, there is also some remarkable effort in the food industry and the associated animal production, especially in the case of some Flaviviridal viruses (BVD), where>80% of all cattle herds are found to be infected. These viruses can cause tremendous economic losses of calfs and embryos (Ames, 1990). Because of these facts, there is a continuous endeavour for improving the manufacturing of therapeutics or preventing agents such as vaccines for the treatment of cattle. The competitive economic situation and the specific market demands still require effective and high yield production methods, especially in the case of one of the most widespread viral diseases in cattle like BVD (Ames, 1990).We have succeeded in establishing an improved method for the production of BVD on the basis of a continuous fermentation mode, that consist of modifications of the corresponding process and media improvements.     

动物转基因新技术研究进展

动物转基因技术是21世纪发展最为迅速的生物高新技术之一, 它是指通过基因工程技术将外源基因整合到受体动物基因组中, 从而使其得以表达和遗传的生物技术。动物转基因的关键限制因素是转基因效率和基因表达的精确调控。目前有多种转基因技术, 每一种技术各有其优缺点, 仍然需要进一步研究。随着研究的深入, 转基因技术必将在探讨基因功能、动物遗传改良、生物反应器、动物疾病模型、器官移植等领域有广阔的应用前景。文章综述了近年发展的提高转基因效率的生殖干细胞法、提高转基因精确性的基因打靶法、RNA干扰(RNAi)介导的基因沉默技术和诱导多能干细胞(iPS)转基因技术。新的转基因技术为转基因动物的研究提供了更好的平台, 可以加快促进人类医药卫生、畜牧生产等领域的发展。     

No need for particle tracing: From accumulating fluid properties to novel blood coagulation model in the lattice Boltzmann method

The accumulation of a fluid property from the standpoint of a particle moving with non-steady fluid flow (i.e., platelet/blood-cell damage index in pulsating blood flow) is a challenged computational problem due to the current need for particle-tracing methods. The method we developed (dubbed VPI) enables the approximation of the Lagrangian integral in real-time for any point in space and time for the entire domain and which is easily integrated into the the lattice Boltzmann method. As an illustrative numerical example we applied our method to a blood coagulation model which was shown to accurately capture the coagulation characteristics observed in experiments, and therefore opening a door for more detailed study of systems which are currently hard to study using particle tracing methods.     

Avenues for biofortification of zinc in barley for human and animal health: a meta-analysis

Plant and Soil - Zinc (Zn) deficiency in humans is of worldwide concern and is primarily associated with a plant-based diet of crops grown in Zn-deficient soils. This work explores the effects of...     

Back to the future: antibody-based strategies for the treatment of infectious diseases

Before antibiotics, sera from immune animals and humans were used to treat a variety of infectious diseases, often with successful results. After the discovery of antimicrobial agents, serum therapy for bacterial infections was rapidly forsaken. In the last two decades, problems with treatment of newly emerged, reemerged, or persistent infectious diseases necessitated researchers to develop new and/or improved antibody-based therapeutic approaches. This article reviews some information on the use of antibodies for the treatment of infectious diseases, with special reference to the most seminal discoveries and current advances as well as available treatment approaches in this field.