ДОКЛИНИЧЕСКИЕ И КЛИНИЧЕСКИЕ АСПЕКТЫ РАЗРАБОТКИ БИОМЕДИЦИНСКИХ КЛЕТОЧНЫХ ПРОДУКТОВ

The article reviews literature data on development and clinical use of biomedical cell products (BCPs) — a new class of medicines which could be approved for distribution and use only after their specific activity and safety have been thoroughly examined at the stage of experimental research. The article describes main characteristics of BCPs approved in the Russian Federation, as well as specific aspects of their formulation and use. It analyses the main stages of preclinical studies (requirements for animal models, testing of general toxicity, immunogenicity, oncogenicity, tumorigenicity, etc.) that do not cover medicine quality evaluation. The article also dwells upon requirements for the clinical stage of BCPs development. It was shown that the choice of clinically relevant efficacy and safety endpoints could be substantiated by respective preclinical data and accumulated experience of the clinical use of medicines for a particular condition.Проведен обзор данных литературы, посвященных разработке и внедрению в клиническую практику биомедицинских клеточных продуктов (БМКП) — нового класса препаратов, реализация и применение которых возможны при условии подробного изучения их специфической активности и безопасности на этапе экспериментальных исследований. Представлена характеристика основных типов БМКП, разрешенных в Российской Федерации, особенности их состава и практического применения. Проанализированы основные этапы проведения доклинических исследований БМКП (требования к моделям животных, исследование общей токсичности, иммуногенности, онкогенности, туморогенности и др.), не включающие оценку качества препарата. Рассмотрены требования, предъявляемые к клиническому этапу разработки БМКП. Отмечено, что для обоснования выбора клинически значимых конечных точек оценки эффективности и безопасности БМКП могут применяться данные соответствующих доклинических исследований препаратов, а также накопленный опыт клинического применения для изучаемой патологии

“Usage a CRISPR/Cas9-based for obtaining knockouts of economically significant cattle genes”

An experimental work dealing with the gene modification using the Cas9 RNA-based editing system was performed. Point site-specific breakpoints in gDNA were introduced at the zygote stage by microinjection of spCas9 mRNA protein and guide RNAs into the zygote cytoplasm. Oocytes that extruded the first and second polar bodies were used for the injection. 2 series of microinjections of gene editing designs for early bovine embryos were made. The degeneration ranged from 10% to 56% in different groups. A total of 100 injections were performed. Cleavage was started by 78% of the surviving oocytes; 5 embryos reached the blastocyst stage, which was 16% of the number of dividing embryos. All the resulting embryos were analyzed to evaluate the efficiency of editing. gDNA was isolated from all embryos that had reached the blastocyst stage. Using Sanger sequencing of genes of interest in pre-implantation bovine embryos and biopsies from them, it was shown that in 5 out of 17 embryos resulting from microinjections of guide RNA against the BLG gene and SpCas9 mRNA, and in 2 out of 9 embryos after microinjections of guide RNA against CD209 gene and SpCas9 mRNA, the required genome modifications were found. This is indicative of the high efficiency of this delivery method of the editing system

Assessment of biotechnological products specific activity

The review looks into various aspects of assessing specific activity of biotechnological products, which is one of their key quality parameters. Approaches to the analysis of this parameter and the choice of test procedures are governed by the nature and characteristics of a medicinal product. Test procedures should be adequate and have sufficient sensitivity and specificity. Specific activity of the products in question can be assessed by biological methods both in vivo using laboratory animals, which demonstrate the most adequate response to the tested product, and in vitro using sensitive cell lines. Assessment of specific biological activity helps to characterize the product’s pharmacological action and systematically examine the mechanisms of therapeutic effects in clinical practice. Therefore, specific activity of biotechnological products should be assessed using methods appropriate for the proposed mechanism of action. Many biotechnological products, such as cytokine system products, mAbs, fusion proteins and some others call for individual methods for assessment of their specific activity. Biotechnological products are successfully used in the treatment of autoimmune, infectious, oncological, and allergic diseases

PRECLINICAL AND CLINICAL ASPECTS OF THE DEVELOPMENT OF BIOMEDICAL CELL PRODUCTS

The article reviews literature data on development and clinical use of biomedical cell products (BCPs) — a new class of medicines which could be approved for distribution and use only after their specific activity and safety have been thoroughly examined at the stage of experimental research. The article describes main characteristics of BCPs approved in the Russian Federation, as well as specific aspects of their formulation and use. It analyses the main stages of preclinical studies (requirements for animal models, testing of general toxicity, immunogenicity, oncogenicity, tumorigenicity, etc.) that do not cover medicine quality evaluation. The article also dwells upon requirements for the clinical stage of BCPs development. It was shown that the choice of clinically relevant efficacy and safety endpoints could be substantiated by respective preclinical data and accumulated experience of the clinical use of medicines for a particular condition

Особенности определения специфической активности биотехнологических лекарственных средств

The review looks into various aspects of assessing specific activity of biotechnological products, which is one of their key quality parameters. Approaches to the analysis of this parameter and the choice of test procedures are governed by the nature and characteristics of a medicinal product. Test procedures should be adequate and have sufficient sensitivity and specificity. Specific activity of the products in question can be assessed by biological methods both in vivo using laboratory animals, which demonstrate the most adequate response to the tested product, and in vitro using sensitive cell lines. Assessment of specific biological activity helps to characterize the product’s pharmacological action and systematically examine the mechanisms of therapeutic effects in clinical practice. Therefore, specific activity of biotechnological products should be assessed using methods appropriate for the proposed mechanism of action. Many biotechnological products, such as cytokine system products, mAbs, fusion proteins and some others call for individual methods for assessment of their specific activity. Biotechnological products are successfully used in the treatment of autoimmune, infectious, oncological, and allergic diseases.Обзор посвящен вопросам оценки специфической активности биотехнологических лекарственных средств, которая является одним из основных показателей их качества. Подходы к изучению данного показателя и выбор методик зависят от природы и свойств лекарственного препарата. Методики должны быть адекватными и обладать достаточной чувствительностью и специфичностью. Для оценки специфической активности указанной группы лекарственных препаратов могут быть использованы биологические методы исследования как в условиях in vivo на лабораторных животных, характеризующихся наиболее адекватным ответом на исследуемый препарат , так и в условиях in vitro с использованием чувствительных клеточных линий. Оценка специфической биологической активности позволяет охарактеризовать фармакологическое действие препарата и направленно изучить механизмы его терапевтических эффектов при клиническом применении. Поэтому специфическую активность биотехнологических препаратов предпочтительно оценивать с использованием методов, соответствующих предполагаемому механизму действия препарата. Для многих биотехнологических лекарственных средств, включая препараты системы цитокинов, МкАТ, белков слияния/фьюжен белков и др., используются индивидуальные методы оценки специфической активности. Биотехнологические лекарственные препараты успешно применяются для лечения заболеваний аутоиммунной природы, инфекционных, онкологических и аллергических заболеваний