Therapeutic proteins characteristics

A measurable DNA/RNA or protein characteristic that is an indicator of normal biological process, pathogenic process and/or response to therapeutic or other inventions, used as diagnostic and prognostic indicators. 

A prerequisite to pharmacokinetic/pharmacodynamic studies is the availability of a sufficiently selective and sensitive assay. The assay must be capable of detecting and accurately quantifying the therapeutic protein in the presence of a complex soup of contaminant molecules characteristic of tissue extracts/body fluids. As described in Chapter 7, specific proteins are usually detected and quantified either via immunoassay or bioassay. Additional analytical approaches occasionally used include liquid chromatography (e.g. HPLC) or the use of radioactively labelled protein. 

Pharmacokinetic and indeed pharmacodynamic characteristics of therapeutic proteins can be rendered (even more) complicated by a number of factors, including ... 

Differences in post-translational modification (PTM) detail. Human therapeutic proteins produced in several recombinant systems (e.g. yeast-, plant- and insect-based systems Chapter 5) can display altered PTM detail, particularly in the context of glycosylation (Chapter 2). Some sugar residues/motifs characteristic of these systems can be highly immunogenic in humans. 

Table 4.3 Therapeutic proteins engineered in some way in order to alter pharmacokinetic or other pharmacological characteristics. Full details of specific products are provided in the chapter indicated...

As of today, there are no commercially available pharmaceutical products of this technology. The pharmaceutical industry however, is involved in developing nanoparticle-based delivery systems. Use of nanospheres to modify the blood-brain barrier (BBB)—limiting characteristics of the drug enables targeted brain delivery via BBB transporters and provides a sustained release in brain tissue and vaccine delivery systems to deliver therapeutic protein antigens into the potent immune cells are under investigation.103... 

There are two mechanisms by which therapeutic proteins induce antibodies the classical activation of the immune system by foreign proteins and the breaking of B cell tolerance by human proteins. The two mechanisms differ in time of onset and response level as we have described extensively previously [2]- Also the immunological mechanisms behind the two types of immune activation differ fundamentally and therefore also the characteristics of the product that are involved in induction of antibodies. 

Gender, age, and ethnic background have all been reported to influence the incidence of antibody response to specific therapeutic proteins. However, the only patient characteristic that consistently has been identified for a number of different products is the disease that the patients suffer from. Cancer patients are less likely to produce antibodies to therapeutic protein than other patients. The most widely accepted explanation for this difference is the immune-compromised state of cancer patients, both by the disease as by anticancer treatment. Also the median survival of patients on treatment by therapeutic proteins may be too short to develop an antibody response. In any case, cancer reduces the probability of an antibody response to a protein considerably. 

Key Requirements to Consider Before Preformulations and Formulations of Biopharmaceuticals Begin Applied formulation scientists today face formidable challenges in their quest to formulate stable recombinant protein therapeutics. Proteins possess unique characteristics. We are dealing with very... 

Given the complexities of the pharmacology and pharmacokinetics of therapeutic proteins, the effect of race would not be expected to be important. There is no known difference between racial characteristics that would cause additional PK variability. Attempts have been made to examine the effect of race as a covariate, but it has only rarely been identified once patient weight or sex and other covariates (particularly those related to disease) were taken into account. Such was the case for cetuximab (70). 

Tliis provides mechanisms for producing therapeutic proteins and for the modification of production chaiacteristics. Efforts to introduce specific characteristics which involve the integration of additional with existing biochemical pathways and homeostasis require higher levels of transcriptional and translational control. ... 

Many factors influence the immune response induced by therapeutic proteins. These can be divided into product, patient, and treatment characteristics, and several factors are still unknown. 

Also the treatment characteristics can have an influence on the immunogenicity of therapeutic proteins. Usually antibodies are only induced after prolonged treatment of the protein. The intramuscular (i.m.) route of administration is less immunogenic than subcutaneous (s.c.) administration. Intravenous (i.v.) administration usually is the least immunogenic route of administration. 

Little, if any, of the expertise, analytical methods and in-house standards, specifics of the production process, historical process, and validation data or full characterization data required for comparability assessment of therapeutic proteins are available in the public domain. As a rule, they are proprietary knowledge. It is inconceivable, in most cases, that another manufacturer, on the basis of the patent or published data, is able to manufacture a protein pharmaceutical that can be assumed similar enough to the original innovative product that only a limited documentation of physico-chemical characteristics would be sufficient to show equivalence. In most cases only limited data are available in pharmacopoeial monographs and scientific papers. Moreover, even the most sophisticated analytical tools are not sensitive enough to fully predict the biological and clinical characteristics of the product. 

A biosimilar is dehned as any therapeutic protein by its own manufacturing process that may influence the characteristics of the product itself but also introduce specihc process-related impurities. The producers of biosimilars therefore need to demonstrate consistency and robustness of their production process. They need to do formulation studies showing stability and compatibility, even if the formulation is identical to the reference product. 

The companies marketing biosimilars will need to show their capacity to manage postmarketing protocols, not only to monitor rare side effects but also because the biological and clinical characteristics of therapeutic proteins cannot be completely predicted by physico-chemical analyses, and possible batch-associated side effects need to be identihed. 

An easily recognized phenotypic characteristic can be coexpressed in an engineered product (e.g. tomatoes that contain a therapeutic protein can be selected to grow in a colorless variety of fruit). 

Apart from polyplexes, various nanoscale assemblies of cationic polysaccharides are also proposed to promote the surface-mediated delivery of DNA to cells. These approaches are classified into one of two broad categories (i) methods based upon the physical adsorption of preformed polyplex on polymeric surfaces like PLGA or collagen films and these polyplex functionalized films promoted surface-mediated transfection of cells in vitro and in vivof (ii) methods for layer-by-layer adsorption of DNA and cationic polymers on surfaces to fabricate multilayered thin films. Recently, degradable carbohydrate-based nanogels were proposed for codelivery of pDNA and therapeutic proteins. These systems were designed to possess stimuli-sensitive characteristics where the temperature-sensitive property of nanogels allowed the facile encapsulation of biomaterials, while... 

---