Of Biotechnology Derived Therapeutic Drugs

Bussiere, and Andrea B. Weir 6.2 Regulatory Overview of Biological Therapeutic 6.2.1 ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived 6.2.2 Relevant Animal 6.2.3 Nature of the Test 6.2.4 FDA 6.3 Types of Studies Considered Appropriate for 6.3.1 Safety Pharmacology 6.3.2 Exposure 6.3.3 Single-Dose Toxicity 6.3.4 Repeated-Dose Toxicity Studies 144 6.3.5 Immunotoxicity 6.3.6 Reproductive Performance and Developmental Toxicity Studies 146 6.3.7...

MuocENic Activity of IGF1

In the JECFA safety review,39 information on the mitogenic effects of IGF-1 were considered it is a mitogen for a number of various cell types and has been associated with the growth of tumors, including those of the colon, breast, lung, and osteosar-coma.132-134 The mitogenic effect could also result in proliferative reactions locally in the gut. Thus, orally administered IGF-1 increased the cellularity of the intestinal mucosa of rats in vivo127 and increased the rate of proliferation in...

Food Safety Assessment For Use Of bsT

The use of bST in dairy cows to increase milk production was considered to be controversial by some who were concerned about the safety of its use in food production. Part of this opposition, particularly in Europe, was related to their ban on the use of steroid hormone growth promotants in beef production. Steroid hormones, such as estrogen, have been safely used as growth promotants by cattle farmers in the United States for many years. They improve daily gain and feed efficiency, resulting...

CoLeopteranacnvE Corn Cry3Bb1 and Cry34Ab1Cry35Ab1

The western corn rootworm and the northern corn rootworm (Diabrotica barberi Smith & Lawrence) are important pests of corn in the U.S. Midwest. Corn expressing either Cry3Bb1 or the binary protein Cry34Ab1 Cry35Ab1 is currently available for corn rootworm control. As with the lepidopteran-active Cry1 proteins, assessments of the nontarget effects of Cry3Bb1 by the EPA have focused on confirming the protein's range of toxicity by testing on nontarget species not closely related to corn...

To Modify Endogenous Plant Metabolic Pathways

Modulation of regulatory control proteins and regulatory processes has occurred during plant domestication through both natural and selected breeding of improved crop varieties.128131 For example, the changes responsible for improved wheat yields as part of the green revolution involved selection for mutant Reduced height-1 genes through conventional breeding.132 The proteins encoded by these genes are regulators of endogenous gene transcription that make wheat plants insensitive to giberellin,...

Summary of safety assessments on proteins

As discussed earlier, the oral bioavailability of digestible proteins is negligible, thus their potential to exert systemic adverse effects, if such activity were to be characteristic, is also very low. As a consequence, there is not normally the scientific case to subject proteins screened for introduction into food and feed crops to the same extensive battery of safety tests required for low-molecular-weight chemicals that end up in food or feed. As discussed in preceding chapters, no...

Summary and conclusions

Here we present a scheme for describing the life cycle of bacterial protein toxins and a framework for studying the energetics of the conformational changes required for their mode of action. The coupling of structural and molecular biology with thermodynamics allows one to paint a detailed picture of the function of bacterial toxins which can be leveraged to create novel toxins that may be used in crop protection, therapeutic protein discovery, biodefense, biosensor nanotechnology, etc. Figure...

Epidemiology of Human Populations Exposed to Aerial Bt Sprays

Shortly after the use of Bt insecticides became common in forestry, several large-scale epidemiological studies were conducted on human populations exposed to commercial formulations of Btk. In these studies, exposure of humans to Bt formulations was confirmed by a variety of techniques, including nose swabs, but there were no adverse effects attributable to the exposure in the populations exam-ined.83 84 It was later suggested that the low number of reported cases where Bt could have been a...

Protein Structure

Chymotrypsin Structure

The structures that proteins can assume following their synthesis in the cell can be divided into four categories primary, secondary, tertiary, and quaternary. The amino acid sequence of a protein (primary structure) determines the capacity of a protein to fold into specific three-dimensional conformations that give the protein its unique structural and functional properties. Primary structure also includes cova-lently interconnected bonds between the sulfhydryl groups of cysteine molecules to...

IGF1 in Milk and Body Fluids39

Gastrointestinal secretions (saliva) Gastrointestinal secretions (gastric juice) Gastrointestinal secretions (pancreatic juice) Gastrointestinal secretions (bile) Gastrointestinal secretions (jejunal chime) Daily production of adult humans It is also produced in the human gastrointestinal mucosa and is found in saliva, bile, and pancreatic secretions.127 Using the average IGF-1 concentrations of the five human gastrointestinal secretions,128 a molecular weight of 7.5 kDa for IGF-1,119 and the...

Establishing the Identity of the Purired Proteins of Interest

The primary amino acid sequence of the protein determines its secondary and tertiary structure and, therefore, the protein's biological activity. The information about amino acid sequence is usually deduced from the nucleotide sequence and consequently confirmed by N-terminal sequencing and peptide fingerprinting. N-terminal sequencing is based on Edman degradation chemistry, which allows the ordered amino acid composition of a protein's N-terminus to be confirmed. Usually up to 15 amino acids...

Current Allergy Assessment Process

Because potential allergens cannot at present be accurately identified based on a single characteristic, the allergy assessment testing strategy, as originally proposed by the U.S. Food and Drug Administration (FDA) in 1992 and further modified by the Food and Agricultural Organization of the United Nations and World Health Organization (FAO WHO) and the U.S. Codex Office, Food Safety and Inspection Service, U.S. Department of Agriculture (Codex) scientific panels,1518 recommends that all...

Protein Functions Plants

Proteins also comprise a significant percentage of the plant cell by weight it has been estimated that a typical plant cell contains 5000 to 10,000 different polypeptides and millions of individual protein molecules.7 Some proteins are structurally and or functionally related to mammalian proteins as they fulfill similar biochemical roles in the plant cell. Examples of biological functions fulfilled by proteins within plant cells are as follows Structural structural proteins maintain the...

Conclusions

The primary goal of the protein allergenicity assessment process is characterization of transgenic proteins prior to their inclusion in foods so that risk of allergenic protein exposure remains low. An excellent example of the success of this process was the proposed transfer of a Brazil nut 2S albumin encoding gene into soybean in an attempt to improve nutritional quality.68 Because the Brazil nut was a known allergenic food, the 2S albumin was assessed for its potential allergenicity. Using...

Immunogenicity of biological products

Overall, it is accepted that the administration of an exogenous protein to animals or humans has the potential to elicit an antibody response against the protein if the immune system recognizes the protein as foreign. Immunogenicity is a unique property of biological therapeutics that distinguishes biologicals from traditional small-molecule drug products. An immune response to a biological drug can occur in nonclinical animal species or in clinical trial subjects and patients, and the more the...

Long Introduction To Food Poisoning

Since World War II, synthetic organic insecticides have been used extensively throughout the world for controlling insects and mites that attack crops. Hundreds of millions of pounds of these chemicals are still used annually and have enabled production of a bountiful food supply in most countries. Despite continuing use, the detrimental effects of these chemicals on nontarget vertebrate and invertebrate populations have been recognized for decades. Moreover, the public is now more concerned...

Role of the Acute Mouse Gavage study to Assess Protein safety

Although the vast majority of proteins that are present in our diet do not pose any hazard to human health, a small number of proteins are toxins. Proteins that are toxic usually act via acute mechanisms almost immediately upon consumption.42,43 Hence, evaluation of protein toxicity through acute administration of a single high dose of the protein is considered to be an appropriate test. An additional advantage of the oral gavage (in comparison, for example, with intravenous administration) is...

Framework for Conducting Protein Intake Assessments

There is no recognized standard process for selecting appropriate screening and or refined methods for estimating protein intakes. However, a good framework would include initial tiers that review existing assessments and that use screening methods that are quick and easy to conduct. To facilitate the discussion, a three-step framework is proposed, along with examples of results that would be obtained using a typical analysis in each step. An Example Intake of an introduced protein expressed in...

Contents

4.2 Commercial History of Plant Insecticidal 4.3 Framework for Ecological Safety Assessment of Insecticidal Proteins 105 4.4 Regulatory Perspective on Insecticidal Protein Ecological Safety 107 4.5 Problem Formulation Characterization of the Nature of Insecticidal Proteins and Their Anticipated Ecological 4.6 Characterization of Exposure and Effects of Insecticidal Proteins on Nontarget 4.6.1 Lepidopteran-Active Corn Cry1Ab and 4.6.2 Coleopteran-Active Corn Cry3Bb1 and Cry34Ab1 Cry35Ab1 113...

Commercial Bt Strains as a Putative Cause of Food Poisoning

Commercial strains of Bt used in pest and vector control, such as Btk and Bti, are all sibling species of B. cereus. Years after many products employing these strains were registered as the active ingredients of commercial insecticides, B. cereus was shown to be a relatively minor cause of food poisoning events in humans the poisoning due to protein toxins produced during vegetative growth. The only consistent phenotypic difference between B. cereus and Bt is that the latter species produces...

Alternative approaches employed for the safety assessment of biologicals

In certain cases, alternative approaches to evaluating safety in a pharmacologically relevant standard model must be used for the safety assessment of biologicals. These cases include, but are not limited to, the clinical product being active in only humans the clinical product being active only in humans and chimpanzees or the clinical product being active in at least one species of laboratory animal, but with immuno-genicity-imposed limitations on the ability to conduct a thorough safety...

Protein degradation in the cell

Proteins produced in cells have a finite life depending, in part, on their function in the cell. Some proteins do not fold properly during or after synthesis on the ribo-some, or are unfolded later due to environmental stresses such as heat, and others fail to link up with a partner subunit in a larger protein complex. When this occurs, there is often an exposed area of hydrophobic amino acids on the surface of the protein, which is a signal that the protein is defective. The protein is marked...

Safety of Bt Corn to Nontarget Invertebrates

To turn to corn, one of the first studies followed up on previous studies of Bt corn carried out in Iowa. In the new studies, the effect of Cry1Ab corn on the target pest, the European corn borer (O. nubilalis), and several generalist insect predators and one parasitic wasp (a specialist on this pest) were carried out in Iowa over a two-year period (1997-1998).117 The predators included two beetle species along with the lacewing (C. carnea) and a heteropteran. The hymenopteran parasite was...

Protein synthesis

Although there is considerable diversity in the kinds of proteins produced in animal and plants cells, all of these proteins are made from the same 20 amino acids common to all living organisms. The template used to make the diverse proteins found in all living organisms resides within the genes present in each organism. In mammalian cells, the DNA is found in the nucleus of each cell. Genes are composed of four different nucleic acids adenine (A), cytosine (C), guanine (G), and thymine (T)....

In Vitro Digestibility Assays

One biophysical aspect shared by many, but not all, food allergens is resistance to pepsin digestion in a low-pH environment. The premise on which this assay is based is that the allergen or fragments of the allergen that contain IgE-binding epitopes must be resistant to digestion in the human gastrointestinal (GI) tract and, thus, be available to interact with immune system cells. Standard laboratory conditions have been described whereby proteins are evaluated for their resistance to pH 1.2-2...

The Safety of Microbial Enzymes Used in Food Processing

5.3 Safety Evaluation 5.4 Evaluating Protein Safety Microbial enzymes used in food processing are not pure substances. Rather, they are complex mixtures that include the desired enzyme as well as other metabolites generated by the production strain, in addition to intentionally added materials such as preservatives and stabilizers. Accordingly, safety evaluation of food enzyme preparations poses special challenges that are not typically encountered with other food ingredients. To address these...

For use in dairy cows

Somatotropin, also known as growth hormone, is a protein produced in the pituitary of vertebrate species that promotes postnatal growth.1 It shares similar tertiary structure to related polypeptide hormones prolactin and placental lactogen.1 The amino acid sequence of somatotropin is similar for nonprimates but has diverged more during vertebrate evolution of primates. The amino acid sequence for primate somatotropin differs by approximately 35 from that of nonprimates such as the bovine.1 bST...

Residues of Sometribove in Meat and Milk of Dairy Cattle

The exogenous administration of commercial doses of sometribove to dairy cows does not produce significantly elevated residues of sometribove in meat due to its susceptibility to enzymatic degradation Table 7.3 . Sometribove was formulated in vegetable oil for subcutaneous injection so that it could be protected long enough from enzymatic degradation in tissues to provide sustained release over a two-week period between injections. Administration of 500 mg sometribove to dairy cows every two...