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Cross-reactivity studies

The affinity and cross-reactivity of the whole serum and Fab fragments were determined using equilibrium dialysis for the affinity determination and RIA for the cross-reactivity studies. The average intrinsic affinity constant (Ko) of the antibody (Nisonoff and Pressman 1958) changed very little throughout the... [Pg.129]

RIA-Specificity The specificity of the antiserum initially is evaluated by cross-reactivity studies involving all the flurazepam metabolites known to be present in plasma. The mono-as well as di-desethylmetabolites exhibited a cross-reactivity of 17 and 3.7% respectively, while other possible competitors cross-reacted less than 1% as shown in Table 32.1. [Pg.497]

Tissue cross-reactivity studies for monoclonal antibody products were originally intended to explore off-target tissue binding. Studies have thus been used to screen candidates to avoid off-target binding. As stated in ICH S6, an animal species that does not express the desired epitope may be of some relevance for assessing toxicity if comparable unintentional tissue cross-reactivity to... [Pg.55]

In vitro Studies Table 5.3 shows the in vitro preclinical studies conducted for the 34 biopharmaceuticals. Most were in vitro genotoxicity studies that are not required by the ICH S6 guideline. This is not the case of poor understanding of the ICH S6. In vitro genotoxicity studies are usually conducted at the early stage of development. Almost all the in vitro genotoxicity studies examined by the JPMA survey in 2001 were conducted before the ICH S6 notification. The cross-reactivity studies were used to understand interspecies reactivity to a biopharmaceutical, especially in case of antibodies. [Pg.98]

Chromosomal aberration test Mouse lymphoma TK test Cross reactivity study... [Pg.99]

This chapter will discuss various experimental approaches used to select the relevant species for conduct of toxicology studies for biopharmaceuticals, as well as highlight advances made in scientific approaches and technologies to facilitate this process. Methods discussed include the traditional immunohisto-chemistry and tissue cross-reactivity studies, flow cytometry, protein sequencing, and functional in vitro assays, as well as newer approaches such as utilization of microarray databases for genomic mRNA expression data and use of transcript profiling studies as an adjunct to functional assays, to understand similarity in pharmacological responsiveness between animals and humans. [Pg.182]

An example of results from a tissue cross-reactivity study comparing binding of a monoclonal antibody therapeutic to human, cynomolgus monkey, and mouse tissues is shown in Table 9.2. A cell line that did not express the target was used as negative control tissue the same cell line transfected with the... [Pg.192]

TABLE 9.2 Cross-species tissue cross-reactivity study of a monoclonal antibody... [Pg.193]

Tissue Cross-Reactivity Studies for Monoclonal Antibodies Predictive Value and Use for Selection of Relevant Animal Species for Toxicity Testing... [Pg.207]

Biological Relevance of Human Tissue Cross-Reactivity Studies 233... [Pg.207]

TISSUE CROSS-REACTIVITY STUDIES FOR MONOCLONAL ANTIBODIES... [Pg.208]

As mentioned earlier, the purpose of this review is not to detail the actual methods used for tissue cross-reactivity studies but rather to highlight the many important factors that must be taken under consideration during the conduct, evaluation, and regulatory review and of the study. Specific details for tissue collection, generation of control materials, and staining procedures themselves are readily available in the literature. [Pg.215]

Human Tissues According to the Points-to-Consider and other regulatory documents, tissues from at least three unrelated human donors should be evaluated in a tissue cross-reactivity study in order to screen for individual variation. In a 3-donor, 37-tissue cross-reactivity study, up to 111 different donors could theoretically be represented. To the extent possible, both males and females should be equally represented. [Pg.216]

Tissue banks are the most common source of human tissues. While surgical biopsy accessions are preferred, they are limited in availability and often unavailable for many tissues (e.g., brain and other vital organs). Therefore the majority of tissue samples used in cross-reactivity studies are those acquired at autopsy. For autopsy accessions all efforts must be made to minimize the time interval between death and tissue collection. Information provided with specimens generally includes age, gender, and usually race and some clinical history and/or cause of death. As suggested in the Points-to-Consider document, the tissues used in a standard tissue cross-reactivity study are acquired from adults (>18 years of age). Pediatric tissues are often very difficult to obtain and are usually not used in a standard tissue cross-reactivity study unless there is a clear pediatric indication for the test article. [Pg.216]

The following factors should be considered when choosing a staining method for a tissue cross-reactivity study (1) test article forms that are available, (2) test article affinity, (3) proposed plasma level for clinical studies, (4) epitope stability, and (5) ability to scale up the method to stain a large number of tissues. These various issues are addressed below. [Pg.220]

As mentioned earlier, there are other ways to label antibodies for use in tissue cross-reactivity studies. Detailed discussion of various labels and staining methods associated with them are beyond the scope of this review. However,... [Pg.221]

Proposed Plasma Level for Clinical Studies The tissue cross-reactivity study is an immunohistochemistry assay, which, because of its nature, does not replicate the conditions obtained in vivo. Moreover, one is looking at tissue sections where the cells are cleaved and all portions of the tissues and cells (membrane, cytoplasm, and nucleus) and surrounding milieu are exposed to the same concentration of the antibody, which is different from the intravascular and perivascular concentrations observed in vivo (see below). Since buffers, protein types, and electrolytes also differ in vivo compared to the immunohistochemistry conditions, one cannot expect to attain high concentra-... [Pg.222]

Staining adequacy is addressed by staining replicate cryosections from each tissue for an antigen known to be expressed on components common to all tissues (e.g., CD31, [T-microglobulin, transferrin receptor), as discussed previously. This ensures that the tissue can be stained using immunohistochemical methods and thus is a suitable sample for the tissue cross-reactivity study. [Pg.226]

We have reviewed information from 161 typical cross-reactivity studies conducted by PAI-CRL.3 These studies were selected from more than approximately 800 studies conducted between 1990 and 2006. The information is presented as percentages of total, but it is important to note that the percentages may exceed 100% as not all the studies had identical study design. For example, several studies included more than one test article, but the calculations were based on a per study basis. The specific data are proprietary, and only generalities are presented in the summary tables. The types and forms of the test articles and their epitopes are listed in Table 10.3, and the frequency of unexpected cross-reactivity is listed in Table 10.4. [Pg.227]

TABLE 10.3 Test articles examined in 161 PAI-CRL tissue cross-reactivity studies... [Pg.227]


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Cross reactivity

Cross-reactivity studies animal tissue

Cross-reactivity studies antibodies

Cross-reactivity studies concentration selection

Cross-reactivity studies human tissue

Cross-reactivity studies monoclonal antibodies

Cross-reactivity studies preclinical safety evaluation

Cross-reactivity studies staining methods

Cross-reactivity study procedure

Reactivity studies

Safety pharmacology cross-reactivity studies

Toxicity studies tissue cross-reactivity testing

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