Animal testing molecular modification

Tissue cross-reactivity studies, although burdensome, provide a rational in vitro assay to determine the range and intensity of distribution of potential epitopes reactive with a monoclonal antibody test article prior to its administration to humans. In addition, cross-reactivity studies provide a useful tool to identify animal species for safety assessment. The cross-reactivity profiles of different species can be compared to the profiles obtained in human tissues. The predictive value of the assay lies in incorporating the characteristics of the monoclonal antibody (isotype, subtype, and other molecular modifications) with the biological activity of the molecule itself, and the potential in vivo distribution of it. 

Since the yields of active dimeric alkaloids from Catharanthus roseus is the lowest of any medicinally useful compounds (yield of VCR == 3 x 10 " %), material for studies of structure-activity relations has been scarce. Nevertheless, such studies were performed with VLB and it has been claimed that some of the products of molecular modification are more active in animal tests than VLB itself. 

Protein Type of ptdymer or modification Molecular mass (kDa) 11/2 t 1/10 Test animal... 

A CCA is intended to work in conjunction with a PBPK as a tool to test and refine mechanistic hypotheses. A molecular model can be embedded in a tissue model which is embedded in the PBPK. Thus, the molecular model is related to the overall metabohc response. The PBPK can be made an exact replica of the CCA the predicted response and measured CCA, response should exactly match if the PBPK contains a complete and accurate description of the molecular mechanisms. In the CCA, aU flow rates, the number of cells in each compartment, and the levels of each enzyme can be measured independently, so no adjustable parameters are required. If the PBPK predictions and CCA results disagree, then the description of the molecular mechanisms is incomplete. The CCA and PBPK can be used in an iterative manner to test modifications in the proposed mechanism. When the PBPK is extended to describe the whole animal, failure to predict animal response would be due to inaccurate description of transport (particularly withiu an organ), inability to accurately measure kinetic parameters (e.g., in vivo enzyme levels or activities), or the presence in vivo or metabohc activities not present in the cultured cells or tissues. Advances in tissue engineering wiU provide tissue constructs to use in a CCA that will display more authentic metaboHsm than isolated cell cultures. 

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