Cd 2 T3 Cd C

aApproved by Germany. bApproved by China.

Abbreviations-. CD, cluster of differentiation; HER2, human epidermal growth factor receptor 2; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; Ig, immunoglobulin; Fab, fragment antigen binding; TNF, tumor necrosis factor; RSV, respiratory syncytial virus. Source: From Refs. 10-14.

18 Boswell et al.

TABLE 2 In Vitro and In Vivo Methods Used in Preclinical Studies of Antibody Therapeutics

In Vitro Methods

Antigen identification and quantification on target cells Normal tissue screen Evaluation of target specificity Immunoreactivity/avidity binding constant Potency assay (e.g., cytotoxicity, etc.)

Fc receptor binding affinity (e.g., FcRn, FcgR) Target antigen-binding affinity Cellular metabolism studies

In Vivo Methods

Pharmacokinetics studies

Target/tissue distribution studies Dosimetry studies Toxicology studies

Assessment of toxicological model validity (target homology, expression, distribution) Metabolism studies

Imaging studies in animal disease model Determination of circulating antigen content Therapy studies in animal disease model

Abbreviations: FcRn, neonatal fragment crystallizable receptor; FcgR, fragment crystallizable g receptors.

numerous combinations of these parameters, we will simplify the presentation by organizing topics primarily on the basis of the in vitro data. Specific and recent examples of cited correlative studies involving both naked Abs and radioimmunoconjugates may be found throughout these various sections. In addition, we will explore in detail correlative studies involving selected Abs conjugated to potent cytotoxic drugs termed antibody-drug conjugates (ADCs). These armed immunoconjugates possess unique properties and are designed to achieve excellent localization of a small-molecule drug at the desired site to optimize the therapeutic effect of the agent.

This chapter appears to be one of the first attempts at summarizing the available PK, PD, and metabolism information in the exciting area of IVIVC of mAbs. Despite the apparent slow progress in this area, the corresponding success for SMD illustrates the potential benefit of using these IVIVC tools to drive toward a better mechanistic understanding of the PK, PD, and metabolism of mAbs as well as to accelerate the drug discovery and development processes, in particular the selection of successful drug candidates.

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