Conclusions

The development and application of IVIVCs for Ab-based therapeutic drugs will continue to represent an exciting area of scientific exploration upon evaluation of numerous drug candidates. Significant breakthroughs in protein engineering technology continue to impact the availability of Ab derivatives beyond those originally identified by the murine immune system, yielding variations in IgG structures, receptor binding affinities, and other critical parameters (24). There are currently more than 100 mAbs in various phases of clinical evaluation for treatment of various disease states. Through the use of radioimmunoconjugates, the coupling of immunotherapy with molecular imaging allows confirmation of the presence of a given target prior to initiation of therapy and permits monitoring of the progress of treatment during the course of therapy (12). In addition, ADCs continue to prove efficacious with acceptable toxicities and will extend our therapeutic range from unconjugated mAbs to a broad array of highly active and specific immunoconjugates (154). Because of this potential diversity in Ab characteristics, IVIVC will prove invaluable in estimating the in vivo behavior (e.g., PK, PD) on the basis of in vitro information (e.g., Fc receptor binding affinity).

The principles involved in developing IVIVCs for Abs are inherently more complex than those needed to establish IVIVCs for SMD. The challenging nature of Ab IVIVC can be explained by the existence of unique interactions between Abs and biological molecules coupled with the structural complexity and diversity of the macromolecules themselves. Because of such complications, more progress is needed to establish predictive IVIVC tools similar to those already existing in the area of SMD.

Continual improvements in the accuracy, sensitivity, and ruggedness of in vitro assays will play an integral role in the evolution of IVIVC for Abs. A major limiting factor in the development of high-throughput assays has been the low number of candidates in preclinical evaluation; however, this number is ever increasing, and the demand for efficient in vitro measurements will likely begin to reflect this trend. In vivo tools will also help drive the use of Ab IVIVCs, especially considering the very rapid growth of the molecular imaging field within the past decade (35). Imaging is especially well suited to clinical applications owing to its noninvasive nature and compatibility with extended dynamic measurements. Specifically, both PET and SPECT may be powerful tools in preclinical drug development by (i) providing therapeutic rationale, (ii) enabling collection of data for rational drug dosing, (iii) permitting verification of binding of a drug to its receptor, and (iv) allowing evaluation of a drug's mechanism of action (155). To summarize, it is likely that the anticipated growth of three fields—Ab engineering, in vitro assay technologies, and in vivo detection methods—will influence the establishment of new IVIVCs for Abs in the near term. The resulting IVIVC data will be valuable in providing mechanistic insight into the relationships that exist between Ab PK, PD, and, ultimately, clinical efficacy.

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