Abstract
Monoclonal antibodies have provided many validated and potential new therapeutic candidates for various diseases encompassing the realms of neurology, ophthalmology, immunology, and especially oncology. The mechanism of action for these biological molecules typically involves specific binding to a soluble ligand or cell surface protein in order to block or alter a molecular pathway, induce a desired cellular response, or deplete a target cell. Many antigens reside within the interstitial space, the fluid-filled compartment that lies between the outer endothelial vessel wall and the plasma membranes of cells. This mini-review examines the concepts relevant to the kinetics and behavior of antibodies within the interstitium with a special emphasis on radiometric measurement of quantitative pharmacology. Molecular probes are discussed to outline chemical techniques, selection criteria, data interpretation, and relevance to the study of antibody pharmacokinetics. The importance of studying the tissue uptake of antibodies at a compartmental level is highlighted, including a brief overview of receptor occupancy and its interpretation in radiotracer studies. Experimental methods for measuring the spatial composition of tissues are examined in terms of relative vascular, interstitial, and cellular volumes using solid tumors as a representative example. Experimental methods and physiologically based pharmacokinetic modeling are introduced as distinct approaches to distinguish between free and bound fractions of interstitial antibody. Overall, the review outlines the available methods for pharmacokinetic measurements of antibodies and physiological measurements of the compartments that they occupy, while emphasizing that such approaches may not fully capture the complexities of dynamic, heterogeneous tumors and other tissues.
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Abbreviations
- ADME:
-
Adsorption distribution, metabolism, and excretion
- Fc:
-
Crystallizable fragment
- DTPA:
-
Diethylenetriaminepentaacetic acid
- DOTA:
-
1,4,7,20-Tetraazacyclododecane N,N′,N″,N″′-tetraacetic acid
- %ID/g:
-
Percentage of injected dose per gram of tissue
- C tissue :
-
Whole-tissue antibody concentration (μg/mL)
- RO:
-
Receptor occupancy
- AR :
-
Antibody–receptor complex
- R :
-
Free receptor
- A :
-
Free antibody
- k on/k off :
-
Rates of association/dissociation
- K D :
-
Dissociation constant
- CPM:
-
Counts per minute
- V v :
-
Vascular volume
- V i :
-
Interstitial volume
- C b :
-
Concentration of antibody in whole blood
- C tissue, blood-corrected :
-
Blood-corrected tissue concentration
- C i :
-
Concentration of antibody in interstitial fluid
- ϕ:
-
Fractional interstitial volume
- γ :
-
Fractional vascular volume
- k :
-
Rate of extravasation from blood to interstitial space
- L :
-
Rate of lymphatic fluid flow
- K a :
-
Association constant
- B 0 :
-
Total number of binding sites
- RBC:
-
Red blood cell
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ACKNOWLEDGMENTS
The authors would like to thank Ruedi Port, Frank-Peter Theil, Gregory Ferl, and Martin Brechbiel for helpful discussions.
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All authors hold financial interest in Hoffmann-La Roche.
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Guest Editors: Craig Svensson, Joseph Balthasar, and Frank-Peter Theil
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Boswell, C.A., Bumbaca, D., Fielder, P.J. et al. Compartmental Tissue Distribution of Antibody Therapeutics: Experimental Approaches and Interpretations. AAPS J 14, 612–618 (2012). https://doi.org/10.1208/s12248-012-9374-1
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DOI: https://doi.org/10.1208/s12248-012-9374-1