Integrating antibody–drug conjugate bioanalytical measures using PK–PD modeling & simulation Review
A
B kdeg mAb/ADC kdis Drug Time units
Total antibody (TmAb) Conjugated antibody (CmAb)
C
Unconjugated drug Drug–antibody ratio (DAR)
D Nonspecific uptake ADCFree
Binding Ag
ADC dissociation DrugFree
Drug influx
Drug efflux Extracellular milieu Arbitrary time units
ADC in media ADC in cell pellet
Released drug in cell pellet Released drug in media
Figure 1. In vitro PK of antibody–drug conjugates. (A) Analytes obtained following an in vitro stability experiment of ADC in buffer or plasma. (B) ADC PK model capable of simultaneously characterize all the bioanalytical data obtained from in vitro stability experiment. (C) Analytes obtained from a cellular PK experiment of ADC conducted on target expressing cancer cells. (D) Cellular level systems PK model of ADC that is capable of simultaneously characterizing all the bioanalytical data obtained from a cellular PK study. ADC: Antibody–drug conjugate; Ag: Antigen concentrations on the cell surface; DAR: Drug–antibody ratio; mAb: Antibody.
biological matrix, and traditionally it is believed to represent the tissue concentrations of drugs well. Fol- lowing administration of ADC in animals or human there are multiple formats in which the bioanalytical scientists can measure and report the concentrations of ADC and its components [1]. Which format to choose depends on: the analytical capabilities, ADC characteristics (e.g., cleavable vs noncleavable) and the understanding about which analyte is primarily responsible for the efficacy/toxicity of the ADC. How- ever, it is important to note that till date there is no consensus on which analyte is the best one to correlate with ADC pharmacology. Consequently, the plasma
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concentrations of ADCs and their component are rou- tinely reported in various formats that are shown in Figure 2A. The PK of parent mAb given alone and the PK of
TmAb after ADC administration is compared to find out the extent of alteration in the PK of mAb follow- ing conjugation of the drug. If the difference between the PK of parent mAb and TmAb is substantial, it can be detrimental for the development of ADC. The PK of ADC is routinely reported as CmAb concentra- tions, and it is compared with TmAb PK to find out the stability of linker in vivo. The PK of TmAb and CmAb can be characterized simultaneously using the
www.future-science.com 1635 ADCBound ADCcell Internalization
DrugFree Binding
Degradation + Target
Cell DrugBound
DAR
Arbitrary molar conc. units
Molar conc. units
DAR
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