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A mechanistic compartmental model for total antibody uptake in tumors.

ABSTRACT: Antibodies are under development to treat a variety of cancers, such as lymphomas, colon, and breast cancer. A major limitation to greater efficacy for this class of drugs is poor distribution in vivo. Localization of antibodies occurs slowly, often in insufficient therapeutic amounts, and distributes heterogeneously throughout the tumor. While the microdistribution around individual vessels is important for many therapies, the total amount of antibody localized in the tumor is paramount for many applications such as imaging, determining the therapeutic index with antibody drug conjugates, and dosing in radioimmunotherapy. With imaging and pretargeted therapeutic strategies, the time course of uptake is critical in determining when to take an image or deliver a secondary reagent. We present here a simple mechanistic model of antibody uptake and retention that captures the major rates that determine the time course of antibody concentration within a tumor including dose, affinity, plasma clearance, target expression, internalization, permeability, and vascularization. Since many of the parameters are known or can be estimated in vitro, this model can approximate the time course of antibody concentration in tumors to aid in experimental design, data interpretation, and strategies to improve localization.

SUBMITTER: Thurber GM

PROVIDER: S-EPMC3729444 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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A mechanistic compartmental model for total antibody uptake in tumors.

Thurber Greg M GM Dane Wittrup K K

Journal of theoretical biology 20120906

Antibodies are under development to treat a variety of cancers, such as lymphomas, colon, and breast cancer. A major limitation to greater efficacy for this class of drugs is poor distribution in vivo. Localization of antibodies occurs slowly, often in insufficient therapeutic amounts, and distributes heterogeneously throughout the tumor. While the microdistribution around individual vessels is important for many therapies, the total amount of antibody localized in the tumor is paramount for man ...[more]

PMID: 22974563

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Project description:Kinetic parameters describing hepatic uptake in hepatocytes are frequently estimated without appropriate incorporation of bidirectional passive diffusion, intracellular binding, and metabolism. A mechanistic two-compartment model was developed to describe all of the processes occurring during the in vitro uptake experiments performed in freshly isolated rat hepatocytes plated for 2 h. Uptake of rosuvastatin, pravastatin, pitavastatin, valsartan, bosentan, telmisartan, and repaglinide was investigated over a 0.1 to 300 ?M concentration range at 37°C for 2 or 45-90 min; nonspecific binding was taken into account. All concentration-time points were analyzed simultaneously by using a mechanistic two-compartment model describing uptake kinetics [unbound affinity constant (K(m,u)), maximum uptake rate (V(max)), unbound active uptake clearance (CL(active,u))], passive diffusion [unbound passive diffusion clearance (P(diff,u))], and intracellular binding [intracellular unbound fraction (fu(cell))]. When required (telmisartan and repaglinide), the model was extended to account for the metabolism [unbound metabolic clearance (CL(met,u))]. The CL(active,u) ranged 8-fold, reflecting a 11-fold range in uptake K(m,u), with telmisartan and valsartan showing the highest affinity for uptake transporters (K(m,u) <10 ?M). Both P(diff,u) and fu(cell) span over two orders of magnitude and reflected the lipophilicity of the drugs in the dataset. An extended incubation time allowed steady state to be reached between media and intracellular compartment concentrations and reduced the error in certain parameter estimates observed with shorter incubation times. Active transport accounted for >70% of total uptake for all drugs investigated and was 4- and 112-fold greater than CL(met,u) for telmisartan and repaglinide, respectively. Modeling of uptake kinetics in conjunction with metabolism improved the precision of the uptake parameter estimates for repaglinide and telmisartan. Recommendations are made for uptake experimental design and modeling strategies.

Project description:Introduction: Arthroplasty-associated bone loss remains a clinical problem: stiff metallic implants disrupt load transfer to bone and, hence, its remodeling stimulus. The aim of this research was to analyze how load transfer to bone is affected by different forms of knee arthroplasty: isolated partial knee arthroplasty (PKA), compartmental arthroplasty [combined partial knee arthroplasty (CPKA), two or more PKAs in the same knee], and total knee arthroplasty (TKA). Methods: An experimentally validated subject-specific finite element model was analyzed native and with medial unicondylar, lateral unicondylar, patellofemoral, bi-unicondylar, medial bicompartmental, lateral bicompartmental, tricompartmental, and total knee arthroplasty. Three load cases were simulated for each: gait, stair ascent, and sit-to-stand. Strain shielding and overstraining were calculated from the differences between the native and implanted states. Results: For gait, the TKA femoral component led to mean strain shielding (30%) more than three times higher than that of PKA (4%-7%) and CPKA (5%-8%). Overstraining was predicted in the proximal tibia (TKA 21%; PKA/CPKA 0%-6%). The variance in the distribution for TKA was an order of magnitude greater than for PKA/CPKA, indicating less physiological load transfer. Only the TKA-implanted femur was sensitive to the load case: for stair ascent and gait, almost the entire distal femur was strain-shielded, whereas during sit-to-stand, the posterior femoral condyles were overstrained. Discussion: TKA requires more bone resection than PKA and CPKA. These finite element analyses suggest that a longer-term benefit for bone is probable as partial and multi-compartmental knee procedures lead to more natural load transfer compared to TKA. High-flexion activity following TKA may be protective of posterior condyle bone resorption, which may help explain why bone loss affects some patients more than others. The male and female bone models used for this research are provided open access to facilitate future research elsewhere.

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A mechanistic compartmental model for total antibody uptake in tumors.

Publications

A mechanistic compartmental model for total antibody uptake in tumors.

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