Practical theoretic guidance for the design of tumor-targeting agents - PubMed (original) (raw)

Practical theoretic guidance for the design of tumor-targeting agents

K Dane Wittrup et al. Methods Enzymol. 2012.

Abstract

Theoretical analyses of targeting agent pharmacokinetics provides specific guidance with respect to desirable design objectives such as agent size, affinity, and target antigen. These analyses suggest that IgG-sized macromolecular constructs exhibit the most favorable balance between systemic clearance and vascular extravasation, resulting in maximal tumor uptake. Quantitative predictions of the effects of dose and binding affinity on tumor uptake and penetration are also provided. The single bolus dose required for saturation of xenografted tumors in mice can be predicted from knowledge of antigen expression level and metabolic half-life. The role of high binding affinity in tumor uptake can be summarized as: essential for small peptides, less important for antibodies, and negligible for nanoparticles.

Copyright © 2012 Elsevier Inc. All rights reserved.

PubMed Disclaimer

Figures

Figure 10.1

Figure 10.1

The relationship between tumor uptake and size of the molecular targeting agent (Schmidt and Wittrup, 2009). On the left, a schematic diagram of a compartmental model for targeting biodistribution is shown. On the right, the predicted maximum tumor uptake is plotted as a function of the size of the targeting agent, with scFv and IgG sizes indicated with arrows. The parameters used were appropriate for HER2 binding molecules with K_d = 1n_M and labeled with 99mTc, and the size effects on the plasma clearance rate constant _k_clear, tumor vascular permeability P, and tumor void fraction ε were correlated from published experimental measurements of these parameters.

Figure 10.2

Figure 10.2

Biodistribution of targeted and nontargeted nanoparticles for the antigens transferrin receptor (TfR; Bartlett et al., 2007), HER2 (Kirpotin et al., 2006; Lub-de Hooge et al., 2004), EGFR (Mamot et al., 2005; Ping Li et al., 2008), EpCAM (Goldrosen et al., 1990; Hussain et al., 2007), CD19 (Lopes de Menezes et al., 1998), PSMA (Gu et al., 2008; Smith-Jones et al., 2003), and the folate receptor (FR; Coliva et al., 2005; Gabizon et al., 2003). Data are for 24-h postinjection in all cases, and all of the nanoparticles were ~100nm in diameter. Negative controls for the nanoparticle studies are generally irrelevant ligands. In the panel on the right, a compartmental model is used to predict what proportion of observed tumor uptake at 24h could be attained via the enhanced permeability and retention (EPR) effect without the use of ligand targeting (Schmidt and Wittrup, 2009).

Figure 10.3

Figure 10.3

Topographical plot of the effect of size and binding affinity on tumor uptake 24h following a bolus dose of targeting agent (Schmidt and Wittrup, 2009).

Figure 10.4

Figure 10.4

Predicted bolus dose required to achieve tumor saturation in a mouse. The gray band represents the combination of doses and expression levels for which ϕ2 = 1, the threshold at which degradative consumption equals extravasation, when the degradation half-life for antibody/antigen complexes is in the range 10–54h, typical for constitutive turnover. The high-affinity limit for (K_d = 10p_M) is represented. Other parameters are (Schmidt and Wittrup, 2009): ε = 0.24, D = 2.5 × 10−7cm2/s, P = 3.9 × 10−7 cm2/s, _R_cap = 8µm, _R_Krogh = 60µm, mouse blood volume = 2ml, and tumor density = 3 × 108 cells/ml (Schmidt et al., 2008).

References

    1. Bartlett DW, Su H, Hildebrandt IJ, Weber WA, Davis ME. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl. Acad. Sci. USA. 2007;104(39):15549–15554. - PMC - PubMed
    1. Blumenthal RD, Fand I, Sharkey RM, Boerman OC, Kashi R, Goldenberg DM. The effect of antibody protein dose on the uniformity of tumor distribution of radioantibodies: An autoradiographic study. Cancer Immunol. Immunother. 1991;33(6):351–358. - PMC - PubMed
    1. Coliva A, Zacchetti A, Luison E, Tomassetti A, Bongarzone I, Seregni E, Bombardieri E, Martin F, Giussani A, Figini M, Canevari S. 90Y Labeling of monoclonal antibody MOv18 and preclinical validation for radioimmunotherapy of human ovarian carcinomas. Cancer Immunol. Immunother. 2005;54(12):1200–1213. - PMC - PubMed
    1. DeNardo SJ, DeNardo GL, Miers LA, Natarajan A, Foreman AR, Gruettner C, Adamson GN, Ivkov R. Development of tumor targeting bioprobes ((111)In-chimeric L6 monoclonal antibody nanoparticles) for alternating magnetic field cancer therapy. Clin. Cancer Res. 2005;11(19 Pt 2):7087s–7092s. - PubMed
    1. Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J. Natl. Cancer Inst. 2006;98(5):335–344. - PubMed

MeSH terms

Substances

LinkOut - more resources