Factors determining antibody distribution in tumors

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Trends in Pharmacological Sciences (Impact Factor: 9.99). 03/2008; 29(2):57-61. DOI: 10.1016/
Source: PubMed

ABSTRACT The development of antibody therapies for cancer is increasing rapidly, primarily owing to their specificity. Antibody distribution in tumors is often extremely uneven, however, leading to some malignant cells being exposed to saturating concentrations of antibody, whereas others are completely untargeted. This is detrimental because large regions of cells escape therapy, whereas other regions might be exposed to suboptimal concentrations that promote a selection of resistant mutants. The distribution of antibody depends on a variety of factors, including dose, affinity, antigens per cell and molecular size. Because these parameters are often known or easily estimated, a quick calculation based on simple modeling considerations can predict the uniformity of targeting within a tumor. Such analyses should enable experimental researchers to identify in a straightforward way the limitations in achieving evenly distributed antibody, and design and test improved antibody therapeutics more rationally.

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Available from: Greg M Thurber, Mar 27, 2014
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    • "The transport model was employed approximating the shape of the tumor spheroids as being strictly spherical. While the spheroids generated in this work were not perfect spheres, spherical coordinates have been utilized in several previous studies describing drug transport in tumor spheroids (Goodman et al. 2008; Thurber and Wittrup 2008), and have provided a reasonable shape estimate of the spheroids to describe drug penetration in this model. "
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    • "Targets having widespread non-tumour tissue expression may affect tumour uptake of a target therapeutic and vice versa. Additionally, attributes of the antibody such as size, molecular weight and target affinity (Adams et al., 2001; Minchinton and Tannock, 2006) as well as tumour physiology, including degree of vascularity , antigen density and necrosis (Jain, 1999; Minchinton and Tannock, 2006; Thurber et al., 2008; Tabrizi et al., 2010) can influence antibody distribution to and within the tumour, so it is understandable that all tumour-associated target antigens may not be accessible to the antibody. The implications of these limitations on therapeutic efficacy warrant a detailed understanding of the relationship between antibody PK, biodistribution and tumour uptake. "
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    • "However, the whole immunoglobulin format has limitations for some targeted applications. Their relatively large size makes them inefficient at penetrating deep tissue antigens (Yokota et al. 1993; Graff and Wittrup 2003; Thurber et al. 2008), while poor vascularisation within the tumor microenvironment can impede high dose antibody delivery (Jain 1999; Fukumura and Jain 2008). Further, in such cases where there is poor vascularization or if a patient is immunocompromised the Fc effector function of whole antibodies becomes largely redundant due to a limited supply of lymphocytes and macrophages (Badger et al. 1987). "
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