Antibody tumor penetration: Transport opposed by systemic and antigen-mediated clearance☆ Greg M. Thurber a , Michael M. Schmidt b , and K. Dane Wittrup a,b,* a Department Chemical Engineering, Massachusetts Institute of Technology, USA b Department Biological Engineering, Massachusetts Institute of Technology, USA Abstract Antibodies have proven to be effective agents in cancer imaging and therapy. One of the major challenges still facing the field is the heterogeneous distribution of these agents in tumors when administered systemically. Large regions of untargeted cells can therefore escape therapy and potentially select for more resistant cells. We present here a summary of theoretical and experimental approaches to analyze and improve antibody penetration in tumor tissue. Keywords Tumor targeting; Antibodies; Binding site barrier; Cellular trafficking; Drug distribution; Pharmacokinetics; Mathematical modeling; Affinity; Immunotherapy 1. Poor drug microdistribution in tumor tissues Heterogeneous distribution of systemically administered antibodies in tumor tissue has been a recognized issue for immunotherapy for over twenty years [1] (Fig. 1). More recently, the same phenomenon has been observed with small molecule chemotherapeutics [2]. The presence of completely untreated cells in a tumor is an obvious problem for even the most potent and specific drugs — however a more insidious outcome is the fostering of drug resistance in zones of only marginally toxic drug concentration. In this review we consider the basic mechanisms of macromolecular distribution in tumor tissue, and examine potential strategies for improving total uptake and homogeneity of antibody distribution. 1.1. Previous mathematical models of antibody distribution in tumors Antibody targeting of tumors is a complex process involving the distribution and clearance of antibody in the plasma, blood flow through the tumor, extravasation, convection and diffusion, binding, and internalization. Both inter- and intra-tumor heterogeneity further complicate the interpretation of experiments. Because of the multitude of factors influencing distribution and inability to precisely control in vivo conditions, mathematical models play a key role in understanding the fundamental factors influencing antibody distribution. It is a necessity that these models are quantitative since there are direct trade-offs between many of the conditions, such as antibody dose versus number of binding sites. Many of these parameters vary by several orders of magnitude, so qualitative arguments, such as a ‘fast’ rate or ‘high’ concentration, ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Delivery Systems for the Targeted Radiotherapy of Cancer”. © 2008 Elsevier B.V. All rights reserved. * Corresponding author. Department Chemical Engineering, Massachusetts Institute of Technology, USA. E-mail address: Wittrup@mit.edu (K.D. Wittrup). NIH Public Access Author Manuscript Adv Drug Deliv Rev. Author manuscript; available in PMC 2010 February 11. Published in final edited form as: Adv Drug Deliv Rev. 2008 September ; 60(12): 1421. doi:10.1016/j.addr.2008.04.012. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript