Theoretic Criteria for Antibody Penetration into Solid Tumors and Micrometastases

Abstract

Targeting tumors with antibody-based therapeutics is a complex task presenting multiple kinetic barriers. Antibody internalization and clearance inhibit uptake both in solid tumors, limited by tumor vascular permeability, and in micrometastases, limited by diffusion. Methods: A modeling exercise is used to introduce 2 simple criteria that must be less than unity for saturation of both tumors and micrometastases. The clearance modulus and the Thiele modulus are ratios of the plasma clearance rate and antibody catabolism, respectively, to the tumor tissue penetration rate. Results: Even low rates of antigen internalization from constitutive membrane turnover can significantly retard antibody penetration. Rapid clearance of single-chain variable fragments also hinders uptake, often more than counterbalancing their more rapid extravasation and diffusion. Conclusion: The model illustrates that with the large resistance from the tumor capillary, antibodies may be more suitable for targeting micrometastases than vascularized tumors.Key Words: molecular imaging; monoclonal antibodies; radionuclide therapy; biodistribution; penetration; pharmacokinetics Ant ibodies and antibody fragments are promising agents for cancer detection and treatment. One of the major restrictions of these drugs for cancer therapy is poor transport, which results in low concentrations and a lack of targeting of all cells in a tumor (1). Delivery of antibodies to tumor cells is a complex task with many rates involved, as illustrated in Figure 1. Effective therapy requires treatment of both solid, vascularized tumors and micrometastases with different pharmacokinetic parameters.Several different models have been developed to illustrate some fundamental trends in targeting. van Osdol et al. have shown that antibodies tend to exhibit a ''binding site barrier'' because of their clearance and penetration (2), and extensive work on fluid flow and macromolecular distribution has been performed by Jain (1). Using a simplified model, Graff and Wittrup highlighted the importance of antibody dose for saturating tissue and the necessity of high affinity for retention in the tumor (3).Although providing useful insights, these prior models have not fully delineated the microscopic distribution effects of antibody catabolism. The turnover rate was not examined quantitatively, and one would expect differences between an antibody binding a receptor internalized by a clathrin-coated pit mechanism, constitutive membrane turnover, and extracellular matrix protein turnover. Internalization of ErbB receptor family members, targets for 2 antibody drugs approved by the Food and Drug Administration, is well characterized (4,5). A multitude of other antibodies against various targets have also been shown to internalize at broadly varying rates (6,7), demonstrating the need for an in-depth consideration of the effects of internalization on tumor targeting. This analysis reveals that internalization has the potential to severely limit the penetration of antibodies. MATERIAL...

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

“…This inverse relationship is termed the "binding-site barrier" hypothesis and can be offset by factors such as dose and antibody elimination half-life. For antibody fragments with rapid clearance rates (t 1/2 ≈ minutes for single-chain variable fragment; hours for fragments with antigen binding) and under nonsteady-state conditions, tumor penetration is predicted to be highly influenced by antibody affinity (45)(46)(47). However, full-length antibodies generally have a long elimination half-life and are administered frequently, i.e., weekly, biweekly, or monthly, where steady-state serum concentrations are achieved.…”

“…In addition to tumor properties (outlined in next section), penetration of antibodies into tumors can be influenced by factors such as antibody affinity, antigen internalization, and antibody metabolism by the tumor. A number of comprehensive reviews have recently addressed this topic in detail (44)(45)(46)(47). Under nonsteady-state conditions, an inverse relationship between antibody affinity and tumor penetration has been predicted (48).…”

“…However, full-length antibodies generally have a long elimination half-life and are administered frequently, i.e., weekly, biweekly, or monthly, where steady-state serum concentrations are achieved. Under steady-state conditions, which is a condition generally met in clinical practice, binding equilibrium between antibody and antigen is achieved rapidly, and the movement of antibody through the tumor can be governed by antigen turnover rate, antigen density, as well as the antibody concentration gradient (45)(46)(47)(48). In general, cell-associated antigens undergo internalization at constitutive rates, ranging from minutes to days.…”

“…The newly synthesized antigen following resurfacing can then interact with the unbound antibody. Again under nonsteadystate conditions, it is predicted that tumor exposure can be reduced by the rate of antigen recycling (45)(46)(47)(48).…”

A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio

“…Intact antibodies with a molecular weight of ~150 kDa have long circulation times in blood, ranging from a few days to weeks, due to slow plasma clearance. Tumor targeting may also be hampered because of the slow and incomplete diffusion into solid tumors (17,18). In comparison, the smaller monovalent Fab' (~50 kDa) and the divalent F(ab') 2 (~100 kDa) fragments derived from the parent antibody are expected to exhibit shorter circulating half-lives, better tumor penetration, and are thus more likely to yield better imaging results (19,20).…”