Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Abstract

Abstract. The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…1) (3,5,10). Interaction of antibody with soluble or cell-associated targets provides a unique opportunity for selection and evaluation of relevant biomarkers during the early preclinical stage (4,10). Proof-of-mechanism (POM) biomarkers should allow for evaluation of antibody interaction with the molecular target while proof-of-principle (POP) biomarkers further address whether target modulation results in measurable downstream activity and signaling.…”

“…Application of QP can greatly facilitate the seamless flow of information across various development stages (5,10,12,13). Similar to small-molecule drugs, the relationship between the antibody dose or concentration(s) and the observed pharmacological response(s) can be characterized by linear and log-linear, sigmoid E max , biophase distribution, or indirect response models (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”

“…Many factors can regulate or impact antibody pharmacokinetics and a number of comprehensive reviews have addressed this topic in detail (21,27,32). Briefly, antigen properties, such as antigen distribution (soluble versus cell-associated), antigen concentration, as well as Fc receptor (both FcRn and FcγR) expression and distribution can influence antibody pharmacokinetics and biodistribution (10,26). Other factors, such as antibody structure and engineering, host factors, concurrent medications, and immunogenicity can also alter antibody pharmacokinetic profiles (32).…”

Investigation of a Thromboxane A 2 Receptor–Based Vaccine for Managing Thrombogenesis

“…This is because the distribution of antibodies to compartments other than the vascular is, in general, restricted because of poor penetration of the endothelial cell layer 61, 62, 63. Thus, these approaches may allow us to address bleeding time and thrombosis under conditions of selective modulation of the platelet TPRs, but not those TPRs of the smooth muscle64, 65, 66 (which are known to affect bleeding time).…”

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

“…It must be kept in mind that the drug is typically present at a lower concentration in tissue than in the central compartment. For example, antibody concentrations in blood have been reported to be ∼10‐fold higher than in epithelial lining fluid of lung, 1000‐fold higher than in cerebrospinal fluid, and fivefold higher than in synovial fluid 56. As a result, free receptor blockade in blood is expected to be higher than in many other tissues.…”