Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease

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.

Fig. 1

Movement of molecules from blood to body tissues. In general, the rate of distribution may be limited by blood flow (perfusion-rate limited, a) or the membrane permeability (permeability-rate limited, b). Mechanisms of transvascular transport: convection, due to the pressure gradient (c), and diffusion, primarily due to the concentration gradient (d)

Fig. 2

Fcγ receptor-mediated clearance of antibody–antigen (i.e., omalizumab–IgE) complexes (a). Theoretical impact of antibody affinity and antibody–antigen clearance (CL_Complex) relative to free antibody clearance (solid line CL_Complex=CL_Antibody; dashed line CL_Complex=x2CL_Antibody; dotted line CL_Complex=x10CL_Antibody) on the free antibody serum concentration–time profiles at a simulated affinity of 200 pM (b) and 1,000 pM (c). Theoretical impact of changes in affinity on antibody exposure was evaluated using a bimolecular interaction PK–PD model. The model accounted for free antibody PK (CL and volume of distribution), bimolecular interactions between antigen and antibody, and the elimination of free antigen. The impact of changes in antibody affinity and clearance of antibody–antigen complex on antibody exposure was evaluated

Fig. 3

Biodistribution of anti-RSV antibodies to the lung compartment is a critical requirement for pulmonary viral load neutralization following systemic administration (a). Relationships between viral neutralization and MEDI-524 in serum (adapted from (75)) and estimated BALF concentrations assuming a k _P of 0.001 (b). Serum concentration–time profiles for MEDI-524 and MEDI-524-YTE following a single-dose administration in monkeys generated from pharmacokinetic parameters estimate reported previously (75) (c)

Fig. 4

a Theoretical improvements in area under the antigen suppression curves (Y axis) following changes in both antibody half-life (from 12 to 18 days) and affinity (from 10 to 2 pM). These improvements resulted in a more pronounced (40% to 70%) and prolonged antigen suppression following a monthly administration of 40- to 70-mg doses relative to administration of a 40-mg dose twice monthly with antibody affinity of 10 pM and half-life (t _1/2) of 12 days (not shown). Theoretical impact of improvements in antibody affinity on antigen suppression time profiles in synovial fluid is shown in b. Simulations were generated using a bimolecular interaction PK–PD model as described for Fig. 2

Fig. 5

Concentrations of endogenous IgG subclass in the CSF and sera of normal subjects (n = 7). The line in each box represents the median and the box shows the range. Data adapted from (90)

Fig. 6

Dose-dependent depletion of CD20+ B lymphocytes in cynomolgus monkey tissues following administration of three weekly doses of rituximab (tissues were collected and analyzed 3 days after administration of the third dose on day 15). The method is described in (110). Ax. LN. axillary lymph nodes, Mes. LN. mesenteric lymph nodes, Ing. LN. inguinal lymph nodes