Pharmacokinetics and pharmacodynamics of therapeutic antibodies in tumors and tumor-draining lymph nodes

Abstract

The signaling axis from the primary tumor to the tumor-draining lymph node (TDLN) has emerged as a crucial mediator for the efficacy of immunotherapies in neoadjuvant settings, challenging the primary use of immunotherapy in adjuvant settings. TDLNs are regarded as highly opportunistic sites for cancer cell dissemination and promote further spread via several primary tumor-dependent mechanisms. Lesion-level mixed responses to antibody immunotherapy have been traced to local immune signatures present in the TDLN and the organ-specific primary tumors that they drain. However, the pharmacokinetics (PK) and biodistribution gradients of antibodies in primary tumors and TDLNs have not been systemically evaluated. These concentration gradients are critical in ensuring adequate antibody pharmacodynamic (PD) T-cell activation and/or anti-tumor response. The current work reviews the knowledge for developing physiologically-based PK and pharmacodynamic (PBPK/PD) models to quantify antibody biodistribution gradients in anatomically distinct primary tumors and TDLNs as a means to characterize the clinically observed heterogeneous responses to antibody therapies. Several clinical and pathophysiological considerations in modeling the primary tumor-TDLN axis, as well as a summary of both preclinical and clinical PK/PD lymphatic antibody disposition studies, will be provided.

Keywords: PK/PD modeling; monoclonal antibody (mAb); physiologically-based pharmacokinetic (PBPK) models; target-mediated drug disposition (TMDD); tumor-draining lymph nodes (TDLNs).

Figure 1.

Generalized lymphatic drainage map and transit of therapeutic antibodies after either intravenous or subcutaneous administration. (a) Lymph node clusters (green dots), scattered throughout the body, drain lymph from surrounding tissues and into one of two subclavian veins (yellow and red stars). Lymphatic drainage is asymmetrical; the right lymph duct (yellow star) drains the right side of the head and neck, right arm/upper right core, whereas the thoracic duct (red star) drains the entire remainder of the body. (b) The flow after subcutaneous administration to the upper left arm is dependent on the (c) local system lymphatics to reach the systemic circulation.

Figure 2.

FDA-approved anti-PD-1 pembrolizumab cancer indications (2019) [26].

Figure 3.. PBPK modeling allows for evaluation of mAb disposition and binding in tumor-specific organs and TDLNs.

(a) A series of mass-balance differential equations describing the time course of antibody concentrations in both primary tumors (PT) and TDLNs are derived and implemented into the model; every organ-specific primary tumor and TDLN serves as its own physiological compartment. Typically, these compartments are connected via blood flow (black arrows), and lymph flow (green structures) is secondary; however, when considering antibody disposition, the lymphatic vasculature must be emphasized. Fr denotes the flow fraction of blood/lymph to a given tissue (i.e., tumors), which varies across tissues, tumor types/sizes, and tumor vascular structure. (b) Tissue- and organ-specific schematic and model parameters in primary tumors and TDLNs: Organ blood flow (Q_organ), vascular reflection coefficient (σ_v), lymphatic reflection coefficient (σ_L), afferent lymph flow (L_aff), efferent lymph flow (L_eff), organ lymph flow (L_organ), mAb clearance from central compartment (CL_p), interstitial space (IS). Green circular structures denote T-cells in both tumor and TDLN IS compartments interacting with draining antibody. (c) Example simulation illustrating antibody disposition (SUV, standard uptake value) in plasma (blue), primary tumor (red), tumor-positive TDLN (solid green), and tumor-negative TDLN (dashed green). The purple and green arrows denote the concentration gradients between PT-TDLN and the effect of antibody binding in the TDLN, respectively (i.e., metastasis to TDLN). For further exploration on PBPK models, please consult the following references [32,34,35].

Figure 4.

mPBPK model structure of antibody disposition in plasma, primary tumors and TDLNs. (a) Sequential mAb flow as it extravastates from the vascular space into the tumor interstitial space (IS), subsequently into the TDLN IS via afferent lymph flow, and then exits via efferent lymph flow. Membrane-bound antigen present at any site (i.e., tumors) will retain bound antibody, and only free (i.e., unbound) antibody will remain in circulation. (b) Antibody-antigen binding in the primary tumor IS space is described via a quasi-equilibrium target-mediated drug disposition (QE-TMDD) model. Free antibody leaving the tumor IS compartment will then travel via the lymphatic vessels to the TDLN where a second QE-TMDD model can be applied in the TDLN, assuming antigen (i.e., tumor) is present. Efferent flow will then deliver remaining antibody back into the plasma. Symbols are defined below. (Figure prepared in BioRender).