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

Eric Salgado; Yanguang Cao; Eric Salgado; Yanguang Cao

doi:10.3934/mbe.2021006

Mathematical Biosciences and Engineering

2021, Volume 18, Issue 1: 112-131. doi: 10.3934/mbe.2021006

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Review

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

Eric Salgado ¹,
Yanguang Cao ^{1,2
,
,}

1.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
2.
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, NC, USA

Received: 13 June 2020 Accepted: 10 November 2020 Published: 19 November 2020

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.
Citation: Eric Salgado, Yanguang Cao. Pharmacokinetics and pharmacodynamics of therapeutic antibodies in tumors and tumor-draining lymph nodes[J]. Mathematical Biosciences and Engineering, 2021, 18(1): 112-131. doi: 10.3934/mbe.2021006

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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.

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