Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models

Kurino, Taiki; Matsuda, Reiko; Terui, Ayu; Suzuki, Hiroyuki; Kokubo, Tomomi; Uehara, Tomoya; Arano, Yasushi; Hisaka, Akihiro; Hatakeyama, Hiroto

doi:10.1136/jitc-2019-000400

Cited by 24 publications

(18 citation statements)

References 30 publications

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“…51 In addition, anti-PD-1 is systemically distributed after intraperitoneal injection. 52 Thus, the clodronate liposome treatment would inhibit the internalization of anti-PD-1 by macrophages, thus resulting in an enhancement in the antitumor effect. It is possible that the activation of macrophages by the STING-LNP may also enhance the engulfment of anti-PD-1.…”

Section: Discussionmentioning

confidence: 99%

STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation

Nakamura

Sato

Endo

et al. 2021

J Immunother Cancer

138

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BackgroundResistance to an immune checkpoint inhibitor (ICI) is a major obstacle in cancer immunotherapy. The causes of ICI resistance include major histocompatibility complex (MHC)/histocompatibility locus antigen (HLA) class I loss, neoantigen loss, and incomplete antigen presentation. Elimination by natural killer (NK) cells would be expected to be an effective strategy for the treatment of these ICI-resistant tumors. We previously demonstrated that a lipid nanoparticle containing a stimulator of an interferon gene (STING) agonist (STING-LNP) efficiently induced antitumor activity via the activation of NK cells. Thus, we evaluated the potential of reducing ICI resistance by STING-LNPs.MethodsLung metastasis of a B16-F10 mouse melanoma was used as an anti-programmed cell death 1 (anti-PD-1)-resistant mouse model. The mice were intravenously injected with the STING-LNP and the mechanism responsible for the improvement of anti-PD-1 resistance by the STING-LNPs was analyzed by RT-qPCR and flow cytometry. The dynamics of STING-LNP were also investigated.ResultsAlthough anti-PD-1 monotherapy failed to induce an antitumor effect, the combination of the STING-LNP and anti-PD-1 exerted a synergistic antitumor effect. Our results indicate that the STING-LNP treatment significantly increased the expression of CD3, CD4, NK1.1, PD-1 and interferon (IFN)-γ in lung metastases. This change appears to be initiated by the type I IFN produced by liver macrophages that contain the internalized STING-LNPs, leading to the systemic activation of NK cells that express PD-1. The activated NK cells appeared to produce IFN-γ, resulting in an increase in the expression of the PD ligand 1 (PD-L1) in cancer cells, thus leading to a synergistic antitumor effect when anti-PD-1 is administered.ConclusionsWe provide a demonstration to show that a STING-LNP treatment can overcome PD-1 resistance in a B16-F10 lung metastasis model. The mechanism responsible for this indicates that NK cells are activated by stimulating the STING pathway which, in turn, induced the expression of PD-L1 on cancer cells. Based on the findings reported herein, the STING-LNP represents a promising candidate for use in combination therapy with anti-PD-1-resistant tumors.

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Section: Discussionmentioning

confidence: 99%

STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation

Nakamura

Sato

Endo

et al. 2021

J Immunother Cancer

138

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“…Depending on the antibody internalisation, [ 89 Zr] remains trapped inside the cell after antibody internalisation and degradation leading to an accumulation over time of the signal in the tumour or targeted cell (21,55). In 2020, Kurino et al (56) performed the biodistribution of the 10F.9G2, which is the same clone as in our study. They investigated the biodistribution and the radiometabolism of the antibody using Iodine-125 (covalent binding) and Indium-111 (radiolabelling by chelation as it is for [ 89 Zr]).…”

Section: Biodistribution Of [ 89 Zr]dfo-anti-pdl1 In Lung Cancer-grafted Micementioning

confidence: 89%

Preclinical Pharmacokinetics and Dosimetry of an 89Zr Labelled Anti-PDL1 in an Orthotopic Lung Cancer Murine Model

et al. 2022

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Anti-PDL1 is a monoclonal antibody targeting the programmed death-cell ligand (PD-L1) by blocking the programmed death-cell (PD-1)/PD-L1 axis. It restores the immune system response in several tumours, such as non-small cell lung cancer (NSCLC). Anti-PDL1 or anti-PD1 treatments rely on PD-L1 tumoural expression assessed by immunohistochemistry on biopsy tissue. However, depending on the biopsy extraction site, PD-L1 expression can vary greatly. Non-invasive imaging enables whole-body mapping of PD-L1 sites and could improve the assessment of tumoural PD-L1 expression.MethodsPharmacokinetics (PK), biodistribution and dosimetry of a murine anti-PDL1 radiolabelled with zirconium-89, were evaluated in both healthy mice and immunocompetent mice with lung cancer. Preclinical PET (μPET) imaging was used to analyse [89Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans.ResultsOrgan distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoural uptake occurred within 24 h post-injection of [89Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) and image quality. An in vivo blocking study confirmed that [89Zr]DFO-anti-PDL1 specifically targeted PD-L1 in CMT167 lung tumours in mice. AUC in organs was estimated using a 1-compartment PK model and extrapolated to human (using allometric scaling) in order to estimate the radiation exposure in human. Human-estimated effective dose was 131 μSv/MBq.ConclusionThe predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging.

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“…Furthermore, few papers are available in the literature regarding the PK characterization of a-PD-1 and a-PD-L1. These characterizations are based mainly on imaging methods and even radioactivity levels [14,24]. In the studies on a-PD-1 or a-PD-L1 quantification in different matrices, most of the data correspond to human or primate serum samples with clear differences in the results across ELISA data [19,[25][26][27].…”

Section: Discussionmentioning

confidence: 99%

“…DPBS without calcium and magnesium and fetal bovine serum (FBS) were purchased from Gibco ® (Madrid, Spain). Rat a-mouse-PD-1 mAb (CD279; clone RMP1- 14) and rat a-mouse PD-L1 (B7-H1, clone 10F.9G2) were obtained from BioXCell ® (West Lebanon, NH, USA). The Goat a-Rat IgG, (H+L) antibody, Biotin Conjugated was purchased from Thermo scientific ® (Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, physiological PK models seem to improve the characterization of drug behavior, providing the most relevant platform to achieve appropriate human dose escalation [13]. However, the studies on the biodistribution of these biological agents in animals have been done in many cases by imaging experiments [14][15][16], highlighting the need to develop selective and sensitive analytical techniques to quantify plasma and tissue antibody concentrations accurately. In this way, the enzyme-linked immunosorbent assay (ELISA) is the most popular analytical assay to measure mAbs in different biological matrices [17].…”

Section: Introductionmentioning

confidence: 99%

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Quantification of Pharmacokinetic Profiles of PD-1/PD-L1 Antibodies by Validated ELISAs

et al. 2020

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Immunotherapy has changed the paradigm of cancer treatments. In this way, several combinatorial strategies based on monoclonal antibodies (mAb) such as anti (a)-PD-1 or anti (a)-PD-L1 are often reported to yield promising clinical benefits. However, the pharmacokinetic (PK) behavior of these mAbs is a critical issue that requires selective analytical techniques. Indeed, few publications report data on a-PD1/a-PD-L1 exposure and its relationship with therapeutic or toxic effects. In this regard, preclinical assays allow the time profiles of antibody plasma concentrations to be characterized rapidly and easily, which may help to increase PK knowledge. In this study, we have developed and validated two in-house ELISAs to quantify a-PD-1 and a-PD-L1 in plasma collected from tumor-bearing mice. The linear range for the a-PD-1 assay was 2.5–125 ng/mL and 0.11–3.125 ng/mL for the a-PD-L1 assay, whereas the intra-and inter-day precision was lower than 20% for both analytes. The PK characterization revealed a significant decrease in drug exposure after administration of multiple doses. Plasma half-life for a-PD-1 was slightly shorter (22.3 h) than for a-PD-L1 (46.7 h). To our knowledge, this is the first reported preclinical ELISA for these immune checkpoint inhibitors, which is sufficiently robust to be used in different preclinical models. These methods can help to understand the PK behavior of these antibodies under different scenarios and the relationship with response, thus guiding the choice of optimal doses in clinical settings.

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Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models

Cited by 24 publications

References 30 publications

STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation

STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation

Preclinical Pharmacokinetics and Dosimetry of an 89Zr Labelled Anti-PDL1 in an Orthotopic Lung Cancer Murine Model

Quantification of Pharmacokinetic Profiles of PD-1/PD-L1 Antibodies by Validated ELISAs

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