Treatment-induced and pre-existing anti-PEG antibodies: Prevalence, clinical implications, and future perspectives


血清アルブミンに存在する超硫黄の解析と創薬応用

血清アルブミンに存在する超硫黄の解析と創薬応用

Journal of the Pharmaceutical Society of Japan


イオン液体を利用した外用剤・経皮吸収製剤の開発と疾患治療への応用

イオン液体を利用した外用剤・経皮吸収製剤の開発と疾患治療への応用


Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products


The challenge to deliver oxaliplatin (l-OHP) to solid tumors: development of liposomal l-OHP formulations


The new delivery strategy of albumin carrier utilizing the interaction with albumin receptors


最新の免疫腫瘍微小環境の理解とADC，DDSの革新的イノベーション

最新の免疫腫瘍微小環境の理解とADC，DDSの革新的イノベーション


An RNAi therapeutic, DFP-10825, for intraperitoneal and intrapleural malignant cancers

RNA interference (RNAi), a potent post-transcriptional gene-silencing action, has received considerable attentions as a novel therapeutic tool to treat intractable cancers. In recent days, we have developed a novel RNAi-based therapeutic formulation, DFP-10825, for the treatment of intractable advanced cancers developed in coelomic cavities. DFP-10825 was composed of chemically synthesized short hairpin RNA (shRNA) against thymidylate synthase (TS), a key enzyme for cancer proliferation, and cationic liposomes, and achieved high therapeutic effect on the mouse models of peritoneally disseminated gastric and ovarian cancers and malignant pleural mesothelioma without severe side effects by intracoelomic direct treatment. We further designed a freeze-dried DFP-10825 formulation for mass industrial production. DFP-10825 is undergoing in pre-clinical phase and goes to clinical trials. This review introduces a DFP-10825 formulation, a potent novel RNAi-based therapeutic maximizing the benefit of RNAi molecule (shRNA).


Anti-PEG antibodies: Properties, formation and role in adverse immune reactions to PEGylated nano-biopharmaceuticals


Drug Delivery System for Refractory Cancer Therapy via an Endogenous Albumin Transport System


Foreward in Recent advances in research on particulate formulations such as lipoproteins, liposomes, extracellular vesicles, and iPS-derived cells


タンパクのPEG修飾によるPEG免疫応答の誘導

タンパクのPEG修飾によるPEG免疫応答の誘導


臨床応用可能な体腔内投与型RNAi 製剤(DFP-10825)の開発と難治性がんに対する治療


リポソームDDS 製剤開発における免疫系の制御と動態解析の重要性

リポソームDDS 製剤開発における免疫系の制御と動態解析の重要性


ナノフィブリル化バクテリアセルロース(Fibnano)を用いた腹腔内投与型がん治療製剤への応用


フルーツ由来新奇酢酸菌によるナノセルロースの合成とその応用

フルーツ由来新奇酢酸菌によるナノセルロースの合成とその応用


PEGylated liposomes: immunological responses

A commonly held view is that nanocarriers conjugated to polyethylene glycol (PEG) are non-immunogenic. However, many studies have reported that unexpected immune responses have occurred against PEG-conjugated nanocarriers. One unanticipated response is the rapid clearance of PEGylated nanocarriers upon repeat administration, called the accelerated blood clearance (ABC) phenomenon. ABC involves the production of antibodies toward nanocarrier components, including PEG, which reduces the safety and effectiveness of encapsulated therapeutic agents. Another immune response is the hypersensitivity or infusion reaction referred to as complement (C) activation-related pseudoallergy (CARPA). Such immunogenicity and adverse reactivities of PEGylated nanocarriers may be of potential concern for the clinical use of PEGylated therapeutics. Accordingly, screening of the immunogenicity and CARPA reactogenicity of nanocarrier-based therapeutics should be a prerequisite before they can proceed into clinical studies. This review presents PEGylated liposomes, immunogenicity of PEG, the ABC phenomenon, C activation and lipid-induced CARPA from a toxicological point of view, and also addresses the factors that influence these adverse interactions with the immune system.

Science and Technology of Advanced Materials


生体内動態の理解を基盤としたリポソームDDSの開発∼臨床応用を目指して∼ 第11回日本DDS学会水島賞によせて


Control of EPR effect by tumor-targeted NO donor via endogenous albumin transport system

内因性アルブミン輸送システムを利用した腫瘍選択的NO供与によるEPR効果の制御

A unique phenomenon in solid tumors, enhanced permeability and retention(EPR) effect, is very famous for the development of macromolecular anticancer therapy. However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. An intrinsic vascular modulator such as nitric oxide(NO) could augment the intrinsic EPR effect. We have demonstrated that S-nitrosated human serum albumin dimer(SNO-HSA Dimer) becomes an enhancer of the EPR effect in various tumor-bearing mice models. Here, we summarized the enhanced effect of SNO-HSA Dimer on the anticancer effect of two types of macromolecular anticancer drugs, namely PEGylated liposomal doxorubicin(Doxil®) and albumin bound paclitaxel nanoparticle(Abraxane®). In C26-bearing mice with highly permeable vasculature, SNO-HSA Dimer could increase tumor accumulation of these anticancer drugs and thereby their anticancer effects. Interestingly, the tumor accumulation of Doxil® in B16-bearing mice, which are characterized by a low permeable vasculature, increased more 6-fold in the presence of SNO-HSA Dimer, and the improved accumulation of Doxil® led to increased survival and decreased tumor volume. On the other hand, SNO-HSA Dimer also augmented the tumor growth inhibition of Abraxane® in low vascular permeability B16-bearing mice. Furthermore, Abraxane® combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. We also showed that the administration of SNO-HSA Dimer had no effect on blood pressure, heart rate and biochemical parameters, suggesting that SNO-HSA Dimer alone is very safe. Accordingly, we conclude that SNO-HSA Dimer is promising for regulating the EPR effect and enhanced therapeutic effects of many macromolecular anticancer drugs.

EPR効果は，高分子抗がん療法の開発の基礎となり得るが，低い血管透過性を有するがん領域では，このEPR効果のみでは十分な送達性が得られない．したがって，一酸化窒素(NO)のような血管調節分子で内因性EPR効果を増強することは極めて有望な戦略である．筆者らは，ヒト血清アルブミン二量体のS―ニトロソ化体(SNO―HSA Dimer)がEPR効果の増強剤であることを検討してきた．ここでは，すでに承認されたPEG化リポソーム・ドキソルビシン(Doxil®)およびアルブミン結合型パクリタキセル・ナノ粒子(Abraxane®)の2種類の高分子抗がん剤を用い，血管透過性が高いC26や血管透過性が低いB16担がんモデル，臨床病態に近いとされているSUIT2ヒト膵臓がん同所性モデルにて得られた結果を中心に報告する．


Accelerated blood clearance (ABC) 現象における動物種差


Metronomic chemotherapy and nanocarrier platforms

The therapeutic concept of administering chemotherapeutic agents continuously at lower doses, relative to the maximum tolerated dose (MTD) without drug-free breaks over extended periods -known as "metronomic chemotherapy"- is a promising approach for anti-angiogenic cancer therapy. In comparison with MTD chemotherapy regimens, metronomic chemotherapy has demonstrated reduced toxicity. However, as a monotherapy, metronomic chemotherapy has failed to provide convincing results in clinical trials. Therapeutic approaches including combining the anti-angiogenic "metronomic" therapy with conventional radio-/chemo-therapy and/or targeted delivery of chemotherapeutic agents to tumor tissues via their encapsulation with nanocarrier-based platforms have proven to potentiate the overall therapeutic outcomes. In this review, therefore, we focused on the mutual contribution made by nanoscale drug delivery platforms to the therapeutic efficacy of metronomic-based chemotherapy. In addition, the influence that the dosing schedule has on the overall therapeutic efficacy of metronomic chemotherapy is discussed.


ナノ粒子に対する補体活性化の功罪

ナノ粒子に対する補体活性化の功罪


Liposomal delivery systems: design optimization and current applications

The liposome, a closed phospholipid bilayered vesicular system, has received considerable attention as a pharmaceutical carrier of great potential over the past 30 years. The ability of liposomes to encapsulate both hydrophilic and hydrophobic drugs, coupled with their biocompatibility and biodegradability, make liposomes attractive vehicles in the field of drug delivery. In addition, great technical advances such as remote drug loading, triggered release liposomes, ligand-targeted liposomes, liposomes containing combinations of drugs, and so on, have led to the widespread use of liposomes in diverse areas as delivery vehicles for anti-cancer, bio-active molecules, diagnostics, and therapeutic agents. In this review, we summarize design optimization of liposomal systems and invaluable applications of liposomes as effective delivery systems.


Characteristics, evaluation and suppression of anti-poly(ethylene glycol) antibody

Modification with PEG(poly(ethylene glycol)), so-called PEGylation, is a golden standard to increase stability of biological medicine. However, PEGylated materials cause anti-PEG antibody after first injection. Then, the anti-PEG antibody induce the accelerated blood clearance(ABC) phenomenon of subsequent dose of PEGylated materials. So far, it has been reported that anti-PEG antibody production occurs not only in experimental animals, but also in human. In addition, characteristics of anti-PEG antibody induced by one PEGylated material differ from that of anti-PEG antibody induced by other PEGylated materials. In order to preserve the merit of PEGylation technology, it is important to understand the correct characteristics of anti-PEG immune response and develop strategy for escaping the immune response. In this review, we show the characteristics, evaluation and suppression of anti-PEG antibody.

PEG(poly(ethylene glycol))修飾は，バイオ医薬品の生体内安定性を向上させる最も標準的な方法である．しかし，PEG修飾体投与後にPEGに特異的な抗体(抗PEG抗体)が誘導され，繰り返し投与時のPEG修飾体の血中滞留性を著しく低下させることが明らかになっている．これまでに，実験動物だけでなく，ヒトにおいても抗PEG抗体の誘導が確認されている．また，さまざまなPEG修飾体投与によって，さまざまな特性を持った抗PEG抗体が誘導されることも明らかになっている．PEG修飾技術による治療効果の向上を損なわないためにも，抗PEG免疫応答の正しい理解と抑制法の開発は非常に重要である．本稿では，抗PEG抗体の特性・評価・抑制法について概説する．


PEGに対する免疫反応∼PEG修飾製剤の安全性に関する研究∼

PEGに対する免疫反応∼PEG修飾製剤の安全性に関する研究∼


Selective delivery of oxaliplatin to tumor tissue by nanocarrier system enhances overall therapeutic efficacy of the encapsulated oxaliplatin

Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum; l-OHP), a third-generation platinum antitumor drug, is currently approved in combination with 5-flurouracil (5-FU)/leucovorin (FOLFOX) for standard first- and second-line treatment of metastatic or advanced-stage colorectal cancer. Despite l-OHP's better tolerability in comparison with other platinum compounds such as cisplatin and carboplatin, its clinical efficiency is limited by the dose-limiting side effects including cumulative neurotoxicity and acute dysesthesias. In addition, like other platinum chemotherapeutic agents, l-OHP therapy is limited by reduced accumulation levels in tumor tissues, nonselective accumulation in healthy organs and/or tissues, inactivation by conjugation with glutathione, and the development of drug resistance. Accordingly, successful outcome of cancer treatment using l-OHP requires selective delivery of a relatively high concentration of the drug to tumor tissues. In this review we focus on utilization of different drug-delivery vehicles such as liposomes, polymeric nanocarriers, and carbon nanotubes in enhancing selective delivery of l-OHP to tumor tissues and consequently improving overall efficacy of l-OHP-containing drug-delivery systems.


The accelerated blood clearance (ABC) phenomenon: Clinical challenge and approaches to manage

Despite the clinical introduction of an increasing number of polyethylene glycol (PEG)-conjugated substances, PEG has been named as the cause of an unexpected immunogenic response known as the "accelerated blood clearance (ABC) phenomenon." This phenomenon has been extensively observed during the repeated administration of PEG-conjugated substances and PEGylated nanocarriers including PEGylated liposomes, PEGylated nanoparticles, PEGylated micelles, etc., resulting in the increased clearance and reduced efficacy of PEG-conjugated substances/PEGylated nanocarriers. In this review, therefore, we focused on the possible mechanisms underlying the induction of such a phenomenon and emphasized the factors affecting its magnitude. In addition, the clinical implications of the ABC phenomenon on the therapeutic efficacy of PEG-conjugated substances/PEGylated nanocarriers, along with the new approaches that can be applied to manage and/or abrogate the induction of the ABC phenomenon, are also discussed.


Anti-polyethyleneglycol (PEG) antibody response to PEGylated substances.

In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.


PEG修飾製剤による抗PEG抗体分泌誘導

PEG修飾製剤による抗PEG抗体分泌誘導


Alteration of tumor microenvironment for improved delivery and intratumor distribution of nanocarriers.

Nanocarrier-based cancer chemotherapeutics are thought to increase therapeutic efficiency and reduce the side effects of associated chemotherapeutic agents by altering the agents' pharmacokinetics and tissue distribution following intravenous administration. In spite of these favorable properties, nanocarrier-based cancer chemotherapeutics are not always effective because of their heterogeneous intratumoral localization. Homogeneous distribution of nanocarriers in a tumor would improve the efficacy of nanocarrier-based cancer chemotherapeutics. In this article, we describe and discuss some trials that attempt to manipulate the barriers in the tumor microenvironment that hinder extravasation through the tumor vasculature and penetration of nanocarriers in solid tumors. Alterations of the tumor microenvironment that relate directly to the intratumoral distribution of nanocarriers may be potential strategies to improve the delivery of nanocarrier-based cancer chemotherapeutics.


リポソームDDSの開発研究∼トランスレーショナルリサーチの実現を目指して∼

リポソームDDSの開発研究∼トランスレーショナルリサーチの実現を目指して∼

Journal of Pharmaceutical Science and Technology, Japan


PEG修飾リポソーム製剤繰り返し投与による血中滞留性低下

PEG修飾リポソーム製剤繰り返し投与による血中滞留性低下


Development of efficient and safe drug delivery system with liposomes : the 2nd Encouragement Award in the 26th Annual Meeting of the Japan Society of Drug Delivery System

生体内動態検討を基盤としたリポソームDDSの開発∼第2回日本DDS学会奨励賞(臨床)受賞によせて∼


Targeting anticancer drugs to tumor vasculature using cationic liposomes.

Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.


Elucidation of Accelerated Blood Clearance Phenomenon Caused by Repeat Injection of PEGylated Nanocarriers

Liposomes modified with polyethylene glycol (PEG) can stably exist in the bloodstream because the PEG on the liposomes attracts a water shell to the liposomal surface. Since these liposomes are long circulating nanocarriers, they are used as drug and gene delivery tools. Repeat injection of PEGylated liposomes, however, is known to induce the accelerated blood clearance (ABC) phenomenon. In the ABC phenomenon, PEGylated liposomes that are injected subsequent to the first injection are cleared rapidly from the bloodstream and accumulate in the liver, resulting in loss of their long-circulating characteristics. The induction of ABC phenomenon is related to the production of anti-PEG IgM from splenic B cells. To elucidate the mechanism of the phenomenon, we firstly examined the relationship between the induction of ABC phenomenon and the concentration of PEGylated liposomes, and observed that the high dose of those did not induce the phenomenon. Next, we investigated whether polymeric micelles trigger ABC phenomenon or not. Finally, the size-dependency of ABC phenomenon was investigated by use of variously sized PEGylated liposomes and polymeric micelles having PEG chains. Our data suggest that the initiation of ABC phenomenon would be size-dependent, and particles smaller than 30 nm did not induce ABC phenomenon. We anticipate that the elucidation of the ABC phenomenon will be helpful for the development of DDS formulations.

Journal of the Pharmaceutical Society of Japan


Recent advances in tumor vasculature targeting using liposomal drug delivery systems.

Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells).


siRNA を利用したArgonaute2 遺伝子knockdown によるがん治療法の開発


Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes.

We and a Dutch group reported that "empty" PEGylated liposomes (approximately 100 nm) lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). Very recently, we showed that anti-PEG IgM, induced by the first dose of "empty" PEGylated liposomes, is responsible for inducing the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no or lower immunogenicity. However, the results indicated evidence that unexpected immune responses occur even to such polymer-coated liposomes. Such immunogenicity of "empty" liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. In addition, through series of our studies, it was demonstrated that the magnitude of the ABC phenomenon depends on the physicochemical property of injected liposomes as a first dose, time interval between injection, lipid dose and drug-encapsulation.


Accelerated Blood Clearance (ABC) Phenomenon Induced by Administration of PEGylated Liposome(Symposium Reviews)

ポリエチレングリコール修飾リポソーム投与時に生ずるaccelerated blood clearance (ABC)現象

PEGylated liposomes (approximately 100nm in diameter) lose their long-circulating characteristic upon repeated injection at certain intervals in the same animal (referred to as the "accelerated blood clearance (ABC) phenomenon"), as described by our group and by researchers in the Netherlands. Recently, it was demonstrated by our group that anti-PEG IgM, induced by the first dose of PEGylated liposomes, is responsible for the ABC phenomenon. The IgM produced in this manner then selectively bound to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no immunogenicity. However, unexpected immune responses occurred even in response to polymer-coated liposomes. This immunogenicity to PEGylated liposomes presents a serious concern in the development and clinical use of liposomal formulations. In this review, we demonstrate our recent observations regarding with the ABC phenomenon against liposomes.


腫瘍血管の構造変化がナノ粒子抗がん剤の効果を変化させる

腫瘍血管の構造変化がナノ粒子抗がん剤の効果を変化させる


ポリマー修飾ナノ微粒子投与による免疫活性化に関する研究

ポリマー修飾ナノ微粒子投与による免疫活性化に関する研究


デリバリーによる新たな創薬

デリバリーによる新たな創薬


リポソームと細胞の相互作用(DDSへの応用)

リポソームと細胞の相互作用(DDSへの応用)


Safe and efficient drug delivery system with liposomes for intrathecal application of an antivasospastic drug, fasudil.

Pharmacological treatment for cerebral ischemia and cerebral vasospasm following subarachnoid hemorrhage (SAH) cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. We recently developed a liposomal drug delivery system for intrathecal application that can maintain effective concentrations of cerebral vasodilator, fasudil, in the CSF. A single intrathecal injection of liposomal fasudil could maintain a therapeutic drug concentration in the CSF over a period time due to their sustained-release property, significantly decreasing infarct size in a rat model of acute ischemia and reducing vasoconstriction of the rat and dog basilar artery in a model of SAH. In this review, we are introducing our new less-invasive intrathecal drug delivery system that provides an alternative and safe method to deliver therapeutic agents.


がん治療を目指した機能性リポソームの開発研究

がん治療を目指した機能性リポソームの開発研究


リポソームDDSの開発研究

リポソームDDSの開発研究


Accelerated blood clearance of PEGylated liposomes after repeated injection

ポリエチレングリコール表面修飾リポソームの繰り返し投与時に発現するaccelerated blood clearance(ABC)現象

We and a Dutch group have recently reported the accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes, that is the enhanced accumulation of PEGylated liposomes in liver and consequently rapidly cleared the liposomes from blood circulation. The phenomenon is a general characteristic of liposomes and the induction of the phenomenon depends on the physicochemical property and dose of liposomes and animal species. In addition, our study indicated that the IgM secreted in response to first dose is involved in the occurrence of the phenomenon. In this article, our and a Dutch group's recent results related to the ABC phenomenon were described.


Development of Drug Delivery System for Intrathecal Administration and Its Therapeutic Effect on Cerebral Vasospasm and Ischemia

脳脊髄腔投与可能なDDSの開発とその脳保護効果の検討

To date, the pharmacologic approach to cerebral vasospasm and ischemia has been hampered in part by an inability to attain sufficiently high concentrations of drugs in the cerebrospinal fluid (CSF). To overcome this limitation of current drug therapy, we have developed a sustained-release preparation of the protein kinase inhibitor fasudil. Experimental cerebral vasospasm in rats and dogs was induced by double injection of autologous arterial blood into the cisterna magna. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. A single intrathecal injection of liposomal fasudil can maintain a therapeutic the drug concentration in the CSF due to the sustained-release property of liposomes, significantly decreasing intarct size of acute ischemia and decreasing vasoconstriction of the basilar artery in cerebral vasospasm. This novel approach for the treatment of cerebral vasospasm and ischemia may have significant potential for use in the clinical setting.


脳脊髄腔内直接投与可能なDDSの開発とその脳保護効果

脳脊髄腔内直接投与可能なDDSの開発とその脳保護効果


機能性リポソームの開発とその癌治療への応用

機能性リポソームの開発とその癌治療への応用


リポソームへの機能性の付加による細胞内薬物送達システムの開発

リポソームへの機能性の付加による細胞内薬物送達システムの開発


Pharmacokinetics of Targeting with Liposomes

Critcal Reviews in Therapeutic Drug Carrier Systems


Interactions of Liposomes with Cells In Vitro and In Vivo:Opsonins and Receptors


MDRモジュレーターとリポソーム化抗癌剤による多剤耐性癌克服の試み

MDRモジュレーターとリポソーム化抗癌剤による多剤耐性癌克服の試み