Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates

Mahalingaiah, Prathap Kumar S.; Ciurlionis, Rita; Durbin, Kenneth R.; Yeager, Ronnie L.; Philip, Binu K.; Bawa, Bhupinder; Mantena, Srinivasa R.; Enright, Brian; Liguori, Michael J.; Vleet, Terry R. Van

doi:10.1016/j.pharmthera.2019.04.008

Cited by 109 publications

(63 citation statements)

References 180 publications

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“…Preparation of DXL-Immobilized Fe 3 O 4 /SiO 2 /PVA/SH NPs (5) and (6): In a glass test tube (13 by 100 mm, equipped with a threaded cap), Fe 3 O 4 /SiO 2 /PVA/SH NPs (0.1 g) were well dispersed in ethanol (3.0 mL) via ultrasonication (for 15 min). Subsequently, 2.0 mL of 0.1 m solution of DXL in ethanol was added into the tube.…”

Section: Synthesis Of Fe 3 O 4 /Sio 2 /Pva Nps (3)mentioning

confidence: 99%

“…[ 4,5 ] To further improve the efficiencies of the established drugs, various treatment strategies, such as preparation of protein–drug conjugates and the design of nanoscale drug‐carriers, are used to increase the efficacy of therapeutic agents. [ 6–8 ] Several effective nano‐carrier systems were designed to deliver anti‐cancer cytotoxic agents to tumor cells with high selectivity and efficacy while minimizing negative side effects. [ 9,10 ] Drug nano‐carriers provide multiple advantages, such as convenient uptake and internalization, reduced drug interactions, optimized lifetime, and widened therapeutic windows.…”

Section: Introductionmentioning

confidence: 99%

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Multi‐Stimuli Nanocomposite Therapeutic: Docetaxel Targeted Delivery and Synergies in Treatment of Human Breast Cancer Tumor

Taheri‐Ledari

Zhang

Radmanesh

et al. 2020

Small

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To further improve the efficiencies of the established drugs, various treatment strategies, such as preparation of protein-drug conjugates and the design of nanoscale drug-carriers, are used to increase the efficacy of therapeutic agents. [6-8] Several effective nanocarrier systems were designed to deliver anti-cancer cytotoxic agents to tumor cells with high selectivity and efficacy while minimizing negative side effects. [9,10] Drug nano-carriers provide multiple advantages, such as convenient uptake and internalization, reduced drug interactions, optimized lifetime, and widened therapeutic windows. [11] In this regard, the synthetic design and applications of different types of iron oxide nanoparticles (Fe 3 O 4 NPs) have received significant attention since these NPs can be magnetically directed inside target tissues and their surface can be easily functionalized with diverse polymers and organic compounds. [12-16] Previously, we have reported several magnetic systems in micro-and nanoscale for diverse functional applications. [17-24] To further expand upon this work, we utilized one of the most commonly employed polymers, polyvinyl alcohol (PVA), to encapsulate magnetic Fe 3 O 4 NPs by virtue of its extended hydrogen bonding and to provide a selective release medium for DXL. [25] Drug molecules, such as DXL, can be incorporated into a PVA gel when polymer chains are in a shrunk state at low temperatures, and subsequently released in a target tissue upon a PVA transition into a swollen gel at 37 °C. [26] PVA features several important advantages. First is the ability to form a gel owing to multiple hydrogen bonding by OH groups. A versatile breast cancer-targeting nanocomposite therapeutic combining docetaxel (DXL), polyvinyl alcohol (PVA) network for controlled release, and silica-protected magnetic iron oxide nanoparticles (Fe 3 O 4 NPs) for targeted delivery and gold nanoparticles (AuNPs) for plasmonic photothermal therapy (PPTT) is presented in this work. First, the designed nanocomposite is magnetically directed for cancer-targeted therapy confirmed by computerized tomography (CT) scans. Second, 10% DXL by mass is loaded into PVA, a pH and temperature responsive gel, for controlled release. Third, PPTT is confirmed with Au/Fe 3 O 4 /PVA-10%DXL using a prototype circulation system and then for tumor treatment in vivo; Au/Fe 3 O 4 /PVA-10%DXL is conveniently directed and the entrapped DXL is selectively released (≈96%) via the interaction of green and near-infrared (NIR) light with the localized surface plasmon resonance of AuNPs. A 75% cell death is reported from in vitro studies with DXL doses as low as 20 µg mL −1 of Au/Fe 3 O 4 /PVA-10%DXL, and a 70% tumor growth inhibition is demonstrated by in vivo experiments with the biosafety studies confirming minimal side effects to other organs. Overall, the developed Au/Fe 3 O 4 /PVA-10%DXL has a strong potential to simultaneously enhance CT imaging contrast together with the targeted delivery of DXL.

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Section: Synthesis Of Fe 3 O 4 /Sio 2 /Pva Nps (3)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multi‐Stimuli Nanocomposite Therapeutic: Docetaxel Targeted Delivery and Synergies in Treatment of Human Breast Cancer Tumor

Taheri‐Ledari

Zhang

Radmanesh

et al. 2020

Small

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show abstract

“…In such a scenario, a significant proportion of the administered TDC might be expected to not bind and deliver payload to the tumor whereas a greater proportion of the TXC administered does so. Given that the primary driver of ADC toxicity, nonspecific uptake in normal tissues, is likely linearly related to payload dose, the supra-linear improvements in efficacy that we observed with cytotoxic high-DAR TXCs against CD22 may portend an improved therapeutic index versus conventional ADCs 52,53 . It is possible also that TXCs will be more excluded than conventional ADCs from normal tissues due to the size or charge of the attached XTEN further improving the therapeutic index, as has been shown recently for PEGylated ADCs 54 .…”

Section: Discussionmentioning

confidence: 90%

A homogeneous high-DAR antibody-drug conjugate platform combining THIOMABTM antibodies and XTEN polypeptides

Zacharias¹,

Podust

Kajihara³

et al. 2021

Preprint

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Antibody-drug conjugates (ADCs) enable cell-specific delivery of small molecules and are validated anti-cancer therapeutics. One factor limiting ADC advancement and broader application is the drug-to-antibody ratio (DAR), which dictates the number of payloads that can be delivered per antibody. With few exceptions, efficacious ADCs with DAR > 4 are inaccessible due to aggregation or rapid clearance in vivo. Here, we report a versatile platform for the generation of homogeneous ADCs with DAR up to 18, combining Cys-engineered THIOMAB antibodies and XTEN polypeptides to give “TXCs”. We show that high-DAR TXCs are stable biochemically and in vivo. We demonstrate that two different cytotoxic TXCs directed toward a tumor xenograft and one TXC targeting Staphylococcus aureus have comparable pharmacokinetics, but significantly enhanced efficacy in vivo versus conventional low-DAR ADCs. Our data suggest that high-DAR TXCs may ultimately offer several advantages versus conventional ADCs, including increased therapeutic index and efficacious delivery of less potent payloads.

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“…Trastuzumab-based ADC, T-DM1, was developed for treatment of resistant tumors by directly conjugating the chemotherapeutic drug, mertansine, on the antibody to boost cytotoxicity (34). A potential problem with ADCs is their intrinsically highly toxicity, which can cause non-specific off-target effects in normal tissues due to their long circulation times (35). Hapuarachchige et al (23,24) has reported a pretargeting strategy driven by bioorthogonal click chemistry to circumvent this issue.…”

Section: Examples Of Pretargeted Theranostics Pretargeted Theranosticmentioning

confidence: 99%

Theranostic Pretargeting Drug Delivery and Imaging Platforms in Cancer Precision Medicine

Hapuarachchige

Artemov

2020

Front. Oncol.

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Theranostics are nano-size or molecular-level agents serving for both diagnosis and therapy. Structurally, they are drug delivery systems integrated with molecular or targeted imaging agents. Theranostics are becoming popular because they are targeted therapeutics and can be used with no or minimal changes for diagnostic imaging to aid in precision medicine. Thus, there is a close relation between theranostics and image-guided therapy (IGT), and theranostics are actually a subclass of IGT in which both therapeutic and imaging functionalities are attributed to a single platform. An important theranostics strategy is biological pretargeting. In pretargeted IGT, first, the target is identified by a target-specific natural or synthetic bioligand followed by a nano-scale or molecular drug delivery component, which form therapeutic clusters by in situ conjugation reactions. If pretargeted drug delivery platforms are labeled with multimodal imaging probes, they can be used as theranostics for both diagnostic imaging and therapy. Optical and nuclear imaging techniques have mostly been used in proof-of-concept studies with pretargeted theranostics. The concept of pretargeting in theranostics is comparatively novel and generally requires a confirmed overexpression of surface receptors on targeted cells/tissue. In addition, the receptors should have natural or synthetic bioligands to be used as pretargeting components. Therefore, applications of pretargeting theranostics are still limited to several cancer types, which overexpress cell-surface markers on the target cancer cells. In this review, recent discoveries of pretargeting theranostics in breast, ovarian, prostate, and colorectal cancers are discussed to highlight main strengths and potential limitations the strategy.

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Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates

Cited by 109 publications

References 180 publications

Multi‐Stimuli Nanocomposite Therapeutic: Docetaxel Targeted Delivery and Synergies in Treatment of Human Breast Cancer Tumor

Multi‐Stimuli Nanocomposite Therapeutic: Docetaxel Targeted Delivery and Synergies in Treatment of Human Breast Cancer Tumor

A homogeneous high-DAR antibody-drug conjugate platform combining THIOMABTM antibodies and XTEN polypeptides

Theranostic Pretargeting Drug Delivery and Imaging Platforms in Cancer Precision Medicine

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