A Revisit to the Pretargeting Concept—A Target Conversion

Liu, Guozheng

doi:10.3389/fphar.2018.01476

Cited by 28 publications

(22 citation statements)

References 97 publications

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“…Despite these challenges, several clinical trials that show the safety and feasibility of TF2 bsAb and hapten pretargeting strategies have been concluded [13, 23]. Recently, Liu published a more quantitative description of the pretargeting concept which contributes to overcoming the challenges of clinical translation [24]. For fluorescence image-guided surgery, also, translation of the preclinical setup to the clinical setup at the operating rooms might be challenging.…”

Section: Discussionmentioning

confidence: 99%

A pretargeted multimodal approach for image-guided resection in a xenograft model of colorectal cancer

et al. 2019

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Background Image-guided surgery may improve surgical outcome for colorectal cancer patients. Here, we evaluated the feasibility of a pretargeting strategy for multimodal imaging in colorectal cancer using an anti-carcinoembryonic antigen (CEA) x anti-histamine-succinyl-glycine (HSG) bispecific antibody (TF2) in conjunction with the dual-labeled diHSG peptide (RDC018), using both a fluorophore for near-infrared fluorescence imaging and a chelator for radiolabeling. Methods Nude mice with subcutaneous (s.c) CEA-expressing LS174T human colonic tumors and CEA-negative control tumors were injected with TF2. After 16 h, different doses of 111 In-labeled IMP-288 (non-fluorescent) or its fluorescent derivative RDC018 were administered to compare biodistributions. MicroSPECT/CT and near-infrared fluorescence imaging were performed 2 and 24 h after injection. Next, the biodistribution of the dual-labeled humanized anti-CEA IgG antibody [ 111 In]In-DTPA-hMN-14-IRDye800CW (direct targeting) was compared with the biodistribution of 111 In-RDC018 in mice with TF2-pretargeted tumors, using fluorescence imaging and gamma counting. Lastly, mice with intraperitoneal LS174T tumors underwent near-infrared fluorescence image-guided resection combined with pre- and post-resection microSPECT/CT imaging. Results 111 In-RDC018 showed specific tumor targeting in pretargeted CEA-positive tumors (21.9 ± 4.5 and 10.0 ± 4.7% injected activity per gram (mean ± SD %IA/g), at 2 and 24 hours post-injection (p.i.), respectively) and a biodistribution similar to 111 In-IMP288. Both fluorescence and microSPECT/CT images confirmed preferential tumor accumulation. At post mortem dissection, intraperitoneal tumors were successfully identified and removed using pretargeting with TF2 and 111 In-RDC018. Conclusion A pretargeted approach for multimodal image-guided resection of colorectal cancer in a preclinical xenograft model is feasible, enables preoperative SPECT/CT, and might facilitate intraoperative fluorescence imaging. Electronic supplementary material The online version of this article (10.1186/s13550-019-0551-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A pretargeted multimodal approach for image-guided resection in a xenograft model of colorectal cancer

et al. 2019

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“…The pretargeting concept was developed to overcome the limitations encountered during direct targeting of tumors with radiolabeled antibodies [ 14 ]. It relies on four main steps ( Figure 1 ) [ 7 , 15 , 16 , 17 ]. The first step consists of the administration of an unlabeled and modified biovector (i.e., monoclonal antibody) possessing the ability to bind an antigen or receptor and a radiolabeled small molecule.…”

Section: The Emergence Of the Pretargeting Approachmentioning

confidence: 99%

IEDDA: An Attractive Bioorthogonal Reaction for Biomedical Applications

2021

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The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide–alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature. However, due to their incomplete biocompatibility and slow kinetics, the inverse-electron demand Diels-Alder (IEDDA) reaction was advanced in 2008 by Blackman et al. as an optimal bioorthogonal reaction. The IEDDA is the fastest bioorthogonal reaction known so far. Its biocompatibility and ideal kinetics are very appealing for pretargeting applications. The use of a trans-cyclooctene (TCO) and a tetrazine (Tz) in the reaction encouraged researchers to study them deeply. It was found that both reagents are sensitive to acidic or basic conditions. Furthermore, TCO is photosensitive and can be isomerized to its cis-conformation via a radical catalyzed reaction. Unfortunately, the cis-conformer is significantly less reactive toward tetrazine than the trans-conformation. Therefore, extensive research has been carried out to optimize both click reagents and to employ the IEDDA bioorthogonal reaction in biomedical applications.

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“…The key goals of pretargeted radioimmunotherapy are to increase the tumor uptake of the radionuclide and reduce nonspecific uptake in the vital organs (33)(34)(35). However, the multistep pretargeted treatment strategy has not been widely used in clinical settings because of the immunogenic nature of many pretargeting protein tags (e.g., streptavidin) and technical difficulties of delivering radionuclides (33)(34)(35). Our recent study demonstrates that these challenges can be overcome by using NP-based bioorthogonal strain-promoted alkyne-azide cycloaddition between fully synthetic ligands (e.g., DBCO and azide) (15).…”

Section: Downloaded Frommentioning

confidence: 99%

Pretargeted delivery of PI3K/mTOR small-molecule inhibitor–loaded nanoparticles for treatment of non-Hodgkin’s lymphoma

Wang

Park

2020

Sci. Adv.

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Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin’s lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)–based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR–expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.

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A Revisit to the Pretargeting Concept—A Target Conversion

Cited by 28 publications

References 97 publications

A pretargeted multimodal approach for image-guided resection in a xenograft model of colorectal cancer

A pretargeted multimodal approach for image-guided resection in a xenograft model of colorectal cancer

IEDDA: An Attractive Bioorthogonal Reaction for Biomedical Applications

Pretargeted delivery of PI3K/mTOR small-molecule inhibitor–loaded nanoparticles for treatment of non-Hodgkin’s lymphoma

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