Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy

Si, Yingnan; Kim, Seulhee; Ou, Jianfa; Yun, Lingsong; Erñst, Patrick; Chen, Kai; Whitt, Jason; Carter, Angela M.; Markert, James M.; Bibb, James A.; Chen, Herbert; Zhou, Lufang; Jaskula-Sztul, Renata; Liu, Margaret

doi:10.1038/s41417-020-0196-5

Cited by 29 publications

(50 citation statements)

References 59 publications

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“…SSTR2 is considered as a good target for low-grade (G1/G2) of NETs. Our previous immunohistochemistry staining of G1 and G2 NET patient tissues (n = 37) showed that 76% samples had high SSTR2 expression [36]. Leijon et al also reported 74.8% of 151 NET tissues, including 13/14 metastasized samples, overexpressed SSTR2 [33].…”

Section: Sstr2 and Cxcr4 Surface Expression And Dual Targetingmentioning

confidence: 87%

“…The in vitro uptake of mAbs-EV by NET cell lines was confirmed with two-or three-color confocal microscopy [24,36,51,52]. The cytoplasm and nucleus were stained with BacMam GFP Transduction Control (Green); the nucleus was stained with DAPI (blue); and the Liss Rhod fluorescent dye (red) was used to monitor the uptake of mAbs-EV.…”

Section: Confocal Imagingmentioning

confidence: 97%

“…In this study, the fine polishing using Protein A chromatography was not performed. The purified EV were used for surface tagging and drug packing or supplemented with 25 mM trehalose for long-term storage at −80 • C. Second, following the reported procedure [24,36], the anti-SSTR2 mAb was produced by hybridoma cells in 2-L bioreactors and purified using New Generation Chromatography (NGC) system (Bio-Rad, Hercules, CA, USA) equipped with Protein A column. The anti-SSTR2 mAb was titrated using high performance liquid chromatography (HPLC) system (Shimadzu, Columbia, MD, USA) equipped with a UV detector and a viva C-8 column (Phenomenex, Torrance, CA, USA).…”

Section: Construction Of Mabs-ev-ver-a/dm1mentioning

confidence: 99%

“…The anti-SSTR2 mAb or anti-CXCR4 mAb (RD Systems, Minneapolis, MN, USA) was labelled with an Alexa Fluor™ 647 labelling kit to generate fluorescent AF647-mAb. The staining conditions are 1 µg AF647-mAb per million cells at 4 • C for 30 min as reported before [24,36,51,52].…”

Section: Flow Cytometrymentioning

confidence: 99%

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Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment

Guan

et al. 2020

Pharmaceutics

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Neuroendocrine (NE) cancers arise from cells within the neuroendocrine system. Chemotherapies and endoradiotherapy have been developed, but their clinical efficacy is limited. The objective of this study was to develop a dual-targeted extracellular vesicles (EV)-delivered combined therapies to treat NE cancer. Specifically, we produced EV in stirred-tank bioreactors and surface tagged both anti-somatostatin receptor 2 (SSTR 2) monoclonal antibody (mAb) and anti-C-X-C motif chemokine receptor 4 (CXCR4) mAb to generate mAbs-EV. Both live-cell confocal microscopy imaging and In Vivo Imaging System (IVIS) imaging confirmed that mAbs-EV specifically targeted and accumulated in NE cancer cells and NE tumor xenografts. Then the highly potent natural cytotoxic marine compound verrucarin A (Ver-A) with IC50 of 2.2–2.8 nM and microtubule polymerization inhibitor mertansine (DM1) with IC50 of 3.1–4.2 nM were packed into mAbs-EV. The in vivo maximum tolerated dose study performed in non-tumor-bearing mice indicated minimal systemic toxicity of mAbs-EV-Ver-A/DM1. Finally, the in vivo anticancer efficacy study demonstrated that the SSTR2/CXCR4 dual-targeted EV-Ver-A/DM1 is more effective to inhibit NE tumor growth than the single targeting and single drug. The results from this study could expand the application of EV to targeting deliver the combined potent chemotherapies for cancer treatment.

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Section: Sstr2 and Cxcr4 Surface Expression And Dual Targetingmentioning

confidence: 87%

Section: Confocal Imagingmentioning

confidence: 97%

Section: Construction Of Mabs-ev-ver-a/dm1mentioning

confidence: 99%

Section: Flow Cytometrymentioning

confidence: 99%

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Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment

Guan

et al. 2020

Pharmaceutics

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“…The surface binding and internalization of anti-EGFR ADC in TNBC cells was evaluated using confocal microscopy following our reported protocol [36][37][38]. Briefly, the MDA-MB-468 cells were infected with Bac-Mam GFP transduction control (BacMam 2.0) for plasma and nucleus staining for 24 h and observed using an Olympus 1X-81 confocal microscope with an Olympus FV-1000 laser scan head (Olympus IX81, Center Valley, PA).…”

Section: Live-cell Confocal Imagingmentioning

confidence: 99%

Anti‐EGFR antibody‐drug conjugate for triple‐negative breast cancer therapy

Guan³

et al. 2020

Engineering in Life Sciences

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Triple‐negative breast cancers (TNBCs) are highly aggressive, metastatic and recurrent. Cytotoxic chemotherapies with limited clinical benefits and severe side effects are the standard therapeutic strategies, but, to date, there is no efficacious targeted therapy. Literature and our data showed that epidermal growth factor receptor (EGFR) is overexpressed on TNBC cell surface and is a promising oncological target. The objective of this study was to develop an antibody‐drug conjugate (ADC) to target EGFR+ TNBC and deliver high‐potency drug. First, we constructed an ADC by conjugating anti‐EGFR monoclonal antibody with mertansine which inhibits microtubule assembly via linker Sulfo‐SMCC. Second, we confirmed the TNBC‐targeting specificity of anti‐EGFR ADC by evaluating its surface binding and internalization in MDA‐MB‐468 cells and targeting to TNBC xenograft in subcutaneous mouse mode. The live‐cell and live‐animal imaging with confocal laser scanning microscopy and In Vivo Imaging System (IVIS) confirmed the TNBC‐targeting. Finally, both in vitro toxicity assay and in vivo anti‐cancer efficacy study in TNBC xenograft models showed that the constructed ADC significantly inhibited TNBC growth, and the pharmacokinetics study indicated its high circulation stability. This study indicated that the anti‐EGFR ADC has a great potential to against TNBC.

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Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

Zhang,

Hu,

Aras

et al. 2024

ChemMedChem

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Conventional chemotherapy is insufficient for precise cancer treatment due to its lack of selectivity and inevitable side effects. Targeted drugs have emerged as a promising solution for precise cancer treatment. A common strategy is to conjugate therapeutic agents with ligands that can specifically bind to tumor cells, providing targeted therapy. Similar to the more successful antibody drug conjugates (ADCs), small molecule drug conjugates (SMDCs) are another promising class of targeted drugs, consisting of three parts: targeting ligand, cleavable linker and payload. Compared to ADCs, SMDCs have the advantages of smaller size, better permeability, simpler preparation process and non‐immunogenicity, making them a promising alternative to ADCs. This review describes the characteristics of the targeting ligand, linker and payload of SMDCs and the criteria for selecting a suitable one. We also discuss recently reported SMDCs and list some successful SMDCs that have entered clinical trials.

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Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy

Cited by 29 publications

References 59 publications

Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment

Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment

Anti‐EGFR antibody‐drug conjugate for triple‐negative breast cancer therapy

Small Molecule‐Drug Conjugates: Opportunities for the Development of Targeted Anticancer Drugs

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