An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer

Li, Hongwen; Yu, Chao; Jiang, Jing; Huang, Changjiang; Yao, Xiaobo; Xu, Qiaoyu; Yu, Fang; Lou, Liguang; Fang, Jianmin

doi:10.1080/15384047.2016.1139248

Cited by 72 publications

(76 citation statements)

References 43 publications

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“…Our results demonstrated that the chemistry used for ADC preparation did not diminish rituximab-specific binding to cell surface CD20. In agreement of our study, similar results were also found in previous studies [27][28][29][30][31][32].…”

Section: Discussionsupporting

confidence: 94%

A developed antibody–drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line

Abdollahpour‐Alitappeh

Karouei

Lotfinia

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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Rituximab is a chimeric monoclonal antibody directed against B-lymphocyte specific antigen CD20, which is used for the treatment of B-cell malignancies. However, the effectiveness of rituximab is limited partly due to treatment resistance. The aim of this study was to develop rituximab-based antibody drug conjugate (ADC) to enhance rituximab activity. In this study, monomethyl auristatin E (MMAE) was covalently conjugated to dithiothreitol -reduced rituximab via a valine-citrulline peptide linker (rituximab-vcMMAE). The conjugates were then characterized by using nonreducing sodium dodecyl sulfate-polyacrylamide electrophoresis (SDS-PAGE) and cell-based enzyme-linked immunosorbent assay (ELISA). The cytotoxic activity of the ADC was evaluated against Raji (human B-cell lymphoma; CD20-positive) and MOLT-4 (T lymphoblast; acute lymphoblastic leukemia; CD20-negative) cell lines. In addition, the colony formation assay was used to identify the propagation ability of ADC-treated cells in vitro. Results from nonreducing SDS-PAGE revealed various species of rituximab-MC-Val-Cit-PABC-MMAE (rituximab-vcMMAE), as compared with unconjugated rituximab. The binding capacity of rituximab-vcMMAE to the CD20-positive cell was similar to that of the parental rituximab. Most importantly, our results revealed that rituximab-vcMMAE was highly potent against the CD20-positive cell line, but not against the CD20-negative cell. At the same time, rituximab-vcMMAE was able to inhibit colony formation in CD20-positive cells. These data indicate that rituximab-vcMMAE may be a highly effective and selective therapy for the treatment of B-cell lymphoma.

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Section: Discussionsupporting

confidence: 94%

A developed antibody–drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line

Abdollahpour‐Alitappeh

Karouei

Lotfinia

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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“…MMAE is a highly potent cytotoxin that can block microtubulin polymerization but has never been tested in NETs. (40)(41)(42)(43) In this study, the IC50 values of MMAE, ADC from our mAb, and ADC from the commercial mAb were 2.00, 4.27, and 5.62 nM, respectively (Fig. 5D).…”

Section: In Vitro Anti-cancer Toxicity Of Adcmentioning

confidence: 49%

Anti-SSTR2 Antibody-Drug Conjugate for Neuroendocrine Cancer Therapy

Kim

Guenter

et al. 2019

Preprint

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Neuroendocrine (NE) cancers include a diverse spectrum of hormone-secreting neoplasms that arise from the endocrine and nervous systems. Current chemo-and radio-therapies have marginal curative benefits. This study aimed to develop an innovative antibody-drug conjugate (ADC) to effectively treat NE tumors (NETs). We first confirmed that somatostatin receptor 2 (SSTR2) is an ideal surface target by analyzing 38 patient-derived NET tissues, 33 normal organs, and 3 NET cell lines. We then developed a new monoclonal antibody (mAb, IgG1 and kappa) to target two extracellular domains of SSTR2, which showed strong and specific surface binding to NETs. The ADC was constructed by conjugating the anti-SSTR2 mAb and antimitotic monomethyl auristatin E. In vitro evaluations indicated that the ADC can effectively bind, internalize, release payload, and kill NET cells effectively. Finally, the ADC was evaluated in vivo using a NET xenografted mouse model to determine cancer targeting, maximal tolerated dosage, pharmacokinetics, and anticancer efficacy. The anti-SSTR2 ADC was able to exclusively target and kill NETs with minimal toxicity and high stability in vivo. This study demonstrates that the anti-SSTR2 mAb-based ADC has high therapeutic values for NET therapy.

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“…Fortunately, hG7-BM3 exhibited all of these properties. Therefore, we generated an hG7-BM3-VcMMAE conjugate, which increased the anti-tumor potency of hG7-BM3 and broadened the therapeutic window of MMAE [ 35 , 36 ]. The observable decrease in tumor volume in the in vivo assay indicated that the anti-tumor efficacy of hG7-BM3-VcMMAE was dramatically improved in comparison with either parental hG7-BM3 or native MMAE alone.…”

Section: Discussionmentioning

confidence: 99%

Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design

et al. 2017

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Cluster of differentiation 24 (CD24) is a specific surface marker involved in the tumorigenesis and progression of hepatocellular carcinoma (HCC). However, all reported anti-CD24 antibodies are murine ones with inevitable immunogenicity. To address this, a method using both molecular structure and docking-based complementarity determining region (CDR) grafting was employed for humanization. After xenogeneic CDR grafting into a human antibody, three types of canonical residues (in the VL/VH interface core, in the loop foundation, and interaction with loop residues) that support loop conformation and residues involved in the antigen-binding interface were back-mutated. Four engineered antibodies were produced, among which hG7-BM3 has virtually identical 3-D structure and affinity parameters with the parental chimeric antibody cG7. In vitro, hG7-BM3 demonstrated superior immunogenicity and serum stability to cG7. Antibody-dependent cellular cytotoxicity (ADCC), tumor cell internalization and in vivo targeting assays indicate that hG7-BM3 has the potential for development as an antibody-drug conjugate (ADC). We therefore generated the hG7-BM3-VcMMAE conjugate, which was shown to induce tumor cell apoptosis and effectively suppress nude mice bearing HCC xenografts. In conclusion, our study provides new inspiration for antibody humanization and an ADC candidate for laboratory study and clinical applications.

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An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer

Cited by 72 publications

References 43 publications

A developed antibody–drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line

A developed antibody–drug conjugate rituximab-vcMMAE shows a potent cytotoxic activity against CD20-positive cell line

Anti-SSTR2 Antibody-Drug Conjugate for Neuroendocrine Cancer Therapy

Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design

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