An HER3-targeting antibody–drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC

Yonesaka, Kimio; Takegawa, Naoki; Watanabe, Satomi; Haratani, Koji; Kawakami, Hisato; Sakai, Kazuko; Chiba, Yasutaka; Maeda, Naoyuki; Kagari, Takashi; Hirotani, Kenji; Nishio, Kazuto; Nakagawa, Kazuhiko

doi:10.1038/s41388-018-0517-4

Cited by 74 publications

(56 citation statements)

References 29 publications

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“…However, patritumab did not show any significant survival benefit in previous clinical trials in NSCLC and HNC, requiring the development of other strategies to fight against HER3-expressing cancers (22,23). U3-1402, a potential first-in-class anti-HER3 ADC (with patritumab as the carrier and DXd as the payload), is currently under development to act on these targets (24). Indeed, an early report of a clinical trial suggested that U3-1402 could be safely administered and demonstrated promising antitumor efficacy in heavily treated HER3-expressing (immunohistochemical HER3 score of tumor cells was 2+/3+) metastatic breast cancer (the ORR was 47%, and the disease control rate was 94%, both of which were far superior to that of the historical control) (25).…”

Section: Introductionmentioning

confidence: 99%

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

Haratani¹,

Yonesaka²,

Takamura³

et al. 2019

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

Haratani¹,

Yonesaka²,

Takamura³

et al. 2019

Journal of Clinical Investigation

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“…To date, uncleavable saporin‐ or MMAF‐conjugated HER3‐specific ADCs have been preclinically proposed as monotherapy for melanoma . The anti‐HER3 antibody patritumab conjugated to a topoisomerase I inhibitor via a cleavable linker is currently tested in phase I/II trials for patients with metastatic breast cancer and has been preclinically demonstrated to be an effective treatment for EGFR‐mutant NSCLC with acquired resistance to EGFR TKIs . However, no HER3‐specific ADC linked to a cleavable MMAE has been proposed for the radiosensitization of pancreatic tumors.…”

Section: Discussionmentioning

confidence: 94%

“…Together with IGF‐1R, HER3 can also serve as drivers of tumor growth and resistance to standard‐of‐care chemotherapy in metastatic PDAC . In such case of disseminated PDAC where irradiation is not recommended, combining HER3‐ADC with chemotherapy could resensitize pancreatic cancer cells to chemotherapy, similarly as those observed with patritumab‐ADC in TKI‐resistant NSCLC …”

Section: Discussionmentioning

confidence: 99%

“…42,43 The anti-HER3 antibody patritumab conjugated to a topoisomerase I inhibitor via a cleavable linker is currently tested in phase I/II trials for patients with metastatic breast cancer 44 and has been preclinically demonstrated to be an effective treatment for EGFR-mutant NSCLC with acquired resistance to EGFR TKIs. 45 However, no HER3-specific ADC linked to a cleavable MMAE has been proposed for the radiosensitization of pancreatic tumors. Our MMAE-based HER3-ADC is derived from the 9F7-F11 antibody that has a completely novel pharmacological profile (nonligand competing allosteric drug) and higher anticancer efficacy in the presence of its ligand NRG1.…”

Section: Discussionmentioning

confidence: 99%

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An auristatin‐based antibody‐drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer

Bourillon

Bourgier

Gaborit

et al. 2019

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the nonligand competing anti‐HER3 antibody 9F7–F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7–F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody‐drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE‐based HER3 antibody‐drug conjugate (HER3‐ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3‐positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3‐ADC decreased the clonogenic survival of irradiated cells by increasing DNA double‐strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3‐ADC favored the inhibition of the AKT‐induced survival pathway, together with more efficient caspase 3/PARP‐mediated apoptosis. Incubation with HER3‐ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3‐ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient‐derived xenografts, and reduced proliferation (KI67‐positive cells). Combining auristatin radiosensitizer delivery via an HER3‐ADC with radiotherapy is a new promising therapeutic strategy in PDAC.

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“…Anti-tumor effects of patritumab-based antibodydrug conjugate (ADC) on HER1 tyrosine kinase inhibitorresistant lung cancer cells have been recently reported [48], therefore, we compared the character between present anti-HER3 rat mAb and patritumab. Patritumab is an anti-HER3 fully human mAb directed to the ECD of HER3 and possessed IGH (V4-34*07/ D1-26*01, D2-15*01 orD3-22*01/J2*01), IGK (V4-1*01/J1*01), and classified to fifth group with no homology with CDRs of rat mAbs.…”

Section: Discussionmentioning

confidence: 99%

Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers

et al. 2020

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Copyright: Okita et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACTResistance of progressive cancers against chemotherapy is a serious clinical problem. In this context, human epidermal growth factor receptor 3 (HER3) can play important roles in drug resistance to HER1-and HER2-targeted therapies. Since clinical testing of anti-HER3 monoclonal antibodies (mAbs) such as patritumab could not show remarkable effect compared with existing drugs, we generated novel mAbs against anti-HER3. Novel rat mAbs reacted with HEK293 cells expressing HER3, but not with cells expressing HER1, HER2 or HER4. Specificity of mAbs was substantiated by the loss of mAb binding with knockdown by siRNA and knockout of CRISPR/ Cas9-based genome-editing. Analyses of CDR sequence and germline segment have revealed that seven mAbs are classified to four groups, and the binding of patritumab was inhibited by one of seven mAbs. Seven mAbs have shown reactivity with various human epithelial cancer cells, strong internalization activity of cell-surface HER3, and inhibition of NRG1 binding, NRG1-dependent HER3 phosphorylation and cell growth. Anti-HER3 mAbs were also reactive with in vivo tumor tissues and cancer tissue-originated spheroid. Ab4 inhibited in vivo tumor growth of human colon cancer cells in nude mice. Present mAbs may be superior to existing anti-HER3 mAbs and support existing anti-cancer therapeutic mAbs.

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An HER3-targeting antibody–drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC

Cited by 74 publications

References 29 publications

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

An auristatin‐based antibody‐drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer

Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers

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