Preclinical pharmacokinetics of a novel anti-c-Met antibody–drug conjugate, SHR-A1403, in rodents and non-human primates

Yang, Changyong; Zhao, Xiaoping; Sun, Xu; Li, Jinlong; Wang, Weiqiang; Zhang, Lianshan; Gou, Shaohua

doi:10.1080/00498254.2018.1534030

Cited by 16 publications

(12 citation statements)

References 31 publications

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“…In the present study, we established a novel strategy for overcoming AZD9291 resistance in HCC827 NSCLC cells using SHR‐A1403, a novel ADC consisting of a c‐Met mAb conjugated to a microtubule inhibitor . Unlike the c‐Met inhibitor crizotinib, which only overcame AZD9291 resistance caused by high levels of phospho‐c‐Met, SHR‐A1403 more effectively inhibited the proliferation of AZD9291‐resistant, c‐Met‐overexpressing HCC827 cells, an effect that was dependent on c‐Met expression levels only, irrespective of the involvement of c‐Met or EGFR signaling in AZD9291 resistance.…”

Section: Introductionmentioning

confidence: 99%

SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

Tong

Gao

et al. 2019

Cancer Science

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as the first‐line treatment of non‐small cell lung cancers (NSCLC) harboring EGFR‐activating mutations, but acquired resistance is ubiquitous and needs to be solved urgently. Here, we introduce an effective approach for overcoming resistance to the EGFR‐TKI, AZD9291, in NSCLC cells using SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met)‐targeting antibody‐drug conjugate (ADC) consisting of an anti‐c‐Met monoclonal antibody (c‐Met mAb) conjugated to a microtubule inhibitor. Resistant cells were established by exposing HCC827 to increasing concentrations of EGFR‐TKI. c‐Met was found to be overexpressed in most resistant cells. AZD9291 resistance was partially restored by combination of AZD9291 and crizotinib only in resistant cells overexpressing phospho‐c‐Met, which synergistically inhibited c‐Met‐mediated phosphorylation of the downstream targets ERK1/2 and AKT. In resistant cells overexpressing c‐Met, neither crizotinib nor c‐Met mAb was able to overcome AZD9291 resistance. In contrast, SHR‐A1403 strongly inhibited proliferation of AZD9291‐resistant HCC827 overexpressing c‐Met, regardless of the levels of c‐Met phosphorylation. SHR‐A1403 bound to resistant cells overexpressing c‐Met was internalized into cells and released associated microtubule inhibitor, resulting in cell‐killing activity that was dependent on c‐Met expression levels only, irrespective of the involvement of c‐Met or EGFR signaling in AZD9291 resistance. Consistent with its activity in vitro, SHR‐A1403 significantly inhibited the growth of AZD9291‐resistant HCC827 tumors and caused tumor regression in vivo. Thus, our findings show that SHR‐A1403 efficiently overcomes AZD9291 resistance in cells overexpressing c‐Met, and further indicate that c‐Met expression level is a biomarker predictive of SHR‐A1403 efficacy.

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Section: Introductionmentioning

confidence: 99%

SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

Tong

Gao

et al. 2019

Cancer Science

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“…In this model, tumour-bearing mice were given SHR-A1403 10 mg/kg, SHR-A1403 mAb 10 mg/kg, SHR152852 0.11 mg/kg, or a combination of SHR-A1403 mAb+SHR152852 were injected intravenously into tumour-bearing mice. The SHR-A1403 dose was selected as the maximum safe dose of 10 mg/kg in mice based on previous experimental data (15,16). The mAb and SHR152852 equivalent toxic doses were converted from this SHR-A1403 dose.…”

Section: Shr-a1403 Has Significant Anti-tumour Activity In Xenograft mentioning

confidence: 99%

“…The drug has completed preclinical pharmacokinetic studies in rodents and non-human primates, which showed that SHR-A1403 has a high affinity for human c-MET. Furthermore, almost no free toxin was detected in rats and cynomolgus monkeys after administration (15). SHR-A1403 has shown significant anti-tumour activity in a variety of tumour cell lines with high c-MET levels, xenograft mouse models, and patient-derived xenografts (PDX) models of HCC.…”

Section: Introductionmentioning

confidence: 99%

A Novel c-MET-Targeting Antibody-Drug Conjugate for Pancreatic Cancer

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated death in the United States and has a 5-year survival rate of <4%. Although much effort has been invested in the research and development of pancreatic cancer drugs over the past 30 years, due to the lack of effective targetable carcinogenic drivers, no new targeted therapies that can improve patient prognosis have been approved for clinical use. SHR-A1403 is a new c-mesenchymal-epithelial transition factor (c-MET) antibody-drug conjugate that can be used for the targeted treatment of PDAC with high c-MET expression. This study reports for the first time the application prospects of SHR-A1403 in preclinical models of PDAC. SHR-A1403 significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells and induced cell cycle arrest and apoptosis. These changes were caused by inhibition of intracellular cholesterol biosynthesis by SHR-A1403. Therefore, targeting c-MET through SHR-A1403 showed strong preclinical anti-tumour efficacy in pancreatic cancer. Our work suggests the potential application of c-MET-targeted antibody-drug conjugate treatment for PDAC in clinical practise.

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“…The resulting SHR-A1403 ADC, having a DAR of 2, has a favorable PK profile in animals including the cynomolgus monkey with minimal dissociation in vivo . In mice bearing xenografts expressing MET, exposure to SHR-A1403 is proportional to the dose administrated with a low clearance (CL: 0.58–0.78 ml/h/kg) and a relatively long terminal half-life (t½: 6.1 day) [ 85 ]. Similar PK profiles are also observed when rats are used as the model [ 59 , 60 , 85 ].…”

Section: Introductionmentioning

confidence: 99%

“…In mice bearing xenografts expressing MET, exposure to SHR-A1403 is proportional to the dose administrated with a low clearance (CL: 0.58–0.78 ml/h/kg) and a relatively long terminal half-life (t½: 6.1 day) [ 85 ]. Similar PK profiles are also observed when rats are used as the model [ 59 , 60 , 85 ]. The PK profile of SHR-A1403 in the cynomolgus monkey shows a non-linear behavior with an average t½ at 5.5 days and CL at 0.39–0.822 ml/h/kg.…”

Section: Introductionmentioning

confidence: 99%

MET and RON receptor tyrosine kinases in colorectal adenocarcinoma: molecular features as drug targets and antibody-drug conjugates for therapy

Yao

Tong

Hudson

et al. 2020

J Exp Clin Cancer Res

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Advanced colorectal adenocarcinoma (CRAC), featured by distinctive histopathological appearance, distant organ metastasis, acquired chemoresistance, and tumorigenic stemness is a group of heterogeneous cancers with unique genetic signatures and malignant phenotypes. Treatment of CRAC is a daunting task for oncologists. Currently, various strategies including molecular targeting using therapeutic monoclonal antibodies, small molecule kinase inhibitors and immunoregulatory checkpoint therapy have been applied to combat this deadly disease. However, these therapeutic modalities and approaches achieve only limited success. Thus, there is a pharmaceutical need to discover new targets and develop novel therapeutics for CRAC therapy. MET and RON receptor tyrosine kinases have been implicated in CRAC pathogenesis. Clinical studies have revealed that aberrant MET and/or RON expression and signaling are critical in regulating CRAC progression and malignant phenotypes. Increased MET and/or RON expression also has prognostic value for CRAC progression and patient survival. These features provide the rationale to target MET and RON for clinical CRAC intervention. At present, the use of small molecule kinase inhibitors targeting MET for CRAC treatment has achieved significant progress with several approvals for clinical application. Nevertheless, antibody-based biotherapeutics, although under clinical trials for more than 8 years, have made very little progress. In this review, we discuss the importance of MET and/or RON in CRAC tumorigenesis and development of anti-MET, anti-RON, and MET and RON-dual targeting antibody-drug conjugates for clinical application. The findings from both preclinical studies and clinical trials highlight the potential of this novel type of biotherapeutics for CRAC therapy in the future.

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Preclinical pharmacokinetics of a novel anti-c-Met antibody–drug conjugate, SHR-A1403, in rodents and non-human primates

Cited by 16 publications

References 31 publications

SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate, overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

A Novel c-MET-Targeting Antibody-Drug Conjugate for Pancreatic Cancer

MET and RON receptor tyrosine kinases in colorectal adenocarcinoma: molecular features as drug targets and antibody-drug conjugates for therapy

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