A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers

Fujita, Ryo; Blot, Vincent; Wong, Eley; Stewart, Christine P; Lieuw, Vincent; Richardson, Robyn; Banah, Ammar; Villicana, Jose; Timmer, Anjuli M.; Coronella, Julia; Newman, Roland; Gymnopoulos, Marco

doi:10.1080/15384047.2020.1737490

Cited by 14 publications

(8 citation statements)

References 39 publications

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“…Precise quantification of plasma membrane MET receptors was performed as described previously (23). Briefly, pancreatic cancer cells were stained with an anti-MET conjugated with Alexa Fluor 488 and then analyzed on a BD Accuri Flow Cytometer (BD Biosciences).…”

Section: Quantitative Flow Cytometrymentioning

confidence: 99%

A MET Targeting Antibody–Drug Conjugate Overcomes Gemcitabine Resistance in Pancreatic Cancer

Cazes

Betancourt

Esparza

et al. 2021

Clinical Cancer Research

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Purpose: Pancreatic cancer is an aggressive disease associated with a poor 5-year overall survival. Most patients are ineligible for surgery due to late diagnosis and are treated primarily with chemotherapy with very limited success. Pancreatic cancer is relatively insensitive to chemotherapy due to multiple factors, including reduced bioavailability of drugs to tumor cells. One strategy to improve drug efficacy with reduced toxicity is the development of antibody-drug conjugates (ADC), which have now been used successfully to treat both solid and liquid tumors. Here, we evaluate the efficacy of TR1801-ADC, a newly developed ADC composed of a MET antibody conjugated to the highly potent pyrrolobenzodiazepine toxin-linker, tesirine.Experimental Design: We first evaluated MET expression and subcellular localization in pancreatic cancer cell lines, human tumors, and patient-derived xenografts (PDX). We then tested TR1801-ADC efficacy in vitro in pancreatic cancer cell lines. Preclinical evaluation of TR1801-ADC efficacy was conducted on PDXs selected on the basis of their MET expression level.Results: We show that MET is highly expressed and located at the plasma membrane of pancreatic cancer cells. We found that TR1801-ADC induces a specific cytotoxicity in pancreatic cancer cell lines and a profound tumor growth inhibition, even in a gemcitabine-resistant tumor. We also noted synergism between TR1801-ADC and gemcitabine in vitro and an improved response to the combination in vivo.Conclusions: Together, these results suggest the promise of agents such as TR1801-ADC as a novel approach to the treatment of pancreatic cancer.

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Section: Quantitative Flow Cytometrymentioning

confidence: 99%

A MET Targeting Antibody–Drug Conjugate Overcomes Gemcitabine Resistance in Pancreatic Cancer

Cazes

Betancourt

Esparza

et al. 2021

Clinical Cancer Research

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“…Furthermore, ABBV‐399 was valuable for those reluctant to c‐Met pathway suppression therapies as well, with significantly shrinking the tumor size in xenograft models. Similarly, a recently developed ADC, P3D12‐vc‐MMAF, which utilized a high‐affinity c‐Met antibody (P3D12) conjugated to the tubulin inhibitor toxin MMAF, exhibited robust suppression of tumor growth both in c‐Met amplified and non‐amplified cancers 82 …”

Section: Potential Anticancer Strategies By Hgf/c‐met Regulationmentioning

confidence: 99%

Targeting hepatocyte growth factor/c‐mesenchymal–epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies

Chen

Lai

2020

Medicinal Research Reviews

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Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. The outcome of current standard treatments, as well as targeted therapies in advanced stages, are still unsatisfactory. Attention has been drawn to novel strategies for better treatment efficacy. Hepatocyte growth factor/c‐mesenchymal–epithelial transition factor (HGF/c‐Met) axis has been known as an essential element in the regulation of liver diseases and as an oncogenic factor in HCC. In this review, we collected the evidence of HGF/c‐Met as a tumor progression and prognostic marker, discussed the anti‐c‐Met therapy in vitro, summarized the outcome of c‐Met inhibitors in clinical trials, and identified potential impetus for future anti‐c‐Met treatments. We also analyzed the inconsistency of HGF/c‐Met from various publications and offered reasonable explanations based on the current understanding in this area. In conclusion, HGF/c‐Met plays a crucial role in the progression and growth of HCC, and the strategies to inhibit this pathway may facilitate the development of new and effective treatments for HCC patients.

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“…TR1801 is currently in phase I clinical trials (NCT03859752). The anti-MET hD12 is derived from mouse anti-MET mAb P3D12 (IgG1) and was based on its strong binding affinity, robust induction of receptor internalization, and minimal agonistic activities [ 86 ]. P3D12 and another anti-MET mAb P1E2 have been conjugated with MMAF to form ADCs P3D12-vc-MMAF and P1E2-vc-MMAF, which have superior potencies in MET amplified and non-amplified cancer models [ 86 ].…”

Section: Introductionmentioning

confidence: 99%

“…The anti-MET hD12 is derived from mouse anti-MET mAb P3D12 (IgG1) and was based on its strong binding affinity, robust induction of receptor internalization, and minimal agonistic activities [ 86 ]. P3D12 and another anti-MET mAb P1E2 have been conjugated with MMAF to form ADCs P3D12-vc-MMAF and P1E2-vc-MMAF, which have superior potencies in MET amplified and non-amplified cancer models [ 86 ]. Modification of P3D12 through humanization, IgG subclass switching, and site-specific cysteine incorporation results in hD12 for TR1801-ADC development [ 58 ].…”

Section: Introductionmentioning

confidence: 99%

“…Also, CRAC cell lines expressing low to moderate levels of MET (5,000 to 90,000 MET receptor molecules per cell) are sensitive to TR1801-ADC [ 58 ]. In a comparative analysis, TR1801-ADC is far more efficient than P3D12-vc-MMAF and another anti-MET ADC MET-vc-MMAE in killing MET expressing cancer cells [ 58 , 86 ]. It appears from the in vitro studies that among all anti-MET ACDs tested, TR1801-ADC is the most potent in killing cancer cells expressing variable levels of MET.…”

Section: Introductionmentioning

confidence: 99%

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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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A novel non-agonist c-Met antibody drug conjugate with superior potency over a c-Met tyrosine kinase inhibitor in c-Met amplified and non-amplified cancers

Cited by 14 publications

References 39 publications

A MET Targeting Antibody–Drug Conjugate Overcomes Gemcitabine Resistance in Pancreatic Cancer

A MET Targeting Antibody–Drug Conjugate Overcomes Gemcitabine Resistance in Pancreatic Cancer

Targeting hepatocyte growth factor/c‐mesenchymal–epithelial transition factor axis in hepatocellular carcinoma: Rationale and therapeutic strategies

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

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