A phase I, first-in-human study of argx-111, a monoclonal antibody targeting c-met in patients with solid tumors.

Aftimos, Philippe; Barthélémy, Philippe; Rolfo, Christian; Hanssens, Valérie; Jonge, Natalie De; Silence, Karen; Dreier, Torsten; Haard, Hans de; Peeters, Marc; Thibault, Alain; Awada, Ahmad

doi:10.1200/jco.2015.33.15_suppl.2580

Cited by 11 publications

(10 citation statements)

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“…As mentioned previously, a number of antibodies targeting MET are currently being evaluated in clinical trials (13,14,(16)(17)(18)(19)(20)(21)(22), but none of these agents are commercially available. Here, we chose to compare Sym015 with a cloned analogue of emibetuzumab, one of the most clinically advanced MET-targeting therapeutic antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, other antibodies targeting MET have entered the clinic. These include ABT-700, which has demonstrated activity in patients with MET-amplified tumors (17,18), and ARGX-111, which has been glycoengineered to enhance secondary effector functions and also demonstrated efficacy in a single patient with MET gene amplification (19,20). One of the most advanced MET-targeting antibody therapeutics in clinical development is emibetuzumab (LY2875358), a humanized IgG4 reported to block ligand binding and induce receptor internalization (21).…”

Section: Introductionmentioning

confidence: 99%

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Sym015: A Highly Efficacious Antibody Mixture against MET-Amplified Tumors

Poulsen

Grandal

Skartved

et al. 2017

Clinical Cancer Research

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Activation of the receptor tyrosine kinase MET is associated with poor clinical outcome in certain cancers. To target MET more effectively, we developed an antagonistic antibody mixture, Sym015, consisting of two humanized mAbs directed against nonoverlapping epitopes of MET. We screened a large panel of well-annotated human cancer cell lines and identified a subset with highly elevated MET expression. In particular, cell lines of lung cancer and gastric cancer origin demonstrated high MET expression and activation, and Sym015 triggered degradation of MET and significantly inhibited growth of these cell lines. Next, we tested Sym015 in patient- and cell line-derived xenograft models with high MET expression and/or exon 14 skipping alterations, and in models harboring amplification as a mechanism of resistance to EGFR-targeting agents. Sym015 effectively inhibited tumor growth in all these models and was superior to an analogue of emibetuzumab, a monoclonal IgG4 antibody against MET currently in clinical development. Sym015 also induced antibody-dependent cellular cytotoxicity (ADCC) , suggesting that secondary effector functions contribute to the efficacy of Sym015.Retrospectively, all responsive, high MET-expressing models were scored as highly-amplified by hybridization, pointing to amplification as a predictive biomarker for efficacy. Preclinical toxicology studies in monkeys showed that Sym015 was well tolerated, with a pharmacokinetic profile supporting administration of Sym015 every second or third week in humans. The preclinical efficacy and safety data provide a clear rationale for the ongoing clinical studies of Sym015 in patients with -amplified tumors..

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sym015: A Highly Efficacious Antibody Mixture against MET-Amplified Tumors

Poulsen

Grandal

Skartved

et al. 2017

Clinical Cancer Research

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“…Furthermore, several of these MET antibodies also show efficacy in preclinical models that harbor MET-ex14 mutations (15,17,20,21). Although multiple MET antibodies have entered the clinic in recent years (21)(22)(23)(24)(25)(26)(27), it is unclear how effective these antibodies will be in MET-altered cancers.…”

Section: Introductionmentioning

confidence: 99%

A Biparatopic Antibody That Modulates MET Trafficking Exhibits Enhanced Efficacy Compared with Parental Antibodies in MET-Driven Tumor Models

DaSilva

Yang

Bay

et al. 2020

Clinical Cancer Research

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Purpose: Recent clinical data demonstrate that tumors harboring MET genetic alterations (exon 14 skip mutations and/or gene amplification) respond to small-molecule tyrosine kinase inhibitors, validating MET as a therapeutic target. Although antibody-mediated blockade of the MET pathway has not been successful in the clinic, the failures are likely the result of inadequate patient selection strategies as well as suboptimal antibody design. Thus, our goal was to generate a novel MET blocking antibody with enhanced efficacy. Experimental Design: Here, we describe the activity of a biparatopic METÂMET antibody that recognizes two distinct epitopes in the MET Sema domain. We use a combination of in vitro assays and tumor models to characterize the effect of our antibody on MET signaling, MET intracellular trafficking, and the growth of METdependent cells/tumors. Results: In MET-driven tumor models, our biparatopic antibody exhibits significantly better activity than either of the parental antibodies or the mixture of the two parental antibodies and outperforms several clinical-stage MET antibodies. Mechanistically, the biparatopic antibody inhibits MET recycling, thereby promoting lysosomal trafficking and degradation of MET. In contrast to the parental antibodies, the biparatopic antibody fails to activate METdependent biological responses, consistent with the observation that it recycles inefficiently and induces very transient downstream signaling. Conclusions: Our results provide strong support for the notion that biparatopic antibodies are a promising therapeutic modality, potentially having greater efficacy than that predicted from the properties of the parental antibodies.

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“… 28 – 33 , 93 – 95 Moreover, outcomes from clinical studies at different phases are disappointing. 93 – 100 Currently, conventional anti-MET TMABs, although under clinical trials for almost 10 years, have not been approved for clinical application, mainly due to the lack of therapeutic efficacy but not pharmacokinetic or toxicological issues. 93 – 100 …”

Section: Met Therapeutics With Different Mechanisms Of Actionmentioning

confidence: 99%

Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase

2021

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Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants contributing to cancerous initiation, progression, malignancy, and stemness. Moreover, integration of the MET pathway into the cellular signaling network as an addiction mechanism for survival has made this receptor an attractive pharmaceutical target for oncological intervention. For the last 20 years, MET-targeting small-molecule kinase inhibitors (SMKIs), conventional therapeutic monoclonal antibodies (TMABs), and antibody-based biotherapeutics such as bispecific antibodies, antibody–drug conjugates (ADC), and dual-targeting ADCs have been under intensive investigation. Outcomes from preclinical studies and clinical trials are mixed with certain successes but also various setbacks. Due to the complex nature of MET dysregulation with multiple facets and underlying mechanisms, mechanism-based validation of MET-targeting therapeutics is crucial for the selection and validation of lead candidates for clinical trials. In this review, we discuss the importance of various types of mechanism-based pharmaceutical models in evaluation of different types of MET-targeting therapeutics. The advantages and disadvantages of these mechanism-based strategies for SMKIs, conventional TMABs, and antibody-based biotherapeutics are analyzed. The demand for establishing new strategies suitable for validating novel biotherapeutics is also discussed. The information summarized should provide a pharmaceutical guideline for selection and validation of MET-targeting therapeutics for clinical application in the future.

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A phase I, first-in-human study of argx-111, a monoclonal antibody targeting c-met in patients with solid tumors.

Cited by 11 publications

References 0 publications

Sym015: A Highly Efficacious Antibody Mixture against MET-Amplified Tumors

Sym015: A Highly Efficacious Antibody Mixture against MET-Amplified Tumors

A Biparatopic Antibody That Modulates MET Trafficking Exhibits Enhanced Efficacy Compared with Parental Antibodies in MET-Driven Tumor Models

Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase

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