Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms

Grandal, Michael V.; Havrylov, Serhiy; Poulsen, Thomas Tuxen; Koefoed, Klaus; Dahlman, Anna; Galler, Gunther R.; Conrotto, Paolo; Collins, Stuart G.; Eriksen, Kathrine Krageskov; Kaufman, Dafna; Woude, George F. Vande; Jacobsen, Helle J.; Horak, Ivan D.; Kragh, Michael; Lantto, Johan; Bouquin, Thomas; Park, Morag; Pedersen, Mikkel W.

doi:10.1158/1535-7163.mct-17-0374

Cited by 25 publications

(32 citation statements)

References 49 publications

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“…The concept of enhancing the internalization and degradation of receptors by promoting the formation of antibody/receptor clusters on the cell surface has been explored fairly extensively (19,20,31,32,(37)(38)(39)(40)(41)(42)(43). The ability of antibodies to promote receptor degradation could result from an increased rate of receptor internalization, a decrease in receptor recycling or both.…”

Section: Discussionmentioning

confidence: 99%

“…In an attempt to block MET function more effectively, several groups have generated antibodies (emibetuzumab, ABT-700, ARGX-111, SAIT301, and Sym015) that promote MET degradation, enabling efficacy in MET-amplified tumor models where MET signals, at least partially, in a ligand-independent fashion (15)(16)(17)(18)(19)(20). Furthermore, several of these MET antibodies also show efficacy in preclinical models that harbor MET-ex14 mutations (15,17,20,21).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Various strategies have been developed to improve the efficacy of c‐MET inhibitors. For example, a mixture of two monoclonal antibodies against c‐MET (Sym015) has also been developed . In addition to targeting MET , downstream molecules have also been targeted and immunotherapy drugs are under development.…”

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confidence: 99%

Forty‐nine gastric cancer cell lines with integrative genomic profiling for development of c‐MET inhibitor

Kim

Kang

Kwon

et al. 2018

Intl Journal of Cancer

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Receptor tyrosine kinase MET (c-MET) has received considerable attention as a potential target for gastric cancer (GC) therapy and a number of c-MET inhibitors have been developed. For successful drug development, proper preclinical studies especially using patient derived cancer cell lines are very important. We profiled MET and MET-related characteristics in 49 GC cell lines to utilize them as models in preclinical studies of GC. Forty-nine cell lines were analyzed for genetic, biological, and molecular status to characterize MET and MET-related molecules. Four c-MET inhibitors were tested to elucidate the dependency on MET pathway in the 49 GC cell lines. Six of 49 cell lines were MET amplified with overexpression of c-MET and p-MET. The variants of MET were not associated with c-MET expression or amplification. Hs746T showed an exon 14 deletion in conjunction with MET amplification. The cell lines were divided into 6 MET amplified, 2 c-MET overexpressed, 2 hepatocyte growth factor (HGF) overexpressed, and 39 MET-negative subgroups. Except tivantinib, the c-MET inhibitors showed higher inhibition (%) in MET amplified than in MET nonamplified cell lines that MET amplified cell lines showed MET pathway dependency. However, the c-MET overexpressed and HGF overexpressed cell lines showed moderate dependency on MET pathway. Well-characterized cell lines are very important in studying drug development. Our 49 GC cell lines had various characteristics of MET and MET-related molecules and MET pathway dependency. These provide a promising platform for development of various RTK inhibitors including c-MET inhibitors.

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“…Because of the superiority of Sym015 over emibetuzumab in vivo (Fig. 1C and D), and previous reports that Sym015 induces secondary effector functions (19,20), it was speculated that this might also contribute to the effect of Sym015 in resistant settings. The ability of Sym015 to induce ADCC was therefore investigated.…”

Section: Sym015 Overcomes Emibetuzumab Resistance In Vivo Mainly Due mentioning

confidence: 99%

“…Their diverse mechanisms of action include ligand blockade, internalization/ degradation of MET, and activation of secondary effector functions such as antibody-dependent cellular cytotoxicity (ADCC). All these antibodies demonstrated promising preclinical results, and some have shown activity in early clinical settings (15)(16)(17)(18)(19)(20)(21)(22). Despite huge efforts devoted to development of MET-targeted agents, disappointing results were obtained in later clinical trials, including failure of onartuzumab in phase III and limited activity of emibetuzumab in both NSCLC and gastric cancer patients in phase II (23)(24)(25)(26)(27), warranting more in-depth investigation of mechanisms of resistance to MET-targeted agents.…”

Section: Introductionmentioning

confidence: 99%

Acquired Resistance to a MET Antibody In Vivo Can Be Overcome by the MET Antibody Mixture Sym015

Pollmann

Calvert

Rao

et al. 2018

Molecular Cancer Therapeutics

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Failure of clinical trials due to development of resistance to MET-targeting therapeutic agents is an emerging problem. Mechanisms of acquired resistance to MET tyrosine kinase inhibitors are well described, whereas characterization of mechanisms of resistance toward MET-targeting antibodies is limited. This study investigated mechanisms underlying resistance to two antibody therapeutics currently in clinical development: an analogue of the MET-targeting antibody emibetuzumab and Sym015, a mixture of two antibodies targeting nonoverlapping epitopes of MET. Upon long-term treatment of a -amplified gastric cancer xenograft model (SNU-5), emibetuzumab-resistant, but not Sym015-resistant, tumors emerged. Resistant tumors were isolated and used to establish resistant cell lines. Characterization of both tumors and cell lines using extensive protein and signaling pathway activation mapping along with next-generation sequencing revealed two distinct resistance profiles, one involving loss and the other involving activation of the PI3K pathway, likely via and copy number gains. loss left one model unaffected by PI3K/AKT targeting but sensitive to mTOR targeting, while the PI3K pathway-activated model was partly sensitive to targeting of multiple PI3K pathway proteins. Importantly, both resistant models were sensitive to treatment with Sym015 due to antibody-dependent cellular cytotoxicity-mediated tumor growth inhibition, MET degradation, and signaling inhibition. Taken together, our data provide key insights into potential mechanisms of resistance to a single MET-targeting antibody, demonstrate superiority of Sym015 in preventing acquired resistance, and confirm Sym015 antitumor activity in tumors resistant to a single MET antibody. .

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Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms

Cited by 25 publications

References 49 publications

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

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

Forty‐nine gastric cancer cell lines with integrative genomic profiling for development of c‐MET inhibitor

Acquired Resistance to a MET Antibody In Vivo Can Be Overcome by the MET Antibody Mixture Sym015

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