A trispecific antibody targeting EGFR/cMET/VEGF-A demonstrates multiple mechanisms of action to inhibit wild-type and mutant NSCLC animal models
IntroductionNon-small cell lung cancer (NSCLC) patients who do not respond to standard of care treatment can have activating mutations in the epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition factor (cMET) signaling pathways, as well as having enhanced levels of vascular...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1533059/full |
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| author | Ying Jin Ping Sun Peng Chen Yuqiang Xu Guangmao Mu Zhengxia Zha Simin Wu Meixia Fu Hao Jiang Sheng Huang Fulai Zhou Chao Han Chao Han Mark L. Chiu Mark L. Chiu |
| author_facet | Ying Jin Ping Sun Peng Chen Yuqiang Xu Guangmao Mu Zhengxia Zha Simin Wu Meixia Fu Hao Jiang Sheng Huang Fulai Zhou Chao Han Chao Han Mark L. Chiu Mark L. Chiu |
| author_sort | Ying Jin |
| collection | DOAJ |
| description | IntroductionNon-small cell lung cancer (NSCLC) patients who do not respond to standard of care treatment can have activating mutations in the epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition factor (cMET) signaling pathways, as well as having enhanced levels of vascular endothelial growth factor (VEGF). To combat such resistance mechanisms, TAVO412, was engineered to control aberrant cMET, VEGF-A, and EGFR activities.MethodsIn vitro assays assessed TAVO412’s cell binding, ligand blockade, phosphorylation inhibition, and Fc effector functions. In vivo efficacy was evaluated in NSCLC xenograft models, with subsequent tumor resection for ex vivo quantification of EGFR and cMET levels.ResultsTAVO412 robustly suppressed ligand-induced phosphorylation of EGFR and cMET in NSCLC cell lines. TAVO412 demonstrated more potent antitumor activity than amivantamab and cetuximab in NSCLC xenograft models using cell lines with varying levels of mutant and wild-type EGFR and cMET. In addition, TAVO412 had both EGFR/ cMET receptor degradation and enhanced Fc effector functions for tumor cell cytotoxicity. Moreover, TAVO412 in combination with osimertinib, lazertinib, docetaxel, and radiotherapy, resulted in complete and durable regression of NSCLC xenograft tumors.DiscussionThese findings highlight TAVO412 as a promising therapeutic agent with multiple mechanisms of action and strong potential for synergistic combinations in NSCLC treatment. |
| format | Article |
| id | doaj-art-1aaccb5d5e654b329f31e1bb50e8c2f5 |
| institution | OA Journals |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj-art-1aaccb5d5e654b329f31e1bb50e8c2f52025-08-20T01:50:59ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-05-011510.3389/fonc.2025.15330591533059A trispecific antibody targeting EGFR/cMET/VEGF-A demonstrates multiple mechanisms of action to inhibit wild-type and mutant NSCLC animal modelsYing Jin0Ping Sun1Peng Chen2Yuqiang Xu3Guangmao Mu4Zhengxia Zha5Simin Wu6Meixia Fu7Hao Jiang8Sheng Huang9Fulai Zhou10Chao Han11Chao Han12Mark L. Chiu13Mark L. Chiu14Research & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development, Tavotek Biotherapeutics, Spring House, PA, United StatesResearch & Development Department, Tavotek Biotherapeutics, Suzhou, Jiangsu, ChinaResearch & Development, Tavotek Biotherapeutics, Spring House, PA, United StatesIntroductionNon-small cell lung cancer (NSCLC) patients who do not respond to standard of care treatment can have activating mutations in the epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition factor (cMET) signaling pathways, as well as having enhanced levels of vascular endothelial growth factor (VEGF). To combat such resistance mechanisms, TAVO412, was engineered to control aberrant cMET, VEGF-A, and EGFR activities.MethodsIn vitro assays assessed TAVO412’s cell binding, ligand blockade, phosphorylation inhibition, and Fc effector functions. In vivo efficacy was evaluated in NSCLC xenograft models, with subsequent tumor resection for ex vivo quantification of EGFR and cMET levels.ResultsTAVO412 robustly suppressed ligand-induced phosphorylation of EGFR and cMET in NSCLC cell lines. TAVO412 demonstrated more potent antitumor activity than amivantamab and cetuximab in NSCLC xenograft models using cell lines with varying levels of mutant and wild-type EGFR and cMET. In addition, TAVO412 had both EGFR/ cMET receptor degradation and enhanced Fc effector functions for tumor cell cytotoxicity. Moreover, TAVO412 in combination with osimertinib, lazertinib, docetaxel, and radiotherapy, resulted in complete and durable regression of NSCLC xenograft tumors.DiscussionThese findings highlight TAVO412 as a promising therapeutic agent with multiple mechanisms of action and strong potential for synergistic combinations in NSCLC treatment.https://www.frontiersin.org/articles/10.3389/fonc.2025.1533059/fulltrispecific antibodiesNSCLCEGFR cancer cells +cmetVEGF |
| spellingShingle | Ying Jin Ping Sun Peng Chen Yuqiang Xu Guangmao Mu Zhengxia Zha Simin Wu Meixia Fu Hao Jiang Sheng Huang Fulai Zhou Chao Han Chao Han Mark L. Chiu Mark L. Chiu A trispecific antibody targeting EGFR/cMET/VEGF-A demonstrates multiple mechanisms of action to inhibit wild-type and mutant NSCLC animal models Frontiers in Oncology trispecific antibodies NSCLC EGFR cancer cells + cmet VEGF |
| title | A trispecific antibody targeting EGFR/cMET/VEGF-A demonstrates multiple mechanisms of action to inhibit wild-type and mutant NSCLC animal models |
| title_full | A trispecific antibody targeting EGFR/cMET/VEGF-A demonstrates multiple mechanisms of action to inhibit wild-type and mutant NSCLC animal models |
| title_fullStr | A trispecific antibody targeting EGFR/cMET/VEGF-A demonstrates multiple mechanisms of action to inhibit wild-type and mutant NSCLC animal models |
| title_full_unstemmed | A trispecific antibody targeting EGFR/cMET/VEGF-A demonstrates multiple mechanisms of action to inhibit wild-type and mutant NSCLC animal models |
| title_short | A trispecific antibody targeting EGFR/cMET/VEGF-A demonstrates multiple mechanisms of action to inhibit wild-type and mutant NSCLC animal models |
| title_sort | trispecific antibody targeting egfr cmet vegf a demonstrates multiple mechanisms of action to inhibit wild type and mutant nsclc animal models |
| topic | trispecific antibodies NSCLC EGFR cancer cells + cmet VEGF |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1533059/full |
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