Skip to main content
SpringerLink
Log in

Progress of antibody–drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies

  • Review Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

The cell-surface receptor tyrosine kinase c-mesenchymal-epithelial transition factor (c-Met) is overexpressed in a wide range of solid tumors, making it an appropriate target antigen for the development of anticancer therapeutics. Various antitumor c-Met-targeting therapies (including monoclonal antibodies [mAbs] and tyrosine kinases) have been developed for the treatment of c-Met-overexpressing tumors, most of which have so far failed to enter the clinic because of their efficacy and complications. Antibody–drug conjugates (ADCs), a new emerging class of cancer therapeutic agents that harness the target specificity of mAbs to deliver highly potent small molecules to the tumor with the minimal damage to normal cells, could be an attractive therapeutic approach to circumvent these limitations in patients with c-Met-overexpressing tumors. Of great note, there are currently nine c-Met-targeting ADCs being examined in different phases of clinical studies as well as eight preclinical studies for treating various solid tumors. The purpose of this study is to present a broad overview of clinical- and preclinical-stage c-Met-targeting ADCs.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The data included in this review were retrieved from published studies.

References

  1. Kim KH, Kim H. Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy. Exp Mol Med. 2017;49(3): e307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Tempest PR, Stratton MR, Cooper CS. Structure of the met protein and variation of met protein kinase activity among human tumour cell lines. Br J Cancer. 1988;58(1):3–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gherardi E, Birchmeier W, Birchmeier C, Vande WG. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012;12(2):89–103.

    Article  CAS  PubMed  Google Scholar 

  4. Mo HN, Liu P. Targeting MET in cancer therapy. Chronic Dis Transl Med. 2017;3(3):148–53.

    PubMed  PubMed Central  Google Scholar 

  5. Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018;17(1):45.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Donate LE, Gherardi E, Srinivasan N, Sowdhamini R, Aparicio S, Blundell TL. Molecular evolution and domain structure of plasminogen-related growth factors (HGF/SF and HGF1/MSP). Protein Sci. 1994;3(12):2378–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4(12):915–25.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang Y, Guo L, Li Y, Feng GH, Teng F, Li W, et al. MicroRNA-494 promotes cancer progression and targets adenomatous polyposis coli in colorectal cancer. Mol Cancer. 2018;17(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhang Z, Li D, Yun H, Tong J, Liu W, Chai K, et al. Opportunities and challenges of targeting c-Met in the treatment of digestive tumors. Front Oncol. 2022;12: 923260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gu FF, Zhang Y, Liu YY, Hong XH, Liang JY, Tong F, et al. Lung adenocarcinoma harboring concomitant SPTBN1-ALK fusion, c-Met overexpression, and HER-2 amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy. J Hematol Oncol. 2016;9(1):66.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225(1):1–26.

    Article  CAS  PubMed  Google Scholar 

  12. Nakamura M, Ono YJ, Kanemura M, Tanaka T, Hayashi M, Terai Y, et al. Hepatocyte growth factor secreted by ovarian cancer cells stimulates peritoneal implantation via the mesothelial-mesenchymal transition of the peritoneum. Gynecol Oncol. 2015;139(2):345–54.

    Article  CAS  PubMed  Google Scholar 

  13. Zeng ZS, Weiser MR, Kuntz E, Chen CT, Khan SA, Forslund A, et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 2008;265(2):258–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mizuno S, Nakamura T. HGF-MET cascade, a key target for inhibiting cancer metastasis: the impact of NK4 discovery on cancer biology and therapeutics. Int J Mol Sci. 2013;14(1):888–919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sattler M, Reddy MM, Hasina R, Gangadhar T, Salgia R. The role of the c-Met pathway in lung cancer and the potential for targeted therapy. Ther Adv Med Oncol. 2011;3(4):171–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Blumenschein GR Jr, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol. 2012;30(26):3287–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene. 2001;20(56):8125–35.

    Article  CAS  PubMed  Google Scholar 

  18. Koochekpour S, Jeffers M, Rulong S, Taylor G, Klineberg E, Hudson EA, et al. Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res. 1997;57(23):5391–8.

    CAS  PubMed  Google Scholar 

  19. Ma PC, Jagadeeswaran R, Jagadeesh S, Tretiakova MS, Nallasura V, Fox EA, et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 2005;65(4):1479–88.

    Article  CAS  PubMed  Google Scholar 

  20. Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr, et al. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2013;31(32):4105–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fujita S, Sugano K. Expression of c-met proto-oncogene in primary colorectal cancer and liver metastases. Jpn J Clin Oncol. 1997;27(6):378–83.

    Article  CAS  PubMed  Google Scholar 

  22. Resnick MB, Routhier J, Konkin T, Sabo E, Pricolo VE. Epidermal growth factor receptor, c-MET, beta-catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin Cancer Res. 2004;10(9):3069–75.

    Article  CAS  PubMed  Google Scholar 

  23. Lengyel E, Prechtel D, Resau JH, Gauger K, Welk A, Lindemann K, et al. C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer. 2005;113(4):678–82.

    Article  CAS  PubMed  Google Scholar 

  24. Sawada K, Radjabi AR, Shinomiya N, Kistner E, Kenny H, Becker AR, et al. c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res. 2007;67(4):1670–9.

    Article  CAS  PubMed  Google Scholar 

  25. Verhoef EI, Kolijn K, De Herdt MJ, van der Steen B, Hoogland AM, Sleddens HF, et al. MET expression during prostate cancer progression. Oncotarget. 2016;7(21):31029–36.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Cazes A, Betancourt O, Esparza E, Mose ES, Jaquish D, Wong E, et al. A MET targeting antibody-drug conjugate overcomes gemcitabine resistance in pancreatic cancer. Clin Cancer Res. 2021;27(7):2100–10.

    Article  CAS  PubMed  Google Scholar 

  27. Lee HE, Kim MA, Lee HS, Jung EJ, Yang HK, Lee BL, et al. MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br J Cancer. 2012;107(2):325–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ansell PJ, Camidge DR, Baijal S, Xia X, Vasilopoulos A, Li M, et al. Evaluation of the prevalence of MET and protein tyrosine kinase 7 expression in non-small cell lung cancer to evaluate overlap of ADC antigens. J Clin Oncol. 2023;41(16_suppl):e21105–e.

    Article  Google Scholar 

  29. Lin E, Lo Y, Parikh K, Smrecek N, Goliwas K, Deshane J, et al. 4P Optimizing utilization of antibody-drug conjugates in NSCLC by identification of subsets using RNA sequencing. ESMO Open. 2023;8(1).

  30. Liu X, Newton RC, Scherle PA. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med. 2010;16(1):37–45.

    Article  CAS  PubMed  Google Scholar 

  31. Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer. 2010;46(7):1260–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Peters S, Adjei AA. MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol. 2012;9(6):314–26.

    Article  CAS  PubMed  Google Scholar 

  33. Lee D, Sung ES, Ahn JH, An S, Huh J, You WK. Development of antibody-based c-Met inhibitors for targeted cancer therapy. Immunotargets Ther. 2015;4:35–44.

    PubMed  PubMed Central  Google Scholar 

  34. Parikh PK, Ghate MD. Recent advances in the discovery of small molecule c-Met Kinase inhibitors. Eur J Med Chem. 2018;143:1103–38.

    Article  CAS  PubMed  Google Scholar 

  35. Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol. 2011;6(5):942–6.

    Article  PubMed  Google Scholar 

  36. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298–308.

    Article  CAS  PubMed  Google Scholar 

  37. Yap TA, Olmos D, Brunetto AT, Tunariu N, Barriuso J, Riisnaes R, et al. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol. 2011;29(10):1271–9.

    Article  CAS  PubMed  Google Scholar 

  38. Aoyama A, Katayama R, Oh-Hara T, Sato S, Okuno Y, Fujita N. Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter-mediated drug resistance. Mol Cancer Ther. 2014;13(12):2978–90.

    Article  CAS  PubMed  Google Scholar 

  39. Sheridan C. Genentech to salvage anti-MET antibody with subgroup analysis. Nat Biotechnol. 2014;32(5):399–400.

    Article  CAS  PubMed  Google Scholar 

  40. Garber K. MET inhibitors start on road to recovery. Nat Rev Drug Discov. 2014;13(8):563–5.

    Article  CAS  PubMed  Google Scholar 

  41. Grullich C. Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. Recent Results Cancer Res. 2014;201:207–14.

    Article  PubMed  Google Scholar 

  42. Heigener DF, Reck M. Crizotinib. Recent Results Cancer Res. 2014;201:197–205.

    Article  CAS  PubMed  Google Scholar 

  43. Monzavi N, Zargar SJ, Gheibi N, Azad M, Rahmani B. Angiopoietin-like protein 8 (betatrophin) may inhibit hepatocellular carcinoma through suppressing of the Wnt signaling pathway. Iran J Basic Med Sci. 2019;22(10):1166–71.

    PubMed  PubMed Central  Google Scholar 

  44. Asadian S, Piryaei A, Gheibi N, Aziz Kalantari B, Reza Davarpanah M, Azad M, et al. Rhenium Perrhenate ((188)ReO(4)) induced apoptosis and reduced cancerous phenotype in liver cancer cells. Cells. 2022;11(2).

  45. Fujiwara Y, Kenmotsu H, Yamamoto N, Shimizu T, Yonemori K, Ocampo C, et al. Phase 1 study of telisotuzumab vedotin in Japanese patients with advanced solid tumors. Cancer Med. 2021;10(7):2350–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang Y, Jain RK, Zhu M. Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment. Biomedicines. 2015;3(1):149–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pietronave S, Forte G, Locarno D, Merlin S, Zamperone A, Nicotra G, et al. Agonist monoclonal antibodies against HGF receptor protect cardiac muscle cells from apoptosis. Am J Physiol Heart Circ Physiol. 2010;298(4):H1155–65.

    Article  CAS  PubMed  Google Scholar 

  48. Prat M, Crepaldi T, Pennacchietti S, Bussolino F, Comoglio PM. Agonistic monoclonal antibodies against the Met receptor dissect the biological responses to HGF. J Cell Sci. 1998;111(Pt 2):237–47.

    Article  CAS  PubMed  Google Scholar 

  49. Jin H, Yang R, Zheng Z, Romero M, Ross J, Bou-Reslan H, et al. MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res. 2008;68(11):4360–8.

    Article  CAS  PubMed  Google Scholar 

  50. Patnaik A, Weiss GJ, Papadopoulos KP, Hofmeister CC, Tibes R, Tolcher A, et al. Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma. Br J Cancer. 2014;111(2):272–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jun HT, Sun J, Rex K, Radinsky R, Kendall R, Coxon A, et al. AMG 102, a fully human anti-hepatocyte growth factor/scatter factor neutralizing antibody, enhances the efficacy of temozolomide or docetaxel in U-87 MG cells and xenografts. Clin Cancer Res. 2007;13(22 Pt 1):6735–42.

    Article  CAS  PubMed  Google Scholar 

  52. Fujita R, Blot V, Wong E, Stewart C, Lieuw V, Richardson R, et al. 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. Cancer Biol Ther. 2020;21(6):549–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lai KC, Muvaffak A, Li M, Themeles M, Sikka S, Donahue K, et al. Abstract 45: In vitro and in vivo activity of a novel c-Met-targeting antibody-drug conjugate using a DNA-alkylating, indolinobenzodiazepine payload. Cancer Res. 2017;77(13_Supplement):45-.

    Article  Google Scholar 

  54. Yaghoubi S, Karimi MH, Lotfinia M, Gharibi T, Mahi-Birjand M, Kavi E, et al. Potential drugs used in the antibody-drug conjugate (ADC) architecture for cancer therapy. J Cell Physiol. 2020;235(1):31–64.

    Article  CAS  PubMed  Google Scholar 

  55. Abdollahpour-Alitappeh M, Lotfinia M, Gharibi T, Mardaneh J, Farhadihosseinabadi B, Larki P, et al. Antibody-drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes. J Cell Physiol. 2019;234(5):5628–42.

    Article  CAS  PubMed  Google Scholar 

  56. Najminejad Z, Dehghani F, Mirzaei Y, Mer AH, Saghi SA, Abdolvahab MH, et al. Clinical perspective: Antibody-drug conjugates for the treatment of HER2-positive breast cancer. Mol Ther. 2023;31(7):1874–903.

    Article  CAS  PubMed  Google Scholar 

  57. Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Esapa B, Jiang J, Cheung A, Chenoweth A, Thurston DE, Karagiannis SN. Target antigen attributes and their contributions to clinically approved antibody-drug conjugates (ADCs) in haematopoietic and solid cancers. Cancers (Basel). 2023;15(6).

  59. Marcucci F, Caserta CA, Romeo E, Rumio C. Antibody-drug conjugates (ADC) against cancer stem-like cells (CSC)-is there still room for optimism? Front Oncol. 2019;9:167.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Fan J, Zhuang X, Yang X, Xu Y, Zhou Z, Pan L, et al. A multivalent biparatopic EGFR-targeting nanobody drug conjugate displays potent anticancer activity in solid tumor models. Signal Transduct Target Ther. 2021;6(1):320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Joubert N, Beck A, Dumontet C, Denevault-Sabourin C. Antibody-drug conjugates: The last decade. Pharmaceuticals (Basel). 2020;13(9).

  62. Hussain AF, Grimm A, Sheng W, Zhang C, Al-Rawe M, Brautigam K, et al. Toward homogenous antibody drug conjugates using enzyme-based conjugation approaches. Pharmaceuticals (Basel). 2021;14(4).

  63. Conilh L, Sadilkova L, Viricel W, Dumontet C. Payload diversification: a key step in the development of antibody–drug conjugates. J Hematol Oncol. 2023;16(1):3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Strickler JH, Weekes CD, Nemunaitis J, Ramanathan RK, Heist RS, Morgensztern D, et al. First-in-human phase I, dose-escalation and -expansion study of telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, in patients with advanced solid tumors. J Clin Oncol. 2018;36(33):3298–306.

    Article  CAS  PubMed  Google Scholar 

  65. Wang J, Anderson MG, Oleksijew A, Vaidya KS, Boghaert ER, Tucker L, et al. ABBV-399, a c-Met antibody-drug conjugate that targets both MET-amplified and c-Met-overexpressing tumors, irrespective of MET pathway dependence. Clin Cancer Res. 2017;23(4):992–1000.

    Article  CAS  PubMed  Google Scholar 

  66. Camidge DR, Morgensztern D, Heist RS, Barve M, Vokes E, Goldman JW, et al. Phase I study of 2- or 3-week dosing of telisotuzumab vedotin, an antibody-drug conjugate targeting c-Met, monotherapy in patients with advanced non-small cell lung carcinoma. Clin Cancer Res. 2021;27(21):5781–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Horinouchi H, Shibata Y, Looman J, Sui Y, Noon E, Lu S. Phase 2 study of telisotuzumab vedotin (Teliso-V) monotherapy in patients with previously untreated MET-amplified locally advanced/metastatic non-squamous non-small cell lung cancer (NSQ NSCLC). J Clin Oncol. 2023;41(16_suppl):TPS9149–TPS.

    Article  Google Scholar 

  68. Batth IS, Jaiswal BS, Maji D, Sparks R, Glauser W, Uziel T, et al. c-MET mutations sensitize to antibody-drug conjugate telisotuzumab vedotin through efficient internalization and rapid intracellular drug delivery. Cancer Res. 2023;83(7_Supplement):540-.

    Article  Google Scholar 

  69. Strickler JH, Nemunaitis JJ, Weekes CD, Ramanathan RK, Angevin E, Morgensztern D, Heist RS, et al. Phase 1, open-label, dose-escalation and expansion study of ABBV-399, an antibody drug conjugate (ADC) targeting c-Met, in patients (pts) with advanced solid tumors. Am Soc Clin Oncol. 2016;2510–2510.

  70. Angevin E, Kelly K, Heist R, Morgensztern D, Weekes C, Bauer T, et al. First-in-human phase 1, dose-escalation and-expansion study of ABBV-399, an antibody-drug conjugate (ADC) targeting c-Met, in patients (pts) with advanced solid tumors. Ann Oncol. 2016;27:vi118.

    Article  Google Scholar 

  71. Camidge DR, Barlesi F, Goldman JW, Morgensztern D, Heist R, Vokes E, et al. A phase 1b study of telisotuzumab vedotin in combination with nivolumab in patients with NSCLC. JTO Clin Res Rep. 2022;3(1):100262.

    PubMed  Google Scholar 

  72. Camidge DR, Barlesi F, Goldman JW, Morgensztern D, Heist R, Vokes E, et al. Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-met protein-expressing non-small-cell lung cancer. J Clin Oncol. 2023;41(5):1105–15.

    Article  CAS  PubMed  Google Scholar 

  73. Camidge, D. Ross, Fabrice Barlesi, Jonathan W. Goldman, Daniel Morgensztern, Rebecca Heist, Everett Vokes, Alex Spira et al. Phase Ib study of telisotuzumab vedotin in combination with erlotinib in patients with c-met protein–expressing non–small-cell lung cancer. J Clin Oncol. 2019;41(5):1105.

  74. Camidge R, Heist RS, Goldman J, Angevin E, Strickler J, Morgensztern D, et al. An open-label, multicenter, phase I study of ABBV-399 (telisotuzumab vedotin, teliso-V) as monotherapy (T) and in combination with erlotinib (T+ E) in non-small cell lung cancer (NSCLC). Ann Oncol. 2018;29:viii496–7.

    Article  Google Scholar 

  75. Angevin E, Strickler J, Weekes C, Heist R, Morgensztern D, Fan X, et al. MA09. 09 First-in-human phase 1 study of ABBV-399, an antibody-drug conjugate (ADC) targeting c-Met, in patients with non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017;12(1):S395–6.

    Article  Google Scholar 

  76. Murakami H, Wakuda K, Kenmotsu H, Todaka A, Yokota T, Yamamoto N, et al. Preliminary results of safety and PK of Telisotuzumab Vedotin (T) in Japanese patients with advanced solid tumors. Ann Oncol. 2019;30:vi125.

    Article  Google Scholar 

  77. Camidge D, Goldman J, Cole G, Sun Z, Ocampo C, Komarnitsky P, et al. 1414TiP evaluating telisotuzumab vedotin in combination with osimertinib in patients with advanced non-small cell lung cancer: a phase I/Ib study cohort. Ann Oncol. 2020;31:S894.

    Article  Google Scholar 

  78. Camidge DR, Bar J, Horinouchi H, Goldman JW, Moiseenko FV, Filippova E, Cicin I, et al. Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC). 2022;9016–6.

  79. Camidge D, Moiseenko F, Cicin I, Horinouchi H, Filippova E, Bar J, et al. OA15. 04 telisotuzumab vedotin (teliso-v) monotherapy in patients with previously treated c-met+ advanced non-small cell lung cancer. J Thorac Oncol. 2021;16(10):S875.

    Article  Google Scholar 

  80. Waqar SN, Redman MW, Arnold SM, Hirsch FR, Mack PC, Schwartz LH, et al. A phase II study of telisotuzumab vedotin in patients with c-met-positive stage IV or recurrent squamous cell lung cancer (LUNG-MAP Sub-study S1400K, NCT03574753). Clin Lung Cancer. 2021;22(3):170–7.

    Article  CAS  PubMed  Google Scholar 

  81. Camidge DR, Goldman J, Vasilopoulos A, Ansell P, Xia S, Bolotin E, et al. Abstract CT214: Preliminary efficacy of telisotuzumab vedotin (Teliso-V) treatment in the 2L/3L setting in MET gene amplified (MET Amp), c-Met protein overexpressing (c-Met OE), non-squamous, non-small cell lung cancer (NSQ NSCLC): Retrospective analysis of LUMINOSITY. Cancer Res. 2023;83(8_Supplement):CT214–CT.

    Article  Google Scholar 

  82. Jin Y, Zhang Z, Zou S, Li F, Chen H, Peng C, et al. A novel c-MET-targeting antibody-drug conjugate for pancreatic cancer. Front Oncol. 2021;11: 634881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yang CY, Wang L, Sun X, Tang M, Quan HT, Zhang LS, et al. SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models. Acta Pharmacol Sin. 2019;40(7):971–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. The light of life extension: Hengrui's heavy-handed ADC, a dose of "later medicine". 17 Sep 2023. Available from: https://inf.news/en/news/0aaae0b499c153cb6f27d667cd74e0dc.html.

  85. Yang C, Zhao X, Sun X, Li J, Wang W, Zhang L, et al. Preclinical pharmacokinetics of a novel anti-c-Met antibody-drug conjugate, SHR-A1403, in rodents and non-human primates. Xenobiotica. 2019;49(9):1097–105.

    Article  CAS  PubMed  Google Scholar 

  86. Tong M, Gao M, Xu Y, Fu L, Li Y, Bao X, et al. 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. Cancer Sci. 2019;110(11):3584–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gymnopoulos M, Betancourt O, Blot V, Fujita R, Galvan D, Lieuw V, et al. TR1801-ADC: a highly potent cMet antibody-drug conjugate with high activity in patient-derived xenograft models of solid tumors. Mol Oncol. 2020;14(1):54–68.

    Article  CAS  PubMed  Google Scholar 

  88. RemeGen and Innovent Collaborate on Clinical Trials to Evaluate the Potential of RC88 and RC108 Combined with PD-1 Therapy for Advanced Solid Tumors. 09 Jul, 2023. Available from: https://www.prnewswire.com/news-releases/remegen-and-innovent-collaborate-on-clinical-trials-to-evaluate-the-potential-of-rc88-and-rc108-combined-with-pd-1-therapy-for-advanced-solid-tumors-301872574.html.

  89. Innovent and RemeGen Enter into Clinical Trial Collaboration Investigating Combination Therapy of TYVYT® (sintilimab injection) and Novel ADC Candidates for Advanced Solid Tumors in China. 25 Jun, 2023. Available from: https://www.prnewswire.com/news-releases/innovent-and-remegen-enter-into-clinical-trial-collaboration-investigating-combination-therapy-of-tyvyt-sintilimab-injection-and-novel-adc-candidates-for-advanced-solid-tumors-in-china-301862538.html.

  90. Targeting c-Met, Remegen ADC drug RC108 was approved for clinical use in the United States for the treatment of solid tumors. 03 Jan 2023. Available from: https://www.echemi.com/cms/1144318.html.

  91. Zhou HY, Wang SJ, Liu ZH, Ma K, Wang L, Jiang J. The PK bioanalysis method study of c-Met antibody-drug conjugate (RC108) in cynomolgus monkey. Acta Pharm Sinica. 2023;1663–8.

  92. Groothuis PG, Jacobs DCH, Hermens IAT, Damming D, Berentsen K, Mattaar-Hepp E, et al. Preclinical profile of BYON3521 predicts an effective and safe MET antibody-drug conjugate. Mol Cancer Ther. 2023;22(6):765–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Patrick G, Daniëlle J, Inge H, Désirée D, Ellen M, Myrthe R, et al. BYON3521, a novel effective and safe c-Met targeting antibody-drug conjugate. 2021. Available from: https://www.byondis.com/what-we-do/posters-publications/aacr2021/byon3521.

  94. Kotecki N, van Herpen CML, Curigliano C, Hendriks M, Vermaas TC, Corrigan L, et al. Abstract CT185: First in human dose-escalation trial with the c-MET targeting antibody-drug conjugate BYON3521. Cancer Res. 2023;83(8_Supplement):CT185-CT.

    Article  Google Scholar 

  95. Groothuis P, Jacobs D, Hermens I, Damming D, Mattaar E, Rouwette M, et al. Abstract 926: BYON3521, a novel effective and safe c-Met targeting antibody-drug conjugate. Cancer Res. 2021;81(13_Supplement):926-.

    Article  Google Scholar 

  96. Gera N, Fitzgerald K, Ramesh V, Patel P, Kien L, Kanojia D, et al. Abstract 5000: MYTX-011: A novel cMET-targeting antibody drug conjugate (ADC) engineered to increase on-target uptake in and efficacy against cMET expressing tumors. Cancer Res. 2023;83(7_Supplement):5000-.

    Article  Google Scholar 

  97. Spira AI, Johnson ML, Blumenschein GR, Burns TF, Thompson JR, Deshpande A, Comb WC, Fiske B, Gallant G, Heist RS. Phase 1 multicenter dose escalation and dose expansion study of antibody-drug conjugate (ADC) MYTX-011 in subjects with non-small cell lung cancer. 2023;TPS9147–7.

  98. Reilly RM, Ji C, Matuszak RP, Anderson MG, Tucker L, Klunder N, et al. ABBV-400: An ADC delivering a novel topoisomerase 1 inhibitor to c-Met-positive solid tumors. Cancer Res. 2023;83(7_Supplement):6311-.

    Article  Google Scholar 

  99. Sharma M, Kuboki Y, Camidge DR, Perets R, Sommerhalder D, Yamamoto N, Bar J, et al. Dose escalation results from a first-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors. 2023;3015–5.

  100. Shimizu T, Powderly J, Sharma MR, Guan X, Vasilopoulos A, Li M, et al. MO4-2 Phase 1 study of ABBV-400, a novel anti-Met antibody drug conjugate, in advanced solid tumors. Ann Oncol. 2023;34:S1397.

    Article  Google Scholar 

  101. Oh SY, Lee YW, Lee EJ, Kim JH, Park Y, Heo SG, et al. Preclinical study of a biparatopic METxMET antibody-drug conjugate, REGN5093-M114, overcomes MET-driven acquired resistance to EGFR TKIs in EGFR-mutant NSCLC. Clin Cancer Res. 2023;29(1):221–32.

    Article  CAS  PubMed  Google Scholar 

  102. DaSilva JO, Yang K, Surriga O, Nittoli T, Kunz A, Franklin MC, et al. A biparatopic antibody-drug conjugate to Treat MET-expressing cancers, including those that are unresponsive to MET pathway blockade. Mol Cancer Ther. 2021;20(10):1966–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Perez Bay AE, Faulkner D, DaSilva JO, Young TM, Yang K, Giurleo JT, et al. A bispecific METxMET antibody-drug conjugate with cleavable linker is processed in recycling and late endosomes. Mol Cancer Ther. 2023;22(3):357–70.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Oh SY, Lim SM, Lee YW, Lee EJ, Kim JH, Heo SG, et al. Abstract LB515A: A MET targeting biparatopic antibody-drug conjugates (ADC), REGN5093-M114, has an antitumor efficacy in NSCLC harboring MET gene alterations. Cancer Res. 2022;82(12_Supplement):LB515A–LBA.

    Article  Google Scholar 

  105. Drilon AE, Awad MM, Gadgeel SM, Villaruz LC, Sabari JK, Perez J, Daly C, et al. A phase 1/2 study of REGN5093-M114, a METxMET antibody-drug conjugate, in patients with mesenchymal epithelial transition factor (MET)-overexpressing NSCLC. 2022;TPS8593–3.

  106. Comer F, Mazor Y, Hurt E, Yang C, Fleming R, Shandilya H, et al. Abstract 5736: AZD9592: An EGFR-cMET bispecific antibody-drug conjugate (ADC) targeting key oncogenic drivers in non-small-cell lung cancer (NSCLC) and beyond. Cancer Res. 2023;83(7_Supplement):5736-.

    Article  Google Scholar 

  107. McGrath L, Zheng Y, Christ S, Sachs CC, Khelifa S, Windmüller C, et al. Evaluation of the relationship between target expression and in vivo anti-tumor efficacy of AZD9592, an EGFR/c-MET targeted bispecific antibody drug conjugate. Cancer Res. 2023;83(7_Supplement):5737-.

    Article  Google Scholar 

  108. Aggarwal C, Azzoli CG, Spira AI, Solomon BJ, Le X, Rolfo C, Planchard D, et al. EGRET: a first-in-human study of the novel antibody-drug conjugate (ADC) AZD9592 as monotherapy or combined with other anticancer agents in patients (pts) with advanced solid tumors. 2023;TPS3156–6.

  109. Fu Y, Gros E, Lee A, Johnson K, Zhang H, Yalamanchili S, et al. Abstract P2–16–03: C-Met is a potential therapeutic target for antibody-drug conjugates in breast cancer. Cancer Res. 2015;75(9_Supplement):P2–16–03.

    Article  Google Scholar 

  110. Li L, Fells C, Guo J, Muyot P, Gros E, Zhang Y, et al. Abstract 3897: A novel c-Met targeting antibody drug conjugate for NSCLC. Cancer Res. 2016;76(14_Supplement):3897-.

    Article  Google Scholar 

  111. Fu Y, Gros E, Lee A, Johnson K, Zhang H, Yalamanchili S, Sun Y, Motamed K, Chen G, Jones B, Kaufmann GF. C-Met is a potential therapeutic target for antibody-drug conjugates in breast cancer. In: Proceedings of the thirty-seventh annual CTRC-AACR San Antonio breast cancer symposium. San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl): Abstract nr P2-16-03.

  112. Min B, Jin J, Kim H, Her NG, Park C, Kim D, et al. cIRCR201-dPBD, a novel pyrrolobenzodiazepine dimer-containing site-specific antibody-drug conjugate targeting c-Met overexpression tumors. ACS Omega. 2020;5(40):25798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Datta-Mannan A, Choi H, Jin Z, Lu J, Liu L, Stokell D, Murphy A, Dunn K, Martinez M, Feng Y. Reducing target binding affinity improves the therapeutic index of anti-MET antibody drug conjugate in tumor bearing animals. Authorea Preprints. 2023.

  114. Hudson R, Yao H-P, Suthe SR, Patel D, Wang M-H. Antibody-drug conjugate PCMC1D3-Duocarmycin SA as a novel therapeutic entity for targeted treatment of cancers aberrantly expressing MET receptor tyrosine kinase. Curr Cancer Drug Targets. 2022;22(4):312–27.

    Article  CAS  PubMed  Google Scholar 

  115. Sellmann C, Doerner A, Knuehl C, Rasche N, Sood V, Krah S, et al. Balancing selectivity and efficacy of bispecific epidermal growth factor receptor (EGFR) x c-MET antibodies and antibody-drug conjugates. J Biol Chem. 2016;291(48):25106–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chen G, Li L, Muyot P, Gros E, Zhang Y, Sun Y, et al. Abstract LB-002: A novel c-Met/EGFR bispecific targeting antibody drug conjugate for NSCLC. Cancer Res. 2015;75(15_Supplement):LB-002–LB-

    Article  Google Scholar 

Download references

Acknowledgements

We would like to thank the authors and researchers whose valuable studies resulted in writing the manuscript.

Funding

The authors received no financial support for the research, authorship, and publication of this manuscript.

Author information

Authors and Affiliations

  1. Department of Nursing, Mergasour Technical Institute, Erbil Polytechnic University, Erbil, Iraq

    Ali Hussein Mer

  2. Department of Medical Biochemical Analysis, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq

    Yousef Mirzaei

  3. Student Research Committee, Larestan University of Medical Sciences, Larestan, Iran

    Fatemeh Misamogooe & Alireza Shahedi

  4. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, 8813733450, Iran

    Nader Bagheri

  5. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

    Ahmadreza Bazyari

  6. Department of Nursing, School of Nursing and Midwifery, Community Based Psychiatric Care Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Zahra Keshtkaran

  7. Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Anna Meyfour

  8. Department of Nursing, School of Nursing, Larestan University of Medical Sciences, Larestan, Iran

    Zahra Amirkhani

  9. Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Ameneh Jafari

  10. Department of Genetics, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

    Nesa Barpour

  11. Department of Research and Development, Orchidgene Co, Tehran, 1387837584, Iran

    Saeed Jahandideh

  12. Laparoscopy Research Center, Department of Surgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Fars Province, Iran

    Behzad Rezaei

  13. Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Yousef Nikmanesh

  14. Cellular and Molecular Biology Research Center, Larestan University of Medical Sciences, Larestan, Iran

    Meghdad Abdollahpour‐Alitappeh

Authors
  1. Ali Hussein Mer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yousef Mirzaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatemeh Misamogooe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nader Bagheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmadreza Bazyari
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zahra Keshtkaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna Meyfour
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alireza Shahedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zahra Amirkhani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ameneh Jafari
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nesa Barpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Saeed Jahandideh
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Behzad Rezaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yousef Nikmanesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Meghdad Abdollahpour‐Alitappeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.A.A. and Y.N. Conceptualized and designed the study. N.Bagheri., Z.K., A.M., and S.J. also helped and participated in the study design. A.H.M., Y.M., F.M., A.B., Z.K., A.M., A.Sh., Z.A., A.J., N.B., and S.J. researched, collected the data, and prepared the original draft. F.M., A.H.M., Y.M., and A.Sh. retrieved data from the clinical trials (https://clinicaltrials.gov). M.A.A. and A.B. draw the figures. M.A.A., Y.N., Z.K., Z.A., A.H.M., and Y.M. draw the tables. A.H.M., Y.M., F.M., N.Bagheri., A.B., Z.K., A.M., A.Sh., Z.A., A.J., N.B., and S.J. prepared the original draft. M.A.A., Y.N., N.Bagheri., Z.K., and A.J. discussed the necessity for writing this manuscript. M.A.A. and Y.N. reviewed and edited the manuscript, and provided detailed feedback. All the authors read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Yousef Nikmanesh or Meghdad Abdollahpour‐Alitappeh.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All the authors read and agreed to the published version of the manuscript.

Competing interests

The authors declare that they have no potential conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mer, A.H., Mirzaei, Y., Misamogooe, F. et al. Progress of antibody–drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01564-3

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13346-024-01564-3

Keywords

Search

Navigation