Lung cancer is one of the malignant tumor diseases with high morbidity and high mortality in the world. Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. Currently, chemotherapy, targeted therapy, immunotherapy or combination therapy is the main treatment for NSCLC, but it is still inevitably faced with the challenges of acquired drug resistance and tumor progression. The birth of antibody conjugator provides a new choice for its treatment. Antibody conjugator is a new type of biotherapeutic drug which is connected by monoclonal antibody via linker and cytotoxic drug. It has the characteristics of precision, high efficiency and low toxicity, etc. In recent years, its research and development and clinical trials have been endless. It shows that this new type of drug has great potential in the field of tumor therapy. In this paper, the structural characteristics, mechanism of action, current application, research achievements, challenges, countermeasures and development of ADC in NSCLC treatment are reviewed.
References
[1]
Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249. https://doi.org/10.3322/caac.21660
[2]
Liu, Z.C., Li, Z.X., Zhang, Y., et al. (2019) Interpretation of 2020 Global Cancer Statistics Report. Journal of Integrated Cancer Therapy Electronic, 7, 1-14.
[3]
Zhang, X. (2019) Application of Gefitinib Targeted Therapy Combined with Concurrent Chemoradiotherapy in Patients with Non-Small Cell Lung Cancer. Chinese Journal of Medical Sciences, 35, 29-31+38.
[4]
Gauzy-Lazo, L., Sassoon, I. and Brun, M. (2020) Advances in Antibody-Drug Conjugate Design: Current Clinical Landscape and Future Innovations. SLAS Discovery, 25, 843-868. https://doi.org/10.1177/2472555220912955
[5]
Drago, J.Z., Modi, S. and Chandarlapaty, S. (2021) Unlocking the Potential of Antibody-Drug Conjugates for Cancer Therapy. Nature Reviews Clinical Oncology, 18, 327-344. https://doi.org/10.1038/s41571-021-00470-8
[6]
Zheng, H., Zheng, Y.Q., Shi, Y.C., et al. (2019) Research Progress of HER-2 Targeting Antibody Coupling Drugs. Chinese Journal of Immunology, 39, 640-645+652. (In Chinese)
[7]
Yao, X.J. (2019) Research Progress of Antibody Drug Conjugations. Journal of Chinese and Foreign Medical Research, 18, 185-188. (In Chinese)
[8]
Li, B.L., Feng, H.L., Wei, F., et al. (2019) Research Progress and Challenges of Drug Conjugations for Tumor Antibodies. Chinese Oncology Clinic, 49, 850-857. (In Chinese)
[9]
Li, J., Wu, Y.L., Ma, C.C., et al. (2019) Research Progress of Antibody Conjugation Drugs. West China Pharmaceutical Journal, 38, 586-592. (In Chinese)
[10]
Diamantis, N. and Banerji, U. (2016) Antibody-Drug Conjugates—An Emerging Class of Cancer Treatment. British Journal of Cancer, 114, 362-367. https://doi.org/10.1038/bjc.2015.435
[11]
Feng, T., Zhang, H.L. and Tong, H. (2022) Research Progress of Antibody-Drug Conjugate for Tumor Targeting Drugs. Hebei Medicine, 44, 447-452. (In Chinese)
[12]
Oh, D. and Bang, Y. (2019) Her2-targeted Therapies—A Role Beyond Breast Cancer. Nature Reviews Clinical Oncology, 17, 33-48. https://doi.org/10.1038/s41571-019-0268-3
[13]
Lambert, J.M. and Berkenblit, A. (2018) Antibody-Drug Conjugates for Cancer Treatment. Annual Review of Medicine, 69, 191-207. https://doi.org/10.1146/annurev-med-061516-121357
[14]
Liao, S., Wang, B., Zeng, R., Bao, H., Chen, X., Dixit, R., et al. (2021) Recent Advances in Trophoblast Cell-Surface Antigen 2 Targeted Therapy for Solid Tumors. Drug Development Research, 82, 1096-1110. https://doi.org/10.1002/ddr.21870
[15]
Hafeez, U., Parakh, S., Gan, H.K. and Scott, A.M. (2020) Antibody-Drug Conjugates for Cancer Therapy. Molecules, 25, Article No. 4764. https://doi.org/10.3390/molecules25204764
[16]
Waldmann, H. (2018) Human Monoclonal Antibodies: The Benefits of Humanization. In: Steinitz, M., Ed., Human Monoclonal Antibodies, Springer New York, 1-10. https://doi.org/10.1007/978-1-4939-8958-4_1
Liu, W.C., Li, H.F. and Hu, C.H. (2023) Current Situation and Prospect of Anti-Body Coupling Drugs. Progress in Biochemistry and Biophysics, 50, 1167-1189.
[19]
Shi, F., Liu, Y., Zhou, X., Shen, P., Xue, R. and Zhang, M. (2022) Disitamab Vedotin: A Novel Antibody-Drug Conjugates for Cancer Therapy. Drug Delivery, 29, 1335-1344. https://doi.org/10.1080/10717544.2022.2069883
[20]
Ji, S.M., Wang, Y.Z. and Yang, J.B. (2021) Study on the Molecular Characteristics and Pharmacokinetics of Antibody-Coupled Drugs. Chinese Journal of Clinical Pharmacology, 37, 777-782. (In Chinese)
[21]
Tang, H., Liu, Y., Yu, Z., Sun, M., Lin, L., Liu, W., et al. (2019) The Analysis of Key Factors Related to ADCs Structural Design. Frontiers in Pharmacology, 10, Article No. 373. https://doi.org/10.3389/fphar.2019.00373
[22]
Dumontet, C., Reichert, J.M., Senter, P.D., Lambert, J.M. and Beck, A. (2023) Antibody-Drug Conjugates Come of Age in Oncology. Nature Reviews Drug Discovery, 22, 641-661. https://doi.org/10.1038/s41573-023-00709-2
[23]
Yang, Y., Meng, Y., Fan, X.S., et al. (2015) Expression of HER2 and COX-2 in Non-Small Cell Lung Cancer. Cancer Progress, 13, 533-537.
[24]
Xu, F., Yang, G., Xu, H., Yang, L., Qiu, W. and Wang, Y. (2020) Treatment Outcome and Clinical Characteristics of HER2 Mutated Advanced Non-Small Cell Lung Cancer Patients in China. Thoracic Cancer, 11, 679-685. https://doi.org/10.1111/1759-7714.13317
[25]
Wang, X.G. (2016) Clinical Significance of HER-2 Protein Overexpression and Gene Abnormality in Non-Small Cell Lung Cancer. Shanxi Medical University.
[26]
Wolska-Washer, A. and Robak, T. (2019) Safety and Tolerability of Antibody-Drug Conjugates in Cancer. Drug Safety, 42, 295-314. https://doi.org/10.1007/s40264-018-0775-7
[27]
Cretella, D., Saccani, F., Quaini, F., Frati, C., Lagrasta, C., Bonelli, M., et al. (2014) Trastuzumab Emtansine Is Active on HER-2 Overexpressing NSCLC Cell Lines and Overcomes Gefitinib Resistance. Molecular Cancer, 13, Article No. 143. https://doi.org/10.1186/1476-4598-13-143
[28]
Li, B.T., Shen, R., Buonocore, D., Olah, Z.T., Ni, A., Ginsberg, M.S., et al. (2018) Ado-trastuzumab Emtansine for Patients with HER2-Mutant Lung Cancers: Results from a Phase II Basket Trial. Journal of Clinical Oncology, 36, 2532-2537. https://doi.org/10.1200/jco.2018.77.9777
[29]
Li, B.T., Michelini, F., Misale, S., Cocco, E., Baldino, L., Cai, Y., et al. (2020) HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers. Cancer Discovery, 10, 674-687. https://doi.org/10.1158/2159-8290.cd-20-0215
[30]
Linehan, A.S., Fitzpatrick, O.M. and Morris, P.G. (2021) Profile of Trastuzumab Deruxtecan in the Management of Patients with HER2-Positive Unresectable or Metastatic Breast Cancer: An Evidence-Based Review. Breast Cancer: Targets and Therapy, 13, 151-159. https://doi.org/10.2147/bctt.s245024
[31]
Pommier, Y. (2006) Topoisomerase I Inhibitors: Camptothecins and beyond. Nature Reviews Cancer, 6, 789-802. https://doi.org/10.1038/nrc1977
[32]
Li, B.T., Smit, E.F., Goto, Y., Nakagawa, K., Udagawa, H., Mazières, J., et al. (2022) Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. New England Journal of Medicine, 386, 241-251. https://doi.org/10.1056/nejmoa2112431
[33]
Goto, K., Sang-We, K., Kubo, T., Goto, Y., Ahn, M., Planchard, D., et al. (2022) LBA55 Trastuzumab Deruxtecan (T-DXd) in Patients (Pts) with HER2-Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC): Interim Results from the Phase 2 DESTINY-Lung02 Trial. Annals of Oncology, 33, S1422. https://doi.org/10.1016/j.annonc.2022.08.057
[34]
Planchard, D., Brahmer, J.R., Yang, J.C., Chen, Y., Lee, K., Suksombooncharoen, T., et al. (2022) Abstract CT572: Phase 1b Dose-Escalation and Dose-Expansion Study Evaluating Trastuzumab Deruxtecan (T-DXd) in Combination with Durvalumab and Cisplatin, Carboplatin, or Pemetrexed in Advanced or Metastatic, HER2-Overexpressing, Nonsquamous Non-Small Cell Lung Cancer (NSCLC): Destiny-Lung03. Cancer Research, 82, CT572. https://doi.org/10.1158/1538-7445.am2022-ct572
[35]
Li, B.T., Ahn, M., Goto, K., Mazieres, J., Padda, S.K., William, W.N., et al. (2022) Open-Label, Randomized, Multicenter, Phase 3 Study Evaluating Trastuzumab Deruxtecan (T-DXd) as First-Line Treatment in Patients with Unresectable, Locally Advanced, or Metastatic Non-small Cell Lung Cancer (NSCLC) Harboring HER2 Exon 19 or 20 Mutations (DESTINY-Lung04). Journal of Clinical Oncology, 40, TPS9137. https://doi.org/10.1200/jco.2022.40.16_suppl.tps9137
[36]
Jin, Y.B., Cai, Q., Ji, J., et al. (2019) Inhibitory Effect of Antibody-Coupled Drug Vedicetuzumab on Gastric Cancer Cells with Different Expression Levels of HER-2 in Vitro. Journal of Clinical Oncology, 28, 1-7.
[37]
Lenárt, S., Lenárt, P., Šmarda, J., Remšík, J., Souček, K. and Beneš, P. (2020) Trop2: Jack of All Trades, Master of None. Cancers, 12, Article No. 3328. https://doi.org/10.3390/cancers12113328
[38]
Goldenberg, D.M., Stein, R. and Sharkey, R.M. (2018) The Emergence of Trophoblast Cell-Surface Antigen 2 (TROP-2) as a Novel Cancer Target. Oncotarget, 9, 28989-29006. https://doi.org/10.18632/oncotarget.25615
[39]
Long, Y., Xie, F. and Zhou, X.F. (2019) Datopotamab Deruxtecan, an Antibody-Coupled Drug Targeting Trophoblast Cell Surface antigen 2. Journal of Clinical Pharmacotherapy, 22, 18-22.
[40]
Mito, R., Matsubara, E., Komohara, Y., Shinchi, Y., Sato, K., Yoshii, D., et al. (2020) Clinical Impact of TROP2 in Non-small Lung Cancers and Its Correlation with Abnormal P53 Nuclear Accumulation. Pathology International, 70, 287-294. https://doi.org/10.1111/pin.12911
[41]
Liu, X., Deng, J., Yuan, Y., Chen, W., Sun, W., Wang, Y., et al. (2022) Advances in Trop2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast Cancer. Pharmacology & Therapeutics, 239, Article ID: 108296. https://doi.org/10.1016/j.pharmthera.2022.108296
[42]
Chen, L.L. and Song, Q.B. (2019) New Progress of Dato-DXd in the Treatment of Advanced Non-Small Cell Lung Cancer. Cancer Prevention Research, 51, 535-541. (In Chinese)
[43]
Girard, N., Okamoto, I., Lisberg, A.E., Pons-Tostivint, E., Cornelissen, R., Hong, M.H., et al. (2024) 59P Datopotamab Deruxtecan (Dato-Dxd) in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC): Nonsquamous (NSQ) Histology in the Phase III TROPION-Lung01 Trial. ESMO Open, 9, Article ID: 102638. https://doi.org/10.1016/j.esmoop.2024.102638
[44]
Goto, Y., Su, W., Levy, B.P., Rixe, O., Yang, T., Tolcher, A.W., et al. (2023) TROPION-Lung02: Datopotamab Deruxtecan (Dato-Dxd) Plus Pembrolizumab (Pembro) with or without Platinum Chemotherapy (pt-Ct) in Advanced Non-Small Cell Lung Cancer (aNSCLC). Journal of Clinical Oncology, 41, 9004-9004. https://doi.org/10.1200/jco.2023.41.16_suppl.9004
[45]
Borghaei, H., Waqar, S.N., Bruno, D.S., Kitazono, S., Wakuda, K., Spira, A.I., et al. (2023) TROPION-Lung04: Phase 1b, Multicenter Study of Datopotamab Deruxtecan (Dato-DXd) in Combination with Immunotherapy ± Carboplatin in Advanced/Metastatic Non-Small Cell Lung Cancer (mNSCLC). Journal of Clinical Oncology, 41, TPS3158. https://doi.org/10.1200/jco.2023.41.16_suppl.tps3158
[46]
Ahn, M., Cho, B.C., Goto, Y., Yoh, K., Su, W., Shimizu, J., et al. (2023) 552P TROPION-Lung05: Datopotamab Deruxtecan (Dato-DXd) in Asian Patients (Pts) with Previously Treated Non-Small Cell Lung Cancer (NSCLC) with Actionable Genomic Alterations (AGAs). Annals of Oncology, 34, S1684-S1685. https://doi.org/10.1016/j.annonc.2023.10.630
[47]
Sun, L.P. and Miao, Q.-F. (2023) Research Progress of Antibody Coupling Drugs Targeting TROP2. Chinese Journal of Pharmaceutical Biotechnology, 18, 428-434. (In Chinese)
[48]
Ocean, A.J., Starodub, A.N., Bardia, A., Vahdat, L.T., Isakoff, S.J., Guarino, M., et al. (2017) Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2-SN-38 Antibody-Drug Conjugate for the Treatment of Diverse Epithelial Cancers: Safety and Pharmacokinetics. Cancer, 123, 3843-3854. https://doi.org/10.1002/cncr.30789
[49]
Bardia, A., Messersmith, W.A., Kio, E.A., Berlin, J.D., Vahdat, L., Masters, G.A., et al. (2021) Sacituzumab Govitecan, a Trop-2-Directed Antibody-Drug Conjugate, for Patients with Epithelial Cancer: Final Safety and Efficacy Results from the Phase I/II IMMU-132-01 Basket Trial. Annals of Oncology, 32, 746-756. https://doi.org/10.1016/j.annonc.2021.03.005
[50]
Reck, M., Liu, S.V., Owen, S.P., Garon, E.B., Neal, J.W., Vicente, D., et al. (2022) EP08.02-098 Phase 2 EVOKE-02 Study of Sacituzumab Govitecan and Pembrolizumab ± Platinum in First-Line Metastatic NSCLC. Journal of Thoracic Oncology, 17, S448. https://doi.org/10.1016/j.jtho.2022.07.781
[51]
Cheng, Y., Yuan, X., Tian, Q., Huang, X., Chen, Y., Pu, Y., et al. (2022) Preclinical Profiles of SKB264, a Novel Anti-TROP2 Antibody Conjugated to Topoisomerase Inhibitor, Demonstrated Promising Antitumor Efficacy Compared to IMMU-132. Frontiers in Oncology, 12, Article ID: 951589. https://doi.org/10.3389/fonc.2022.951589
[52]
Fang, W., Cheng, Y., Chen, Z., Wang, W., Yin, Y., Li, Y., et al. (2023) SKB264 (TROP2-ADC) for the Treatment of Patients with Advanced NSCLC: Efficacy and Safety Data from a Phase 2 Study. Journal of Clinical Oncology, 41, 9114-9114. https://doi.org/10.1200/jco.2023.41.16_suppl.9114
[53]
Liu, L.-Q., Pan, X.-Q., Su, Z., et al. (2019) U3-1402, an Antibody-Coupling Drug Targeting HER3. Journal of Clinical Pharmacotherapy, 17, 1-4.
[54]
Waqar, S.N., Redman, M.W., Arnold, S.M., Hirsch, F.R., Mack, P.C., Schwartz, L.H., et al. (2021) 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). Clinical Lung Cancer, 22, 170-177. https://doi.org/10.1016/j.cllc.2020.09.013
[55]
Lyu, H., Han, A., Polsdofer, E., Liu, S. and Liu, B. (2018) Understanding the Biology of HER3 Receptor as a Therapeutic Target in Human Cancer. Acta Pharmaceutica Sinica B, 8, 503-510. https://doi.org/10.1016/j.apsb.2018.05.010
[56]
Jänne, P.A., Baik, C., Su, W., Johnson, M.L., Hayashi, H., Nishio, M., et al. (2021) Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer. Cancer Discovery, 12, 74-89. https://doi.org/10.1158/2159-8290.cd-21-0715
[57]
Yu, H.A., Goto, Y., Hayashi, H., Felip, E., Chih-Hsin Yang, J., Reck, M., et al. (2023) HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer after Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. Journal of Clinical Oncology, 41, 5363-5375. https://doi.org/10.1200/jco.23.01476
[58]
Janne, P.A., Johnson, M.L., Goto, Y., Yang, J.C., Vigliotti, M., Dong, Q., et al. (2021) HERTHENA-Lung01: A Randomized Phase 2 Study of Patritumab Deruxtecan (HER3-DXd) in Previously Treated Metastatic EGFR-Mutated NSCLC. Journal of Clinical Oncology, 39, TPS9139. https://doi.org/10.1200/jco.2021.39.15_suppl.tps9139
[59]
Puppo, F., Thomé, V., Lhoumeau, A., Cibois, M., Gangar, A., Lembo, F., et al. (2010) Protein Tyrosine Kinase 7 Has a Conserved Role in Wnt/β-Catenin Canonical Signalling. EMBO Reports, 12, 43-49. https://doi.org/10.1038/embor.2010.185
[60]
Maitland, M.L., Sachdev, J.C., Sharma, M.R., Moreno, V., Boni, V., Kummar, S., et al. (2021) First-in-Human Study of PF-06647020 (Cofetuzumab Pelidotin), an Antibody-Drug Conjugate Targeting Protein Tyrosine Kinase 7, in Advanced Solid Tumors. Clinical Cancer Research, 27, 4511-4520. https://doi.org/10.1158/1078-0432.ccr-20-3757
[61]
Ko, B., He, T., Gadgeel, S. and Halmos, B. (2017) MET/HGF Pathway Activation as a Paradigm of Resistance to Targeted Therapies. Annals of Translational Medicine, 5, Article No. 4. https://doi.org/10.21037/atm.2016.12.09
[62]
Wang, J., Anderson, M.G., Oleksijew, A., Vaidya, K.S., Boghaert, E.R., Tucker, L., et al. (2017) ABBV-399, a c-Met Antibody-Drug Conjugate That Targets both MET-Amplified and c-Met-Overexpressing Tumors, Irrespective of MET Pathway Dependence. Clinical Cancer Research, 23, 992-1000. https://doi.org/10.1158/1078-0432.ccr-16-1568
[63]
Camidge, D.R., Morgensztern, D., Heist, R.S., Barve, M., Vokes, E., Goldman, J.W., et al. (2021) 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. Clinical Cancer Research, 27, 5781-5792. https://doi.org/10.1158/1078-0432.ccr-21-0765
[64]
Camidge, D.R., Barlesi, F., Goldman, J.W., Morgensztern, D., Heist, R., Vokes, E., et al. (2023) Phase Ib Study of Telisotuzumab Vedotin in Combination with Erlotinib in Patients with C-Met Protein-Expressing Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 41, 1105-1115. https://doi.org/10.1200/jco.22.00739
[65]
Abuhelwa, Z., Alloghbi, A. and Nagasaka, M. (2022) A Comprehensive Review on Antibody-Drug Conjugates (ADCs) in the Treatment Landscape of Non-Small Cell Lung Cancer (NSCLC). Cancer Treatment Reviews, 106, Article ID: 102393. https://doi.org/10.1016/j.ctrv.2022.102393
[66]
Phillips, G.D.L., Fields, C.T., Li, G., Dowbenko, D., Schaefer, G., Miller, K., et al. (2014) Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy. Clinical Cancer Research, 20, 456-468. https://doi.org/10.1158/1078-0432.ccr-13-0358
[67]
Ritchie, M., Tchistiakova, L. and Scott, N. (2013) Implications of Receptor-Mediated Endocytosis and Intracellular Trafficking Dynamics in the Development of Antibody Drug Conjugates. mAbs, 5, 13-21. https://doi.org/10.4161/mabs.22854
[68]
Hamblett, K.J., Jacob, A.P., Gurgel, J.L., Tometsko, M.E., Rock, B.M., Patel, S.K., et al. (2015) SLC46A3 Is Required to Transport Catabolites of Noncleavable Antibody Maytansine Conjugates from the Lysosome to the Cytoplasm. Cancer Research, 75, 5329-5340. https://doi.org/10.1158/0008-5472.can-15-1610
[69]
Dean, A.Q., Luo, S., Twomey, J.D. and Zhang, B. (2021) Targeting Cancer with Antibody-Drug Conjugates: Promises and Challenges. MABs, 13, Article ID: 1951427. https://doi.org/10.1080/19420862.2021.1951427
[70]
Khoury, R., Saleh, K., Khalife, N., Saleh, M., Chahine, C., Ibrahim, R., et al. (2023) Mechanisms of Resistance to Antibody-Drug Conjugates. International Journal of Molecular Sciences, 24, Article No. 9674. https://doi.org/10.3390/ijms24119674
