The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 Jan 2024
11 Jan 2024
Historique:
received:
03
12
2022
accepted:
14
12
2023
medline:
12
1
2024
pubmed:
12
1
2024
entrez:
11
1
2024
Statut:
epublish
Résumé
Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.
Identifiants
pubmed: 38212321
doi: 10.1038/s41467-023-44533-z
pii: 10.1038/s41467-023-44533-z
doi:
Banques de données
ClinicalTrials.gov
['NCT03451162']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
466Informations de copyright
© 2024. The Author(s).
Références
Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).
pubmed: 3798106
doi: 10.1126/science.3798106
Stern, H. M. Improving treatment of HER2-positive cancers: opportunities and challenges. Sci. Transl. Med. 4, 127rv2 1–10 (2012).
doi: 10.1126/scitranslmed.3001539
Junttila, T. T. et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15, 429–440 (2009).
pubmed: 19411071
doi: 10.1016/j.ccr.2009.03.020
Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).
pubmed: 11248153
doi: 10.1056/NEJM200103153441101
Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).
pubmed: 16236738
doi: 10.1056/NEJMoa052122
Franklin, M. C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5, 317–328 (2004).
pubmed: 15093539
doi: 10.1016/S1535-6108(04)00083-2
Lewis Phillips, G. D. et al. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Cli. n Cancer Res. 20, 456–468 (2014).
doi: 10.1158/1078-0432.CCR-13-0358
Gianni, L. et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 13, 25–32 (2012).
pubmed: 22153890
doi: 10.1016/S1470-2045(11)70336-9
Piccart, M. et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 years’ follow up. J. Clin. Oncol. 39, 1448–1457 (2021).
pubmed: 33539215
doi: 10.1200/JCO.20.01204
Swain, S. M. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N. Engl. J. Med. 372, 724–734 (2015).
pubmed: 25693012
pmcid: 5584549
doi: 10.1056/NEJMoa1413513
Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 68, 9280–9290 (2008).
pubmed: 19010901
doi: 10.1158/0008-5472.CAN-08-1776
Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2012).
pubmed: 23020162
pmcid: 5125250
doi: 10.1056/NEJMoa1209124
von Minckwitz, G. et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N. Engl. J. Med. 380, 617–628 (2019).
doi: 10.1056/NEJMoa1814017
Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610–621 (2020).
pubmed: 31825192
doi: 10.1056/NEJMoa1914510
Cortes, J. et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N. Engl. J. Med. 386, 1143–1154 (2022).
pubmed: 35320644
doi: 10.1056/NEJMoa2115022
Shitara, K. et al. Trastuzumab Deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. 382, 2419–2430 (2020).
pubmed: 32469182
doi: 10.1056/NEJMoa2004413
Ogitani, Y. et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase 1 inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin. Cancer Res. 22, 5097–5108 (2016).
pubmed: 27026201
doi: 10.1158/1078-0432.CCR-15-2822
Martinez-Saez, O. & Prat, A. Current and future management of HER2-positive metastatic breast cancer. J. Oncol. Pract. 17, 594–605 (2021).
doi: 10.1200/OP.21.00172
Shen, B.-Q. et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates. Nat. Biotechnol. 30, 184–191 (2012).
pubmed: 22267010
doi: 10.1038/nbt.2108
Pillow, T. H. et al. Modulating therapeutic activity and toxicity of pyrrolobenzodiazepine antibody-drug conjugates with self-immolative disulfide linkers. Mol. Cancer Ther. 16, 871–878 (2017).
pubmed: 28223423
doi: 10.1158/1535-7163.MCT-16-0641
Lewis Phillips, G. et al. Trastuzumab does not bind rat or moue ErbB2/neu: implications for selection of non-clinical safety models for trastuzumab-based therapeutics. Breast Cancer Res. Treat. 191, 303–317 (2022).
pubmed: 34708303
doi: 10.1007/s10549-021-06427-w
Sadowsky, J. D. et al. Development of efficient chemistry to generate site-specific disulfide-linked protein- and peptide-payload conjugates: application to THIOMAB antibody-drug conjugates. Bioconjugate Chem. 28, 2086–2098 (2017).
doi: 10.1021/acs.bioconjchem.7b00258
Girish, S. et al. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemother. Pharmacol. 69, 1229–1240 (2012).
pubmed: 22271209
pmcid: 3337408
doi: 10.1007/s00280-011-1817-3
Hartley, J. A. et al. DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo(2,1-c)benzodiazepine dimer SG2057. Invest. N. Drugs 30, 950–958 (2012).
doi: 10.1007/s10637-011-9647-z
Lewis, G. D. et al. Growth regulation of human breast and ovarian tumor cells by heregulin: evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res. 56, 1457–1465 (1996).
pubmed: 8640840
Kovtun, Y. V. et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 66, 3214–3221 (2006).
pubmed: 16540673
doi: 10.1158/0008-5472.CAN-05-3973
Li, F. et al. Intracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 76, 2710–2719 (2016).
pubmed: 26921341
doi: 10.1158/0008-5472.CAN-15-1795
Beck, A., Goetsch, L., Dumontet, C. & Corvaia, N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat. Rev. Drug Discov. 16, 315–337 (2017).
pubmed: 28303026
doi: 10.1038/nrd.2016.268
Pedersen, M. W. et al. Targeting three distinct HER2 domains with a recombinant antibody mixture overcomes trastuzumab resistance. Mol. Cancer Ther. 14, 669–680 (2015).
pubmed: 25612619
doi: 10.1158/1535-7163.MCT-14-0697
Li, J. Y. et al. A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29, 117–129 (2016).
pubmed: 26766593
doi: 10.1016/j.ccell.2015.12.008
Tu, W.-Z. et al. γH2AX foci formation in the absence of DNA damage: mitotic H2AX phosphorylation is mediated by the DNA-PKcs/CHK2 pathway. FEBS Lett. 587, 3437–3443 (2013).
pubmed: 24021642
doi: 10.1016/j.febslet.2013.08.028
Cardillo, T. M. et al. Humanized anti-TROP-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys. Clin. Cancer Res. 17, 3157–3169 (2011).
pubmed: 21372224
pmcid: 10766325
doi: 10.1158/1078-0432.CCR-10-2939
Wolff, A. C. et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J. Clin. Oncol. 31, 3997–4014 (2013).
pubmed: 24101045
doi: 10.1200/JCO.2013.50.9984
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).
pubmed: 19097774
doi: 10.1016/j.ejca.2008.10.026
Drago, J. Z., Modi, S. & Chandarlapaty, S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat. Rev. Clin. Oncol. 18, 327–344 (2021).
pubmed: 33558752
pmcid: 8287784
doi: 10.1038/s41571-021-00470-8
Miller, M. L. et al. A DNA-interacting payload designed to eliminate cross-linking improves the therapeutic index of antibody-drug conjugates (ADCs). Mol. Cancer Ther. 17, 650–660 (2018).
pubmed: 29440292
doi: 10.1158/1535-7163.MCT-17-0940
Miller, M. L. et al. A new class of antibody-drug conjugates with potent DNA alkylating activity. Mol. Cancer Ther. 15, 1870–1878 (2016).
pubmed: 27216304
doi: 10.1158/1535-7163.MCT-16-0184
Gregson, S. J. et al. Efficacy, tolerability, and pharmacokinetic studies of antibody-drug conjugates containing a low-potency pyrrolobenzodiazepine dimer. Mol. Cancer Ther. 21, 1439–1448 (2022).
pubmed: 35793464
doi: 10.1158/1535-7163.MCT-22-0145
Dokter, W. et al. Preclinical profile of the HER2-targeting ADC SYD983/985: introduction of a new duocarmycin-based linker-drug platform. Mol. Cancer Ther. 13, 2618–2629 (2014).
pubmed: 25189543
doi: 10.1158/1535-7163.MCT-14-0040-T
Banerji, U. et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 20, 1124–1135 (2019).
pubmed: 31257177
doi: 10.1016/S1470-2045(19)30328-6
Kurebayashi, J. et al. Isolation and characterization of a new human breast cancer cell line, KPL-4, expressing the ErbB family of receptors and interleukin-6. Br. J. Cancer 79, 707–717 (1999).
pubmed: 10070858
pmcid: 2362677
doi: 10.1038/sj.bjc.6690114
dela Cruz-Chuh, J. et al. Preclinical optimization of Ly6E-targeted ADCs for increased durability and efficacy of anti-tumor response. MABS 13, e18622452 (2020).
Staben, L. R. et al. Systematic variation of pyrrolobenzodiazepine (PBD)-dimer payload physicochemical properties impacts efficacy and tolerability of the corresponding antibody-drug conjugates. J. Med. Chem. 63, 9603–9622 (2020).
pubmed: 32787101
doi: 10.1021/acs.jmedchem.0c00691
Li, S. et al. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 4, 1116–1130 (2013).
pubmed: 24055055
doi: 10.1016/j.celrep.2013.08.022
Forrest, W. F. et al. Generalized additive mixed modeling of longitudinal tumor growth reduces bias and improves decision making in translational oncology. Cancer Res. 80, 5089–5097 (2020).
pubmed: 32978171
doi: 10.1158/0008-5472.CAN-20-0342
Lee, M. V., Kaur, S. & Saad, O. M. Conjugation site influences antibody-conjugated drug PK assays: case studies for disulfide-linked, self-immolating next-generation antibody drug conjugates. Anal. Chem. 98, 12168–12175 (2020).
doi: 10.1021/acs.analchem.0c00773