CD3-engaging bispecific antibodies trigger a paracrine regulated wave of T-cell recruitment for effective tumor killing.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
13 Aug 2024
13 Aug 2024
Historique:
received:
26
04
2024
accepted:
05
08
2024
medline:
14
8
2024
pubmed:
14
8
2024
entrez:
13
8
2024
Statut:
epublish
Résumé
The mechanism of action of bispecific antibodies (bsAbs) directing T-cell immunity to solid tumors is incompletely understood. Here, we screened a series of CD3xHER2 bsAbs using extracellular matrix (ECM) embedded breast cancer tumoroid arrays exposed to healthy donor-derived T-cells. An initial phase of random T-cell movement throughout the ECM (day 1-2), was followed by a bsAb-dependent phase of active T-cell recruitment to tumoroids (day 2-4), and tumoroid killing (day 4-6). Low affinity HER2 or CD3 arms were compensated for by increasing bsAb concentrations. Instead, a bsAb binding a membrane proximal HER2 epitope supported tumor killing whereas a bsAb binding a membrane distal epitope did not, despite similar affinities and intra-tumoroid localization of the bsAbs, and efficacy in 2D co-cultures. Initial T-cell-tumor contact through effective bsAbs triggered a wave of subsequent T-cell recruitment. This critical surge of T-cell recruitment was explained by paracrine signaling and preceded a full-scale T-cell tumor attack.
Identifiants
pubmed: 39138287
doi: 10.1038/s42003-024-06682-9
pii: 10.1038/s42003-024-06682-9
doi:
Substances chimiques
Antibodies, Bispecific
0
CD3 Complex
0
Receptor, ErbB-2
EC 2.7.10.1
ERBB2 protein, human
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
983Subventions
Organisme : Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)
ID : 2019.022
Informations de copyright
© 2024. The Author(s).
Références
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
doi: 10.1038/nature11412
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
doi: 10.1038/35021093
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).
doi: 10.1126/science.3798106
Owens, M. A., Horten, B. C. & Da Silva, M. M. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin. Breast Cancer 5, 63–69 (2004).
doi: 10.3816/CBC.2004.n.011
Baselga, J. et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J. Clin. Oncol. 14, 737–744 (1996).
doi: 10.1200/JCO.1996.14.3.737
Vogel, C. L. et al. Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer. J. Clin. Oncol. 41, 1638–1645 (2023).
doi: 10.1200/JCO.22.02516
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).
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).
doi: 10.1056/NEJMoa052122
Hudis, C. A. Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007).
doi: 10.1056/NEJMra043186
Modi, S. et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N. Engl. J. Med. 387, 9–20 (2022).
doi: 10.1056/NEJMoa2203690
Ferraro, E., Drago, J. Z. & Modi, S. Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions. Breast Cancer Res. 23, 84 (2021).
doi: 10.1186/s13058-021-01459-y
Xia, X., Gong, C., Zhang, Y., & Xiong, H. The History and Development of HER2 Inhibitors. Pharmaceuticals 16, 1450 (2023).
Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).
doi: 10.1038/74704
Offner, S., Hofmeister, R., Romaniuk, A., Kufer, P. & Baeuerle, P. A. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol. Immunol. 43, 763–771 (2006).
doi: 10.1016/j.molimm.2005.03.007
Rader, C. Bispecific antibodies in cancer immunotherapy. Curr. Opin. Biotechnol. 65, 9–16 (2020).
doi: 10.1016/j.copbio.2019.11.020
Labrijn, A. F., Janmaat, M. L., Reichert, J. M. & Parren, P. Bispecific antibodies: a mechanistic review of the pipeline. Nat. Rev. Drug Discov. 18, 585–608 (2019).
doi: 10.1038/s41573-019-0028-1
Yu, S. et al. Development and clinical application of anti-HER2 monoclonal and bispecific antibodies for cancer treatment. Exp. Hematol. Oncol. 6, 31 (2017).
doi: 10.1186/s40164-017-0091-4
Bargou, R. et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321, 974–977 (2008).
doi: 10.1126/science.1158545
Topp, M. S. et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 16, 57–66 (2015).
doi: 10.1016/S1470-2045(14)71170-2
Singh, A., Dees, S. & Grewal, I. S. Overcoming the challenges associated with CD3+ T-cell redirection in cancer. Br. J. Cancer 124, 1037–1048 (2021).
doi: 10.1038/s41416-020-01225-5
Junttila, T. T. et al. Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells. Cancer Res. 74, 5561–5571 (2014).
doi: 10.1158/0008-5472.CAN-13-3622-T
Mandikian, D. et al. Relative Target Affinities of T-Cell-Dependent Bispecific Antibodies Determine Biodistribution in a Solid Tumor Mouse Model. Mol. Cancer Ther. 17, 776–785 (2018).
doi: 10.1158/1535-7163.MCT-17-0657
Drost, J. & Clevers, H. Organoids in cancer research. Nat. Rev. Cancer 18, 407–418 (2018).
doi: 10.1038/s41568-018-0007-6
Booij, T. H., Price, L. S. & Danen, E. H. J. 3D Cell-Based Assays for Drug Screens: Challenges in Imaging, Image Analysis, and High-Content Analysis. SLAS Discov. 24, 615–627 (2019).
doi: 10.1177/2472555219830087
Truong, H. H. et al. Automated microinjection of cell-polymer suspensions in 3D ECM scaffolds for high-throughput quantitative cancer invasion screens. Biomaterials 33, 181–188 (2012).
doi: 10.1016/j.biomaterials.2011.09.049
Cattaneo, C. M. et al. Tumor organoid-T-cell coculture systems. Nat. Protoc. 15, 15–39 (2020).
doi: 10.1038/s41596-019-0232-9
Schnalzger, T. E., et al. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. EMBO J. 38, e100928 (2019).
Votanopoulos, K. I. et al. Model of Patient-Specific Immune-Enhanced Organoids for Immunotherapy Screening: Feasibility Study. Ann. Surg. Oncol. 27, 1956–1967 (2020).
doi: 10.1245/s10434-019-08143-8
Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).
doi: 10.1038/s41591-020-0805-8
Dijkstra, K. K. et al. Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids. Cell 174, 1586–1598.e1512 (2018).
doi: 10.1016/j.cell.2018.07.009
Boucherit, N., Gorvel, L. & Olive, D. 3D Tumor Models and Their Use for the Testing of Immunotherapies. Front. Immunol. 11, 603640 (2020).
doi: 10.3389/fimmu.2020.603640
Wardwell-Swanson, J. et al. A Framework for Optimizing High-Content Imaging of 3D Models for Drug Discovery. SLAS Discov. 25, 709–722 (2020).
doi: 10.1177/2472555220929291
Herter, S. et al. A novel three-dimensional heterotypic spheroid model for the assessment of the activity of cancer immunotherapy agents. Cancer Immunol. Immunother. 66, 129–140 (2017).
doi: 10.1007/s00262-016-1927-1
Labrijn, A. F. et al. Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange. Proc. Natl Acad. Sci. USA 110, 5145–5150 (2013).
doi: 10.1073/pnas.1220145110
Labrijn, A. F. et al. Controlled Fab-arm exchange for the generation of stable bispecific IgG1. Nat. Protoc. 9, 2450–2463 (2014).
doi: 10.1038/nprot.2014.169
Gramer, M. J. et al. Production of stable bispecific IgG1 by controlled Fab-arm exchange: scalability from bench to large-scale manufacturing by application of standard approaches. MAbs 5, 962–973 (2013).
doi: 10.4161/mabs.26233
Shen, D. T., Ma, J. S., Mather, J., Vukmanovic, S. & Radoja, S. Activation of primary T lymphocytes results in lysosome development and polarized granule exocytosis in CD4+ and CD8+ subsets, whereas expression of lytic molecules confers cytotoxicity to CD8+ T cells. J. Leukoc. Biol. 80, 827–837 (2006).
doi: 10.1189/jlb.0603298
Bohmer, R. M., Bandala-Sanchez, E. & Harrison, L. C. Forward light scatter is a simple measure of T-cell activation and proliferation but is not universally suited for doublet discrimination. Cytom. A 79, 646–652 (2011).
doi: 10.1002/cyto.a.21096
Lan, H. R., Chen, M., Yao, S. Y., Chen, J. X. & Jin, K. T. Bispecific antibodies revolutionizing breast cancer treatment: a comprehensive overview. Front. Immunol. 14, 1266450 (2023).
doi: 10.3389/fimmu.2023.1266450
Conklin, M. W. & Keely, P. J. Why the stroma matters in breast cancer: insights into breast cancer patient outcomes through the examination of stromal biomarkers. Cell Adh Migr. 6, 249–260 (2012).
doi: 10.4161/cam.20567
Lin, Y. N. et al. Monitoring Cancer Cell Invasion and T-Cell Cytotoxicity in 3D Culture. J. Vis. Exp. 160, e61392 (2020).
Zhou, S. et al. Bifunctional iRGD-anti-CD3 enhances antitumor potency of T cells by facilitating tumor infiltration and T-cell activation. J. Immunother. Cancer 9, e001925 (2021).
Flores-Torres, S. et al. Bioprinted Multicomponent Hydrogel Co-culture Tumor-Immune Model for Assessing and Simulating Tumor-Infiltrated Lymphocyte Migration and Functional Activation. ACS Appl Mater. Interfaces 15, 33250–33262 (2023).
doi: 10.1021/acsami.3c02995
Staflin, K., et al. Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibody. JCI Insight 5, e133757 (2020).
Slaga, D. et al. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3. Sci. Transl. Med. 10, eaat5775 (2018).
doi: 10.1126/scitranslmed.aat5775
Haber, L. et al. Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning. Sci. Rep. 11, 14397 (2021).
doi: 10.1038/s41598-021-93842-0
Bortoletto, N., Scotet, E., Myamoto, Y., D’Oro, U. & Lanzavecchia, A. Optimizing anti-CD3 affinity for effective T cell targeting against tumor cells. Eur. J. Immunol. 32, 3102–3107 (2002).
doi: 10.1002/1521-4141(200211)32:11<3102::AID-IMMU3102>3.0.CO;2-C
Dang, K., et al. Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release. J. Immunother. Cancer 9, e002488 (2021).
Bluemel, C. et al. Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen. Cancer Immunol. Immunother. 59, 1197–1209 (2010).
doi: 10.1007/s00262-010-0844-y
Li, J. et al. Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing. Cancer Cell 31, 383–395 (2017).
doi: 10.1016/j.ccell.2017.02.001
Kamakura, D., Asano, R., Kawai, H. & Yasunaga, M. Mechanism of action of a T cell-dependent bispecific antibody as a breakthrough immunotherapy against refractory colorectal cancer with an oncogenic mutation. Cancer Immunol. Immunother. 70, 177–188 (2021).
doi: 10.1007/s00262-020-02667-9
Ronteix, G. et al. High resolution microfluidic assay and probabilistic modeling reveal cooperation between T cells in tumor killing. Nat. Commun. 13, 3111 (2022).
doi: 10.1038/s41467-022-30575-2
Coban, B. et al. GRHL2 suppression of NT5E/CD73 in breast cancer cells modulates CD73-mediated adenosine production and T cell recruitment. iScience 27, 109738 (2024).
doi: 10.1016/j.isci.2024.109738
Kabat E. A. Sequences of proteins of immunological interest (US Department of Health and Human Services, Public Health Service, National, 1991).
Rajan, N., Habermehl, J., Cote, M. F., Doillon, C. J. & Mantovani, D. Preparation of ready-to-use, storable and reconstituted type I collagen from rat tail tendon for tissue engineering applications. Nat. Protoc. 1, 2753–2758 (2006).
doi: 10.1038/nprot.2006.430
Truong, H. H. et al. beta1 integrin inhibition elicits a prometastatic switch through the TGFbeta-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer. Sci. Signal 7, ra15 (2014).
doi: 10.1126/scisignal.2004751
Schmidt, T., Schütz, G. J., Baumgartner, W., Gruber, H. J. & Schindler, H. Imaging of single molecule diffusion. Proc. Natl Acad. Sci. USA 93, 2926–2929 (1996).
doi: 10.1073/pnas.93.7.2926
Kusumi, A., Sako, Y. & Yamamoto, M. Confined lateral diffusion of membrane receptors as studied by single particle tracking (nanovid microscopy). Effects of calcium-induced differentiation in cultured epithelial cells. Biophys. J. 65, 2021–2040 (1993).
doi: 10.1016/S0006-3495(93)81253-0
Kemper K., et al. Mechanistic and pharmacodynamic studies of DuoBody-CD3x5T4 in preclinical tumor models. Life Sci Alliance 5, e202201481 (2022).
Bostrom, J. et al. Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science 323, 1610–1614 (2009).
doi: 10.1126/science.1165480