A logic-gated trispecific engager enhances macrophage killing of cancer cells in solid tumors
Fenis, A., Demaria, O., Gauthier, L., Vivier, E. & Narni-Mancinelli, E. New immune cell engagers for cancer immunotherapy. Nat. Rev. Immunol. 24, 471–486 (2024).
Google Scholar
Pinto, S., Pahl, J., Schottelius, A., Carter, P. J. & Koch, J. Reimagining antibody-dependent cellular cytotoxicity in cancer: the potential of natural killer cell engagers. Trends Immunol. 43, 932–946 (2022).
Google Scholar
Rolin, C., Zimmer, J. & Seguin-Devaux, C. Bridging the gap with multispecific immune cell engagers in cancer and infectious diseases. Cell. Mol. Immunol. 21, 643–661 (2024).
Google Scholar
Tapia-Galisteo, A., Álvarez-Vallina, L. & Sanz, L. Bi- and trispecific immune cell engagers for immunotherapy of hematological malignancies. J. Hematol. Oncol. 16, 83 (2023).
Google Scholar
Wu, J., Fu, J., Zhang, M. & Liu, D. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J. Hematol. Oncol. 8, 104 (2015).
Google Scholar
Ng, G., Spreter, T., Davies, R. & Wickman, G. ZW38, a novel azymetric bispecific CD19-directed CD3 T cell engager antibody drug conjugate with controlled T cell activation and improved B cell cytotoxicity. Blood 128, 1841 (2016).
Google Scholar
Topp, M. S. et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J. Clin. Oncol. 32, 4134–4140 (2014).
Google Scholar
Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).
Google Scholar
Labrijn, A. F., Janmaat, M. L., Reichert, J. M. & Parren, P. W. H. I. Bispecific antibodies: a mechanistic review of the pipeline. Nat. Rev. Drug Discovery 18, 585–608 (2019).
Google Scholar
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).
Google Scholar
Köhnke, T., Krupka, C., Tischer, J., Knösel, T. & Subklewe, M. Increase of PD-L1 expressing B-precursor ALL cells in a patient resistant to the CD19/CD3-bispecific T cell engager antibody blinatumomab. J. Hematol. Oncol. 8, 111 (2015).
Google Scholar
Thakur, A., Huang, M. & Lum, L. G. Bispecific antibody based therapeutics: strengths and challenges. Blood Rev. 32, 339–347 (2018).
Google Scholar
Dreher, M. R. et al. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J. Natl Cancer Inst. 98, 335–344 (2006).
Google Scholar
Lu, H. et al. PIT565, a first-in-class anti-CD19, anti-CD3, anti-CD2 trispecific antibody for the treatment of B cell malignancies. Blood 140, 3148–3148 (2022).
Google Scholar
Correnti, C. E. et al. Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 co-stimulation. Leukemia 32, 1239–1243 (2018).
Google Scholar
Gauthier, L. et al. Control of acute myeloid leukemia by a trifunctional NKp46–CD16a–NK cell engager targeting CD123. Nat. Biotechnol. 41, 1296–1306 (2023).
Google Scholar
Riley, J. L. & June, C. H. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation. Blood 105, 13–21 (2005).
Google Scholar
Bierer, B. E., Peterson, A., Gorga, J. C., Herrmann, S. H. & Burakoff, S. J. Synergistic T cell activation via the physiological ligands for CD2 and the T cell receptor. J. Exp. Med. 168, 1145–1156 (1988).
Google Scholar
Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).
Google Scholar
Long, E. O., Kim, H. S., Liu, D., Peterson, M. E. & Rajagopalan, S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu. Rev. Immunol. 31, 227–258 (2013).
Google Scholar
Jain, S. et al. Targeted inhibition of CD47–SIRPα requires Fc–FcγR interactions to maximize activity in T-cell lymphomas. Blood 134, 1430–1440 (2019).
Google Scholar
Suter, E. C. et al. Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation. Cell Rep. 36, 109587 (2021).
Google Scholar
Oslund, R. C., Holland, P. M., Lesley, S. A. & Fadeyi, O. O. Therapeutic potential of cis-targeting bispecific antibodies. Cell Chem. Biol. 31, 1473–1489 (2024).
Google Scholar
Peng, K., Fu, Y.-X. & Liang, Y. Engineering cytokines for tumor-targeting and selective T cell activation. Trends Mol. Med. 31, 373–387 (2025).
Google Scholar
Dong, J. et al. A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity. mAbs 3, 273–288 (2011).
Google Scholar
Madsen, A. V. et al. Immobilization-free binding and affinity characterization of higher order bispecific antibody complexes using size-based microfluidics. Anal. Chem. 94, 13652–13658 (2022).
Google Scholar
Croasdale, R. et al. Development of tetravalent IgG1 dual targeting IGF-1R–EGFR antibodies with potent tumor inhibition. Arch. Biochem. Biophys. 526, 206–218 (2012).
Google Scholar
Kühl, L. et al. eIg-based bispecific T-cell engagers targeting EGFR: format matters. mAbs 15, 2183540 (2023).
Google Scholar
Pang, X. et al. Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity. mAbs 15, 2180794 (2023).
Google Scholar
Ring, N. G. et al. Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity. Proc. Natl Acad. Sci. USA 114, E10578–E10585 (2017).
Google Scholar
Vitale, I., Manic, G., Coussens, L. M., Kroemer, G. & Galluzzi, L. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 30, 36–50 (2019).
Google Scholar
Chao, M. P. et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94 (2010).
Google Scholar
Osorio, J. C., Smith, P., Knorr, D. A. & Ravetch, J. V. The antitumor activities of anti-CD47 antibodies require Fc–FcγR interactions. Cancer Cell 41, 2051–2065 (2023).
Google Scholar
Guilbaud, E., Kroemer, G. & Galluzzi, L. Calreticulin exposure orchestrates innate immunosurveillance. Cancer Cell 41, 1014–1016 (2023).
Google Scholar
Logtenberg, M. E. W., Scheeren, F. A. & Schumacher, T. N. The CD47–SIRPα immune checkpoint. Immunity 52, 742–752 (2020).
Google Scholar
Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).
Google Scholar
Krysko, D. V., Ravichandran, K. S. & Vandenabeele, P. Macrophages regulate the clearance of living cells by calreticulin. Nat. Commun. 9, 4644 (2018).
Google Scholar
Feng, M. et al. Macrophages eat cancer cells using their own calreticulin as a guide: roles of TLR and Btk. Proc. Natl Acad. Sci. USA 112, 2145–2150 (2015).
Google Scholar
Feng, M. et al. Programmed cell removal by calreticulin in tissue homeostasis and cancer. Nat. Commun. 9, 3194 (2018).
Google Scholar
Ogden, C. A. et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781–796 (2001).
Google Scholar
Klein, C., Brinkmann, U., Reichert, J. M. & Kontermann, R. E. The present and future of bispecific antibodies for cancer therapy. Nat. Rev. Drug Discov. 23, 301–319 (2024).
Google Scholar
Madsen, A. V., Pedersen, L. E., Kristensen, P. & Goletz, S. Design and engineering of bispecific antibodies: insights and practical considerations. Front. Bioeng. Biotechnol. 12, 2024 (2024).
Google Scholar
Christofides, A. et al. The complex role of tumor-infiltrating macrophages. Nat. Immunol. 23, 1148–1156 (2022).
Google Scholar
Wang, Q. et al. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nat. Commun. 13, 3022 (2022).
Google Scholar
Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003).
Google Scholar
Drouin, M. et al. CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy. Sci. Adv. 8, eabo7621 (2022).
Google Scholar
Park, J. S. et al. Targeting PD-L2–RGMb overcomes microbiome-related immunotherapy resistance. Nature 617, 377–385 (2023).
Google Scholar
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).
Google Scholar
Rohner, E., Yang, R., Foo, K. S., Goedel, A. & Chien, K. R. Unlocking the promise of mRNA therapeutics. Nat. Biotechnol. 40, 1586–1600 (2022).
Google Scholar
Stadler, C. R. et al. Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell-engaging bispecific antibody targeting human claudin 6. Sci. Transl. Med. 16, eadl2720 (2024).
Google Scholar
Zhang, Y. et al. Close the cancer–immunity cycle by integrating lipid nanoparticle–mRNA formulations and dendritic cell therapy. Nat. Nanotechnol. 18, 1364–1374 (2023).
Google Scholar
Fenton, O. S. et al. Customizable lipid nanoparticle materials for the delivery of siRNAs and mRNAs. Angew. Chem. Int. Ed. Engl. 57, 13582–13586 (2018).
Google Scholar
Han, X. et al. An ionizable lipid toolbox for RNA delivery. Nat. Commun. 12, 7233 (2021).
Google Scholar
Riley, R. S. et al. Ionizable lipid nanoparticles for in utero mRNA delivery. Sci. Adv. 7, eaba1028 (2021).
Google Scholar
Fan, N. et al. Manganese-coordinated mRNA vaccines with enhanced mRNA expression and immunogenicity induce robust immune responses against SARS-CoV-2 variants. Sci. Adv. 8, eabq3500 (2022).
Google Scholar
Miao, L. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat. Commun. 11, 2424 (2020).
Google Scholar
Hatit, M. Z. C. et al. Nanoparticle stereochemistry-dependent endocytic processing improves in vivo mRNA delivery. Nat. Chem. 15, 508–515 (2023).
Google Scholar
Da Silva Sanchez, A. J. et al. Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery. J. Control. Release 353, 270–277 (2023).
Google Scholar
Hatit, M. Z. C. et al. Species-dependent in vivo mRNA delivery and cellular responses to nanoparticles. Nat. Nanotechnol. 17, 310–318 (2022).
Google Scholar
Martín, P., Blanco-Domínguez, R. & Sánchez-Díaz, R. Novel human immunomodulatory T cell receptors and their double-edged potential in autoimmunity, cardiovascular disease and cancer. Cell. Mol. Immunol. 18, 919–935 (2021).
Google Scholar
Baaten, B. J. G. et al. CD44 regulates survival and memory development in Th1 cells. Immunity 32, 104–115 (2010).
Google Scholar
Yamada-Hunter, S. A. et al. Engineered CD47 protects T cells for enhanced antitumour immunity. Nature 630, 457–465 (2024).
Google Scholar
Bell, E. A fine balance. Nat. Rev. Immunol. 2, 540–540 (2002).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Google Scholar
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer–immune set point. Nature 541, 321–330 (2017).
Google Scholar
Cerwenka, A. & Lanier, L. L. Natural killer cell memory in infection, inflammation and cancer. Nat. Rev. Immunol. 16, 112–123 (2016).
Google Scholar
Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018).
Google Scholar
Morvan, M. G. & Lanier, L. L. NK cells and cancer: you can teach innate cells new tricks. Nat. Rev. Cancer 16, 7–19 (2016).
Google Scholar
Joller, N., Anderson, A. C. & Kuchroo, V. K. LAG-3, TIM-3, and TIGIT: distinct functions in immune regulation. Immunity 57, 206–222 (2024).
Google Scholar
Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).
Google Scholar
Spolski, R., Li, P. & Leonard, W. J. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat. Rev. Immunol. 18, 648–659 (2018).
Google Scholar
:max_bytes(150000):strip_icc()/Health-GettyImages-1308303089-b6de0431d97a4620ab07d98b08537302.jpg?w=390&resize=390,220&ssl=1 "How To Tell an Ankle Sprain From a Break")
