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Research Article

Engineering of a trispecific tumor-targeted immunotherapy incorporating 4-1BB co-stimulation and PD-L1 blockade

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Article: 2004661 | Received 08 Jul 2021, Accepted 07 Nov 2021, Published online: 02 Dec 2021

References

  • Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):1–17. doi:10.1038/s12276-018-0191-1.
  • Yi M, Niu M, Xu L, Luo S, Wu K. Regulation of PD-L1 expression in the tumor microenvironment. J Hematol Oncol. 2021;14(1):10. doi:10.1186/s13045-020-01027-5.
  • Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637):321–330. doi:10.1038/nature21349.
  • Abe BT, Macian F. Uncovering the mechanisms that regulate tumor-induced T-cell anergy. Oncoimmunology. 2013;2(2):e22679. doi:10.4161/onci.22679.
  • Chester C, Sanmamed MF, Wang J, Melero I. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. Blood. 2018;131(1):49–57. doi:10.1182/blood-2017-06-741041.
  • Vinay DS, Kwon BS. Immunotherapy of cancer with 4-1BB. Mol Cancer Ther. 2012;11(5):1062–1070. doi:10.1158/1535-7163.Mct-11-0677.
  • Bremer E. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy. ISRN Oncol. 2013;2013:371854. doi:10.1155/2013/371854.
  • Choi BK, Lee SC, Lee MJ, Kim YH, Kim YW, Ryu KW, Lee JH, Shin SM, Lee SH, Suzuki S, et al. 4-1BB-based isolation and expansion of CD8+ T cells specific for self-tumor and non-self-tumor antigens for adoptive T-cell therapy. J Immunother. 2014;37(4):225–236. doi:10.1097/cji.0000000000000027.
  • Wolfl M, Kuball J, Ho WY, Nguyen H, Manley TJ, Bleakley M, Greenberg PD. Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood. 2007;110(1):201–210. doi:10.1182/blood-2006-11-056168.
  • Wilcox RA, Tamada K, Flies DB, Zhu G, Chapoval AI, Blazar BR, Kast WM, Chen L. Ligation of CD137 receptor prevents and reverses established energy of CD8+ cytolytic T lymphocytes in vivo. Blood. 2004;103(1):177–184. doi:10.1182/blood-2003-06-2184.
  • Weigelin B, Bolaños E, Teijeira A, Martinez-Forero I, Labiano S, Azpilikueta A, Morales-Kastresana A, Quetglas JI, Wagena E, Sánchez-Paulete AR, et al. Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb. Proc Natl Acad Sci U S A. 2015;112(24):7551–7556. doi:10.1073/pnas.1506357112.
  • Williams JB, Horton BL, Zheng Y, Duan Y, Powell JD, Gajewski TF. The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J Exp Med. 2017;214(2):381–400. doi:10.1084/jem.20160485.
  • Chen S, Lee L-F, Fisher TS, Jessen B, Elliott M, Evering W, Logronio K, Tu GH, Tsaparikos K, Li X, et al. Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model. Cancer Immunol Res. 2015;3(2):149–160. doi:10.1158/2326-6066.Cir-14-0118.
  • Dai M, Yip YY, Hellstrom I, Hellstrom KE. Curing mice with large tumors by locally delivering combinations of immunomodulatory antibodies. Clin Cancer Res. 2015;21(5):1127–1138. doi:10.1158/1078-0432.Ccr-14-1339.
  • Wei H, Zhao L, Hellstrom I, Hellstrom KE, Guo Y. Dual targeting of CD137 co-stimulatory and PD-1 co-inhibitory molecules for ovarian cancer immunotherapy. Oncoimmunology. 2014;3(4):e28248. doi:10.4161/onci.28248.
  • Segal NH, Logan TF, Hodi FS, McDermott D, Melero I, Hamid O, Schmidt H, Robert C, Chiarion-Sileni V, Ascierto PA, et al. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 2017;23(8):1929–1936. doi:10.1158/1078-0432.Ccr-16-1272.
  • Segal NH, He AR, Doi T, Levy R, Bhatia S, Pishvaian MJ, Cesari R, Chen Y, Davis CB, Huang B, et al. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res. 2018;24(8):1816–1823. doi:10.1158/1078-0432.CCR-17-1922.
  • Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, Rasco DW, Di Gravio D, Huang B, Gambhire D, Chen Y, et al. Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res. 2017;23(18):5349–5357. doi:10.1158/1078-0432.Ccr-17-1243.
  • Chin SM, Kimberlin CR, Roe-Zurz Z, Zhang P, Xu A, Liao-Chan S, Sen D, Nager AR, Oakdale NS, Brown C, et al. Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab. Nat Commun. 2018;9(1):4679. doi:10.1038/s41467-018-07136-7.
  • Vanamee ÉS, Faustman DL. Structural principles of tumor necrosis factor superfamily signaling. Sci Signal. 2018;11(511):511. doi:10.1126/scisignal.aao4910.
  • Carter PJ, Lazar GA. Next generation antibody drugs: pursuit of the ‘high-hanging fruit’. Nat Rev Drug Discov. 2018;17(3):197–223. doi:10.1038/nrd.2017.227.
  • Rabu C, Quéméner A, Jacques Y, Echasserieau K, Vusio P, Lang F. Production of recombinant human trimeric CD137L (4-1BBL). Cross-linking is essential to its T cell co-stimulation activity. J Biol Chem. 2005;280(50):41472–41481. doi:10.1074/jbc.M506881200.
  • Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, Wilson NS, Dranoff G, and Brogdon JL. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med. 2013;210(9):1685–1693. doi:10.1084/jem.20130573.
  • Fellermeier S, Beha N, Meyer JE, Ring S, Bader S, Kontermann RE, Müller D. Advancing targeted co-stimulation with antibody-fusion proteins by introducing TNF superfamily members in a single-chain format. Oncoimmunology. 2016;5(11):e1238540. doi:10.1080/2162402x.2016.1238540.
  • Bartkowiak T, Jaiswal AR, Ager CR, Chin R, Chen CH, Budhani P, Ai M, Reilley MJ, Sebastian MM, Hong DS, et al. Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27-dependent pathway. Clin Cancer Res. 2018;24(5):1138–1151. doi:10.1158/1078-0432.Ccr-17-1847.
  • Qi X, Li F, Wu Y, Cheng C, Han P, Wang J, Yang X. Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. Nat Commun. 2019;10(1):2141. doi:10.1038/s41467-019-10088-1.
  • Claus C, Ferrara C, Xu W, Sam J, Lang S, Uhlenbrock F, Albrecht R, Herter S, Schlenker R, Hüsser T, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy. Sci Transl Med. 2019;11(496):496. doi:10.1126/scitranslmed.aav5989.
  • Junttila TT, Li J, Johnston J, Hristopoulos M, Clark R, Ellerman D, Wang B-E, Li Y, Mathieu M, Li G, et al. Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells. Cancer Res. 2014;74(19):5561–5571. doi:10.1158/0008-5472.Can-13-3622-t.
  • Hinner MJ, Aiba RSB, Jaquin TJ, Berger S, Dürr MC, Schlosser C, Allersdorfer A, Wiedenmann A, Matschiner G, Schüler J, et al. Tumor-localized costimulatory T-cell engagement by the 4-1BB/HER2 bispecific antibody-anticalin fusion PRS-343. Clin Cancer Res. 2019;25(19):5878–5889. doi:10.1158/1078-0432.Ccr-18-3654.
  • Compte M, Harwood SL, Muñoz IG, Navarro R, Zonca M, Perez-Chacon G, Erce-Llamazares A, Merino N, Tapia-Galisteo A, Cuesta AM, et al. A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity. Nat Commun. 2018;9(1):4809. doi:10.1038/s41467-018-07195-w.
  • Piha-Paul S, Bendell J, Tolcher A, Hurvitz S, Patnaik A, Shroff R, Pohlmann P, Zettl M, Hahn N, Krishnamurthy A, et al. Phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies. J Immunother Cancer.2020;8(Suppl 1) doi:10.1136/LBA2019.2.
  • Slaga D, Ellerman D, Lombana TN, Vij R, Li J, Hristopoulos M, Clark R, Johnston J, Shelton A, Mai E, et al. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3. Sci Transl Med. 2018;10:463. doi:10.1126/scitranslmed.aat5775.
  • Klein C, Sustmann C, Thomas M, Stubenrauch K, Croasdale R, Schanzer J, Brinkmann U, Kettenberger H, Regula JT, and Schaefer W. Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies. MAbs. 2012;4(6):653–663. doi:10.4161/mabs.21379.
  • Pacchiana G, Chiriaco C, Stella MC, Petronzelli F, De Santis R, Galluzzo M, Carminati P, Comoglio PM, Michieli P, Vigna E, et al. Monovalency unleashes the full therapeutic potential of the DN-30 anti-Met antibody. J Biol Chem. 2010;285(46):36149–36157. doi:10.1074/jbc.M110.134031.
  • Mazor Y, Oganesyan V, Yang C, Hansen A, Wang J, Liu H, Sachsenmeier K, Carlson M, Gadre DV, Borrok MJ, et al. Improving target cell specificity using a novel monovalent bispecific IgG design. MAbs. 2015;7(2):377–389. doi:10.1080/19420862.2015.1007816.
  • Mazor Y, Hansen A, Yang C, Chowdhury PS, Wang J, Stephens G, Wu H, Dall’Acqua WF. Insights into the molecular basis of a bispecific antibody’s target selectivity. MAbs. 2015;7(3):461–469. doi:10.1080/19420862.2015.1022695.
  • Egan TJ, Diem D, Weldon R, Neumann T, Meyer S, Urech DM. Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments. MAbs. 2017;9(1):68–84. doi:10.1080/19420862.2016.1248012.
  • Novarra S, Grinberg L, Rickert KW, Barnes A, Wilson S, Baca M. A hingeless Fc fusion system for site-specific cleavage by IdeS. MAbs. 2016;8(6):1118–1125. doi:10.1080/19420862.2016.1186321.
  • Kabsch W. XDS. Acta Crystallogr D Biol Crystallogr. 2010;66(Pt2):125–132. doi:10.1107/s0907444909047337.
  • McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ. Phaser crystallographic software. J Appl Crystallogr. 2007;40(Pt 4):658–674. doi:10.1107/s0021889807021206.
  • Murshudov GN, Vagin AA, Dodson EJ. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997;53(Pt 3):240–255. doi:10.1107/s0907444996012255.
  • Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010;66(Pt 4):486–501. doi:10.1107/s0907444910007493.
  • Eskiocak U, Guzman W, Wolf B, Cummings C, Milling L, Hj W, Ophir M, Lambden C, Bakhru P, Gilmore DC, et al. Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity. JCI Insight. 2020;5:5. doi:10.1172/jci.insight.133647.
  • Tan S, Liu K, Chai Y, Zhang CW, Gao S, Gao GF, Qi J. Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab. Protein Cell. 2018;9(1):135–139. doi:10.1007/s13238-017-0412-8.
  • Wyzgol A, Müller N, Fick A, Munkel S, Grigoleit GU, Pfizenmaier K, Wajant H. Trimer stabilization, oligomerization, and antibody-mediated cell surface immobilization improve the activity of soluble trimers of CD27L, CD40L, 41BBL, and glucocorticoid-induced TNF receptor ligand. J Immunol. 2009;183(3):1851–1861. doi:10.4049/jimmunol.0802597.
  • Coloma MJ, Morrison SL. Design and production of novel tetravalent bispecific antibodies. Nat Biotechnol. 1997;15(2):159–163. doi:10.1038/nbt0297-159.
  • Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111–122. doi:10.1016/j.immuni.2007.05.016.
  • Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3–potential mechanisms of action. Nat Rev Immunol. 2015;15(1):45–56. doi:10.1038/nri3790.
  • Mayoux M, Roller A, Pulko V, Sammicheli S, Chen S, Sum E, Jost C, Fransen MF, Buser RB, Kowanetz M, et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Sci Transl Med. 2020;12(534):534. doi:10.1126/scitranslmed.aav7431.
  • Oh SA, Wu D-C, Cheung J, Navarro A, Xiong H, Cubas R, Totpal K, Chiu H, Wu Y, Comps-Agrar L, et al. PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer. Nature Cancer. 2020;1(7):681–691. doi:10.1038/s43018-020-0075-x.
  • Peng Q, Qiu X, Zhang Z, Zhang S, Zhang Y, Liang Y, Guo J, Peng H, Chen M, Fu Y-X, et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun. 2020;11(1):4835. doi:10.1038/s41467-020-18570-x.
  • Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, Lamping E, Oyelakin I, Marté JL, Lepone LM, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18(5):587–598. doi:10.1016/s1470-2045(17)30239-5.
  • Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–567. doi:10.1038/nature14011.
  • Lakins MA, Koers A, Giambalvo R, Munoz-Olaya J, Hughes R, Goodman E, Marshall S, Wollerton F, Batey S, Gliddon D, et al. FS222, a CD137/PD-L1 tetravalent bispecific antibody, exhibits low toxicity and antitumor activity in colorectal cancer models. Clin Cancer Res. 2020;26(15):4154–4167. doi:10.1158/1078-0432.Ccr-19-2958.
  • Garralda E, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso P, Türeci Ö, Niewood M, Şahin U, Jure-Kunkel M, et al. First-in-human phase I/IIA trial to evaluate the safety and initial clinical activity of duobody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors. J Immunother Cancer. 2020;8(Suppl 3):A437–A437. SITC Abstract 412. doi:10.1136/jitc-2020-SITC2020.0412.
  • Bol K, Marissen J, Elassiass-Schaap J, Tacken P, Engels S, Wang L-C, Mondal A, Throsby M, Roberts A, Mayes P, et al. MCLA −145 (CD137xPD 145 (CD137xPD -L1): a potent CD137 agonist and immune checkpoint inhibitor that does not show signs of peripheral toxicity in preclinical models. J Immunother Cancer. 2020. SITC 2020 Poster P814. doi:10.1136/jitc-2020-SITC2020.0814.
  • Zhai T, Wang C, Xu Y, Huang W, Yuan Z, Wang T, Dai S, Peng S, Pang T, Jiang W, et al. Generation of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer. J Immunother Cancer. 2021;9(6):6. doi:10.1136/jitc-2020-002131.
  • Jeong S, Park E, Kim HD, Sung E, Kim H, Jeon J, Kim Y, Jung U-J, Son Y-G, Hong Y. Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade. J Immunother Cancer. 2021;9:7. doi:10.1136/jitc-2021-002428.
  • Garralda E, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso P, Tureci O, Niewood M, Sahin U, Jure-Kinkel M, et al. First-in-human phase I/IIA trial to evaluate the safety and initial clinical activity of duobody-PD-L1x4-1BB (GEN1046) in patients with advanced solid tumors. J Immunother Cancer. 2020;8(Suppl 3):Abstract 412. doi:10.1136/jitc-2020-SITC2020.0412.
  • Bol K, Marissen W, Elassiass-Schaap J, Tacken P, Engels S, Wang L-C, Mondal A, Throsby M, Roberts A, Mayes P, et al. MCLA-145 (CD137xPD-L1): a potent CD137 agonist and immune checkpoint inhibitor that that does not show signs of peripheral toxicity. J Immunother Cancer. 2020;8(Suppl 3):Abstract 814. doi:10.1136/jitc-2020-SITC2020.0814.