Targeting a membrane-proximal epitope on mesothelin increases the tumoricidal activity of a bispecific antibody blocking CD47 on mesothelin-positive tumors

References

• Carter PJ, Lazar GA. Next generation antibody drugs: pursuit of the ‘high-hanging fruit’. Nat Rev Drug Discov. 2018;17:197–13. doi:https://doi.org/10.1038/nrd.2017.227.
   PubMed Web of Science ®Google Scholar
• Nicodemus CF. Antibody-based immunotherapy of solid cancers: progress and possibilities. Immunotherapy. 2015;7:923–39. doi:https://doi.org/10.2217/imt.15.57.
   PubMed Web of Science ®Google Scholar
• Corraliza-Gorjón I, Somovilla-Crespo B, Santamaria S, Garcia-Sanz JA, Kremer L. New strategies using antibody combinations to increase cancer treatment effectiveness. Front Immunol. 1804;2017(8).
   Google Scholar
• Kaplon H, Reichert JM. Antibodies to watch in 2019. mAbs. 2019;11:219–38. doi:https://doi.org/10.1080/19420862.2018.1556465.
   PubMed Web of Science ®Google Scholar
• Chames P, Baty D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? mAbs. 2009;1:539–47. doi:https://doi.org/10.4161/mabs.1.6.10015.
   PubMed Web of Science ®Google Scholar
• Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019. doi:https://doi.org/10.1038/s41573-019-0028-1.
   PubMed Web of Science ®Google Scholar
• Piccione EC, Juarez S, Liu J, Tseng S, Ryan CE, Narayanan C, Wang L, Weiskopf K, Majeti R. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. mAbs. 2015;7:946–56.
   PubMed Web of Science ®Google Scholar
• Dheilly E, Moine V, Broyer L, Salgado-Pires S, Johnson Z, Papaioannou A, Cons L, Calloud S, Majocchi S, Nelson R, et al. selective blockade of the ubiquitous checkpoint receptor cd47 is enabled by dual-targeting bispecific antibodies. Mol Ther. 2017;25:523–33. doi:https://doi.org/10.1016/j.ymthe.2016.11.006.
   PubMed Web of Science ®Google Scholar
• Buatois V, Johnson Z, Salgado-Pires S, Papaioannou A, Hatterer E, Chauchet X, Richard F, Barba L, Daubeuf B, Cons L, et al. Preclinical development of a bispecific antibody that safely and effectively targets CD19 and CD47 for the treatment of b-cell lymphoma and leukemia. Mol Cancer Ther. 2018;17:1739–51. doi:https://doi.org/10.1158/1535-7163.MCT-17-1095.
   PubMed Web of Science ®Google Scholar
• Hatterer E, Barba L, Noraz N, Daubeuf B, Aubry-Lachainaye JP, von der Weid B, Richard F, Kosco-Vilbois M, Ferlin W, Shang L, et al. Co-engaging CD47 and CD19 with a bispecific antibody abrogates B-cell receptor/CD19 association leading to impaired B-cell proliferation. mAbs. 2019;11:322–34. doi:https://doi.org/10.1080/19420862.2018.1558698.
   PubMed Web of Science ®Google Scholar
• Cleary KLS, Chan HTC, James S, Glennie MJ, Cragg MS. Antibody distance from the cell membrane regulates antibody effector mechanisms. J Immunol. 2017;198:3999–4011. doi:https://doi.org/10.4049/jimmunol.1601473.
   PubMed Web of Science ®Google Scholar
• Beers SA, Chan CHT, French RR, Cragg MS, Glennie MJ. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol. 2010;47:107–14. doi:https://doi.org/10.1053/j.seminhematol.2010.01.001.
   PubMed Web of Science ®Google Scholar
• Nakano K, Orita T, Nezu J, Yoshino T, Ohizumi I, Sugimoto M, Furugaki K, Kinoshita Y, Ishiguro T, Hamakubo T, et al. Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2009;378:279–84. doi:https://doi.org/10.1016/j.bbrc.2008.11.033.
   PubMed Web of Science ®Google Scholar
• Cragg MS, Morgan SM, Chan HT, Morgan BP, Filatov AV, Johnson PW, French RR, Glennie MJ. Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Blood. 2003;101:1045–52. doi:https://doi.org/10.1182/blood-2002-06-1761.
   PubMed Web of Science ®Google Scholar
• Li J, Stagg NJ, Johnston J, Harris MJ, Menzies SA, DiCara D, Clark V, Hristopoulos M, Cook R, Slaga D, 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. 2017;31:383–95. doi:https://doi.org/10.1016/j.ccell.2017.02.001.
   PubMed Web of Science ®Google Scholar
• Baldo P, Cecco S. Amatuximab and novel agents targeting mesothelin for solid tumors. OncoTargets Ther. 2017;10:5337–53. doi:https://doi.org/10.2147/OTT.
   PubMed Web of Science ®Google Scholar
• Golfier S, Kopitz C, Kahnert A, Heisler I, Schatz CA, Stelte-Ludwig B, Mayer-Bartschmid A, Unterschemmann K, Bruder S, Linden L, et al. Anetumab Ravtansine: A novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther. 2014;13:1537–48. doi:https://doi.org/10.1158/1535-7163.MCT-13-0926.
   PubMed Web of Science ®Google Scholar
• Ho M, Feng M, Fisher RJ, Rader C, Pastan I. A novel high-affinity human monoclonal antibody to mesothelin. Int J Cancer. 2011;128:2020–30. doi:https://doi.org/10.1002/ijc.25557.
   PubMed Web of Science ®Google Scholar
• Scales SJ, Gupta N, Pacheco G, Firestein R, French DM, Koeppen H, Rangell L, Barry-Hamilton V, Luis E, Chuh J, et al. An anti-mesothelin-monomethyl auristatin e conjugate with potent antitumor activity in ovarian, pancreatic, and mesothelioma models. Mol Cancer Ther. 2014;13:2630–40. doi:https://doi.org/10.1158/1535-7163.MCT-14-0487-T.
   PubMed Web of Science ®Google Scholar
• O’Hara M, Stashwick C, Haas AR, Tanyi JL. Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy. Immunotherapy. 2016;8:449–60. doi:https://doi.org/10.2217/imt.16.4.
   PubMed Web of Science ®Google Scholar
• Advani R, Flinn I, Popplewell L, Forero A, Bartlett NL, Ghosh N, Kline J, Roschewski M, LaCasce A, Collins GP, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-hodgkin’s lymphoma. N Engl J Med. 2018;379:1711–21. doi:https://doi.org/10.1056/NEJMoa1807315.
   PubMed Web of Science ®Google Scholar
• Weiskopf K, Jahchan NS, Schnorr PJ, Cristea S, Ring AM, Maute RL, Volkmer AK, Volkmer JP, Liu J, Lim JS, et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest. 2016;126:2610–20. doi:https://doi.org/10.1172/JCI81603.
   PubMed Web of Science ®Google Scholar
• Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci. 2012;109:6662–67. doi:https://doi.org/10.1073/pnas.1121623109.
   PubMed Web of Science ®Google Scholar
• Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, Ozkan E, Fernhoff NB, van de Rijn M, Weissman IL, et al. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science. 2013;341:88–91. doi:https://doi.org/10.1126/science.1238856.
   PubMed Web of Science ®Google Scholar
• Sikic BI, Lakhani N, Patnaik A, Shah SA, Chandana SR, Rasco D, Colevas AD, O’Rourke T, Narayanan S, Papadopoulos K, et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J Clin Oncol. 2019;37:946–53. doi:https://doi.org/10.1200/JCO.18.02018.
   PubMed Web of Science ®Google Scholar
• Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-hodgkin lymphoma. Cell. 2010;142:699–713. doi:https://doi.org/10.1016/j.cell.2010.07.044.
   PubMed Web of Science ®Google Scholar
• Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R. Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res. 2011;71:1374–84. doi:https://doi.org/10.1158/0008-5472.CAN-10-2238.
   PubMed Web of Science ®Google Scholar
• Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M. A binding domain on mesothelin for CA125/MUC16. J Biol Chem. 2009;284:3739–49. doi:https://doi.org/10.1074/jbc.M806776200.
   PubMed Web of Science ®Google Scholar
• Dennis M, Carlos S, Spencer SD, Zhang Y Anti-mesothelin antibodies and immunoconjugates. Patent US 8,911,732 B2, 2014
   Google Scholar
• Ma J, Tang WK, Esser L, Pastan I, Xia D. Recognition of mesothelin by the therapeutic antibody morab-009: structural and mechanistic insights. J Biol Chem. 2012 Sep 28;287(40):33123–31. doi:https://doi.org/10.1074/jbc.M112.381756.
   PubMed Web of Science ®Google Scholar
• Veillette A, Chen J. SIRPα–CD47 Immune Checkpoint blockade in anticancer therapy. Trends Immunol. 2018;39:173–84. doi:https://doi.org/10.1016/j.it.2017.12.005.
   PubMed Web of Science ®Google Scholar
• Matlung HL, Szilagyi K, Barclay NA, van den Berg TK. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol Rev. 2017;276:145–64. doi:https://doi.org/10.1111/imr.12527.
   PubMed Web of Science ®Google Scholar
• Gul N, van Egmond M. Antibody-dependent phagocytosis of tumor cells by macrophages: a potent effector mechanism of monoclonal antibody therapy of cancer. Cancer Res. 2015;75:5008–13. doi:https://doi.org/10.1158/0008-5472.CAN-15-1330.
   PubMed Web of Science ®Google Scholar
• Weiskopf K, Weissman IL. Macrophages are critical effectors of antibody therapies for cancer. mAbs. 2015;7:303–10. doi:https://doi.org/10.1080/19420862.2015.1011450.
   PubMed Web of Science ®Google Scholar
• Richards JO, Karki S, Lazar GA, Chen H, Dang W, Desjarlais JR. Optimization of antibody binding to FcgRIIa enhances macrophage phagocytosis of tumor cells. Mol Cancer Ther. 2008;7:2517–27. doi:https://doi.org/10.1158/1535-7163.MCT-08-0201.
   PubMed Web of Science ®Google Scholar
• Hombach AA, Schildgen V, Heuser C, Finnern R, Gilham DE, Abken H. T Cell activation by antibody-like immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected t cells. J Immunol. 2007;178:4650–57. doi:https://doi.org/10.4049/jimmunol.178.7.4650.
   PubMed Web of Science ®Google Scholar
• Qi J, Li X, Peng H, Cook EM, Dadashian EL, Wiestner A, Park H, Rader C. Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1. Proc Natl Acad Sci. 2018;115:E5467–E5476. doi:https://doi.org/10.1073/pnas.1719905115.
   PubMed Web of Science ®Google Scholar
• Zhao X-Y, Subramanyam B, Sarapa N, Golfier S, Dinter H. Novel antibody therapeutics targeting mesothelin in solid tumors. Clin Cancer Drugs. 2016;3:76–86. doi:https://doi.org/10.2174/2212697X03666160218215744.
   PubMedGoogle Scholar
• Zhang YF, Phung Y, Gao W, Kawa S, Hassan R, Pastan I, Ho M. New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma. Sci Rep. 2015 May;21(5):9928. doi:https://doi.org/10.1038/srep09928.
   Web of Science ®Google Scholar
• Zhang Z 2, Jiang D, Yang H, He Z, Liu X, Qin W, Li L, Wang C, Li Y, Li H, et al. Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor. Cell Death Dis. 2019;10:476. doi:https://doi.org/10.1038/s41419-019-1711-1.
   PubMed Web of Science ®Google Scholar
• Orange JS. Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol. 2008;8:713–25. doi:https://doi.org/10.1038/nri2381.
   PubMed Web of Science ®Google Scholar
• McCann FE, Vanherberghen B, Eleme K, Carlin LM, Newsam RJ, Goulding D, Davis DM. The size of the synaptic cleft and distinct distributions of filamentous actin, ezrin, CD43, and CD45 at activating and inhibitory human NK cell immune synapses. J Immunol. 2003;170:2862–70. doi:https://doi.org/10.4049/jimmunol.170.6.2862.
   PubMed Web of Science ®Google Scholar
• Bakalar MH, Joffe AM, Schmid EM, Son S, Podolski M, Fletcher DA. Size-dependent segregation controls macrophage phagocytosis of antibody-opsonized targets. Cell. 2018 Jun 28;174(1):131–42. doi:https://doi.org/10.1016/j.cell.2018.05.059.
   PubMed Web of Science ®Google Scholar
• Freeman SA, Goyette J, Furuya W, Woods EC, Bertozzi CR, Bergmeier W, Hinz B, van der Merwe PA, Das R, Grinstein S, et al. Integrins form an expanding diffusional barrier that coordinates phagocytosis. Cell. 2016;164:128–40. doi:https://doi.org/10.1016/j.cell.2015.11.048.
   PubMed Web of Science ®Google Scholar
• Goodridge HS, Underhill DM, Touret N. Mechanisms of fc receptor and dectin-1 activation for phagocytosis: mechanisms of Fc Receptor and Dectin-1 activation for phagocytosis. Traffic. 2012;13:1062–71. doi:https://doi.org/10.1111/j.1600-0854.2012.01382.x.
   PubMed Web of Science ®Google Scholar
• Poh AR, Ernst M. Targeting macrophages in cancer: from bench to bedside. Front Oncol. 2018;8:49. doi:https://doi.org/10.3389/fonc.2018.00049.
   PubMed Web of Science ®Google Scholar
• Herter S, Birk MC, Klein C, Gerdes C, Umana P, Bacac M. Glycoengineering of therapeutic antibodies enhances monocyte/macrophage-mediated phagocytosis and cytotoxicity. J Immunol. 2014;192:2252–60. doi:https://doi.org/10.4049/jimmunol.1301249.
   PubMed Web of Science ®Google Scholar
• Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, Chan C, Chung HS, Eivazi A, Yoder SC, et al. Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci. 2006;103:4005–10. doi:https://doi.org/10.1073/pnas.0508123103.
   PubMed Web of Science ®Google Scholar
• Horton HM, Bernett MJ, Pong E, Peipp M, Karki S, Chu SY, Richards JO, Vostiar I, Joyce PF, Repp R, et al. Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res. 2008;68:8049–57. doi:https://doi.org/10.1158/0008-5472.CAN-08-2268.
   PubMed Web of Science ®Google Scholar
• Fanslow WC Kozlosky C, Gudas JM. Anti-mesothelin binding proteins. Patent US 2014/0004121 a1; 2014 Jan.
   Google Scholar
• Oldenborg P-A, Gresham HD, Lindberg FP. CD47-signal regulatory protein alpha (SIRPa) regulates Fcg and complement receptor–mediated phagocytosis. J Exp Med. 2001 Apr 2;193(7):855–62. doi:https://doi.org/10.1084/jem.193.7.855.
   PubMed Web of Science ®Google Scholar
• Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23:225–74. doi:https://doi.org/10.1146/annurev.immunol.23.021704.115526.
   PubMed Web of Science ®Google Scholar
• Okazawa H, Motegi S, Ohyama N, Ohnishi H, Tomizawa T, Kaneko Y, Oldenborg PA, Ishikawa O, Matozaki T. Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system. J Immunol. 2005 Feb 15;174(4):2004–11.
   PubMed Web of Science ®Google Scholar
• Kant AM, De P, Peng X, Yi T, Rawlings DJ, Kim JS, Durden DL. SHP-1 regulates Fcg receptor–mediated phagocytosis and the activation of RAC. Blood. 2002 1;100(5):1852–59.
   PubMed Web of Science ®Google Scholar
• Tsai RK, Discher DE. Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J Cell Biol. 2008;180:989–1003. doi:https://doi.org/10.1083/jcb.200708043.
   PubMed Web of Science ®Google Scholar
• Katano I, Takahashi T, Ito R, Kamisako T, Mizusawa T, Ka Y, Ogura T, Suemizu H, Kawakami Y, Ito M. Predominant development of mature and functional human NK cells in a novel human IL-2–producing transgenic NOG mouse. J Immunol. 2015;194:3513–25. doi:https://doi.org/10.4049/jimmunol.1401323.
   PubMed Web of Science ®Google Scholar
• Katano I, Nishime C, Ito R, Kamisako T, Mizusawa T, Ka Y, Ogura T, Suemizu H, Kawakami Y, Ito M, et al. Long-term maintenance of peripheral blood derived human NK cells in a novel human IL-15- transgenic NOG mouse. Sci Rep. 2017;7:17230. doi:https://doi.org/10.1038/s41598-017-17442-7.
   PubMed Web of Science ®Google Scholar
• Kwong LS, Brown MH, Barclay AN, Hatherley D. Signal-regulatory protein α from the NOD mouse binds human CD47 with an exceptionally high affinity - implications for engraftment of human cells. Immunology. 2014;143:61–67. doi:https://doi.org/10.1111/imm.12290.
   PubMed Web of Science ®Google Scholar
• Fischer N, Elson G, Magistrelli G, Dheilly E, Fouque N, Laurendon A, Gueneau F, Ravn U, Depoisier JF, Moine V, et al. Exploiting light chains for the scalable generation and platform purification of native human bispecific IgG. Nat Commun. 2015;6:6113. doi:https://doi.org/10.1038/ncomms7113.
   PubMed Web of Science ®Google Scholar