Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma
Abstract
:1. Introduction
2. Rationale and Potential Targets of bsAbs in MM
2.1. Rationale and Biological Design of bsAbs
2.2. Potential Targets of bsAbs for MM: From Preclinical to Clinical Trials
3. Clinical Development of bsAbs for MM
3.1. bsAbs Targeting BCMA
3.2. bsAbs Targeting GPRC5D, CD38, FcRH5 and CD19
3.3. Safety Profile of bsAbs in MM
4. Resistance Mechanisms
5. Discussion and Future Directions
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Palumbo, A.; Anderson, K. Multiple myeloma. N. Engl. J. Med. 2011, 364, 1046–1060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kyle, R.A.; Rajkumar, S.V. Multiple myeloma. N. Engl. J. Med. 2004, 351, 1860–1873. [Google Scholar] [CrossRef] [PubMed]
- Castella, M.; Fernandez de Larrea, C.; Martin-Antonio, B. Immunotherapy: A Novel Era of Promising Treatments for Multiple Myeloma. Int. J. Mol. Sci. 2018, 19, 3613. [Google Scholar] [CrossRef] [Green Version]
- Giralt, S.; Costa, L.J.; Maloney, D.; Krishnan, A.; Fei, M.; Antin, J.H. Tandem Autologous-Autologous versus Autologous-Allogeneic Hematopoietic Stem Cell Transplant for Patients with Multiple Myeloma: Long-Term Follow-Up Results from the Blood and Marrow Transplant Clinical Trials Network 0102 Trial. Biol. Blood Marrow Transplant. 2020, 26, 798–804. [Google Scholar] [CrossRef] [PubMed]
- Knop, S.; Engelhardt, M.; Liebisch, P.; Meisner, C.; Holler, E.; Metzner, B. Allogeneic transplantation in multiple myeloma: Long-term follow-up and cytogenetic subgroup analysis. Leukemia 2019, 33, 2710–2719. [Google Scholar] [CrossRef] [PubMed]
- Rasche, L.; Rollig, C.; Stuhler, G.; Danhof, S.; Mielke, S.; Grigoleit, G.U. Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma: Focus on Longitudinal Assessment of Donor Chimerism, Extramedullary Disease, and High-Risk Cytogenetic Features. Biol. Blood Marrow Transplant. 2016, 22, 1988–1996. [Google Scholar] [CrossRef] [Green Version]
- Thorsteinsdottir, S.; Dickman, P.W.; Landgren, O.; Blimark, C.; Hultcrantz, M.; Turesson, I. Dramatically improved survival in multiple myeloma patients in the recent decade: Results from a Swedish population-based study. Haematologica 2018, 103, e412–e415. [Google Scholar] [CrossRef] [Green Version]
- Magen, H.; Muchtar, E. Elotuzumab: The first approved monoclonal antibody for multiple myeloma treatment. Ther. Adv. Hematol. 2016, 7, 187–195. [Google Scholar] [CrossRef]
- Lonial, S.; Dimopoulos, M.; Palumbo, A.; White, D.; Grosicki, S.; Spicka, I. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2015, 373, 621–631. [Google Scholar] [CrossRef] [Green Version]
- Lonial, S.; Weiss, B.M.; Usmani, S.Z.; Singhal, S.; Chari, A.; Bahlis, N.J. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. Lancet 2016, 387, 1551–1560. [Google Scholar] [CrossRef]
- Usmani, S.Z.; Diels, J.; Ito, T.; Mehra, M.; Khan, I.; Lam, A. Daratumumab monotherapy compared with historical control data in heavily pretreated and highly refractory patients with multiple myeloma: An adjusted treatment comparison. Am. J. Hematol. 2017, 92, E146–E152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dimopoulos, M.A.; Oriol, A.; Nahi, H.; San-Miguel, J.; Bahlis, N.J.; Usmani, S.Z. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016, 375, 1319–1331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Palumbo, A.; Chanan-Khan, A.; Weisel, K.; Nooka, A.K.; Masszi, T.; Beksac, M. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016, 375, 754–766. [Google Scholar] [CrossRef] [PubMed]
- Mateos, M.V.; Dimopoulos, M.A.; Cavo, M.; Suzuki, K.; Jakubowiak, A.; Knop, S. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N. Engl. J. Med. 2018, 378, 518–528. [Google Scholar] [CrossRef] [PubMed]
- Chari, A.; Suvannasankha, A.; Fay, J.W.; Arnulf, B.; Kaufman, J.L.; Ifthikharuddin, J.J. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 2017, 130, 974–981. [Google Scholar] [CrossRef] [PubMed]
- Zhou, X.; Steinhardt, M.J.; Grathwohl, D.; Meckel, K.; Nickel, K.; Leicht, H.B.; Krummenast, F.; Einsele, H.; Rasche, L.; Kortum, K.M. Multiagent therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and daratumumab (“Pom-PAD-Dara”) in relapsed/refractory multiple myeloma. Multiagent therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and daratumumab (“Pom-PAD-Dara”) in relapsed/refractory multiple myeloma. Cancer. Med. 2020. [Google Scholar] [CrossRef]
- Wudhikarn, K.; Wills, B.; Lesokhin, A.M. Monoclonal antibodies in multiple myeloma: Current and emerging targets and mechanisms of action. Best Pract. Res. Clin. Haematol. 2020, 33, 101143. [Google Scholar] [CrossRef]
- Fabbri, M.; Smart, C.; Pardi, R. T lymphocytes. Int. J. Biochem. Cell Biol. 2003, 35, 1004–1008. [Google Scholar] [CrossRef]
- Beitinjaneh, A.M.; Saliba, R.; Bashir, Q.; Shah, N.; Parmar, S.; Hosing, C. Durable responses after donor lymphocyte infusion for patients with residual multiple myeloma following non-myeloablative allogeneic stem cell transplant. Leuk. Lymphoma 2012, 53, 1525–1529. [Google Scholar] [CrossRef]
- Tricot, G.; Vesole, D.H.; Jagannath, S.; Hilton, J.; Munshi, N.; Barlogie, B. Graft-versus-myeloma effect: Proof of principle. Blood 1996, 87, 1196–1198. [Google Scholar] [CrossRef] [Green Version]
- Verdonck, L.F.; Lokhorst, H.M.; Dekker, A.W.; Nieuwenhuis, H.K.; Petersen, E.J. Graft-versus-myeloma effect in two cases. Lancet 1996, 347, 800–801. [Google Scholar] [CrossRef]
- Bertz, H.; Burger, J.A.; Kunzmann, R.; Mertelsmann, R.; Finke, J. Adoptive immunotherapy for relapsed multiple myeloma after allogeneic bone marrow transplantation (BMT): Evidence for a graft-versus-myeloma effect. Leukemia 1997, 11, 281–283. [Google Scholar] [CrossRef] [Green Version]
- Lokhorst, H.M.; Schattenberg, A.; Cornelissen, J.J.; Thomas, L.L.; Verdonck, L.F. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood 1997, 90, 4206–4211. [Google Scholar] [CrossRef] [PubMed]
- Lokhorst, H.M.; Schattenberg, A.; Cornelissen, J.J.; van Oers, M.H.; Fibbe, W.; Russell, I. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: Predictive factors for response and long-term outcome. J. Clin. Oncol. 2000, 18, 3031–3037. [Google Scholar] [CrossRef] [PubMed]
- Brinkmann, U.; Kontermann, R.E. The making of bispecific antibodies. mAbs 2017, 9, 182–212. [Google Scholar] [CrossRef]
- Shah, N.; Chari, A.; Scott, E.; Mezzi, K.; Usmani, S.Z. B-cell maturation antigen (BCMA) in multiple myeloma: Rationale for targeting and current therapeutic approaches. Leukemia 2020, 34, 985–1005. [Google Scholar] [CrossRef]
- Madduri, D.; Dhodapkar, M.V.; Lonial, S.; Jagannath, S.; Cho, H.J. SOHO State of the Art Updates and Next Questions: T-Cell-Directed Immune Therapies for Multiple Myeloma: Chimeric Antigen Receptor-Modified T Cells and Bispecific T-Cell-Engaging Agents. Clin. Lymphoma Myeloma Leuk. 2019, 19, 537–544. [Google Scholar] [CrossRef]
- Kontermann, R.E.; Brinkmann, U. Bispecific antibodies. Drug Discov. Today 2015, 20, 838–847. [Google Scholar] [CrossRef] [Green Version]
- Birnbaum, M.E.; Berry, R.; Hsiao, Y.S.; Chen, Z.; Shingu-Vazquez, M.A.; Yu, X. Molecular architecture of the alphabeta T cell receptor-CD3 complex. Proc. Natl. Acad. Sci. USA 2014, 111, 17576–17581. [Google Scholar] [CrossRef] [Green Version]
- Carpenter, R.O.; Evbuomwan, M.O.; Pittaluga, S.; Rose, J.J.; Raffeld, M.; Yang, S. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 2013, 19, 2048–2060. [Google Scholar] [CrossRef] [Green Version]
- Tai, Y.T.; Acharya, C.; An, G.; Moschetta, M.; Zhong, M.Y.; Feng, X. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 2016, 127, 3225–3236. [Google Scholar] [CrossRef] [Green Version]
- Hipp, S.; Tai, Y.T.; Blanset, D.; Deegen, P.; Wahl, J.; Thomas, O. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo. Leukemia 2017, 31, 1743–1751. [Google Scholar] [CrossRef] [PubMed]
- Funaro, A.; Malavasi, F. Human CD38, a surface receptor, an enzyme, an adhesion molecule and not a simple marker. J. Biol. Regul. Homeost. Agents 1999, 13, 54–61. [Google Scholar] [PubMed]
- Lin, P.; Owens, R.; Tricot, G.; Wilson, C.S. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am. J. Clin. Pathol. 2004, 121, 482–488. [Google Scholar] [CrossRef] [PubMed]
- De Weers, M.; Tai, Y.T.; van der Veer, M.S.; Bakker, J.M.; Vink, T.; Jacobs, D.C. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J. Immunol. 2011, 186, 1840–1848. [Google Scholar] [CrossRef]
- Zuch de Zafra, C.L.; Fajardo, F.; Zhong, W.; Bernett, M.J.; Muchhal, U.S.; Moore, G.L. Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell-recruiting Antibody Optimized for Cytotoxicity and Cytokine Release. Clin. Cancer Res. 2019, 25, 3921–3933. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mizuguchi, M.; Otsuka, N.; Sato, M.; Ishii, Y.; Kon, S.; Yamada, M. Neuronal localization of CD38 antigen in the human brain. Brain Res. 1995, 697, 235–240. [Google Scholar] [CrossRef]
- Schneider, M.; Schumacher, V.; Lischke, T.; Lucke, K.; Meyer-Schwesinger, C.; Velden, J. CD38 is expressed on inflammatory cells of the intestine and promotes intestinal inflammation. PLoS ONE 2015, 10, e0126007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Loffler, A.; Kufer, P.; Lutterbuse, R.; Zettl, F.; Daniel, P.T.; Schwenkenbecher, J.M. A recombinant bispecific single-chain antibody, CD19 × CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 2000, 95, 2098–2103. [Google Scholar] [CrossRef]
- Ali, S.; Moreau, A.; Melchiorri, D.; Camarero, J.; Josephson, F.; Olimpier, O. Blinatumomab for Acute Lymphoblastic Leukemia: The First Bispecific T-Cell Engager Antibody to Be Approved by the EMA for Minimal Residual Disease. Oncologist 2020, 25, e709–e715. [Google Scholar] [CrossRef] [Green Version]
- Robillard, N.; Wuilleme, S.; Moreau, P.; Bene, M.C. Immunophenotype of normal and myelomatous plasma-cell subsets. Front. Immunol. 2014, 5, 137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nerreter, T.; Letschert, S.; Gotz, R.; Doose, S.; Danhof, S.; Einsele, H. Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T. Nat. Commun. 2019, 10, 3137. [Google Scholar] [CrossRef] [PubMed]
- Atamaniuk, J.; Gleiss, A.; Porpaczy, E.; Kainz, B.; Grunt, T.W.; Raderer, M. Overexpression of G protein-coupled receptor 5D in the bone marrow is associated with poor prognosis in patients with multiple myeloma. Eur. J. Clin. Investig. 2012, 42, 953–960. [Google Scholar] [CrossRef]
- Pillarisetti, K.; Edavettal, S.; Mendonca, M.; Li, Y.; Tornetta, M.; Babich, A. A T-cell-redirecting bispecific G-protein-coupled receptor class 5 member D × CD3 antibody to treat multiple myeloma. Blood 2020, 135, 1232–1243. [Google Scholar] [CrossRef] [PubMed]
- Elkins, K.; Zheng, B.; Go, M.; Slaga, D.; Du, C.; Scales, S.J. FcRL5 as a target of antibody-drug conjugates for the treatment of multiple myeloma. Mol. Cancer Ther. 2012, 11, 2222–2232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Polson, A.G.; Zheng, B.; Elkins, K.; Chang, W.; Du, C.; Dowd, P. Expression pattern of the human FcRH/IRTA receptors in normal tissue and in B-chronic lymphocytic leukemia. Int. Immunol. 2006, 18, 1363–1373. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ovacik, A.M.; Li, J.; Lemper, M.; Danilenko, D.; Stagg, N.; Mathieu, M. Single cell-produced and in vitro-assembled anti-FcRH5/CD3 T-cell dependent bispecific antibodies have similar in vitro and in vivo properties. mAbs 2019, 11, 422–433. [Google Scholar] [CrossRef] [Green Version]
- Li, J.; Stagg, N.J.; Johnston, J.; Harris, M.J.; Menzies, S.A.; DiCara, D. 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, 383–395. [Google Scholar] [CrossRef] [Green Version]
- Veillette, A.; Guo, H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit. Rev. Oncol. Hematol. 2013, 88, 168–177. [Google Scholar] [CrossRef]
- Chen, D.; Zou, J.; Zong, Y.; Meng, H.; An, G.; Yang, L. Anti-human CD138 monoclonal antibodies and their bispecific formats: Generation and characterization. Immunopharmacol. Immunotoxicol. 2016, 38, 175–183. [Google Scholar] [CrossRef]
- Chan, W.K.; Kang, S.; Youssef, Y.; Glankler, E.N.; Barrett, E.R.; Carter, A.M. A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma. Cancer Immunol. Res. 2018, 6, 776–787. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zou, J.; Chen, D.; Zong, Y.; Ye, S.; Tang, J.; Meng, H. Immunotherapy based on bispecific T-cell engager with hIgG1 Fc sequence as a new therapeutic strategy in multiple myeloma. Cancer Sci. 2015, 106, 512–521. [Google Scholar] [CrossRef] [PubMed]
- Kantarjian, H.; Stein, A.; Gokbuget, N.; Fielding, A.K.; Schuh, A.C.; Ribera, J.M. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N. Engl. J. Med. 2017, 376, 836–847. [Google Scholar] [CrossRef]
- Topp, M.S.; Duell, J.; Zugmaier, G.; Attal, M.; Moreau, P.; Langer, C. Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma. J. Clin. Oncol. 2020, 38, 775–783. [Google Scholar] [CrossRef]
- Raje, N.S.; Jakubowiak, A.; Gasparetto, C.; Cornell, R.F.; Krupka, H.I.; Navarro, D. Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM). Blood 2019, 134 (Suppl. 1), 1869. [Google Scholar] [CrossRef]
- Costa, L.; Wong, S.; Bermúdez, A.; de la Rubia, J.; Mateos, M.; Ocio, E. First Clinical Study of the B-Cell Maturation Antigen (BCMA) 2+1 T Cell Engager (TCE) CC-93269 in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Interim Results of a Phase 1 Multicenter Trial. Blood 2019, 134 (Suppl. 1), 143. [Google Scholar] [CrossRef]
- Usmani, S.Z.; Mateos, M.-V.; Nahi, H.; Krishnan, A.Y.; van de Donk, N.W.C.J.; Miguel, J.S. Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM). J. Clin. Oncol. 2020, 38 (Suppl. 15), 100. [Google Scholar] [CrossRef]
- Pratz, K.; Gojo, I.; Gocke, C.; Matsui, W.; Huff, C.A. Blinatumomab Induced Response of Multiply Refractory Multiple Myeloma in the Context of Secondary Pre-B Cell Acute Lymphoblastic Leukemia. Ann. Hematol. Oncol. 2017, 4, 1174. [Google Scholar] [CrossRef] [Green Version]
- Seimetz, D.; Lindhofer, H.; Bokemeyer, C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) as a targeted cancer immunotherapy. Cancer Treat. Rev. 2010, 36, 458–467. [Google Scholar] [CrossRef]
- Kohnke, T.; Krupka, C.; Tischer, J.; Knosel, 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. 2015, 8, 111. [Google Scholar] [CrossRef] [Green Version]
- Feucht, J.; Kayser, S.; Gorodezki, D.; Hamieh, M.; Doring, M.; Blaeschke, F. T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts. Oncotarget 2016, 7, 76902–76919. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garcia-Diaz, A.; Shin, D.S.; Moreno, B.H.; Saco, J.; Escuin-Ordinas, H.; Rodriguez, G.A. Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression. Cell Rep. 2017, 19, 1189–1201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kobold, S.; Pantelyushin, S.; Rataj, F.; Vom Berg, J. Rationale for Combining Bispecific T Cell Activating Antibodies with Checkpoint Blockade for Cancer Therapy. Front. Oncol. 2018, 8, 285. [Google Scholar] [CrossRef] [PubMed]
- Krupka, C.; Kufer, P.; Kischel, R.; Zugmaier, G.; Lichtenegger, F.S.; Kohnke, T. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: Reversing a T-cell-induced immune escape mechanism. Leukemia 2016, 30, 484–491. [Google Scholar] [CrossRef]
- Gorgun, G.; Samur, M.K.; Cowens, K.B.; Paula, S.; Bianchi, G.; Anderson, J.E. Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma. Clin. Cancer Res. 2015, 21, 4607–4618. [Google Scholar] [CrossRef] [Green Version]
- Schwartz, M.; Damon, L.E.; Jeyakumar, D.; Costello, C.L.; Tzachanis, D.; Schiller, G.J. Blinatumomab in Combination with Pembrolizumab Is Safe for Adults with Relapsed or Refractory B-Lineage Acute Lymphoblastic Leukemia: University of California Hematologic Malignancies Consortium Study 1504. Blood 2019, 134 (Suppl. 1), 3880. [Google Scholar] [CrossRef]
- Fontenot, J.D.; Gavin, M.A.; Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 2003, 4, 330–336. [Google Scholar] [CrossRef]
- Brimnes, M.K.; Vangsted, A.J.; Knudsen, L.M.; Gimsing, P.; Gang, A.O.; Johnsen, H.E. Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR(−)/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma. Scand. J. Immunol. 2010, 72, 540–547. [Google Scholar] [CrossRef]
- Gorgun, G.T.; Whitehill, G.; Anderson, J.L.; Hideshima, T.; Maguire, C.; Laubach, J. Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 2013, 121, 2975–2987. [Google Scholar] [CrossRef] [Green Version]
- Feyler, S.; von Lilienfeld-Toal, M.; Jarmin, S.; Marles, L.; Rawstron, A.; Ashcroft, A.J. CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(-)CD8(-)alphabetaTCR(+) Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br. J. Haematol. 2009, 144, 686–695. [Google Scholar] [CrossRef]
- Duell, J.; Dittrich, M.; Bedke, T.; Mueller, T.; Eisele, F.; Rosenwald, A. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B.-precursor, ALL. Leukemia 2017, 31, 2181–2190. [Google Scholar] [CrossRef] [PubMed]
- Sadelain, M. CD19 CAR T Cells. Cell 2017, 171, 1471. [Google Scholar] [CrossRef] [PubMed]
- Correnti, C.E.; Laszlo, G.S.; de van der Schueren, W.J.; Godwin, C.D.; Bandaranayake, A.; Busch, M.A. Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 co-stimulation. Leukemia 2018, 32, 1239–1243. [Google Scholar] [CrossRef] [PubMed]
- Yuraszeck, T.; Kasichayanula, S.; Benjamin, J.E. Translation and Clinical Development of Bispecific T-cell Engaging Antibodies for Cancer Treatment. Clin. Pharmacol. Ther. 2017, 101, 634–645. [Google Scholar] [CrossRef] [Green Version]
- Danhof, S.; Schreder, M.; Knop, S.; Rasche, L.; Strifler, S.; Loffler, C. Expression of programmed death-1 on lymphocytes in myeloma patients is lowered during lenalidomide maintenance. Haematologica 2018, 103, e126–e129. [Google Scholar] [CrossRef] [Green Version]
- Wang, M.; Pruteanu, I.; Cohen, A.D.; Garfall, A.L.; Milone, M.C.; Tian, L. Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors. Blood 2019, 134 (Suppl. 1), 622. [Google Scholar] [CrossRef]
- Ruella, M.; Maus, M.V. Catch me if you can: Leukemia Escape after CD19-Directed T Cell Immunotherapies. Comput. Struct. Biotechnol. J. 2016, 14, 357–362. [Google Scholar] [CrossRef] [Green Version]
- Turtle, C.J.; Hanafi, L.A.; Berger, C.; Gooley, T.A.; Cherian, S.; Hudecek, M. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Investig. 2016, 126, 2123–2138. [Google Scholar] [CrossRef] [Green Version]
- Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl. J. Med. 2018, 378, 439–448. [Google Scholar] [CrossRef]
- Jabbour, E.; Dull, J.; Yilmaz, M.; Khoury, J.D.; Ravandi, F.; Jain, N. Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatumomab failure: No change in the level of CD19 expression. Am. J. Hematol. 2018, 93, 371–374. [Google Scholar] [CrossRef] [Green Version]
- Topp, M.S.; Gokbuget, N.; Zugmaier, G.; Klappers, P.; Stelljes, M.; Neumann, S. 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. 2014, 32, 4134–4140. [Google Scholar] [CrossRef] [PubMed]
- Sotillo, E.; Barrett, D.M.; Black, K.L.; Bagashev, A.; Oldridge, D.; Wu, G. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov. 2015, 5, 1282–1295. [Google Scholar] [CrossRef] [Green Version]
- Gardner, R.; Wu, D.; Cherian, S.; Fang, M.; Hanafi, L.A.; Finney, O. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 2016, 127, 2406–2410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Braig, F.; Brandt, A.; Goebeler, M.; Tony, H.P.; Kurze, A.K.; Nollau, P. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood 2017, 129, 100–104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cohen, A.D.; Garfall, A.L.; Stadtmauer, E.A.; Melenhorst, J.J.; Lacey, S.F.; Lancaster, E. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J. Clin. Investig. 2019, 129, 2210–2221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brudno, J.N.; Maric, I.; Hartman, S.D.; Rose, J.J.; Wang, M.; Lam, N. T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma. J. Clin. Oncol. 2018, 36, 2267–2280. [Google Scholar] [CrossRef]
- Keats, J.J.; Chesi, M.; Egan, J.B.; Garbitt, V.M.; Palmer, S.E.; Braggio, E. Clonal competition with alternating dominance in multiple myeloma. Blood 2012, 120, 1067. [Google Scholar] [CrossRef]
- Staerz, U.D.; Bevan, M.J. Hybrid hybridoma producing a bispecific monoclonal antibody that can focus effector T-cell activity. Proc. Natl. Acad. Sci. USA 1986, 83, 1453–1457. [Google Scholar] [CrossRef] [Green Version]
- Sanford, M. Blinatumomab: First global approval. Drugs 2015, 75, 321–327. [Google Scholar] [CrossRef]
- Zhao, W.H.; Liu, J.; Wang, B.Y.; Chen, Y.X.; Cao, X.M.; Yang, Y. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J. Hematol. Oncol. 2018, 11, 141. [Google Scholar] [CrossRef]
- Raje, N.; Berdeja, J.; Lin, Y.; Siegel, D.; Jagannath, S.; Madduri, D. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2019, 380, 1726–1737. [Google Scholar] [CrossRef] [PubMed]
- Xu, J.; Chen, L.J.; Yang, S.S.; Sun, Y.; Wu, W.; Liu, Y.F. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc. Natl. Acad. Sci. USA 2019, 116, 9543–9551. [Google Scholar] [CrossRef] [Green Version]
- Jacoby, E.; Bielorai, B.; Avigdor, A.; Itzhaki, O.; Hutt, D.; Nussboim, V. Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Am. J. Hematol. 2018, 93, 1485–1492. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Topp, M.S.; Stelljes, M.; Zugmaier, G.; Barnette, P.; Heffner, L.T.; Trippett, T., Jr. Blinatumomab retreatment after relapse in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia. Leukemia 2018, 32, 562–565. [Google Scholar] [CrossRef] [Green Version]
- Ross, T.; Reusch, U.; Wingert, S.; Haneke, T.; Klausz, K.; Otte, A.K. Preclinical Characterization of AFM26, a Novel B Cell Maturation Antigen (BCMA)-Directed Tetravalent Bispecific Antibody for High Affinity Retargeting of NK Cells Against Myeloma. Blood 2018, 132 (Suppl. 1), 1927. [Google Scholar] [CrossRef]
- Gantke, T.; Weichel, M.; Reusch, U.; Ellwanger, K.; Fucek, I.; Griep, R. Trispecific Antibodies for Selective CD16A-Directed NK-Cell Engagement in Multiple Myeloma. Blood 2016, 128, 4513. [Google Scholar] [CrossRef]
- Banaszek, A.; Bumm, T.G.P.; Nowotny, B.; Geis, M.; Jacob, K.; Wolfl, M. On-target restoration of a split T cell-engaging antibody for precision immunotherapy. Nat. Commun. 2019, 10, 5387. [Google Scholar] [CrossRef]
ClinicalTrials.gov Identifier | Bispecific Antibody | Targets | Study Phase | Estimated Enrollment | Current Status * | Response Rates | AEs ≥ Grade 3 |
---|---|---|---|---|---|---|---|
NCT02514239 | AMG420 | BCMA/CD3 | 1 | 43 patients | Active, not recruiting | 42 patients were treated. ORR: 31% (13/42); at MTD of 400 µg/d: 70% (7/10) including 50% (5/10) MRD-negative CR | 19% (n = 8) infection, 5% (n = 2) peripheral polyneuropathy, 2% (n = 1) edema, and 2% (n = 1) CRS |
NCT03836053 | AMG420 | BCMA/CD3 | 1/2 | 15 patients | Recruiting | N/A | N/A |
NCT03269136 | PF-3135 | BCMA/CD3 | 1 | 80 patients | Recruiting | 17 patients were treated. Response data were available in 16 patients. CBR: 41%; 6% (1/16) MR, 35% (6/16) SD, and 53% (9/16) PD | 18% (n = 3) including elevated transaminase, leukocytopenia, neutropenia, and lymphopenia |
NCT03145181 | JNJ-64007957 | BCMA/CD3 | 1 | 160 patients | Recruiting | Activity was observed in 52 patients who received ≥ 38.4 µg/kg. ORR: 38% (20/52); at 270 µg/kg: 78% (7/9) | 21% (n = 14) infection, 20% (n = 13) neutropenia, 14% (n = 9) anemia, 3% (n = 2) neurotoxicity, 2% (n = 1) delirium, and 2% (n = 1) thrombocytopenia. One patient died due to pneumonia (grade 5) |
NCT03933735 | TNB-383B | BCMA/CD3 | 1 | 72 patients | Recruiting | N/A | N/A |
NCT03486067 | CC-93269 | BCMA/CD3 | 1 | 120 patients | Active, not recruiting | 12 patients were treated with ≥ 6 mg CC-93269. ORR: 83% (10/12) with 58% (7/12) ≥ VGPR and 33% (4/12) sCR; MRD-negative CR rate: 75% (9/12) | 53% (n = 10) neutropenia, 42% (n = 8) anemia, 26% (n = 5) infection, and 21% (n = 4) thrombocytopenia. One patient died due to CRS (grade 5) |
NCT03287908 | AMG-701 | BCMA/CD3 | 1 | 270 patients | Recruiting | N/A | N/A |
NCT03761108 | REGN-5458 | BCMA/CD3 | 1/2 | 74 patients | Recruiting | N/A | N/A |
NCT04083534 | REGN-5459 | BCMA/CD3 | 1/2 | 56 patients | Recruiting | N/A | N/A |
NCT04108195 | JNJ-64007957 JNJ-64407564 | BCMA/CD3 GPRC5D/CD3 | 1 | 100 patients | Recruiting | N/A | N/A |
NCT03399799 | JNJ-64407564 | GPRC5D/CD3 | 1 | 185 patients | Recruiting | N/A | N/A |
NCT03309111 | GBR-1342 | CD38/CD3 | 1 | 125 patients | Recruiting | N/A | N/A |
NCT03445663 | AMG424 | CD38/CD3 | 1 | 120 patients | Recruiting | N/A | N/A |
NCT03275103 | BFCR4350A | FcRH5/CD3 | 1 | 130 patients | Recruiting | N/A | N/A |
NCT03173430 | Blinatumomab | CD19/CD3 | 1 | 6 patients ** | Terminated | N/A | N/A |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Zhou, X.; Einsele, H.; Danhof, S. Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma. J. Clin. Med. 2020, 9, 2166. https://doi.org/10.3390/jcm9072166
Zhou X, Einsele H, Danhof S. Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma. Journal of Clinical Medicine. 2020; 9(7):2166. https://doi.org/10.3390/jcm9072166
Chicago/Turabian StyleZhou, Xiang, Hermann Einsele, and Sophia Danhof. 2020. "Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma" Journal of Clinical Medicine 9, no. 7: 2166. https://doi.org/10.3390/jcm9072166
APA StyleZhou, X., Einsele, H., & Danhof, S. (2020). Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma. Journal of Clinical Medicine, 9(7), 2166. https://doi.org/10.3390/jcm9072166