Anti-CD19 monoclonal antibodies for the treatment of relapsed or refractory B-cell malignancies: a narrative review with focus on diffuse large B-cell lymphoma

Pier Luigi Zinzani, Giorgio Minotti, Pier Luigi Zinzani, Giorgio Minotti

Abstract

Purpose: CD19 is a cell surface protein that is found on both healthy and malignant B cells. Accordingly, it has become an important target for novel treatments for non-Hodgkin lymphomas and B-cell leukaemia. Three anti-CD19 monoclonal antibodies with distinct mechanisms of action have been developed for the treatment of B-cell malignancies.

Methods: We reviewed the preclinical and clinical data on the development of the newly approved anti-CD19 monoclonal antibodies blinatumomab, tafasitamab and loncastuximab tesirine, and consider their place in the treatment of relapsed or refractory B-cell malignancies.

Results: Blinatumomab is a bispecific T-cell engager that binds to both CD19 on B cells and CD3 on T cells, facilitating antibody-dependent cytotoxicity. Blinatumomab significantly prolongs overall survival in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, although cytokine release syndrome and severe neurotoxicity may necessitate discontinuation. Tafasitamab, which has modified anti-CD19 Fab and Fc regions, has significantly enhanced affinity for both CD19 and effector cell receptors compared with unmodified anti-CD19. In L-MIND, tafasitamab plus lenalidomide provided an overall response rate (ORR) of 57.5% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients non-transplant eligible. Loncastuximab tesirine is an antibody-drug conjugate that has been studied as monotherapy and in combination with ibrutinib in 3L + relapsed or refractory DLBCL. The ORR was 48.3% in a phase II trial of loncastuximab tesirine. The optimal place of anti-CD19 monoclonal antibodies in therapy has yet to be determined, but the prospect of improved outcomes for at least some patients with treatment-resistant B-cell malignancies appears likely, particularly in those with limited therapeutic options and poor prognosis.

Keywords: Acute lymphoblastic leukaemia; Anti-CD19; Antibody–drug conjugate; B lymphocytes; Non-Hodgkin lymphoma; Treatment resistance.

Conflict of interest statement

Pier Luigi Zinzani has participated in the speaker bureau for Verastem, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, TG Therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin, Novartis, Incyte, Beigene, has participated in the advisory boards for Verastem, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, TG Therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin, Novartis, Incyte, Beigene, Sandoz, ADC Therapeutics and served as a consultant to Verastem, MSD, Eusapharma and Novartis. Giorgio Minotti declares no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Anti-cancer mechanism of action of antibodies directed against CD19 on the surface of malignant B cells (Hartley ; Duell et al. ; Cheson et al. 2021). Blinatumomab (top left) binds simultaneously to CD19 and to CD3 receptors on T-cells, which brings the effector and malignant cells into close proximity to each other, and facilitates antibody-dependent cellular cytotoxicity (ADCC). Tafasitamab (top right) binds with high affinity to both CD19 and Fc gamma receptors (FcγR) on effector cells. Binding to FcγRIII on natural killer cells facilitates ADCC, while binding to FcγR on macrophages facilitates antibody-dependent cellular phagocytosis (ADCP). Tafasitamab also has direct cytotoxic effects. Loncastuximab tesirine (bottom right) is an anti-CD19 antibody–drug conjugate that contains a cytotoxic pyrrolobenzodiazepine dimer (PBD). Antibody binding to cell surface CD19 leads to internalization of the complex and intracellular release of the PBD payload. The PBD then binds to the minor groove of DNA, and forms inter-strand cross-links that are not recognized by DNA repair mechanisms, thereby leading to cell death

References

    1. Abramson JS, Ghosh N, Smith SM. ADCs, BiTEs, CARs, and small molecules: a new era of targeted therapy in non-Hodgkin lymphoma. Am Soc Clin Oncol Educ Book. 2020;40:302–313. doi: 10.1200/edbk_279043.
    1. Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM. Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation. Blood. 1984;63(6):1424–1433. doi: 10.1182/blood.V63.6.1424.1424.
    1. Awan FT, Lapalombella R, Trotta R, Butchar JP, Yu B, Benson DM, Jr, et al. CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain-engineered monoclonal antibody. Blood. 2010;115(6):1204–1213. doi: 10.1182/blood-2009-06-229039.
    1. Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, et al. Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of B-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2021;325(9):833–842. doi: 10.1001/jama.2021.0669.
    1. Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 doi: 10.1016/s1470-2045(21)00139-x.
    1. Camicia R, Winkler HC, Hassa PO. Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review. Mol Cancer. 2015;14:207. doi: 10.1186/s12943-015-0474-2.
    1. Cheson BD, Nowakowski G, Salles G. Diffuse large B-cell lymphoma: new targets and novel therapies. Blood Cancer J. 2021;11(4):68. doi: 10.1038/s41408-021-00456-w.
    1. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–242. doi: 10.1056/NEJMoa011795.
    1. Coyle L, Morley NJ, Rambaldi A, Mason KD, Verhoef G, Furness CL, et al. Open-Label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2020;61(9):2103–2112. doi: 10.1080/10428194.2020.1759055.
    1. Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–1808. doi: 10.1182/blood-2017-03-769620.
    1. Depaus J, Ervin-Haynes A, Bryan L, Magagnoli M, Gritti G, Chao G et al. Interim results of a phase 1/2 study of loncastuximab tesirine (Lonca) combined with ibrutinib in advanced diffuse large b-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL) [abstract EP1284].In: 25th Congress of the European Hematology Association; 12 June 2020; Virtual Meeting 2020
    1. Diamantis N, Banerji U. Antibody-drug conjugates–an emerging class of cancer treatment. Br J Cancer. 2016;114(4):362–367. doi: 10.1038/bjc.2015.435.
    1. Duell J, Lammers PE, Djuretic I, Chunyk AG, Alekar S, Jacobs I, et al. Bispecific antibodies in the treatment of hematologic malignancies. Clin Pharmacol Ther. 2019;106(4):781–791. doi: 10.1002/cpt.1396.
    1. Duell J, Maddocks KJ, Gonzalez-Barca E, Jurczak W, Liberati AM, De Vos S, et al. Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021 doi: 10.3324/haematol.2020.275958.
    1. European Medicines Agency. Blincyto (blinatumomab) [summary of product characteristics] 2021. . Accessed 1 May 2021.
    1. Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R, Catovsky D. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol. 1998;51(5):364–369. doi: 10.1136/jcp.51.5.364.
    1. Gisselbrecht C, Van Den Neste E. How I manage patients with relapsed/refractory diffuse large B cell lymphoma. Br J Haematol. 2018;182(5):633–643. doi: 10.1111/bjh.15412.
    1. Goebeler ME, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. J Clin Oncol. 2016;34(10):1104–1111. doi: 10.1200/jco.2014.59.1586.
    1. Gribben JG, Fowler N, Morschhauser F. Mechanisms of action of lenalidomide in B-cell non-Hodgkin lymphoma. J Clin Oncol. 2015;33(25):2803–2811. doi: 10.1200/jco.2014.59.5363.
    1. Hamadani M, Radford J, Carlo-Stella C, Caimi PF, Reid E, O'Connor OA, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634–2645. doi: 10.1182/blood.2020007512.
    1. Harris LJ, Patel K, Martin M. Novel therapies for relapsed or refractory diffuse large B-cell lymphoma. Int J Mol Sci. 2020 doi: 10.3390/ijms21228553.
    1. Hartley JA. Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy. Expert Opin Biol Ther. 2020 doi: 10.1080/14712598.2020.1776255.
    1. Horton HM, Bernett MJ, Pong E, Peipp M, Karki S, Chu SY, 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(19):8049–8057. doi: 10.1158/0008-5472.Can-08-2268.
    1. Jain N, Stock W, Zeidan A, Atallah E, McCloskey J, Heffner L, et al. Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia. Blood Adv. 2020;4(3):449–457. doi: 10.1182/bloodadvances.2019000767.
    1. Jamil A, Mukkamalla SKR. Lymphoma. StatPearls Publishing LLC, Treasure Island, FL. 2021. . Accessed 1 May 2021.
    1. Jurczak W, Bryk AH, Mensah P, Gałązka K, Trofimiuk-Müldner M, Wyrobek Ł, et al. Single-agent MOR208 salvage and maintenance therapy in a patient with refractory/relapsing diffuse large B-cell lymphoma: a case report. J Med Case Rep. 2016;10(1):123. doi: 10.1186/s13256-016-0875-x.
    1. Jurczak W, Zinzani PL, Gaidano G, Goy A, Provencio M, Nagy Z, et al. Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2018;29(5):1266–1272. doi: 10.1093/annonc/mdy056.
    1. Jurczak W, Zinzani PL, Hess G, Gaidano G, Provencio M, Nagy Z, et al. A phase IIa, open-label, multicenter study of single-agent tafasitamab (MOR208), an Fc-optimized anti-CD19 antibody, in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma: long-term follow-up, final analysis. Blood. 2019;134(Suppl 1):4078. doi: 10.1182/blood-2019-124297.
    1. Kahl BS, Hamadani M, Radford J, Carlo-Stella C, Caimi P, Reid E, et al. A phase I study of ADCT-402 (loncastuximab tesirine), a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2019;25(23):6986–6994. doi: 10.1158/1078-0432.Ccr-19-0711.
    1. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–847. doi: 10.1056/NEJMoa1609783.
    1. Katz BZ, Herishanu Y. Therapeutic targeting of CD19 in hematological malignancies: past, present, future and beyond. Leuk Lymphoma. 2014;55(5):999–1006. doi: 10.3109/10428194.2013.828354.
    1. Kellner C, Zhukovsky EA, Pötzke A, Brüggemann M, Schrauder A, Schrappe M, et al. The Fc-engineered CD19 antibody MOR208 (XmAb5574) induces natural killer cell-mediated lysis of acute lymphoblastic leukemia cells from pediatric and adult patients. Leukemia. 2013;27(7):1595–1598. doi: 10.1038/leu.2012.373.
    1. Kellner C, Otte A, Cappuzzello E, Klausz K, Peipp M. Modulating cytotoxic effector functions by Fc engineering to improve cancer therapy. Transfus Med Hemother. 2017;44(5):327–336. doi: 10.1159/000479980.
    1. Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, et al. Effect of blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2021;325(9):843–854. doi: 10.1001/jama.2021.0987.
    1. Narkhede M, Cheson BD. Tafasitamab. Monoclonal antibody targeting CD19, treatment of B-cell malignancies. Drugs Fut. 2020;45(9):641. doi: 10.1358/dof.2020.45.9.3176880.
    1. Nowakowski GS, Rodgers TD, Marino D, Frezzato M, Barbui AM, Castellino C, et al. RE-MIND study: a propensity score-based 1:1 matched comparison of tafasitamab + lenalidomide (L-MIND) versus lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) J Clin Oncol. 2020;38(15_suppl):8020. doi: 10.1200/JCO.2020.38.15_suppl.8020.
    1. Olejniczak SH, Stewart CC, Donohue K, Czuczman MS. A quantitative exploration of surface antigen expression in common B-cell malignancies using flow cytometry. Immunol Invest. 2006;35(1):93–114. doi: 10.1080/08820130500496878.
    1. Patriarca A, Gaidano G. Investigational drugs for the treatment of diffuse large B-cell lymphoma. Expert Opin Investig Drugs. 2021;30(1):25–38. doi: 10.1080/13543784.2021.1855140.
    1. Poe JC, Minard-Colin V, Kountikov EI, Haas KM, Tedder TF. A c-Myc and surface CD19 signaling amplification loop promotes B cell lymphoma development and progression in mice. J Immunol. 2012;189(5):2318–2325. doi: 10.4049/jimmunol.1201000.
    1. Rafiq S, Cheney C, Mo X, Jarjoura D, Muthusamy N, Byrd JC. XmAb-5574 antibody demonstrates superior antibody-dependent cellular cytotoxicity as compared with CD52- and CD20-targeted antibodies in adult acute lymphoblastic leukemia cells. Leukemia. 2012;26(7):1720–1722. doi: 10.1038/leu.2012.40.
    1. Roßkopf S, Eichholz KM, Winterberg D, Diemer KJ, Lutz S, Münnich IA, et al. Enhancing CDC and ADCC of CD19 antibodies by combining Fc protein-engineering with Fc glyco-engineering. Antibodies (basel) 2020;9(4):63. doi: 10.3390/antib9040063.
    1. Salles G, Duell J, González Barca E, Tournilhac O, Jurczak W, Liberati AM, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21(7):978–988. doi: 10.1016/s1470-2045(20)30225-4.
    1. Sapkota A, Shaikh H. Non-Hodgkin lymphoma. StatPearls Publishing LLC, Treasure Island, FL. 2020. . Accessed 1 May 2021.
    1. Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v116–v125. doi: 10.1093/annonc/mdv304.
    1. Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann 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. 2014;32(36):4134–4140. doi: 10.1200/jco.2014.56.3247.
    1. Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, 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. 2015;16(1):57–66. doi: 10.1016/s1470-2045(14)71170-2.
    1. US Food and Drug Administration. Zynlonta™(loncastuximab tesirine-lpyl) for injection, for intravenous use [prescribing information]. 2021. . Accessed 1 June 2021.
    1. US Food and Drug Administration. Blincyto® (blinatumomab) for injection, for intravenous use [prescribing information]. 2021. . Accessed 1 May 2021.
    1. van der Horst HJ, Nijhof IS, Mutis T, Chamuleau MED. Fc-engineered antibodies with enhanced Fc-effector function for the treatment of B-cell malignancies. Cancers (basel). 2020 doi: 10.3390/cancers12103041.
    1. Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016;127(11):1410–1416. doi: 10.1182/blood-2015-06-651380.
    1. Viardot A, Hess G, Bargou RC, Morley NJ, Gritti G, Goebeler ME, et al. Durability of complete response after blinatumomab therapy for relapsed/refractory diffuse large B-cell lymphoma. Leuk Lymphoma. 2020;61(11):2767–2770. doi: 10.1080/10428194.2020.1783442.
    1. Woyach JA, Awan F, Flinn IW, Berdeja JG, Wiley E, Mansoor S, et al. A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL. Blood. 2014;124(24):3553–3560. doi: 10.1182/blood-2014-08-593269.
    1. Zalevsky J, Leung IW, Karki S, Chu SY, Zhukovsky EA, Desjarlais JR, et al. The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates. Blood. 2009;113(16):3735–3743. doi: 10.1182/blood-2008-10-182048.
    1. Zammarchi F, Corbett S, Adams L, Tyrer PC, Kiakos K, Janghra N, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018;131(10):1094–1105. doi: 10.1182/blood-2017-10-813493.
    1. Zinzani PL, Barbui AM, Castellino C, Meli E, Fowler N, Salles G, et al. RE-MIND: comparing tafasitamab + lenalidomide (L-MIND) with a real world lenalidomide monotherapy cohort in relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2021 doi: 10.1158/1078-0432.CCR-21-1471.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe