Advertisement

Current Hematologic Malignancy Reports

, Volume 13, Issue 6, pp 417–425 | Cite as

Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia

  • Daniel G. Guy
  • Geoffrey L. UyEmail author
Acute Myeloid Leukemias (H Erba, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Acute Myeloid Leukemias

Abstract

Purpose of review

Bispecific antibodies combine antigen recognition sites from two or more antibodies into a single construct allowing simultaneous binding to multiple targets. Bispecific antibodies exist which can redirect immune effector cells against acute myeloid leukemia (AML) targets. This review will highlight the progress to date and the challenges in developing bispecific antibodies for the treatment of AML.

Recent findings

Currently, a number of bispecific antibody formats including bispecific T cell engagers, dual affinity retargeting proteins, and tandem diabodies are in clinical development for AML. These antibodies target antigens present on AML blasts, including CD33, and the low affinity IL3 receptor, CD123. T cell redirecting bispecific antibodies in early phase clinical trials for AML include AG330, flotetuzumab, JNJ-63709178, and AMV564.

Summary

Bispecific antibodies represent a promising immunotherapeutic approach for the treatment of cancer. The results of ongoing studies in AML will elucidate the potential for these agents in AML.

Keywords

Acute myeloid leukemia Bispecific antibody Dual affinity retargeting protein Bispecific T cell engager 

Notes

Compliance with Ethical Standards

Conflict of Interest

Geoffrey Uy reports personal fees from Glycomimetics, personal fees from Pfizer, personal fees from Curis, personal fees from Jazz, and personal fees from Novartis, outside the submitted work. Daniel Guy declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Perez P, Hoffman RW, Shaw S, Bluestone JA, Segal DM. Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody. Nature. 1985;316(6026):354–6.CrossRefGoogle Scholar
  2. 2.
    Staerz UD, Kanagawa O, Bevan MJ. Hybrid antibodies can target sites for attack by T-cells. Nature. 1985;314(6012):628–31.  https://doi.org/10.1038/314628a0.CrossRefPubMedGoogle Scholar
  3. 3.
    Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–47.  https://doi.org/10.1056/NEJMoa1609783.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Loffler A, Gruen M, Wuchter C, Schriever F, Kufer P, Dreier T, et al. Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Leukemia. 2003;17(5):900–9.  https://doi.org/10.1038/sj.leu.2402890.CrossRefPubMedGoogle Scholar
  5. 5.
    Brennan M, Davison PF, Paulus H. Preparation of bispecific antibodies by chemical recombination of monoclonal immunoglobulin G1 fragments. Science. 1985;229(4708):81–3.CrossRefGoogle Scholar
  6. 6.
    Staerz UD, Bevan MJ. Hybrid hybridoma producing a bispecific monoclonal antibody that can focus effector T-cell activity. Proc Natl Acad Sci U S A. 1986;83(5):1453–7.CrossRefGoogle Scholar
  7. 7.
    • Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;(7):20, 838–847.  https://doi.org/10.1016/j.drudis.2015.02.008 Review summarizing different bispecific antibody formats.
  8. 8.
    Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–25.  https://doi.org/10.1038/nri2155.CrossRefPubMedGoogle Scholar
  9. 9.
    Sheridan C. Despite slow progress, bispecifics generate buzz. Nat Biotechnol. 2016;34(12):1215–7.  https://doi.org/10.1038/nbt1216-1215.CrossRefPubMedGoogle Scholar
  10. 10.
    Rathi C, Meibohm B. Clinical pharmacology of bispecific antibody constructs. J Clin Pharmacol. 2015;55(Suppl 3):S21–8.  https://doi.org/10.1002/jcph.445.CrossRefPubMedGoogle Scholar
  11. 11.
    Arvedson T. Possibility for once-weekly dosing with an anti-CD33 half-life extended BiTE. AACR Annual Meeting 2017; April 1–5, 2017; Washington, DC;. 2017.Google Scholar
  12. 12.
    Johnson S, Burke S, Huang L, Gorlatov S, Li H, Wang W, et al. Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J Mol Biol. 2010;399(3):436–49.  https://doi.org/10.1016/j.jmb.2010.04.001.CrossRefPubMedGoogle Scholar
  13. 13.
    Moore PA, Zhang W, Rainey GJ, Burke S, Li H, Huang L, et al. Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma. Blood. 2011;117(17):4542–51.  https://doi.org/10.1182/blood-2010-09-306449.CrossRefPubMedGoogle Scholar
  14. 14.
    •• Reusch U, Harrington KH, Gudgeon CJ, Fucek I, Ellwanger K, Weichel M, et al. Characterization of CD33/CD3 tetravalent bispecific tandem diabodies (TandAbs) for the treatment of acute myeloid leukemia. Clin Cancer Res. 2016;22(23):5829–38.  https://doi.org/10.1158/1078-0432.CCR-16-0350 Preclinical characterization of AMV564. CrossRefPubMedGoogle Scholar
  15. 15.
    Labrijn AF, Meesters JI, de Goeij BE, van den Bremer ET, Neijssen J, van Kampen MD, et al. Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange. Proc Natl Acad Sci U S A. 2013;110(13):5145–50.  https://doi.org/10.1073/pnas.1220145110.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Moore GL, Bautista C, Pong E, Nguyen DH, Jacinto J, Eivazi A, et al. A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens. MAbs. 2011;3(6):546–57.  https://doi.org/10.4161/mabs.3.6.18123.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25.  https://doi.org/10.1126/scitranslmed.3008226.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154–7.  https://doi.org/10.1182/blood-2013-02-485623.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95.  https://doi.org/10.1182/blood-2014-05-552729.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–20.  https://doi.org/10.1182/blood-2011-10-384388.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.  https://doi.org/10.1056/NEJMoa1215134.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Billiau AD, Roskams T, Van Damme-Lombaerts R, Matthys P, Wouters C. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-g-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood. 2005;105(4):1648–51.  https://doi.org/10.1182/blood-2004-08-2997.CrossRefPubMedGoogle Scholar
  23. 23.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet (London, England). 2015;385(9967):517–28.  https://doi.org/10.1016/s0140-6736(14)61403-3.CrossRefGoogle Scholar
  24. 24.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.  https://doi.org/10.1056/NEJMoa1407222.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dinndorf PA, Andrews RG, Benjamin D, Ridgway D, Wolff L, Bernstein ID. Expression of normal myeloid-associated antigens by acute leukemia cells. Blood. 1986;67(4):1048–53.PubMedGoogle Scholar
  26. 26.
    Hauswirth AW, Florian S, Printz D, Sotlar K, Krauth MT, Fritsch G, et al. Expression of the target receptor CD33 in CD34+/CD38-/CD123+ AML stem cells. Eur J Clin Investig. 2007;37(1):73–82.  https://doi.org/10.1111/j.1365-2362.2007.01746.x.CrossRefGoogle Scholar
  27. 27.
    Nguyen DH, Ball ED, Varki A. Myeloid precursors and acute myeloid leukemia cells express multiple CD33-related Siglecs. Exp Hematol. 2006;34(6):728–35.  https://doi.org/10.1016/j.exphem.2006.03.003.CrossRefPubMedGoogle Scholar
  28. 28.
    Ehninger A, Kramer M, Rollig C, Thiede C, Bornhauser M, von Bonin M, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J. 2014;4:e218.  https://doi.org/10.1038/bcj.2014.39.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    •• Krupka C, Kufer P, Kischel R, Zugmaier G, Bogeholz J, Kohnke T, et al. CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood. 2014;123(3):356–65.  https://doi.org/10.1182/blood-2013-08-523548 Preclincial studies of the BiTE, AMG330. CrossRefPubMedGoogle Scholar
  30. 30.
    Walter RB, Appelbaum FR, Estey EH, Bernstein ID. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood. 2012;119(26):6198–208.  https://doi.org/10.1182/blood-2011-11-325050.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Aigner M, Feulner J, Schaffer S, Kischel R, Kufer P, Schneider K, et al. T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bispecific BiTE antibody construct. Leukemia. 2013;27(5):1107–15.  https://doi.org/10.1038/leu.2012.341.CrossRefPubMedGoogle Scholar
  32. 32.
    Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29(4):369–77.  https://doi.org/10.1200/jco.2010.31.4310.CrossRefPubMedGoogle Scholar
  33. 33.
    Appelbaum FR, Bernstein ID. Gemtuzumab ozogamicin for acute myeloid leukemia. Blood. 2017;130(22):2373–6.  https://doi.org/10.1182/blood-2017-09-797712.CrossRefPubMedGoogle Scholar
  34. 34.
    Arndt C, von Bonin M, Cartellieri M, Feldmann A, Koristka S, Michalk I, et al. Redirection of T cells with a first fully humanized bispecific CD33-CD3 antibody efficiently eliminates AML blasts without harming hematopoietic stem cells. Leukemia. 2013;27(4):964–7.  https://doi.org/10.1038/leu.2013.18.CrossRefPubMedGoogle Scholar
  35. 35.
    Dutour A, Marin V, Pizzitola I, Valsesia-Wittmann S, Lee D, Yvon E, et al. In vitro and in vivo antitumor effect of anti-CD33 chimeric receptor-expressing EBV-CTL against CD33 acute myeloid leukemia. Advances in hematology. 2012;2012:683065.  https://doi.org/10.1155/2012/683065.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    •• Friedrich M, Henn A, Raum T, Bajtus M, Matthes K, Hendrich L, et al. Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia. Mol Cancer Ther. 2014;13(6):1549–57.  https://doi.org/10.1158/1535-7163.MCT-13-0956. Article describing preclinical studies of AMG330 for AML. CrossRefPubMedGoogle Scholar
  37. 37.
    Laszlo GS, Gudgeon CJ, Harrington KH, Dell'Aringa J, Newhall KJ, Means GD, et al. Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML. Blood. 2014;123(4):554–61.  https://doi.org/10.1182/blood-2013-09-527044.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    • Westervelt P, Roboz, GJ et al. Phase 1 first-in-human Trial of AMV564, a bivalent bispecific (2x2) CD33/CD3 T-cell engager, in patients with relapsed/refractory acute myeloid leukemia (AML). Presented at the 23rd Congress of the European Hematology Association (EHA), June 14-17, Stockholm, Sweden; 2018. Initial clinical results of AMV564. Google Scholar
  39. 39.
    Stamova S, Cartellieri M, Feldmann A, Arndt C, Koristka S, Bartsch H, et al. Unexpected recombinations in single chain bispecific anti-CD3-anti-CD33 antibodies can be avoided by a novel linker module. Mol Immunol. 2011;49(3):474–82.  https://doi.org/10.1016/j.molimm.2011.09.019.CrossRefPubMedGoogle Scholar
  40. 40.
    McKoy JM, Angelotta C, Bennett CL, Tallman MS, Wadleigh M, Evens AM, et al. Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res. 2007;31(5):599–604.  https://doi.org/10.1016/j.leukres.2006.07.005.CrossRefPubMedGoogle Scholar
  41. 41.
    Maniecki MB, Hasle H, Bendix K, Moller HJ. Is hepatotoxicity in patients treated with gemtuzumabozogamicin due to specific targeting of hepatocytes? Leuk Res. 2011;35(6):e84–6.  https://doi.org/10.1016/j.leukres.2011.01.025.CrossRefPubMedGoogle Scholar
  42. 42.
    Robinson B. Seattle genetics discontinues phase 3 CASCADE trial of vadastuximab talirine (SGN-CD33A) in frontline acute myeloid leukemia. 2018. http://investor.seattlegenetics.com/phoenix.zhtml?c=124860&p=irol-newsArticle&ID=2281531.
  43. 43.
    Kantarjian HM, DJ DA, Advani AS, Stelljes M, Kebriaei P, Cassaday RD, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol. 2017;4(8):e387–e98.  https://doi.org/10.1016/S2352-3026(17)30103-5.CrossRefPubMedGoogle Scholar
  44. 44.
    Lamba JK, Chauhan L, Shin M, Loken MR, Pollard JA, Wang YC, et al. CD33 splicing polymorphism determines gemtuzumab ozogamicin response in de novo acute myeloid leukemia: report from randomized phase III children’s oncology group trial AAML0531. J Clin Oncol. 2017;35(23):2674–82.  https://doi.org/10.1200/JCO.2016.71.2513.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Munoz L, Nomdedeu JF, Lopez O, Carnicer MJ, Bellido M, Aventin A, et al. Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. Haematologica. 2001;86(12):1261–9.PubMedGoogle Scholar
  46. 46.
    Reddy EP, Korapati A, Chaturvedi P, Rane S. IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled. Oncogene. 2000;19(21):2532–47.  https://doi.org/10.1038/sj.onc.1203594.CrossRefPubMedGoogle Scholar
  47. 47.
    Blalock WL, Weinstein-Oppenheimer C, Chang F, Hoyle PE, Wang XY, Algate PA, et al. Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs. Leukemia. 1999;13(8):1109–66.CrossRefGoogle Scholar
  48. 48.
    Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14(10):1777–84.CrossRefGoogle Scholar
  49. 49.
    Testa U, Riccioni R, Militi S, Coccia E, Stellacci E, Samoggia P, et al. Elevated expression of IL-3Ralpha in acute myelogenous leukemia is associated with enhanced blast proliferation, increased cellularity, and poor prognosis. Blood. 2002;100(8):2980–8.  https://doi.org/10.1182/blood-2002-03-0852.CrossRefPubMedGoogle Scholar
  50. 50.
    Jin L, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell. 2009;5(1):31–42.  https://doi.org/10.1016/j.stem.2009.04.018.CrossRefPubMedGoogle Scholar
  51. 51.
    •• Al-Hussaini M, Rettig MP, Ritchey JK, Karpova D, Uy GL, Eissenberg LG, et al. Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood. 2016;127(1):122–31.  https://doi.org/10.1182/blood-2014-05-575704 Preclinical studies of MGd-006, flotetuzumab for AML. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Chichili GR, Huang L, Li H, Burke S, He L, Tang Q, et al. A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates. Sci Transl Med. 2015;7(289):289ra82.  https://doi.org/10.1126/scitranslmed.aaa5693.CrossRefPubMedGoogle Scholar
  53. 53.
    Campagne O, Delmas A, Fouliard S, Chenel M, Chichili GR, Li H, et al. Integrated pharmacokinetic/pharmacodynamic model of a bispecific CD3xCD123 DART molecule in nonhuman primates: evaluation of activity and impact of immunogenicity. Clin Cancer Res. 2018;24(11):2631–41.  https://doi.org/10.1158/1078-0432.Ccr-17-2265.CrossRefPubMedGoogle Scholar
  54. 54.
    • Uy GL, et al. Preliminary results of a phase 1 study of flotetuzumab, a CD123 x CD3 bispecific Dart® protein, in patients with relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. Blood. 2017;130(Suppl 1):637 Initial clinical results from phase 1 dose escalation study of flotetuzumab. Google Scholar
  55. 55.
    Gaudet FNJ, et al. Development of a CD123xCD3 bispecific antibody (JNJ-63709178) for the treatment of acute myeloid leukemia (AML). Blood. 2016;128(22):2824.Google Scholar
  56. 56.
    Chu SY, Pong E, Chen H, Phung S, Chan EW, Endo NA, et al. Immunotherapy with long-lived anti-CD123 × anti-CD3 bispecific antibodies stimulates potent T cell-mediated killing of human AML cell lines and of CD123+ cells in monkeys: a potential therapy for acute myelogenous leukemia. Blood. 2014;124(21):2316.Google Scholar
  57. 57.
    Gill S, Tasian SK, Ruella M, Shestova O, Li Y, Porter DL, et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood. 2014;123(15):2343–54.  https://doi.org/10.1182/blood-2013-09-529537.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood. 2007;110(7):2659–66.  https://doi.org/10.1182/blood-2007-03-083048.CrossRefPubMedGoogle Scholar
  59. 59.
    Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G, et al. Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood. 2005;106(13):4086–92.  https://doi.org/10.1182/blood-2005-03-1072.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Van Loo PF, Doornbos R, Dolstra H, Shamsili S, Bakker L. Preclinical evaluation of MCLA117, a CLEC12AxCD3 bispecific antibody efficiently targeting a novel leukemic stem cell associated antigen in AML. Blood. 2015;126(23):325.Google Scholar
  61. 61.
    Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295(5562):2097–100.  https://doi.org/10.1126/science.1068440.CrossRefPubMedGoogle Scholar
  62. 62.
    Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105(8):3051–7.  https://doi.org/10.1182/blood-2004-07-2974.CrossRefPubMedGoogle Scholar
  63. 63.
    Gleason MK, Verneris MR, Todhunter DA, Zhang B, McCullar V, Zhou SX, et al. Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production. Mol Cancer Ther. 2012;11(12):2674–84.  https://doi.org/10.1158/1535-7163.Mct-12-0692.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Bruenke J, Barbin K, Kunert S, Lang P, Pfeiffer M, Stieglmaier K, et al. Effective lysis of lymphoma cells with a stabilised bispecific single-chain Fv antibody against CD19 and FcgRIII (CD16). Br J Haematol. 2005;130(2):218–28.  https://doi.org/10.1111/j.1365-2141.2005.05414.x.CrossRefPubMedGoogle Scholar
  65. 65.
    Wiernik A, Foley B, Zhang B, Verneris MR, Warlick E, Gleason MK, et al. Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition. Clin Cancer Res. 2013;19(14):3844–55.  https://doi.org/10.1158/1078-0432.Ccr-13-0505.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Vallera DA, Felices M, McElmurry R, McCullar V, Zhou X, Schmohl JU, et al. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin Cancer Res. 2016;22(14):3440–50.  https://doi.org/10.1158/1078-0432.CCR-15-2710.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Oldenborg PA, Gresham HD, Lindberg FP. CD47-signal regulatory protein alpha (SIRPalpha) regulates Fcg and complement receptor-mediated phagocytosis. J Exp Med. 2001;193(7):855–62.CrossRefGoogle Scholar
  68. 68.
    Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286–99.  https://doi.org/10.1016/j.cell.2009.05.045.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Dheilly E, Moine V, Broyer L, Salgado-Pires S, Johnson Z, Papaioannou A, et al. Selective blockade of the ubiquitous checkpoint receptor CD47 is enabled by dual-targeting bispecific antibodies. Mol Ther. 2017;25(2):523–33.  https://doi.org/10.1016/j.ymthe.2016.11.006.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Boyd-Kirkup J, Thakkar D, Brauer P, Zhou J, Chng W-J, Ingram PJ. HMBD004, a novel anti-CD47xCD33 bispecific antibody displays potent anti-tumor effects in pre-clinical models of AML. Blood. 2017;130(Suppl 1):1378.Google Scholar
  71. 71.
    Harrington KH, Gudgeon CJ, Laszlo GS, Newhall KJ, Sinclair AM, Frankel SR, et al. The broad anti-AML activity of the CD33/CD3 BiTE antibody construct, AMG 330, is impacted by disease stage and risk. PLoS One. 2015;10(8):e0135945.  https://doi.org/10.1371/journal.pone.0135945.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Laszlo GS, Gudgeon CJ, Harrington KH, Walter RB. T-cell ligands modulate the cytolytic activity of the CD33/CD3 BiTE antibody construct, AMG 330. Blood cancer journal. 2015;5:e340.  https://doi.org/10.1038/bcj.2015.68.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Krupka C, Kufer P, Kischel R, Zugmaier G, Lichtenegger FS, Kohnke T, et al. 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(2):484–91.  https://doi.org/10.1038/leu.2015.214.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of OncologyWashington University School of MedicineSt. LouisUSA

Personalised recommendations