Skip to main content

Advertisement

SpringerLink
Log in

Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia

  • Acute Myeloid Leukemias (H Erba, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  9. Sheridan C. Despite slow progress, bispecifics generate buzz. Nat Biotechnol. 2016;34(12):1215–7. https://doi.org/10.1038/nbt1216-1215.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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. 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. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave, CB 8007, St. Louis, MO, 63110, USA

    Daniel G. Guy & Geoffrey L. Uy

Authors
  1. Daniel G. Guy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Geoffrey L. Uy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geoffrey L. Uy.

Ethics declarations

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.

Additional information

This article is part of the Topical Collection on Acute Myeloid Leukemias

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guy, D.G., Uy, G.L. Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia. Curr Hematol Malig Rep 13, 417–425 (2018). https://doi.org/10.1007/s11899-018-0472-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-018-0472-8

Keywords

Search

Navigation