We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Multiple myeloma: therapeutic delivery of antibodies and aptamers

    Neret Pujol-Navarro

    *Author for correspondence:

    E-mail Address: neret.navarro-pujol@strath.ac.uk

    Department of Chemical Engineering, University of Strathclyde, Glasgow, G1 1XL, UK

    Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK

    ,
    Mohammed M Al Qaraghuli

    Department of Chemical Engineering, University of Strathclyde, Glasgow, G1 1XL, UK

    Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK

    ,
    Karina Kubiak-Ossowska

    ARCHIE-WeSt, Department of Physics, University of Strathclyde, Glasgow, G4 0NG, UK

    ,
    Manal M Alsaadi

    Department of Industrial Pharmacy, Faculty of Pharmacy, University of Tripoli, PO Box 13645, Tripoli, Libya

    ,
    Gillian A Horne

    Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G12 0YN, UK

    ,
    Richard L Soutar

    Department of Haematology, Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN, UK

    ,
    Elpiniki Paspali

    Department of Chemical Engineering, University of Strathclyde, Glasgow, G1 1XL, UK

    ,
    Valerie A Ferro

    Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK

    ,
    Mark TS Williams

    Department of Biological & Biomedical Sciences, Glasgow Caledonian University, Glasgow, G4 0BA, UK

    &
    Paul A Mulheran

    Department of Chemical Engineering, University of Strathclyde, Glasgow, G1 1XL, UK

    Published Online:https://doi.org/10.4155/tde-2021-0041

    Multiple myeloma is the second most common hematological malignancy in adults, accounting for 2% of all cancer-related deaths in the UK. Current chemotherapy-based regimes are insufficient, as most patients relapse and develop therapy resistance. This review focuses on current novel antibody- and aptamer-based therapies aiming to overcome current therapy limitations, as well as their respective limitations and areas of improvement. The use of computer modeling methods, as a tool to study and improve ligand-receptor alignments for the use of novel therapy development will also be discussed, as it has become a rapid, reliable and comparatively inexpensive method of investigation.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Kumar SK, Rajkumar V, Kyle RA et al. Multiple myeloma. Nat. Rev. Dis. Primers 3(1), 17046 (2017). •• Provides background to multiple myeloma and should be read to give context to the whole paper. Gives an overview of the disease and a range of drugs used.
    • 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J. Clin. 66(1), 7–30 (2016).
    • 3. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am. J. Hematol. 95(5), 548–567 (2020).
    • 4. Gonsalves WI, Gertz MA, Gupta V et al. Prognostic significance of quantifying circulating plasma cells in multiple myeloma. Clin. Lymphoma Myeloma Leuk. 14, S147 (2014).
    • 5. Blade J, De Larrea CF, Rosinol L. Extramedullary involvement in multiple myeloma. Haematologica 97(11), 1618–1619 (2012).
    • 6. Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell AR. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood 97(9), 2900–2902 (2001).
    • 7. Kyle RA, Gertz MA, Witzig TE et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin. Proc. 78(1), 21–33 (2003).
    • 8. Rajkumar SV, Dimopoulos MA, Palumbo A et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15(12), e538–e548 (2014).
    • 9. Dhodapkar MV. MGUS to myeloma: a mysterious gammopathy of underexplored significance. Blood 128(23), 2599–2606 (2016).
    • 10. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113(22), 5418–5422 (2009).
    • 11. Turesson I, Kovalchik SA, Pfeiffer RM et al. Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden. Blood 123(3), 338–345 (2014).
    • 12. Dispenzieri A, Kyle RA, Katzmann JA et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 111(2), 785–789 (2008).
    • 13. Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021).
    • 14. Huang Y-F, Lin Y-W, Lin Z-H, Chang H-T. Aptamer-modified gold nanoparticles for targeting breast cancer cells through light scattering. J. Nanopart. Res. 11(4), 775–783 (2009).
    • 15. Waxman AJ, Mink PJ, Devesa SS et al. Racial disparities in incidence and outcome in multiple myeloma: a population-based study. Blood 116(25), 5501–5506 (2010).
    • 16. Dimopoulos MA, Moreau P, Terpos E et al. Multiple myeloma: EHA-ESMO clinical practice guidelines for diagnosis, treatment and follow-up†. Ann. Oncol. 32(3), 309–322 (2021).
    • 17. Myeloma UK. Daratumumab (Darzalex®) is accepted for use within NHS Scotland (2021). https://www.myeloma.org.uk/news/daratumumab-approved-for-use-on-nhs-in-scotland/
    • 18. Attal M, Lauwers-Cances V, Marit G et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 366(19), 1782–1791 (2012).
    • 19. Mccarthy PL, Holstein SA, Petrucci MT et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J. Clin. Oncol. 35(29), 3279–3289 (2017).
    • 20. Kumar SK, Mikhael JR, Buadi FK et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus guidelines. Mayo Clin. Proc. 84(12), 1095–1110 (2009).
    • 21. Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood Cancer J. 5(10), e365–e365 (2015).
    • 22. Vu T, Gonsalves W, Kumar S et al. Characteristics of exceptional responders to lenalidomide-based therapy in multiple myeloma. Blood Cancer J. 5(10), e363–e363 (2015).
    • 23. Neben K, Lokhorst HM, Jauch A et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood 119(4), 940–948 (2012).
    • 24. Kumar SK, Lee JH, Lahuerta JJ et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 26(1), 149–157 (2012).
    • 25. King AJ, Eyre T, Sharpley F, Watson C, Ramasamy K, Willan J. Multiple myeloma in the very elderly patient: challenges and solutions. Clin. Interv. Aging 2016, 423–435 (2016).
    • 26. Reghunathan R, Bi C, Liu SC et al. Clonogenic multiple myeloma cells have shared stemness signature associated with patient survival. Oncotarget 4(8), 1230–1240 (2013).
    • 27. Morita Y, Leslie M, Kameyama H, Volk D, Tanaka T. Aptamer therapeutics in cancer: current and future. Cancers (Basel) 10(3), 80 (2018). •• Background to aptamer therapeutics and essential reading for a background into aptamers – gives the advantages and challenges faced with aptamer use in oncology.
    • 28. Baxevanis CN, Perez SA, Papamichail M. Combinatorial treatments including vaccines, chemotherapy and monoclonal antibodies for cancer therapy. Cancer Immunol. Immunother. 58(3), 317–324 (2009).
    • 29. Pisetsky DS. Anti-DNA antibodies — quintessential biomarkers of SLE. Nat. Rev. Rheumatol. 12(2), 102–110 (2016).
    • 30. Sela-Culang I, Kunik V, Ofran Y. The structural basis of antibody-antigen recognition. Front. Immunol. 4, 302 (2013).
    • 31. Irani V, Guy AJ, Andrew D, Beeson JG, Ramsland PA, Richards JS. Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases. Mol. Immunol. 67(2), 171–182 (2015).
    • 32. Lonial S, Dimopoulos M, Palumbo A et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N. Engl. J. Med. 373(7), 621–631 (2015).
    • 33. Dimopoulos MA, Dytfeld D, Grosicki S et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N. Engl. J. Med. 379(19), 1811–1822 (2018).
    • 34. Attal M, Richardson PG, Rajkumar SV et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, Phase III study. Lancet 394(10214), 2096–2107 (2019).
    • 35. Moreau P, Dimopoulos M-A, Mikhael J et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised Phase III trial. Lancet 397(10292), 2361–2371 (2021).
    • 36. Spencer A, Lentzsch S, Weisel K et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica 103(12), 2079–2087 (2018).
    • 37. Dimopoulos MA, Oriol A, Nahi H et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375(14), 1319–1331 (2016).
    • 38. Hsi ED, Steinle R, Balasa B et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin. Cancer Res. 14(9), 2775–2784 (2008).
    • 39. Tai Y-T, Dillon M, Song W et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 112(4), 1329–1337 (2008).
    • 40. Martin TG, Hsu K, Charpentier E et al. A Phase Ib dose escalation trial of SAR650984 (Anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. J. Clin. Oncol. 32(Suppl. 15), 8512–8512 (2014).
    • 41. De Weers M, Tai Y-T, Van Der Veer MS et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J. Immunol. 186(3), 1840–1848 (2011).
    • 42. Lokhorst HM, Plesner T, Gimsing P et al. Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma. J. Clin. Oncol. 31(Suppl. 15), 8512–8512 (2013).
    • 43. Raab MS, Engelhardt M, Blank A et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1–2a trial. Lancet Haematol. 7(5), e381–e394 (2020).
    • 44. Kumar SK, Cornell RF, Landgren O et al. A Phase I first-in-human study of the anti-CD38 dimeric fusion protein TAK-169 for the treatment of patients (pts) with relapsed or refractory multiple myeloma (RRMM) who are proteasome inhibitor (PI)- and immunomodulatory drug (IMiD)-refractory, including Pts relapsed/refractory (R/R) or naïve to daratumumab (dara). Blood 134(Suppl. 1), 1867–1867 (2019).
    • 45. Zojer N, Kirchbacher K, Vesely M, Hübl W, Ludwig H. Rituximab treatment provides no clinical benefit in patients with pretreated advanced multiple myeloma. Leuk. Lymphoma 47(6), 1103–1109 (2006).
    • 46. Hussein M, Berenson JR, Niesvizky R et al. A Phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica 95(5), 845–848 (2010).
    • 47. Ailawadhi S, Kelly KR, Vescio RA et al. A Phase I study to assess the safety and pharmacokinetics of single-agent lorvotuzumab mertansine (IMGN901) in patients with relapsed and/or refractory CD–56-positive multiple myeloma. Clin Lymphoma Myeloma Leuk. 19(1), 29–34 (2019).
    • 48. Mcearchern JA, Smith LM, Mcdonagh CF et al. Preclinical characterization of SGN-70, a humanized antibody directed against CD70. Clin. Cancer Res. 14(23), 7763–7772 (2008).
    • 49. Mahadevan D, Lanasa MC, Farber C et al. Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200. J. Immunother. Cancer. 7(1), 1–13 (2019).
    • 50. Tai Y-T, Muchhal U, Li X-F et al. XmAb®5592 Fc-engineered humanized anti-HM1.24 monoclonal antibody has potent in vitro and in vivo efficacy against multiple myeloma. Blood 114(22), 609–609 (2009).
    • 51. Baz RC, Zonder JA, Gasparetto C, Reu FJ, Strout V. Phase I study of anti-GM2 ganglioside monoclonal antibody BIW-8962 as monotherapy in patients with previously treated multiple myeloma. Oncol. Ther. 4(2), 287–301 (2016).
    • 52. Moreau P, Cavallo F, Leleu X et al. Phase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myeloma. Leukemia 25(5), 872–874 (2011).
    • 53. Atzori F, Tabernero J, Cervantes A et al. A Phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors. Clin. Cancer Res. 17(19), 6304–6312 (2011).
    • 54. Zagouri F, Terpos E, Kastritis E, Dimopoulos MA. Emerging antibodies for the treatment of multiple myeloma. Expert Opin Emerg Drugs. 21(2), 225–237 (2016).
    • 55. Benson DM, Cohen AD, Jagannath S et al. A Phase I trial of the anti-KIR antibody IPH2101 and lenalidomide in patients with relapsed/refractory multiple myeloma. Clin. Cancer Res. 21(18), 4055–4061 (2015).
    • 56. Vey N, Karlin L, Sadot-Lebouvier S et al. A Phase I study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies. Oncotarget 9(25), 17675–17688 (2018).
    • 57. Carlo-Stella C, Guidetti A, Di Nicola M et al. IFN-γ enhances the antimyeloma activity of the fully human anti–human leukocyte antigen-DR monoclonal antibody 1D09C3. Cancer Res. 67(7), 3269–3275 (2007).
    • 58. Belch A, Sharma A, Spencer A et al. A multicenter randomized Phase II trial of mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with bortezomib in patients with relapsed/refractory multiple myeloma (MM). Blood 116(21), 5031–5031 (2010).
    • 59. Brighton TA, Khot A, Harrison SJ et al. Randomized, double-blind, placebo-controlled, multicenter study of siltuximab in high-risk smoldering multiple myeloma. Clin. Cancer Res. 25(13), 3772–3775 (2019).
    • 60. Rossi JF, Fegueux N, Lu ZY et al. Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects. Bone Marrow Transplant. 36(9), 771–779 (2005).
    • 61. Matsuyama Y, Nagashima T, Honne K et al. Successful treatment of a patient with rheumatoid arthritis and IgA-kappa multiple myeloma with tocilizumab. Intern. Med. 50(6), 639–642 (2011).
    • 62. White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE. Results from AMBER, a randomized Phase II study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. Cancer 119(2), 339–347 (2013).
    • 63. Trudel S, Stewart AK, Rom E et al. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood 107(10), 4039–4046 (2006).
    • 64. Kamath AV, Lu D, Gupta P et al. Preclinical pharmacokinetics of MFGR1877A, a human monoclonal antibody to FGFR3, and prediction of its efficacious clinical dose for the treatment of t(4;14)-positive multiple myeloma. Cancer Chemother. Pharmacol. 69(4), 1071–1078 (2012).
    • 65. Vij R, Horvath N, Spencer A et al. An open-label, Phase II trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma. Am. J. Hematol. 84(10), 650–656 (2009).
    • 66. Fulciniti M, Tassone P, Hideshima T et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 114(2), 371–379 (2009).
    • 67. Abdulkadyrov KM, Salogub GN, Khuazheva NK et al. ACE-011, a soluble activin receptor type IIa IgG-Fc fusion protein, increases hemoglobin (Hb) and improves bone lesions in multiple myeloma patients receiving myelosuppressive chemotherapy: preliminary analysis. Blood 114(22), 749–749 (2009).
    • 68. Wichert S, Juliusson G, Johansson Å et al. A single-arm, open-label, Phase II clinical trial evaluating disease response following treatment with BI-505, a human anti-intercellular adhesion molecule-1 monoclonal antibody, in patients with smoldering multiple myeloma. PLoS ONE 12(2), e0171205 (2017).
    • 69. Raje NS, Moreau P, Terpos E et al. Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma. Br. J. Haematol. 176(5), 783–795 (2017).
    • 70. Dulos J, Lilian D, Snippert M et al. Bion-1301: a novel fully blocking APRIL antibody for the treatment of multiple myeloma. Blood 128(22), 2112–2112 (2016).
    • 71. Ghobrial IM, Liu C-J, Redd RA et al. A Phase Ib/II trial of the first-in-class anti-CXCR4 antibody ulocuplumab in combination with lenalidomide or bortezomib plus dexamethasone in relapsed multiple myeloma. Clin. Cancer Res. 26(2), 344–353 (2020).
    • 72. Ochoa MC, Perez-Ruiz E, Minute L et al. Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells. Oncoimmunology 8(7), e1599636 (2019).
    • 73. Mcdonald MM, Reagan MR, Youlten SE et al. Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma. Blood 129(26), 3452–3464 (2017).
    • 74. Toscani D, Bolzoni M, Ferretti M, Palumbo C, Giuliani N. Role of osteocytes in myeloma bone disease: anti-sclerostin antibody as new therapeutic strategy. Front. Immunol. 9, 2467 (2018).
    • 75. Pianko MJ, Funt SA, Page DB et al. Efficacy and toxicity of therapy immediately after treatment with nivolumab in relapsed multiple myeloma. Leuk. Lymphoma 59(1), 221–224 (2018).
    • 76. Jelinek T, Paiva B, Hajek R. Update on PD-1/PD-L1 inhibitors in multiple myeloma. Front. Immunol. 9, 2431 (2018).
    • 77. Von Tresckow B, Boell B, Eichenauer D et al. Anti-epidermal growth factor receptor antibody cetuximab in refractory or relapsed multiple myeloma: a phase II prospective clinical trial. Leuk. Lymphoma 55(3), 695–697 (2014).
    • 78. Nejadmoghaddam M-R, Minai-Tehrani A, Ghahremanzadeh R, Mahmoudi M, Dinarvand R, Zarnani A-H. Antibody-drug conjugates: possibilities and challenges. Avicenna J. Med. Biotechnol. 11(1), 3–23 (2019).
    • 79. Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-drug conjugate-based therapeutics: state of the science. J. Natl Cancer Inst. 111(6), 538–549 (2019). •• Describes the concept of antibody–drug conjugate-based therapeutics – examples of four therapeutics detailed.
    • 80. Ikeda H, Hideshima T, Fulciniti M et al. The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin. Cancer Res. 15(12), 4028–4037 (2009).
    • 81. Kaufman JL, Niesvizky R, Stadtmauer EA et al. Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma. Br. J. Haematol. 163(4), 478–486 (2013).
    • 82. Abrahams CL, Li X, Embry M et al. Targeting CD74 in multiple myeloma with the novel, site-specific antibody-drug conjugate STRO-001. Oncotarget 9(102), 37700–37714 (2018).
    • 83. Krishnan L, Sahni G, Kaur KJ, Salunke DM. Role of antibody paratope conformational flexibility in the manifestation of molecular mimicry. Biophys. J. 94(4), 1367–1376 (2008).
    • 84. Lebovic D, Kaminski MS, Anderson TB et al. A Phase II study of consolidation treatment with Iodione-131 tositumomab (Bexxar™) in multiple myeloma (MM). Blood 120(21), 1854–1854 (2012).
    • 85. Chanan-Khan A, Wolf J, Gharibo M et al. Phase I study of IMGN901, used as monotherapy, in patients with heavily pre-treated CD56-positive multiple myeloma - a preliminary safety and efficacy analysis. Blood 114(22), 2883–2883 (2009).
    • 86. Fatholahi M, Valencia M, Mark A et al. TAK-573, an anti-CD38-targeted attenuated interferon alpha (IFNα) fusion protein, showed anti-myeloma tumor responses in combination with standard of care (SOC) agents in multiple myeloma (MM) xenograft tumor models in vivo. Clin. Lymphoma Myeloma Leuk. 19(10), e116 (2019).
    • 87. Doronina SO, Toki BE, Torgov MY et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat. Biotechnol. 21(7), 778–784 (2003).
    • 88. Lewis TS, Olson D, Gordon K et al. SGN-CD48A: a novel humanized anti-CD48 antibody-drug conjugate for the treatment of multiple myeloma. Blood 128(22), 4470–4470 (2016).
    • 89. Rhode PR, Egan JO, Xu W et al. Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models. Cancer Immunol Res. 4(1), 49–60 (2016).
    • 90. Markham A. Belantamab mafodotin: first approval. Drugs 80(15), 1607–1613 (2020).
    • 91. Kinneer K, Meekin J, Varkey R et al. Preclinical evaluation of MEDI2228, a BCMA-targeting pyrrolobenzodiazepine-linked antibody drug conjugate for the treatment of multiple myeloma. Blood 130(Suppl. 1), 3153–3153 (2017).
    • 92. Lee HC, Raje NS, Landgren O et al. Phase I study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia 35(1), 255–258 (2021).
    • 93. Singh RK, Jones RJ, Shirazi F et al. HDP-101, a novel BCMA-targeted antibody conjugated to α-amanitin, is active against myeloma with preferential efficacy against pre-clinical models of deletion 17p. Clin. Lymphoma Myeloma Leuk. 19(10), e152 (2019).
    • 94. Linderoth E, Helke S, Lee V et al. Abstract 2653: the anti-myeloma activity of TTI-621 (SIRPαFc), a CD47-blocking immunotherapeutic, is enhanced when combined with a proteasome inhibitor. Cancer Res. 77(Suppl. 13), 2653–2653 (2017).
    • 95. Levy MY, Cicic D, Bergonio G, Berger M. Trial in progress: Phase I study of actinium-225 (225Ac)-lintuzumab in patients with refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. 17, S329–S330 (2017).
    • 96. Stewart AK, Krishnan AY, Singhal S et al. Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma. Blood Cancer J. 9(2), (2019).
    • 97. Slaney CY, Wang P, Darcy PK, Kershaw MH. CARs versus BiTEs: a comparison between T cell–redirection strategies for cancer treatment. Cancer Discov. 8(8), 924–934 (2018).
    • 98. Girgis S, Shetty S, Jiao T et al. Exploratory pharmacokinetic/pharmacodynamic and tolerability study of BCMAxCD3 in cynomolgus monkeys. Blood 128(22), 5668–5668 (2016).
    • 99. Li J, Stagg NJ, Johnston J et al. Membrane-proximal epitope facilitates efficient T cell synapse formation by anti-FcRH5/CD3 and is a requirement for myeloma cell killing. Cancer Cell 31(3), 383–395 (2017).
    • 100. Topp MS, Duell J, Zugmaier G et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) Phase I dose escalation study. J. Clin. Oncol. 37(Suppl. 15), 8007–8007 (2019).
    • 101. Seckinger A, Delgado JA, Moser S et al. Target expression, generation, preclinical activity, and pharmacokinetics of the BCMA-T cell bispecific antibody em801 for multiple myeloma treatment. Cancer Cell 31(3), 396–410 (2017).
    • 102. Bahlis NJ, Raje NS, Costello C et al. Efficacy and safety of elranatamab (PF-06863135), a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MM). J. Clin. Oncol. 39(Suppl. 15), 8006–8006 (2021).
    • 103. Moreno L, Zabaleta A, Alignani D et al. New insights into the mechanism of action (MoA) of first-in-class IgG-based BCMA T-cell bispecific antibody (TCB) for the treatment of multiple myeloma (MM). Blood 128(22), 2096–2096 (2016).
    • 104. Buelow B, Choudry P, Clarke S et al. Pre-clinical development of TNB-383B, a fully human T-cell engaging bispecific antibody targeting BCMA for the treatment of multiple myeloma. J. Clin. Oncol. 36(Suppl. 15), 8034–8034 (2018).
    • 105. Gantke T, Weichel M, Herbrecht C et al. Trispecific antibodies for CD16A-directed NK cell engagement and dual-targeting of tumor cells. Protein Eng. Des. Sel. 30(9), 673–684 (2017).
    • 106. Cohen AD, Trudel S, Forsberg PA et al. GO39775: a multicenter Phase I trial evaluating the safety, pharmacokinetics, and activity of BFCR4350A, a FcRH5/CD3 T-cell dependent bispecific antibody, in patients with relapsed or refractory multiple myeloma. J. Clin. Oncol. 38(Suppl. 15), TPS8551–TPS8551 (2020).
    • 107. Zou J, Chen D, Zong Y et al. Immunotherapy based on bispecific T-cell engager with hIgG 1 Fc sequence as a new therapeutic strategy in multiple myeloma. Cancer Sci. 106(5), 512–521 (2015).
    • 108. 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. 38(3), 175–183 (2016).
    • 109. Chan WK, Kang S, Youssef Y et al. A CS1-NKG2D bispecific antibody collectively activates cytolytic immune cells against multiple myeloma. Cancer Immunol. Res. 6(7), 776–787 (2018).
    • 110. Ramadoss NS, Schulman AD, Choi SH et al. An anti-B cell maturation antigen bispecific antibody for multiple myeloma. J. Am. Chem. Soc. 137(16), 5288–5291 (2015).
    • 111. Soldevilla M, Meraviglia-Crivelli De Caso D, Menon A, Pastor F. Aptamer-iRNAs as therapeutics for cancer treatment. Pharmaceuticals 11(4), 108 (2018).
    • 112. Mignani S, Shi X, Ceña V, Majoral J-P. Dendrimer– and polymeric nanoparticle–aptamer bioconjugates as nonviral delivery systems: a new approach in medicine. Drug Discov. Today 25(6), 1065–1073 (2020).
    • 113. Stewart M. Extended duration vascular endothelial growth factor inhibition in the eye: failures, successes, and future possibilities. Pharmaceutics 10(1), 21 (2018).
    • 114. Ludwig H, Weisel K, Petrucci MT et al. Olaptesed pegol, an anti-CXCL12/SDF-1 Spiegelmer, alone and with bortezomib–dexamethasone in relapsed/refractory multiple myeloma: a Phase IIa Study. Leukemia 31(4), 997–1000 (2017).
    • 115. Hori S-I, Herrera A, Rossi J, Zhou J. Current advances in aptamers for cancer diagnosis and therapy. Cancers (Basel) 10(1), 9 (2018).
    • 116. Fu Z, Xiang J. Aptamers, the nucleic acid antibodies, in cancer therapy. Int. J. Mol. Sci. 21(8), 2793 (2020). •• An important read to understnd how aptamers are produced and their application in oncology.
    • 117. Ireson CR, Kelland LR. Discovery and development of anticancer aptamers. Mol. Cancer Ther. 5(12), 2957–2962 (2006).
    • 118. Vater A, Sahlmann J, Kröger N et al. Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12. Clin. Pharmacol. Ther. 94(1), 150–157 (2013).
    • 119. Heo K, Min S-W, Sung HJ et al. An aptamer-antibody complex (oligobody) as a novel delivery platform for targeted cancer therapies. J. Control. Rel. 229, 1–9 (2016).
    • 120. Kim HJ, Sung HJ, Lee YM et al. Therapeutic application of drug-conjugated HER2 Oligobody (HER2-DOligobody). Int. J. Mol. Sci. 21(9), 3286 (2020).
    • 121. Kim M, Kim D-M, Kim K-S, Jung W, Kim D-E. Applications of cancer cell-specific aptamers in targeted delivery of anticancer therapeutic agents. Molecules 23(4), 830 (2018).
    • 122. Adachi T, Nakamura Y. Aptamers: a review of their chemical properties and modifications for therapeutic application. Molecules 24 ( 23),4229 (.2019).
    • 123. Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE. A geometric approach to macromolecule-ligand interactions. J. Mol. Biol. 161(2), 269–288 (1982).
    • 124. Recanatini M. How dynamic docking simulations can help to tackle tough drug targets. Future Med. Chem. 10(24), 2763–2765 (2018).
    • 125. Taylor RD, Jewsbury PJ, Essex JW. A review of protein-small molecule docking methods. J. Comput. Aided Mol. Des. 16(3), 151–166 (2002).
    • 126. Gervasio FL, Laio A, Parrinello M. Flexible docking in solution using metadynamics. J. Am. Chem. Soc. 127(8), 2600–2607 (2005).
    • 127. De Vivo M, Masetti M, Bottegoni G, Cavalli A. Role of molecular dynamics and related methods in drug discovery. J. Med. Chem. 59(9), 4035–4061 (2016).
    • 128. Ferruz N, Doerr S, Vanase-Frawley MA et al. Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs. Sci. Rep. 8(1), (2018).
    • 129. Rougé L, Chiang N, Steffek M et al. Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab. Science 367(6483), 1224–1230 (2020).
    • 130. Kubiak-Ossowska K, Jachimska B, Al Qaraghuli M, Mulheran PA. Protein interactions with negatively charged inorganic surfaces. Curr. Opin. Colloid. Interface Sci. 41, 104–117 (2019). • Example of molecular dynamics simulations in two model proteins.
    • 131. Al Qaraghuli M, Kubiak-Ossowska K, Mulheran P. Thinking outside the laboratory: analyses of antibody structure and dynamics within different solvent environments in molecular dynamics (MD) Simulations. Antibodies 7(3), 21 (2018). • Example of the use of molecular dynamics simulations to study antibodies.
    • 132. Cardoso MM, Peca IN, Roque CAA. Antibody-conjugated nanoparticles for therapeutic applications. Curr. Med. Chem. 19(19), 3103–3127 (2012). •• Comprehensive review of antibody-based nanoparticle therapeutics.
    • 133. Huang Y-H, Vakili M, Molavi O et al. Decoration of anti-CD38 on nanoparticles carrying a STAT3 inhibitor can improve the therapeutic efficacy against myeloma. Cancers (Basel) 11(2), 248 (2019).
    • 134. Detappe A, Reidy M, Yu Y et al. Antibody-targeting of ultra-small nanoparticles enhances imaging sensitivity and enables longitudinal tracking of multiple myeloma. Nanoscale 11(43), 20485–20496 (2019).
    • 135. Zheleznyak A, Shokeen M, Achilefu S. Nanotherapeutics for multiple myeloma. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 10(6), e1526 (2018).
    • 136. Tran S, Degiovanni PJ, Piel B, Rai P. Cancer nanomedicine: a review of recent success in drug delivery. Clin. Transl. Med. 6(1), 44 (2017).
    • 137. Shi F, Li M, Wang J et al. Induction of multiple myeloma cancer stem cell apoptosis using conjugated anti-ABCG2 antibody with epirubicin-loaded microbubbles. Stem Cell. Res. Ther. 9(1), 1–11 (2018).
    • 138. Yang C, Xiong F, Dou J et al. Target therapy of multiple myeloma by PTX-NPs and ABCG2 antibody in a mouse xenograft model. Oncotarget 6(29), 27714–27724 (2015).
    • 139. Liang H, Zhang X-B, Lv Y et al. Functional DNA-containing nanomaterials: cellular applications in biosensing, imaging, and targeted therapy. Acc. Chem. Res. 47(6), 1891–1901 (2014).
    • 140. Park H, Kim D-M, Baek SE, Kim K-S, Kim D-E. Comparison of drug delivery efficiency between doxorubicin intercalated in RNA aptamer and one encapsulated in RNA aptamer-conjugated liposome. Bull. Korean Chem. Soc. 36(10), 2494–2500 (2015).
    • 141. Alshaer W, Hillaireau H, Vergnaud J et al. Aptamer-guided siRNA-loaded nanomedicines for systemic gene silencing in CD-44 expressing murine triple-negative breast cancer model. J. Control. Rel. 271, 98–106 (2018).
    • 142. Moosavian SA, Abnous K, Akhtari J, Arabi L, Gholamzade Dewin A, Jafari M. 5TR1 aptamer-PEGylated liposomal doxorubicin enhances cellular uptake and suppresses tumour growth by targeting MUC1 on the surface of cancer cells. Artif. Cells Nanomed. Biotechnol. 46, 2054–2065 (2017).
    • 143. Xing H, Tang L, Yang X et al. Selective delivery of an anticancer drug with aptamer-functionalized liposomes to breast cancer cells in vitro and in vivo. J. Mater. Chem. B. 1(39), 5288 (2013).
    • 144. Aravind A, Jeyamohan P, Nair R et al. AS1411 aptamer tagged PLGA-lecithin-PEG nanoparticles for tumor cell targeting and drug delivery. Biotechnol. Bioeng. 109(11), 2920–2931 (2012).
    • 145. Chen Z, Tai Z, Gu F, Hu C, Zhu Q, Gao S. Aptamer-mediated delivery of docetaxel to prostate cancer through polymeric nanoparticles for enhancement of antitumor efficacy. Eur. J. Pharm. Biopharm. 107, 130–141 (2016).
    • 146. Farokhzad OC, Cheng J, Teply BA et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl Acad. Sci. USA. 103(16), 6315–6320 (2006).
    • 147. Majidi Zolbanin N, Jafari R, Majidi J et al. Targeted co-delivery of docetaxel and cMET siRNA for treatment of Mucin1 overexpressing breast cancer cells. Adv. Pharm. Bull. 8(3), 383–393 (2018).
    • 148. Taghavi S, Nia AH, Abnous K, Ramezani M. Polyethylenimine-functionalized carbon nanotubes tagged with AS1411 aptamer for combination gene and drug delivery into human gastric cancer cells. Int. J. Pharm. 516(1–2), 301–312 (2017).
    • 149. Wang K, Yao H, Meng Y, Wang Y, Yan X, Huang R. Specific aptamer-conjugated mesoporous silica–carbon nanoparticles for HER2-targeted chemo-photothermal combined therapy. Acta Biomater. 16, 196–205 (2015).
    • 150. Xie X, Li F, Zhang H et al. EpCAM aptamer-functionalized mesoporous silica nanoparticles for efficient colon cancer cell-targeted drug delivery. Eur. J. Pharm. Sci. 83, 28–35 (2016).
    • 151. Ayatollahi S, Salmasi Z, Hashemi M et al. Aptamer-targeted delivery of Bcl-xL shRNA using alkyl modified PAMAM dendrimers into lung cancer cells. Int. J. Biochem. Cell Biol. 92, 210–217 (2017).
    • 152. Xu W, Siddiqui IA, Nihal M et al. Aptamer-conjugated and doxorubicin-loaded unimolecular micelles for targeted therapy of prostate cancer. Biomaterials 34(21), 5244–5253 (2013).
    • 153. Cohen BA, Bergkvist M. Targeted in vitro photodynamic therapy via aptamer-labeled, porphyrin-loaded virus capsids. J. Photochem. Photobiol. B: Biol. 121, 67–74 (2013).
    • 154. Kang H, Trondoli AC, Zhu G et al. Near-infrared light-responsive core–shell nanogels for targeted drug delivery. ACS Nano 5(6), 5094–5099 (2011).
    • 155. Wedekind MF, Denton NL, Chen C-Y, Cripe TP. Pediatric cancer immunotherapy: opportunities and challenges. Pediatric Drugs 20(5), 395–408 (2018).
    • 156. Reck M, Rodríguez-Abreu D, Robinson AG et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N. Engl. J. Med. 375(19), 1823–1833 (2016).
    • 157. Keefe AD, Pai S, Ellington A. Aptamers as therapeutics. Nat. Rev. Drug Discov. 9(7), 537–550 (2010).
    • 158. Sun H, Zhu X, Lu PY, Rosato RR, Tan W, Zu Y. Oligonucleotide aptamers: new tools for targeted cancer therapy. Mol. Ther. Nucleic Acids. 3(8), e182–e182 (2014).
    • 159. Ye M, Hu J, Peng M et al. Generating aptamers by cell-SELEX for applications in molecular medicine. Int. J. Mol. Sci. 13(3), 3341–3353 (2012).
    • 160. Esposito C, Catuogno S, Condorelli G, Ungaro P, De Franciscis V. Aptamer chimeras for therapeutic delivery: the challenging perspectives. Genes 9(11), 529 (2018).
    • 161. Sun H, Zu Y. Aptamers and their applications in nanomedicine. Small 11(20), 2352–2364 (2015).
    • 162. Parekh P, Kamble S, Zhao N, Zeng Z, Portier BP, Zu Y. Immunotherapy of CD30-expressing lymphoma using a highly stable ssDNA aptamer. Biomaterials 34(35), 8909–8917 (2013).
    • 163. Rosenberg JE, Bambury RM, Van Allen EM et al. A Phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma. Invest. New Drugs 32(1), 178–187 (2014).
    • 164. Chang T-C, Chen B-M, Lin W-W et al. Both IgM and IgG antibodies against polyethylene glycol can alter the biological activity of methoxy polyethylene glycol-epoetin beta in mice. Pharmaceutics 12(1), 15 (2019).
    • 165. Hsieh YC, Wang HE, Lin WW et al. Pre-existing anti-polyethylene glycol antibody reduces the therapeutic efficacy and pharmacokinetics of PEGylated liposomes. Theranostics 8(11), 3164–3175 (2018).
    • 166. Yang Q, Jacobs TM, Mccallen JD et al. Analysis of pre-existing IgG and IgM antibodies against polyethylene glycol (PEG) in the general population. Anal. Chem. 88(23), 11804–11812 (2016).
    • 167. Kovacevic KD, Gilbert JC, Jilma B. Pharmacokinetics, pharmacodynamics and safety of aptamers. Adv. Drug Del. Rev. 134, 36–50 (2018).
    • 168. Moreno A, Pitoc GA, Ganson NJ et al. Anti-PEG antibodies inhibit the anticoagulant activity of PEGylated aptamers. Cell. Chem. Biol. 26(5), 634–644.e633 (2019).
    • 169. Ganson NJ, Povsic TJ, Sullenger BA et al. Pre-existing anti–polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer. J. Allergy Clin. Immunol. 137(5), 1610–1613.e1617 (2016).
    • 170. Povsic TJ, Lawrence MG, Lincoff AM et al. Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to pegnivacogin, a PEGylated aptamer. J. Allergy Clin. Immunol. 138(6), 1712–1715 (2016).
    • 171. Cruz E, Kayser V. Monoclonal antibody therapy of solid tumors: clinical limitations and novel strategies to enhance treatment efficacy. Biologics. 13, 33–51 (2019).
    • 172. Thurber GM, Schmidt MM, Wittrup KD. Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Adv. Drug Del. Rev. 60(12), 1421–1434 (2008).
    • 173. Han L, Gao Q, Zhou K et al. The Phase I clinical study of CART targeting BCMA with humanized alpaca-derived single-domain antibody as antigen recognition domain. J. Clin. Oncol. 37(Suppl. 15), 2535–2535 (2019).
    • 174. Saltarella I, Desantis V, Melaccio A et al. Mechanisms of resistance to Anti-CD38 daratumumab in multiple myeloma. Cells 9(1), 167 (2020).
    • 175. Barroso J, Halder M, Whelan M. EURL ECVAM recommendation on non-animal-derived antibodies. Publications Office of the European Union. 1–74 (2020).
    • 176. Avet-Loiseau H. Ultra high-risk myeloma. Hematology 2010(1), 489–493 (2010).
    • 177. Jackson GH, Davies FE, Pawlyn C et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 20(1), 57–73 (2019).
    • 178. Fox TA, Horne GA, Craddock C et al. Trial re-investment to build better research for better impact. Lancet 394(10199), 635–636 (2019).
    • 179. Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J. Hematol. Oncol. 8(1), 1–14 (2015).
    • 180. Hoffmann P, Hofmeister R, Brischwein K et al. Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct. Int. J. Cancer 115(1), 98–104 (2005).
    • 181. Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy: figure 1. Cancer Res. 69(12), 4941–4944 (2009).
    • 182. Bargou R, Leo E, Zugmaier G et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321(5891), 974–977 (2008).
    • 183. Ahamadi-Fesharaki R, Fateh A, Vaziri F et al. Single-chain variable fragment-based bispecific antibodies: hitting two targets with one sophisticated arrow. Mol. Ther. Oncolytics. 14, 38–56 (2019).
    • 184. Bruno J. Predicting the uncertain future of aptamer-based diagnostics and therapeutics. Molecules 20(4), 6866–6887 (2015).
    • 185. Norman RA, Ambrosetti F, Bonvin AMJJ et al. Computational approaches to therapeutic antibody design: established methods and emerging trends. Brief Bioinform. 21(5), 1549–1567 (2020). •• Useful background for understanding the application of computational methods to antibody-based therapeutics.
    • 186. Bell DR, Weber JK, Yin W, Huynh T, Duan W, Zhou R. In silico design and validation of high-affinity RNA aptamers targeting epithelial cellular adhesion molecule dimers. Proc. Natl Acad. Sci. USA. 117(15), 8486–8493 (2020).
    • 187. Rabal O, Pastor F, Villanueva H, Soldevilla MM, Hervas-Stubbs S, Oyarzabal J. In silico aptamer docking studies: from a retrospective validation to a prospective case study-TIM3 aptamers binding. Mol. Ther. Nucleic Acids 5(10), e376 (2016). •• Example of computational methods used to study aptamers.
    • 188. Ahirwar R, Nahar S, Aggarwal S, Ramachandran S, Maiti S, Nahar P. In silico selection of an aptamer to estrogen receptor alpha using computational docking employing estrogen response elements as aptamer-alike molecules. Sci. Rep. 6(1), 21285 (2016).
    • 189. Casalini T. Not only in silico drug discovery: molecular modeling towards in silico drug delivery formulations. J. Control. Rel. 332, 390–417 (2021).
    • 190. Salo-Ahen OMH, Alanko I, Bhadane R et al. Molecular dynamics simulations in drug discovery and pharmaceutical development. Processes 9(1), 71 (2020).