Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Updates on the mechanisms of toxicities associated with monoclonal antibodies targeting growth factor signaling and immune cells in cancer

  • Miso Park (College of Pharmacy, Kangwon National University) ;
  • Ji Won Kim (Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University)
  • Received : 2024.01.03
  • Accepted : 2024.03.15
  • Published : 2024.07.15
⟨ Previous Next ⟩

Abstract

Monoclonal antibody (mAb)-based immunotherapy currently is considered to be an optimal therapeutic approach to cancer treatment, either in combination with surgery, radiation, and/or chemotherapy or alone. Various solid tumors and hematological malignancies have been characterized by distinct molecular targets, which could be utilized as innovative anticancer agents. Notably, receptor tyrosine kinases, including HER2, EGFR, VEGFR, and PDGFR, which act as receptors for growth factors, serve as crucial target proteins, expanding their role in the cancer therapeutic market. In contrast to conventional anticancer agents that directly target cancer cells, the advent of immunotherapy introduces novel approaches, such as immune checkpoint blockers (ICBs) and mAbs targeting surface antigens on immune cells in hematological malignancies and lymphomas. While these immunotherapies have mitigated the acquired resistance observed in traditional targeted therapies, they also exhibit diverse toxicities. Herein, this review focuses on describing the well-established toxicities and newly proposed mechanisms of monoclonal antibody toxicity in recent studies. Understanding these molecular mechanisms is indispensable to overcoming the limitations of mAbs-based therapies, facilitating the development of innovative anticancer agents, and uncovering novel indications for cancer treatment in the future.

Keywords

Acknowledgement

We thank Kangwon national university-Industry Cooperation Foundation. The figures were created with BioRender.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209-249. https://doi.org/10.3322/caac.21660 
  2. Bhullar KS, Lagaron NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV (2018) Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer 17:48. https://doi.org/10.1186/s12943-018-0804-2 
  3. Singal G, Miller PG, Agarwala V, Li G, Kaushik G, Backenroth D, Gossai A, Frampton GM, Torres AZ, Lehnert EM, Bourque D, O'Connell C, Bowser B, Caron T, Baydur E, Seidl-Rathkopf K, Ivanov I, Alpha-Cobb G, Guria A, He J, Frank S, Nunnally AC, Bailey M, Jaskiw A, Feuchtbaum D, Nussbaum N, Abernethy AP, Miller VA (2019) Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic database. JAMA 321:1391-1399. https://doi.org/10.1001/jama.2019.3241 
  4. Roskoski R Jr (2016) Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res 103:26-48. https://doi.org/10.1016/j.phrs.2015.10.021 
  5. Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, Han J, Wei X (2019) Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther 4:62. https://doi.org/10.1038/s41392-019-0095-0 
  6. Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4:349-360. https://doi.org/10.1038/nrc1361 
  7. Vyas S, Chang P (2014) New PARP targets for cancer therapy. Nat Rev Cancer 14:502-509. https://doi.org/10.1038/nrc3748 
  8. Lee YT, Tan YJ, Oon CE (2018) Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol 834:188-196. https://doi.org/10.1016/j.ejphar.2018.07.034 
  9. Wilkes GM (2018) Targeted therapy: attacking cancer with molecular and immunological targeted agents. Asia Pac J Oncol Nurs 5:137-155. https://doi.org/10.4103/apjon.apjon_79_17 
  10. Cai HH (2023) Therapeutic monoclonal antibodies approved by FDA in 2022. J Clin Exp Immunol 8:3 
  11. Owens MA, Horten BC, Da Silva MM (2004) HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer 5:63-69. https://doi.org/10.3816/cbc.2004.n.011 
  12. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, D'Amico R (2012) Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 2012:Cd006243. https://doi.org/10.1002/14651858.CD006243.pub2 
  13. Hudis CA (2007) Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med 357:39-51. https://doi.org/10.1056/NEJMra043186 
  14. Kitani T, Ong SG, Lam CK, Rhee JW, Zhang JZ, Oikonomopoulos A, Ma N, Tian L, Lee J, Telli ML, Witteles RM, Sharma A, Sayed N, Wu JC (2019) Human-induced pluripotent stem cell model of trastuzumab-induced cardiac dysfunction in patients with breast cancer. Circulation 139:2451-2465. https://doi.org/10.1161/circulationaha.118.037357 
  15. Bouwer NI, Jager A, Liesting C, Kofard MJM, Brugts JJ, Kitzen J, Boersma E, Levin MD (2020) Cardiac monitoring in HER2-positive patients on trastuzumab treatment: a review and implications for clinical practice. Breast 52:33-44. https://doi.org/10.1016/j.breast.2020.04.005 
  16. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215-1221. https://doi.org/10.1200/jco.2002.20.5.1215 
  17. Alhussein MM, Mokbel A, Cosman T, Aghel N, Yang EH, Mukherjee SD, Dent S, Ellis PM, Dhesy-Thind S, Leong DP (2021) Pertuzumab cardiotoxicity in patients with HER2-positive Cancer: a systematic review and meta-analysis. CJC Open 3:1372-1382. https://doi.org/10.1016/j.cjco.2021.06.019 
  18. Zhang L, Wang Y, Meng W, Zhao W, Tong Z (2022) Cardiac safety analysis of anti-HER2-targeted therapy in early breast cancer. Sci Rep 12:14312. https://doi.org/10.1038/s41598-022-18342-1 
  19. Alasmari MM (2023) A review of margetuximab-based therapies in patients with HER2-positive metastatic breast cancer. Cancers (Basel) 15:38. https://doi.org/10.3390/cancers15010038 
  20. Eaton H, Timm KN (2023) Mechanisms of trastuzumab induced cardiotoxicity-Is exercise a potential treatment? Cardio-Oncol 9:22. https://doi.org/10.1186/s40959-023-00172-3 
  21. Lemmens K, Fransen P, Sys SU, Brutsaert DL, De Keulenaer GW (2004) Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Circulation 109:324-326. https://doi.org/10.1161/01.Cir.0000114521.88547.5e 
  22. Kabel AM, Elkhoely AA (2017) Targeting proinflammatory cytokines, oxidative stress, TGF-β1 and STAT-3 by rosuvastatin and ubiquinone to ameliorate trastuzumab cardiotoxicity. Biomed Pharmacother 93:17-26. https://doi.org/10.1016/j.biopha.2017.06.033 
  23. Mohan N, Shen Y, Endo Y, ElZarrad MK, Wu WJ (2016) Trastuzumab, but not pertuzumab, dysregulates HER2 signaling to mediate inhibition of autophagy and increase in reactive oxygen species production in human cardiomyocytes. Mol Cancer Ther 15:1321-1331. https://doi.org/10.1158/1535-7163.Mct-15-0741 
  24. Xu Z, Gao Z, Fu H, Zeng Y, Jin Y, Xu B, Zhang Y, Pan Z, Chen X, Zhang X, Wang X, Yan H, Yang X, Yang B, He Q, Luo P (2023) PTX3 from vascular endothelial cells contributes to trastuzumab-induced cardiac complications. Cardiovasc Res 119:1250-1264. https://doi.org/10.1093/cvr/cvad012 
  25. Sasaki R, Kurebayashi N, Eguchi H, Horimoto Y, Shiga T, Miyazaki S, Kashiyama T, Akamatsu W, Saito M (2022) Involvement of kallikrein-PAR2-proinflammatory pathway in severe trastuzumab-induced cardiotoxicity. Cancer Sci 113:3449-3462. https://doi.org/10.1111/cas.15508 
  26. De Sanctis R, Giordano L, D'Antonio F, Agostinetto E, Marinello A, Guiducci D, Masci G, Losurdo A, Zuradelli M, Torrisi R, Santoro A (2021) Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab. Breast 57:80-85. https://doi.org/10.1016/j.breast.2021.03.004 
  27. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391-400. https://doi.org/10.1038/nrd1381 
  28. Kanbayashi Y, Ishikawa T, Tabuchi Y, Sakaguchi K, Ouchi Y, Otsuji E, Takayama K, Taguchi T (2020) Predictive factors for the development of proteinuria in cancer patients treated with bevacizumab, ramucirumab, and aflibercept: a single-institution retrospective analysis. Sci Rep 10:2011. https://doi.org/10.1038/s41598-020-58994-5 
  29. Hatake K, Doi T, Uetake H, Takahashi Y, Ishihara Y, Shirao K (2016) Bevacizumab safety in Japanese patients with colorectal cancer. Jpn J Clin Oncol 46:234-240. https://doi.org/10.1093/jjco/hyv182 
  30. Motoo N, Hayashi Y, Shimizu A, Ura M, Nishikawa R (2019) Safety and effectiveness of bevacizumab in Japanese patients with malignant glioma: a post-marketing surveillance study. Jpn J Clin Oncol 49:1016-1023. https://doi.org/10.1093/jjco/hyz125 
  31. Yagi K, Mitstui M, Zamami Y, Niimura T, Izawa-Ishizawa Y, Goda M, Chuma M, Fukunaga K, Shibata T, Ishida S, Sakurada T, Okada N, Hamano H, Horinouchi Y, Ikeda Y, Yanagawa H, Ishizawa K (2021) Investigation of drugs affecting hypertension in bevacizumab-treated patients and examination of the impact on the therapeutic effect. Cancer Med 10:164-172. https://doi.org/10.1002/cam4.3587 
  32. Kamba T, McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96:1788-1795. https://doi.org/10.1038/sj.bjc.6603813 
  33. Randall LM, Monk BJ (2010) Bevacizumab toxicities and their management in ovarian cancer. Gynecol Oncol 117:497-504. https://doi.org/10.1016/j.ygyno.2010.02.021 
  34. Wang SY, Zou C, Liu XF, Yan YJ, Gu SZ, Li X (2021) Vascular endothelial growth factor ameliorated palmitate-induced cardiomyocyte injury via JNK pathway. In Vitro Cell Dev Biol Anim 57:886-895. https://doi.org/10.1007/s11626-021-00616-z 
  35. Rasanen M, Sultan I, Paech J, Hemanthakumar KA, Yu W, He L, Tang J, Sun Y, Hlushchuk R, Huan X, Armstrong E, Khoma OZ, Mervaala E, Djonov V, Betsholtz C, Zhou B, Kivela R, Alitalo K (2021) VEGF-B promotes endocardium-derived coronary vessel development and cardiac regeneration. Circulation 143:65-77. https://doi.org/10.1161/circulationaha.120.050635 
  36. Noguerido A, Mulet-Margalef N, Matos I, Ros J, Argiles G, Elez E, Tabernero J (2018) The safety of ramucirumab for the treatment of colorectal cancer. Expert Opin Drug Saf 17:945-951. https://doi.org/10.1080/14740338.2018.1506762 
  37. Thomas M (2005) Cetuximab: adverse event profile and recommendations for toxicity management. Clin J Oncol Nurs 9:332-338. https://doi.org/10.1188/05.Cjon.332-338 
  38. Lacouture ME, Anadkat MJ, Bensadoun RJ, Bryce J, Chan A, Epstein JB, Eaby-Sandy B, Murphy BA (2011) Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19:1079-1095. https://doi.org/10.1007/s00520-011-1197-6 
  39. Jost M, Kari C, Rodeck U (2000) The EGF receptor-an essential regulator of multiple epidermal functions. Eur J Dermatol 10:505-510 
  40. Peus D, Hamacher L, Pittelkow MR (1997) EGF-receptor tyrosine kinase inhibition induces keratinocyte growth arrest and terminal differentiation. J Invest Dermatol 109:751-756. https://doi.org/10.1111/1523-1747.ep12340759 
  41. Kobayashi T, Hashimoto K, Okumura H, Asada H, Yoshikawa K (1998) Endogenous EGF-family growth factors are necessary for the progression from the G1 to S phase in human keratinocytes. J Invest Dermatol 111:616-620. https://doi.org/10.1046/j.1523-1747.1998.00331.x 
  42. Pasonen-Seppanen S, Karvinen S, Torronen K, Hyttinen JM, Jokela T, Lammi MJ, Tammi MI, Tammi R (2003) EGF upregulates, whereas TGF-beta downregulates, the hyaluronan synthases Has2 and Has3 in organotypic keratinocyte cultures: correlations with epidermal proliferation and differentiation. J Invest Dermatol 120:1038-1044. https://doi.org/10.1046/j.1523-1747.2003.12249.x 
  43. Mimeault M, Bonenfant D, Batra SK (2004) New advances on the functions of epidermal growth factor receptor and ceramides in skin cell differentiation, disorders and cancers. Skin Pharmacol Physiol 17:153-166. https://doi.org/10.1159/000078818 
  44. Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K (2001) Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. J Biol Chem 276:999-1004. https://doi.org/10.1074/jbc.M003425200 
  45. Woodworth CD, Michael E, Marker D, Allen S, Smith L, Nees M (2005) Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment. Mol Cancer Ther 4:650-658. https://doi.org/10.1158/1535-7163.Mct-04-0238 
  46. Park JH, Kim MY, Choi IS, Kim JW, Kim JW, Lee KW, Kim JS (2022) Identification of immune-related mechanisms of cetuximab induced skin toxicity in colorectal cancer patients. PLoS One 17:e0276497. https://doi.org/10.1371/journal.pone.0276497 
  47. Penniman L, Parmar S, Patel K (2018) Olaratumab (Lartruvo): an innovative treatment for soft tissue sarcoma. P T 43:267-270 
  48. Shirley M (2017) Olaratumab: first global approval. Drugs 77:107-112. https://doi.org/10.1007/s40265-016-0680-2 
  49. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria R Jr, Conti I, Cosaert J, Schwartz GK (2016) Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet 388:488-497. https://doi.org/10.1016/s0140-6736(16)30587-6 
  50. Tzeng DY, Deuel TF, Huang JS, Senior RM, Boxer LA, Baehner RL (1984) Platelet-derived growth factor promotes polymorphonuclear leukocyte activation. Blood 64:1123-1128  https://doi.org/10.1182/blood.V64.5.1123.1123
  51. Pauken KE, Dougan M, Rose NR, Lichtman AH, Sharpe AH (2019) Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol 40:511-523. https://doi.org/10.1016/j.it.2019.04.002 
  52. Conroy M, Naidoo J (2022) Immune-related adverse events and the balancing act of immunotherapy. Nat Commun 13:392. https://doi.org/10.1038/s41467-022-27960-2 
  53. Dougan M, Luoma AM, Dougan SK, Wucherpfennig KW (2021) Understanding and treating the inflammatory adverse events of cancer immunotherapy. Cell 184:1575-1588. https://doi.org/10.1016/j.cell.2021.02.011 
  54. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, Zhao S, Das S, Beckermann KE, Ha L, Rathmell WK, Ancell KK, Balko JM, Bowman C, Davis EJ, Chism DD, Horn L, Long GV, Carlino MS, Lebrun-Vignes B, Eroglu Z, Hassel JC, Menzies AM, Sosman JA, Sullivan RJ, Moslehi JJ, Johnson DB (2018) Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 4:1721-1728. https://doi.org/10.1001/jamaoncol.2018.3923 
  55. Wang SJ, Dougan SK, Dougan M (2023) Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer 9:543-553. https://doi.org/10.1016/j.trecan.2023.04.002 
  56. Bilate AM, Lafaille JJ (2012) Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 30:733-758. https://doi.org/10.1146/annurev-immunol-020711-075043 
  57. Dougan M, Pietropaolo M (2020) Time to dissect the autoimmune etiology of cancer antibody immunotherapy. J Clin Investig 130:51-61. https://doi.org/10.1172/JCI131194 
  58. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee J, Hughes J, Pittaluga S, Oliveira JB, Mefre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345:1623-1627. https://doi.org/10.1126/science.1255904 
  59. de Filette J, Andreescu CE, Cools F, Bravenboer B, Velkeniers B (2019) A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors. Horm Metab Res 51:145-156. https://doi.org/10.1055/a-0843-3366 
  60. Iwama S, De Remigis A, Callahan MK, Slovin SF, Wolchok JD, Caturegli P (2014) Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med 6:230ra245. https://doi.org/10.1126/scitranslmed.3008002 
  61. Caturegli P, Di Dalmazi G, Lombardi M, Grosso F, Larman HB, Larman T, Taverna G, Cosottini M, Lupi I (2016) Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am J Pathol 186:3225-3235. https://doi.org/10.1016/j.ajpath.2016.08.020 
  62. Yamauchi I, Sakane Y, Fukuda Y, Fujii T, Taura D, Hirata M, Hirota K, Ueda Y, Kanai Y, Yamashita Y, Kondo E, Sone M, Yasoda A, Inagaki N (2017) Clinical features of nivolumab-induced thyroiditis: a case series study. Thyroid 27:894-901. https://doi.org/10.1089/thy.2016.0562 
  63. Clotman K, Janssens K, Specenier P, Weets I, De Block CEM (2018) Programmed cell death-1 inhibitor-induced type 1 diabetes mellitus. J Clin Endocrinol Metab 103:3144-3154. https://doi.org/10.1210/jc.2018-00728 
  64. Abu-Sbeih H, Ali FS, Alsaadi D, Jennings J, Luo W, Gong Z, Richards DM, Charabaty A, Wang Y (2018) Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study. J Immunother Cancer 6:142. https://doi.org/10.1186/s40425-018-0461-4 
  65. Thomas AS, Ma W, Wang Y (2021) Ustekinumab for refractory colitis associated with immune checkpoint inhibitors. N Engl J Med 384:581-583. https://doi.org/10.1056/NEJMc2031717 
  66. Yousef RB, Angela S, Donna L, Meghan JM, Alexandra C, Jonathan C, Marina K, Hui Z, Jennifer B, Joseph M, Mari M-K, Michael D (2020) Immune checkpoint inhibitor-associated celiac disease. J Immunother Cancer 8:e000958. https://doi.org/10.1136/jitc-2020-000958 
  67. Baldo BA (2016) Monoclonal antibodies approved for cancer therapy. In: Safety of biologics therapy. pp 57-140. https://doi.org/10.1007/978-3-319-30472-4_3 
  68. Marshall MJE, Stopforth RJ, Cragg MS (2017) Therapeutic antibodies: What have we learnt from targeting CD20 and where are we going? Front Immunol 8:1245. https://doi.org/10.3389/fmmu.2017.01245 
  69. Freeman CL, Sehn LH (2018) A tale of two antibodies: obinutuzumab versus rituximab. Br J Haematol 182:29-45. https://doi.org/10.1111/bjh.15232 
  70. Ghrenassia E, Mariotte E, Azoulay E (2018) Rituximab-related severe toxicity. In: Annual update in intensive care and emergency medicine 2018. Springer, Cham, pp 579-596. https://doi.org/10.1007/978-3-319-73670-9_43 
  71. Lang DS, Keefe DM, Schultz T, Pearson A (2013) Predictors of acute adverse events from rapid rituximab infusion. Support Care Cancer 21:2315-2320. https://doi.org/10.1007/s00520-013-1788-5 
  72. Freeman CL, Morschhauser F, Sehn L, Dixon M, Houghton R, Lamy T, Fingerle-Rowson G, Wassner-Fritsch E, Gribben JG, Hallek M, Salles G, Cartron G (2015) Cytokine release in patients with CLL treated with obinutuzumab and possible relationship with infusion-related reactions. Blood 126:2646-2649. https://doi.org/10.1182/blood-2015-09-670802 
  73. Pei SN, Ma MC, Wang MC, Kuo CY, Rau KM, Su CY, Chen CH (2012) Analysis of hepatitis B surface antibody titers in B cell lymphoma patients after rituximab therapy. Ann Hematol 91:1007-1012. https://doi.org/10.1007/s00277-012-1405-6 
  74. Barone M, Notarnicola A, Lopalco G, Viggiani MT, Sebastiani F, Covelli M, Iannone F, Avolio AW, Di Leo A, Cantarini L, Lapadula G (2015) Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection. Hepatology 62:40-46. https://doi.org/10.1002/hep.27716 
  75. Varisco V, Vigano M, Batticciotto A, Lampertico P, Marchesoni A, Gibertini P, Pellerito R, Rovera G, Caporali R, Todoerti M, Covelli M, Notarnicola A, Atzeni F, Sarzi-Puttini P (2016) Low risk of hepatitis B virus reactivation in HBsAg-negative/Anti-HBc-positive carriers receiving rituximab for rheumatoid arthritis: a retrospective multicenter Italian study. J Rheumatol 43:869-874. https://doi.org/10.3899/jrheum.151105 
  76. Drossler L, Lehmann C, Topelt K, Nierhoff D, Vehreschild JJ, Rybniker J, Hallek M, Fischer J, Stormberg V, Fatkenheuer G (2019) HBsAg-negative/anti-HBc-positive patients treated with rituximab: prophylaxis or monitoring to prevent hepatitis B reactivation? Infection 47:293-300. https://doi.org/10.1007/s15010-019-01271-z 
  77. Marzo B, Vidal-Jordana A, Castillo J, Robles-Sanchez M-A, Otero-Romero S, Tintore M, Montalban X, Buti M, Riveiro-Barciela M (2024) Hepatitis B reactivation is a rare event among patients with resolved infection undergoing anti-CD20 antibodies in monotherapy without antiviral prophylaxis: results from the HEBEM study. J Neurol 271:134-140. https://doi.org/10.1007/s00415-023-11973-y 
  78. Palazzo E, Yahia SA (2012) Progressive multifocal leukoencephalopathy in autoimmune diseases. Joint Bone Spine 79:351-355. https://doi.org/10.1016/j.jbspin.2011.11.002 
  79. Van Der Weyden C, Dickinson M, Whisstock J, Prince HM (2019) Brentuximab vedotin in T-cell lymphoma. Expert Rev Hematol 12:5-19. https://doi.org/10.1080/17474086.2019.1558399 
  80. Prince HM, Hutchings M, Domingo-Domenech E, Eichenauer DA, Advani R (2023) Anti-CD30 antibody-drug conjugate therapy in lymphoma: current knowledge, remaining controversies, and future perspectives. Ann Hematol 102:13-29. https://doi.org/10.1007/s00277-022-05054-9 
  81. Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P, Zinzani PL, Wolter P, Sanches JA, Ortiz-Romero PL, Akilov OE, Geskin L, Trotman J, Taylor K, Dalle S, Weichenthal M, Walewski J, Fisher D, Dreno B, Stadler R, Feldman T, Kuzel TM, Wang Y, Palanca-Wessels MC, Zagadailov E, Trepicchio WL, Zhang W, Lin HM, Liu Y, Huebner D, Little M, Whittaker S, Duvic M (2017) Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet 390:555-566. https://doi.org/10.1016/s0140-6736(17)31266-7 
  82. Mariotto S, Ferrari S, Sorio M, Benedetti F, Tridente G, Cavallaro T, Gajofatto A, Monaco S (2015) Brentuximab vedotin: axonal microtubule's Apollyon. Blood Cancer J 5:e343. https://doi.org/10.1038/bcj.2015.72 
  83. Velasco R, Domingo-Domenech E, Sureda A (2021) Brentuximab-induced peripheral neurotoxicity: a multidisciplinary approach to manage an emerging challenge in hodgkin lymphoma therapy. Cancers (Basel) 13:6125. https://doi.org/10.3390/cancers13236125 
  84. Gandhi MD, Evens AM, Fenske TS, Hamlin P, Coifer B, Engert A, Moskowitz AJ, Ghosh N, Petrich AM, Lomasney J, Chadburn A, Wood GS, Salva K, Nardone B, Triflio SM, Raisch DW, West DP, Gordon LI, Winter JN (2014) Pancreatitis in patients treated with brentuximab vedotin: a previously unrecognized serious adverse event. Blood 123:2895-2897. https://doi.org/10.1182/blood-2014-03-561878 
  85. Truszkowska E, Andrzejewska M, Szymanska C, Wziatek A, Derwich K (2022) Case report: brentuximab vedotin associated acute pancreatitis in a pediatric hodgkin lymphoma patient: case report and literature review. Pathol Oncol Res 28:1610445. https://doi.org/10.3389/pore.2022.1610445 
  86. Chen C-C, Yeh S-P (2017) Fatal pancreatitis occurred in a patient with refractory CD30+ anaplastic large cell lymphoma after brentuximab vedotin treatment. J Canc Res Pr 4:35-37. https://doi.org/10.1016/j.jcrpr.2016.09.002 
  87. Carson KR, Newsome SD, Kim EJ, Wagner-Johnston ND, von Geldern G, Moskowitz CH, Moskowitz AJ, Rook AH, Jalan P, Loren AW, Landsburg D, Coyne T, Tsai D, Raisch DW, Norris LB, Bookstaver PB, Sartor O, Bennett CL (2014) Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project. Cancer 120:2464-2471. https://doi.org/10.1002/cncr.28712 
  88. Burt R, Warcel D, Fielding AK (2019) Blinatumomab, a bispecific B-cell and T-cell engaging antibody, in the treatment of B-cell malignancies. Hum Vaccin Immunother 15:594-602. https://doi.org/10.1080/21645515.2018.1540828 
  89. Turtle CJ, Hanaf L-A, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG (2016) CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Investig 126:2123-2138. https://doi.org/10.1172/JCI85309 
  90. Conde-Royo D, Juarez-Salcedo LM, Dalia S (2020) Management of adverse effects of new monoclonal antibody treatments in acute lymphoblastic leukemia. Drugs. Context 9:2020-7-2. https://doi.org/10.7573/dic.2020-7-2 
  91. Klinger M, Zugmaier G, Nagele V, Goebeler M-E, Brandl C, Stelljes M, Lassmann H, von Stackelberg A, Bargou RC, Kufer P (2020) Adhesion of T cells to endothelial cells facilitates blinatumomab-associated neurologic adverse events. Cancer Res 80:91-101. https://doi.org/10.1158/0008-5472.Can-19-1131 
  92. Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foa R, Bassan R, Arslan O, Sanz MA, Bergeron J, Demirkan F, Lech-Maranda E, Rambaldi A, Thomas X, Horst HA, Bruggemann M, Klapper W, Wood BL, Fleishman A, Nagorsen D, Holland C, Zimmerman Z, Topp MS (2017) Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376:836-847. https://doi.org/10.1056/NEJMoa1609783 
  93. Mieczkowski CA (2023) The evolution of commercial antibody formulations. J Pharm Sci 112:1801-1810. https://doi.org/10.1016/j.xphs.2023.03.026