{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:17:30Z","timestamp":1790716650054,"version":"4.1.0"},"reference-count":46,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,1,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Inotuzumab ozogamicin (InO) is a recently US Food and Drug Administration\u2013approved antibody\u2013drug conjugate for the treatment of relapsed\/refractory B-cell acute lymphoblastic leukemia (ALL). InO consists of a CD22-targeting immunoglobulin G4 humanized monoclonal antibody conjugated to calicheamicin. Although initially developed for the treatment of non-Hodgkin lymphoma (NHL) because of activity in preclinical models and high response rates in indolent lymphomas, a phase 3 trial was negative and further development focused on CD22+ ALL. Although results in NHL were disappointing, parallel testing in early-phase trials of CD22+ ALL demonstrated feasibility and efficacy. Subsequently, the randomized phase 3 Study Of Inotuzumab Ozogamicin Versus Investigator's Choice Of Chemotherapy In Patients With Relapsed Or Refractory Acute Lymphoblastic Leukemia trial showed that InO was superior to standard of care regimens with a significantly improved complete remission (CR) rate in patients with relapsed\/refractory disease (80.7% vs 29.4%, P &amp;lt; .001). Patients achieving CR with InO also had a significantly higher rate of undetectable minimal residual disease compared with chemotherapy (78.4% vs 28.1%, P &amp;lt; .001). InO-specific side effects, including veno-occlusive disease, have been an ongoing area of concern, and consensus guidelines for minimizing toxicities are now available. Ongoing trials are investigating the combination of InO with other agents in the relapse setting and the addition of InO to frontline therapy. This review details the preclinical and clinical development of InO, focusing on how best to use it and future directions for further development.<\/jats:p>","DOI":"10.1182\/bloodadvances.2018026211","type":"journal-article","created":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T21:45:47Z","timestamp":1546983947000},"page":"96-104","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":56,"title":["Inotuzumab: from preclinical development to success in B-cell acute lymphoblastic leukemia"],"prefix":"10.1182","volume":"3","author":[{"given":"Joseph","family":"Wynne","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Chicago Medicine, Chicago, IL; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Wright","sequence":"additional","affiliation":[{"name":"Drug Safety Research and Development, Pfizer, Groton, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Stock","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Chicago Medicine, Chicago, IL; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2019,1,8]]},"reference":[{"issue":"2","key":"2020021108320945500_B1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3322\/caac.21219","article-title":"Childhood and adolescent cancer statistics, 2014","volume":"64","author":"Ward","year":"2014","journal-title":"CA Cancer J Clin"},{"issue":"1","key":"2020021108320945500_B2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1182\/blood-2011-04-347872","article-title":"Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007","volume":"119","author":"Dores","year":"2012","journal-title":"Blood"},{"issue":"6","key":"2020021108320945500_B3","doi-asserted-by":"crossref","first-page":"e577","DOI":"10.1038\/bcj.2017.53","article-title":"Acute lymphoblastic leukemia: a comprehensive review and 2017 update","volume":"7","author":"Terwilliger","year":"2017","journal-title":"Blood Cancer J"},{"key":"2020021108320945500_B4","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1182\/asheducation-2017.1.28","article-title":"Progress in adult ALL: incorporation of new agents to frontline treatment","volume":"2017","author":"Leonard","year":"2017","journal-title":"Hematology Am Soc Hematol Educ Program"},{"issue":"2 Pt A","key":"2020021108320945500_B5","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.molimm.2014.09.014","article-title":"Preclinical and clinical development of inotuzumab-ozogamicin in hematological malignancies","volume":"67","author":"Shor","year":"2015","journal-title":"Mol Immunol"},{"issue":"1","key":"2020021108320945500_B6","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/j.1600-065X.2009.00801.x","article-title":"CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions","volume":"230","author":"Nitschke","year":"2009","journal-title":"Immunol Rev"},{"issue":"12","key":"2020021108320945500_B7","doi-asserted-by":"crossref","first-page":"4470","DOI":"10.4049\/jimmunol.136.12.4470","article-title":"HD39 (B3), a B lineage-restricted antigen whose cell surface expression is limited to resting and activated human B lymphocytes","volume":"136","author":"D\u00f6rken","year":"1986","journal-title":"J Immunol"},{"issue":"26","key":"2020021108320945500_B8","doi-asserted-by":"crossref","first-page":"4010","DOI":"10.1182\/blood-2014-08-596403","article-title":"Monoclonal antibodies in acute lymphoblastic leukemia","volume":"125","author":"Jabbour","year":"2015","journal-title":"Blood"},{"issue":"1","key":"2020021108320945500_B9","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1080\/08820130500496878","article-title":"A quantitative exploration of surface antigen expression in common B-cell malignancies using flow cytometry","volume":"35","author":"Olejniczak","year":"2006","journal-title":"Immunol Invest"},{"issue":"4856","key":"2020021108320945500_B10","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1126\/science.3240341","article-title":"Calicheamicin gamma 1I: an antitumor antibiotic that cleaves double-stranded DNA site specifically","volume":"240","author":"Zein","year":"1988","journal-title":"Science"},{"issue":"17","key":"2020021108320945500_B11","doi-asserted-by":"crossref","first-page":"7464","DOI":"10.1073\/pnas.88.17.7464","article-title":"The carbohydrate domain of calicheamicin gamma I1 determines its sequence specificity for DNA cleavage","volume":"88","author":"Drak","year":"1991","journal-title":"Proc Natl Acad Sci USA"},{"issue":"20","key":"2020021108320945500_B12","doi-asserted-by":"crossref","first-page":"9203","DOI":"10.1073\/pnas.91.20.9203","article-title":"Specific inhibition of formation of transcription complexes by a calicheamicin oligosaccharide: a paradigm for the development of transcriptional antagonists","volume":"91","author":"Ho","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"2020021108320945500_B13","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1021\/bc010021y","article-title":"Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia","volume":"13","author":"Hamann","year":"2002","journal-title":"Bioconjug Chem"},{"issue":"6","key":"2020021108320945500_B14","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s40262-017-0619-0","article-title":"Antibody-drug conjugates: pharmacokinetic\/pharmacodynamic modeling, preclinical characterization, clinical studies, and lessons learned","volume":"57","author":"Hedrich","year":"2018","journal-title":"Clin Pharmacokinet"},{"issue":"1","key":"2020021108320945500_B15","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00262-004-0572-2","article-title":"Antibody-targeted chemotherapy of B-cell lymphoma using calicheamicin conjugated to murine or humanized antibody against CD22","volume":"54","author":"DiJoseph","year":"2005","journal-title":"Cancer Immunol Immunother"},{"issue":"5","key":"2020021108320945500_B16","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1182\/blood-2003-07-2466","article-title":"Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies","volume":"103","author":"DiJoseph","year":"2004","journal-title":"Blood"},{"issue":"24","key":"2020021108320945500_B17","doi-asserted-by":"crossref","first-page":"8620","DOI":"10.1158\/1078-0432.CCR-04-1134","article-title":"Potent and specific antitumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma","volume":"10","author":"DiJoseph","year":"2004","journal-title":"Clin Cancer Res"},{"issue":"1","key":"2020021108320945500_B18","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1158\/1078-0432.CCR-05-1905","article-title":"Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against non-Hodgkin\u2019s B-cell lymphoma","volume":"12","author":"DiJoseph","year":"2006","journal-title":"Clin Cancer Res"},{"issue":"4","key":"2020021108320945500_B19","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s00280-010-1342-9","article-title":"Preclinical anti-tumor activity of antibody-targeted chemotherapy with CMC-544 (inotuzumab ozogamicin), a CD22-specific immunoconjugate of calicheamicin, compared with non-targeted combination chemotherapy with CVP or CHOP","volume":"67","author":"DiJoseph","year":"2011","journal-title":"Cancer Chemother Pharmacol"},{"issue":"11","key":"2020021108320945500_B20","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1038\/sj.leu.2404866","article-title":"Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia","volume":"21","author":"Dijoseph","year":"2007","journal-title":"Leukemia"},{"issue":"2","key":"2020021108320945500_B21","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/sj.leu.2402749","article-title":"Gemtuzumab ozogamicin in pediatric CD33-positive acute lymphoblastic leukemia: first clinical experiences and relation with cellular sensitivity to single agent calicheamicin","volume":"17","author":"Zwaan","year":"2003","journal-title":"Leukemia"},{"issue":"12","key":"2020021108320945500_B22","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1200\/JCO.2009.25.1900","article-title":"Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin\u2019s lymphoma: results of a phase I study","volume":"28","author":"Advani","year":"2010","journal-title":"J Clin Oncol"},{"issue":"8","key":"2020021108320945500_B23","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1111\/j.1349-7006.2010.01601.x","article-title":"Phase I study of inotuzumab ozogamicin (CMC-544) in Japanese patients with follicular lymphoma pretreated with rituximab-based therapy","volume":"101","author":"Ogura","year":"2010","journal-title":"Cancer Sci"},{"issue":"4","key":"2020021108320945500_B24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/bjh.14094","article-title":"A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy","volume":"174","author":"Goy","year":"2016","journal-title":"Br J Haematol"},{"issue":"5","key":"2020021108320945500_B25","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1200\/JCO.2012.42.7211","article-title":"Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I\/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab","volume":"31","author":"Fayad","year":"2013","journal-title":"J Clin Oncol"},{"issue":"5","key":"2020021108320945500_B26","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/j.1349-7006.2012.02241.x","article-title":"Phase I study of anti-CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed\/refractory B-cell non-Hodgkin lymphoma","volume":"103","author":"Ogura","year":"2012","journal-title":"Cancer Sci"},{"issue":"4","key":"2020021108320945500_B27","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1111\/bjh.14820","article-title":"Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed\/refractory aggressive B-cell non-Hodgkin lymphoma","volume":"182","author":"Dang","year":"2018","journal-title":"Br J Haematol"},{"issue":"4","key":"2020021108320945500_B28","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S1470-2045(11)70386-2","article-title":"Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study","volume":"13","author":"Kantarjian","year":"2012","journal-title":"Lancet Oncol"},{"issue":"15","key":"2020021108320945500_B29","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1002\/cncr.28136","article-title":"Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia","volume":"119","author":"Kantarjian","year":"2013","journal-title":"Cancer"},{"issue":"15","key":"2020021108320945500_B30","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1182\/bloodadvances.2016001925","article-title":"Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1\/2 study","volume":"1","author":"DeAngelo","year":"2017","journal-title":"Blood Adv"},{"issue":"8","key":"2020021108320945500_B31","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1056\/NEJMoa1509277","article-title":"Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia","volume":"375","author":"Kantarjian","year":"2016","journal-title":"N Engl J Med"},{"issue":"8","key":"2020021108320945500_B32","doi-asserted-by":"crossref","first-page":"e387","DOI":"10.1016\/S2352-3026(17)30103-5","article-title":"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","volume":"4","author":"Kantarjian","year":"2017","journal-title":"Lancet Haematol"},{"key":"2020021108320945500_B33","article-title":"Liver complications following treatment of hematologic malignancy with anti-cd22-calicheamicin (inotuzumab ozogamicin) [published online ahead of print 18 August 2018]","author":"McDonald","journal-title":"Hepatology"},{"issue":"4","key":"2020021108320945500_B34","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/s41409-017-0019-y","article-title":"Management of important adverse events associated with inotuzumab ozogamicin: expert panel review","volume":"53","author":"Kebriaei","year":"2018","journal-title":"Bone Marrow Transplant"},{"issue":"5","key":"2020021108320945500_B35","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1208\/s12248-016-9929-7","article-title":"Preclinical to clinical translation of antibody-drug conjugates using PK\/PD modeling: a retrospective analysis of inotuzumab ozogamicin","volume":"18","author":"Betts","year":"2016","journal-title":"AAPS J"},{"issue":"10","key":"2020021108320945500_B36","doi-asserted-by":"crossref","first-page":"4168","DOI":"10.1182\/blood-2006-09-047399","article-title":"CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy","volume":"109","author":"Walter","year":"2007","journal-title":"Blood"},{"issue":"suppl 1","key":"2020021108320945500_B37","first-page":"1272","article-title":"Inotuzumab ozogamicin for relapsed\/refractory acute lymphoblastic leukemia in the global phase 3 INO-VATE trial: efficacy and safety by baseline CD22 expression level","volume":"130","author":"Kantarjian","year":"2017","journal-title":"Blood"},{"issue":"1","key":"2020021108320945500_B38","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nm.4441","article-title":"CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy","volume":"24","author":"Fry","year":"2018","journal-title":"Nat Med"},{"issue":"suppl 1","key":"2020021108320945500_B39","first-page":"272","article-title":"Sequential CD22 targeting impacts CD22 CAR-T cell response","volume":"130","author":"Yates","year":"2018","journal-title":"Blood"},{"issue":"suppl 1","key":"2020021108320945500_B40","first-page":"282","article-title":"Comparison of CD22 expression between baseline, end of treatment, and relapse among patients treated with inotuzumab ozogamicin who responded and subsequently relapsed in two clinical trials","volume":"132","author":"Kantarjian","year":"2018","journal-title":"Blood"},{"issue":"2","key":"2020021108320945500_B41","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1001\/jamaoncol.2017.2380","article-title":"Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini\u2013hyper-CVD for patients with relapsed or refractory philadelphia chromosome\u2013negative acute lymphoblastic leukemia","volume":"4","author":"Jabbour","year":"2018","journal-title":"JAMA Oncol"},{"issue":"2","key":"2020021108320945500_B42","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/S1470-2045(18)30011-1","article-title":"Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study","volume":"19","author":"Kantarjian","year":"2018","journal-title":"Lancet Oncol"},{"issue":"1","key":"2020021108320945500_B43","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s13238-017-0408-4","article-title":"Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins","volume":"9","author":"Liu","year":"2017","journal-title":"Protein Cell"},{"issue":"12","key":"2020021108320945500_B44","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1182\/bloodadvances.2018018093","article-title":"Spontaneous reversion of a lineage switch following an initial blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL","volume":"2","author":"W\u00f6lfl","year":"2018","journal-title":"Blood Adv"},{"issue":"6","key":"2020021108320945500_B45","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.ccell.2017.05.014","article-title":"Paradoxical effects of MLL paralogs in MLL-rearranged leukemia","volume":"31","author":"Thirman","year":"2017","journal-title":"Cancer Cell"},{"issue":"6","key":"2020021108320945500_B46","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.ccell.2017.05.002","article-title":"MLL2, not MLL1, plays a major role in sustaining MLL-rearranged acute myeloid leukemia","volume":"31","author":"Chen","year":"2017","journal-title":"Cancer Cell"}],"container-title":["Blood Advances"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/3\/1\/96\/1630192\/advances026211.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/3\/1\/96\/1630192\/advances026211.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T19:21:45Z","timestamp":1694546505000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article\/3\/1\/96\/11151\/Inotuzumab-from-preclinical-development-to-success"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,8]]},"references-count":46,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,1,8]]}},"URL":"https:\/\/doi.org\/10.1182\/bloodadvances.2018026211","relation":{},"ISSN":["2473-9529","2473-9537"],"issn-type":[{"value":"2473-9529","type":"print"},{"value":"2473-9537","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,8]]}}}