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XmAb-5574 antibody demonstrates superior antibody-dependent cellular cytotoxicity as compared with CD52- and CD20-targeted antibodies in adult acute lymphoblastic leukemia cells

Leukemia volume 26, pages 1720–1722 (2012)Cite this article

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Acute lymphoblastic leukemia (ALL) has an age-adjusted incidence rate of 1.7 per 100 000 men and women per year with 40% of total cases occurring in adults.1 ALL is risk-stratified based upon genetic features and lineage (B cell versus T cell). It is traditionally treated based upon lineage (B versus T) and also in part based upon the cytogenetic or molecular features of the disease. For virtually all types of ALL this treatment includes intensive chemotherapy, sometimes accompanied by specific tyrosine kinase inhibitors (BCR-ABL+ ALL) and/or allogeneic stem cell transplant for ALL patients at highest risk of relapsing. Although these intensive treatment approaches have greatly improved outcome for children with ALL, adults with this diagnosis have a higher frequency of toxicity with therapy and significantly lower frequency of cure. ALL patients who relapse following receipt of intensive chemotherapy and/or allogeneic transplant have an extremely poor prognosis with survival measured in terms of months. Despite these grim statistics few new therapies have come forward that have greatly influenced outcome in this disease. Identifying such therapies represents a high priority.

One form of therapy that has greatly influenced outcome in other forms of B-cell malignancy has been CD20 therapeutic antibodies. Rituximab, a chimeric anti-C20 antibody, has been shown to prolong survival in virtually all more mature B-cell malignancies in which it has been tested. Several recent small studies with CD52 (alemtuzumab) or CD20 (rituximab) -directed therapy have been incorporated as single agents in relapsed patients or into traditional therapy for ALL, and have demonstrated some evidence of efficacy prompting several ongoing larger studies.2, 3, 4, 5 Both CD52 and CD20 are variably expressed on ALL cell blasts at modest copy number making these less ideal for tumor-directed antibody therapy.6, 7, 8 Contrasting with this, CD19 is expressed at a very early pro-B phase of B-cell development and is expressed uniformly on virtually all B-ALL cases. Recently, several CD19 antibodies that are engineered either by directed mutagenesis of the Fc-binding domain (XmAb-5574)9, 10 or by afucosylation,11, 12 thereby enhancing their FcγRIIIa-binding affinity and antibody-dependent cytotoxicity, have been reported. We previously have shown that XmAb-5574 mediates superior antibody-dependent cellular cytotoxicity (ADCC) in vitro against primary CLL cells.10 Given the uniform expression of CD19 on B-ALL cells, we sought to compare this antibody with other CD20 and CD52 antibodies currently under study in this disease. Our data demonstrate that XmAb-5574 mediates robust ADCC and modest direct killing with a cross-linking antibody against primary ALL cells, as compared with all the CD20- and CD52-directed antibodies, making it an ideal candidate for future clinical trials in this disease.

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Acknowledgements

We thank the patients for providing research samples used in this study and members of the CLL Experimental Therapeutics laboratory for critical comments. We are grateful for research support from The Leukemia and Lymphoma Society, P50-CA140158, PO1-CA95426, The Harry Mangurian Foundation, and The D Warren Brown Foundation. XENP-5603 and XmAb-5574 were provided by Xencor, Inc.

Author contributions

SR designed and performed experiments, wrote the first draft of the manuscript, contributed to revisions of the paper, and approved the final submitted version. CC provided input into experimental design, performed experiments, and reviewed and approved the final version of the manuscript. DJ and XM assisted in design of experiments, performed the statistical analysis reported, reviewed and approved the final version of the manuscript. NM and JCB obtained funding to perform the research, designed the experiments, participated in the analysis of the data, reviewed multiple drafts of the manuscript and approved the final version for submission.

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Author notes

  1. N Muthusamy and J C Byrd: These two senior authors contributed equally to this work.

Authors and Affiliations

  1. Integrated Biomedical Science Graduate Program, Columbus, OH, USA

    S Rafiq

  2. Department of Internal Medicine, Division of Hematology, Columbus, OH, USA

    S Rafiq, C Cheney, N Muthusamy & J C Byrd

  3. Center for Biostatistics, Columbus, OH, USA

    X Mo & D Jarjoura

  4. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    J C Byrd

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  1. S Rafiq
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Correspondence to N Muthusamy or J C Byrd.

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Rafiq, S., Cheney, C., Mo, X. et al. XmAb-5574 antibody demonstrates superior antibody-dependent cellular cytotoxicity as compared with CD52- and CD20-targeted antibodies in adult acute lymphoblastic leukemia cells. Leukemia 26, 1720–1722 (2012). https://doi.org/10.1038/leu.2012.40

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