Molecular Medicine

, Volume 19, Issue 1, pp 99–108 | Cite as

Anti-CD38 Antibody Therapy: Windows of Opportunity Yielded by the Functional Characteristics of the Target Molecule

  • Antonella Chillemi
  • Gianluca Zaccarello
  • Valeria Quarona
  • Manuela Ferracin
  • Chiara Ghimenti
  • Massimo Massaia
  • Alberto L. Horenstein
  • Fabio Malavasi
Review Article


In vivo use of monoclonal antibodies (mAbs) has become a mainstay of routine clinical practice in the treatment of various human diseases. A number of molecules can serve as targets, according to the condition being treated. Now entering human clinical trials, CD38 molecule is a particularly attractive target because of its peculiar pattern of expression and its twin role as receptor and ectoenzyme. This review provides a range of analytical perspectives on the current progress in and challenges to anti-CD38 mAb therapy. We present a synopsis of the evidence available on CD38, particularly in myeloma and chronic lymphocytic leukemia (CLL). Our aim is to make the data from basic science helpful and accessible to a diverse clinical audience and, at the same time, to improve its potential for in vivo use. The topics covered include tissue distribution and signal implementation by mAb ligation and the possibility of increasing cell density on target cells by exploiting information about the molecule’s regulation in combination with drugs approved for in vivo use. Also analyzed is the behavior of CD38 as an enzyme: CD38 is a component of a pathway leading to the production of adenosine in the tumor microenvironment, thus inducing local anergy. Consequently, not only might CD38 be a prime target for mAb-mediated therapy, but its functional block may contribute to general improvement in cancer immunotherapy and outcomes.



This work was supported by grants from PRIN (Ministry of Education, University, and Research), from FIRB (Fondo per gli Investimenti della Ricerca di Base), from “ex-60%” Program (University of Torino) and from AIRC (Ig 13119 and partly from AIRC 5×1000). Antonella Chillemi and Valeria Quarona are students of the Ph.D. Program in Biomedical Sciences and Oncology at the University of Torino, Torino, Italy. Ada Funaro and Erika Ortolan provided expert assistance in the experiments of internalization and confocal analysis. The contributions of Silvia Deaglio, who provided samples of CLL patients, and Salvatore Oliviero, who contributed a preliminary analysis of the methylation of selected areas of the CD38 promoter, are gratefully acknowledged. Andrea Zito provided useful technical assistance, while Enrico Brunetti extensively reviewed the manuscript. The Fondazione Ricerca Medicina Sperimentale (FIRMS) assisted and supported this research project.


  1. 1.
    Maecker HT, McCoy JP, Nussenblatt R. (2012) Standardizing immunophenotyping for the Human Immunology Project. Nat. Rev. Immunol. 12:191–200.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Alessio M, et al. (1990) CD38 molecule: structural and biochemical analysis on human T lymphocytes, thymocytes, and plasma cells. J. Immunol. 145:878–84.PubMedGoogle Scholar
  3. 3.
    Mallone R, et al. (1998) Characterization of a CD38-like 78-kilodalton soluble protein released from B cell lines derived from patients with X-linked agammaglobulinemia. J. Clin. Invest. 101:2821–30.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Hara-Yokoyama M, et al. (2012) Tetrameric interaction of the ectoenzyme CD38 on the cell surface enables its catalytic and raft-association activities. Structure. 20:1585–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhao YJ, Lam CM, Lee HC. (2012) The membrane-bound enzyme CD38 exists in two opposing orientations. Sci. Signal. 5:ra67.CrossRefPubMedGoogle Scholar
  6. 6.
    Funaro A, et al. (1990) Involvement of the multi-lineage CD38 molecule in a unique pathway of cell activation and proliferation. J. Immunol. 145:2390–6.PubMedGoogle Scholar
  7. 7.
    Terhorst C, et al. (1981) Biochemical studies of the human thymocyte cell-surface antigens T6, T9 and T10. Cell. 23:771–80.CrossRefPubMedGoogle Scholar
  8. 8.
    Fedele G, et al. (2004) CD38 is expressed on human mature monocyte-derived dendritic cells and is functionally involved in CD83 expression and IL-12 induction. Eur. J. Immunol. 34:1342–50.CrossRefPubMedGoogle Scholar
  9. 9.
    Buggins AG, et al. (2010) Interaction with vascular endothelium enhances survival in primary chronic lymphocytic leukemia cells via NF-kappaB activation and de novo gene transcription. Cancer Res. 70:7523–33.CrossRefPubMedGoogle Scholar
  10. 10.
    Ausiello CM, Urbani F, la Sala A, Funaro A, Malavasi F. (1995) CD38 ligation induces discrete cytokine mRNA expression in human cultured lymphocytes. Eur. J. Immunol. 25:1477–80.CrossRefPubMedGoogle Scholar
  11. 11.
    Deaglio S, et al. (1998) Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J. Immunol. 160:395–402.PubMedGoogle Scholar
  12. 12.
    Horenstein AL, Stockinger H, Imhof BA, Malavasi F. (1998) CD38 binding to human myeloid cells is mediated by mouse and human CD31. Biochem. J. 330 (Pt 3):1129–35.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Liu Q, et al. (2005) Crystal structure of human CD38 extracellular domain. Structure. 13:1331–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Malavasi F, et al. (2008) Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol. Rev. 88:841–86.CrossRefPubMedGoogle Scholar
  15. 15.
    Funaro A, et al. (1996) Identification and characterization of an active soluble form of human CD38 in normal and pathological fluids. Int. Immunol. 8:1643–50.Google Scholar
  16. 16.
    Zumaquero E, et al. (2010) Exosomes from human lymphoblastoid B cells express enzymatically active CD38 that is associated with signaling complexes containing CD81, Hsc-70 and Lyn. Exp. Cell. Res. 316:2692–706.CrossRefPubMedGoogle Scholar
  17. 17.
    Damle RN, et al. (1999) Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 94:1840–7.Google Scholar
  18. 18.
    Chiorazzi N. (2012) Implications of new prognostic markers in chronic lymphocytic leukemia. Hematology Am. Soc. Hematol. Educ. Program. 2012:76–87.PubMedGoogle Scholar
  19. 19.
    Malavasi F, et al. (2011) CD38 and chronic lymphocytic leukemia: a decade later. Blood. 118:3470–8.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Funaro A, et al. (1998) CD38 functions are regulated through an internalization step. J. Immunol. 160:2238–47.PubMedGoogle Scholar
  21. 21.
    Dianzani U, Malavasi F. (1995) Lymphocyte adhesion to endothelium. Crit. Rev. Immunol. 15:167–200.CrossRefPubMedGoogle Scholar
  22. 22.
    Newman PJ. (1999) Switched at birth: a new family for PECAM-1. J. Clin. Invest. 103:5–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Deaglio S, et al. (1996) Human CD38 ligand. A 120-KDA protein predominantly expressed on endothelial cells. J. Immunol. 156:727–34.PubMedGoogle Scholar
  24. 24.
    Deaglio S, et al. (2000) CD38/CD31, a receptor/ligand system ruling adhesion and signaling in human leukocytes. Chem. Immunol. 75:99–120.CrossRefPubMedGoogle Scholar
  25. 25.
    Deaglio S, et al. (2007) CD38/CD19: a lipid raft-dependent signaling complex in human B cells. Blood. 109:5390–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Hu H, Li S, Liu J, Ni B. (2012) MicroRNA-193b modulates proliferation, migration, and invasion of non-small cell lung cancer cells. Acta Biochim. Biophys. Sin. (Shanghai). 44:424–30.CrossRefGoogle Scholar
  27. 27.
    Chen J, et al. (2010) MicroRNA-193b represses cell proliferation and regulates cyclin D1 in melanoma. Am. J. Pathol. 176:2520–9.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rauhala HE, et al. (2010) miR-193b is an epigenetically regulated putative tumor suppressor in prostate cancer. Int. J. Cancer. 127:1363–72.CrossRefPubMedGoogle Scholar
  29. 29.
    Li XF, Yan PJ, Shao ZM. (2009) Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer. Oncogene. 28:3937–48.CrossRefPubMedGoogle Scholar
  30. 30.
    Xu C, et al. (2010) MicroRNA-193b regulates proliferation, migration and invasion in human hepatocellular carcinoma cells. Eur. J. Cancer. 46:2828–36.CrossRefPubMedGoogle Scholar
  31. 31.
    Gao XN, et al. (2011) MicroRNA-193b regulates c-Kit proto-oncogene and represses cell proliferation in acute myeloid leukemia. Leuk. Res. 35:1226–32.CrossRefPubMedGoogle Scholar
  32. 32.
    Unno K, Zhou Y, Zimmerman T, Platanias LC, Wickrema A. (2009) Identification of a novel microRNA cluster miR-193b-365 in multiple myeloma. Leuk. Lymphoma. 50:1865–71.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Cirera-Salinas D, et al. (2012) Mir-33 regulates cell proliferation and cell cycle progression. Cell Cycle. 11:922–33.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Najafi-Shoushtari SH, et al. (2010) MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 328:1566–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Wu ZS, et al. (2011) miR-340 inhibition of breast cancer cell migration and invasion through targeting of oncoprotein c-Met. Cancer. 117:2842–52.CrossRefPubMedGoogle Scholar
  36. 36.
    Deaglio S, et al. (2010) CD38/CD31 interactions activate genetic pathways leading to proliferation and migration in chronic lymphocytic leukemia cells. Mol. Med. 16:87–91.CrossRefPubMedGoogle Scholar
  37. 37.
    Ferrero E, Saccucci F, Malavasi F. (1999) The human CD38 gene: polymorphism, CpG island, and linkage to the CD157 (BST-1) gene. Immunogenetics. 49:597–604.CrossRefPubMedGoogle Scholar
  38. 38.
    Drach J, et al. (1994) Retinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha. Cancer Res. 54:1746–52.PubMedGoogle Scholar
  39. 39.
    Aggarwal S, et al. (2006) Nonclassical action of retinoic acid on the activation of the cAMP response element-binding protein in normal human bronchial epithelial cells. Mol. Biol. Cell. 17:566–75.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Uruno A, et al. (2011) All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells: possible involvement of protein kinase C-delta. J. Leukoc. Biol. 90:235–47.CrossRefPubMedGoogle Scholar
  41. 41.
    Le May N, et al. (2012) Poly (adp-ribose) glycohydrolase regulates retinoic acid receptor-mediated gene expression. Mol. Cell. 48:785–98.CrossRefPubMedGoogle Scholar
  42. 42.
    Howard M, et al. (1993) Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. Science. 262:1056–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Kim H, Jacobson EL, Jacobson MK. (1993) Synthesis and degradation of cyclic ADP-ribose by NAD glycohydrolases. Science. 261:1330–3.CrossRefPubMedGoogle Scholar
  44. 44.
    Zocchi E, Franco L, Guida L, Calder L, De Flora A. (1995) Self-aggregation of purified and membrane-bound erythrocyte CD38 induces extensive decrease of its ADP-ribosyl cyclase activity. FEBS Lett. 359:35–40.CrossRefPubMedGoogle Scholar
  45. 45.
    Takasawa S, et al. (1993) Synthesis and hydrolysis of cyclic ADP-ribose by human leukocyte antigen CD38 and inhibition of the hydrolysis by ATP. J. Biol. Chem. 268:26052–4.PubMedGoogle Scholar
  46. 46.
    Aarhus R, Graeff RM, Dickey DM, Walseth TF, Lee HC. (1995) ADP-ribosyl cyclase and CD38 catalyze the synthesis of a calcium-mobilizing metabolite from NADP. J. Biol. Chem. 270:30327–33.CrossRefPubMedGoogle Scholar
  47. 47.
    Guse AH, et al. (1999) Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature. 398:70–3.CrossRefPubMedGoogle Scholar
  48. 48.
    Morra M, Zubiaur M, Terhorst C, Sancho J, Malavasi F. (1998) CD38 is functionally dependent on the TCR/CD3 complex in human T cells. FASEB J. 12:581–92.CrossRefPubMedGoogle Scholar
  49. 49.
    Takasawa S, Nata K, Yonekura H, Okamoto H. (1993) Cyclic ADP-ribose in insulin secretion from pancreatic beta cells. Science. 259:370–3.CrossRefPubMedGoogle Scholar
  50. 50.
    Malavasi F, et al. (2010) The hidden life of NAD+-consuming ectoenzymes in the endocrine system. J. Mol. Endocrinol. 45:183–91.CrossRefPubMedGoogle Scholar
  51. 51.
    Hubert S, et al. (2010) Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. J. Exp. Med. 207:2561–8.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Chiarugi A, Dolle C, Felici R, Ziegler M. (2012) The NAD metabolome—a key determinant of cancer cell biology. Nat. Rev. Cancer. 12:741–52.CrossRefPubMedGoogle Scholar
  53. 53.
    Katada T, et al. (2000) Enzymic and signal transduction properties of CD38/NADase and PC-1/phosphodiesterase. Chem. Immunol. 75:60–78.CrossRefPubMedGoogle Scholar
  54. 54.
    Goding JW, et al. (1998) Ecto-phosphodiesterase/pyrophosphatase of lymphocytes and non-lymphoid cells: structure and function of the PC-1 family. Immunol. Rev. 161:11–26.CrossRefPubMedGoogle Scholar
  55. 55.
    Serra S, et al. (2011) CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood. 118:6141–52.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Giuliani N, et al. (2012) Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation. Leukemia. 26:1391–401.CrossRefPubMedGoogle Scholar
  57. 57.
    Flemming A. (2012) Deal watch: J&J and Genmab deal to push forward CD38 as a blood cancer target. Nat. Rev. Drug Discov. 11:822.CrossRefPubMedGoogle Scholar
  58. 58.
    Verfaillie CM, Miller JS. (1994) CD34+/CD33− cells reselected from macrophage inflammatory protein 1 alpha+interleukin-3—supplemented “stroma-noncontact” cultures are highly enriched for long-term bone marrow culture initiating cells. Blood. 84:1442–9.PubMedGoogle Scholar
  59. 59.
    Horenstein AL, et al. (2009) CD38 and CD157 ectoenzymes mark cell subsets in the human corneal limbus. Mol. Med. 15:76–84.CrossRefPubMedGoogle Scholar
  60. 60.
    Lane D. (2006) Designer combination therapy for cancer. Nat. Biotechnol. 24:163–4.CrossRefPubMedGoogle Scholar
  61. 61.
    Gennarino VA, et al. (2012) Identification of microRNA-regulated gene networks by expression analysis of target genes. Genome Res. 22:1163–72.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Saborit-Villarroya I, et al. (2011) E2A is a transcriptional regulator of CD38 expression in chronic lymphocytic leukemia. Leukemia. 25:479–88.CrossRefPubMedGoogle Scholar
  63. 63.
    Bahri R, Bollinger A, Bollinger T, Orinska Z, Bulfone-Paus S. (2012) Ectonucleotidase CD38 demarcates regulatory, memory-like CD8+ T cells with IFN-gamma-mediated suppressor activities. PLoS One. 7:e45234.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Zhang B. (2012) CD73 promotes tumor growth and metastasis. Oncoimmunology 1:67–70.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Stagg J. (2012) The double-edge sword effect of anti-CD73 cancer therapy. Oncoimmunology 1:217–8.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Pegoraro L, et al. (1989) The human myeloma cell line LP-1: a versatile model in which to study early plasma-cell differentiation and c-myc activation. Blood. 73:1020–7.PubMedGoogle Scholar
  67. 67.
    Quarona V, et al. (2013) CD38 and CD157: a long journey from activation markers to multifunctional molecules. Cytometry B Clin. Cytom. 2013, Apr 10. [Epub ahead of print].Google Scholar
  68. 68.
    Scatolini M, et al. (2010) Altered molecular pathways in melanocytic lesions. Int. J. Cancer. 126:1869–1881.CrossRefPubMedGoogle Scholar
  69. 69.
    Ferracin M, et al. (2011) MicroRNA profiling for the identification of cancers with unknown primary tissue-of-origin. J. Pathol. 225:43–53.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2013

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  • Antonella Chillemi
    • 1
  • Gianluca Zaccarello
    • 1
  • Valeria Quarona
    • 1
  • Manuela Ferracin
    • 3
  • Chiara Ghimenti
    • 4
  • Massimo Massaia
    • 2
    • 5
  • Alberto L. Horenstein
    • 1
    • 2
  • Fabio Malavasi
    • 1
    • 2
    • 6
  1. 1.Laboratory of Immunogenetics, Department of Medical SciencesUniversity of Torino Medical SchoolTorinoItaly
  2. 2.Research Center on Experimental Medicine (CeRMS)University of Torino Medical SchoolTorinoItaly
  3. 3.Laboratory for Technologies of Advanced Therapies (LTTA) and Department of Morphology, Surgery and Experimental MedicineUniversity of FerraraFerraraItaly
  4. 4.Cancer Genomics LaboratoryEdo ed Elvo Tempia FoundationBiellaItaly
  5. 5.Laboratory of Hematological Oncology, Department of Molecular Biotechnology and Health SciencesUniversity of TorinoTorinoItaly
  6. 6.Transplantation Immunology ServiceCittà della Salute e della Scienza HospitalTorinoItaly

Personalised recommendations