Anti-CD38 Antibody Therapy: Windows of Opportunity Yielded by the Functional Characteristics of the Target Molecule
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Anti-CD38 Antibody Therapy: Windows of Opportunity Yielded by the Functional Characteristics of the Target Molecule Antonella Chillemi,1 Gianluca Zaccarello,1 Valeria Quarona,1 Manuela Ferracin,3 Chiara Ghimenti,4 Massimo Massaia,2,5 Alberto L Horenstein,1,2 and Fabio Malavasi1,2,6 1Laboratory of Immunogenetics, Department of Medical Sciences and 2Research Center on Experimental Medicine (CeRMS), University of Torino Medical School, Torino, Italy; 3Laboratory for Technologies of Advanced Therapies (LTTA) and Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 4Cancer Genomics Laboratory, Edo ed Elvo Tempia Foundation, Biella, Italy; 5Laboratory of Hematological Oncology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; and 6Transplantation Immunology Service, Città della Salute e della Scienza Hospital, Torino, Italy 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 re- ceptor 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. Online address: http://www.molmed.org doi: 10.2119/molmed.2013.00009 INTRODUCTION view provides a range of analytical per- loma and chronic lymphocytic leukemia The vast majority of today’s therapeu- spectives on the current progress in and (CLL), where CD38 exerts diagnostic and tic strategies for cancer treatment involve challenges to anti-CD38 mAb therapy. It prognostic roles. Despite recent advances the targeting of surface molecules ex- also recapitulates the available evidence in treatment options, both diseases re- pressed by solid tumors or leukemic cells. concerning CD38 expression and dynam- main incurable. One such molecule is human CD38, ics on cell membranes, as well as the sig- Special attention is given to evaluating whose essential role in normal cells and nals implemented upon mAb ligation, in the possibility of increasing surface ex- in tumor growth has made it useful in the light of the molecule’s dual function as pression of CD38 (crucial in the case of design of effective monoclonal antibody receptor and ectoenzyme. CLL), with information about its regula- (mAb)-mediated therapeutic options for The disease models chosen as candi- tion and on the availability of new drugs several forms of human cancer. This re- dates for anti-CD38 therapy were mye- already approved for in vivo use serving as a basis for potential transferability. Human CD38 is a surface molecule Address correspondence to Fabio Malavasi, Laboratory of Immunogenetics, Department originally defined as a T-cell activation of Medical Sciences, University of Torino Medical School, Via Santena 19, 10126 TORINO, molecule, although it is no longer consid- Italy. Phone: +39-011-696-1734; Fax: +39-011-696-6155; E-mail: [email protected]. ered to be strictly dependent on cell line- Submitted January 23, 2013; Accepted for publication April 16, 2013; Epub age or activation. Mature resting cells (www.molmed.org) ahead of print April 17, 2013. and lymphocytes, however, do express limited to nil amounts of surface CD38. Detailed analysis of the structure and functions of CD38 in humans is aimed at MOL MED 19:99-108, 2013 | CHILLEMI ET AL. | 99 CD38 AS A TARGET IN DESIGNING A mAb-MEDIATED THERAPY Table 1. Phenotype of human myeloma cell lines. giving clinical scientists an access to background knowledge, usually found Cell line CD38a CD56a CD138a PC-1/CD203aa OTRb only in the context of a basic science (1). c DL06 + – +/– – + The intent is that this set of data may im- LP-1d ++ – + – + prove the transferability of mAb- JJN3e +– + – ++ mediated therapeutic protocols in clinics. U266e – – + – +/– OPM-2e ++ + +/– + CD38 AS A SURFACE MOLECULE IM9e +/– – ± – + The protein encoded by CD38 is a NCI-H929e ++ +/– +/– – + single chain type II transmembrane mol- ++, High intensity; +, medium intensity; –, no staining; +/–, low to nil staining. ecule displaying a canonical molecular aCD38, CD56 and CD138 were selected as accepted markers of myeloma transformation. weight of ≈45 kDa; however, the func- b PC-1/CD203a and OTR (oxytocin receptor) were included as original observations of the tional molecule appears as a dimer or a lab (A Chillemi, G Zaccarello, V Quarona, Mirca Lazzaretti, Eugenia Martella, Nicola Giuliani, multimer (2–4) or is expressed on the cy- Riccardo Ferracini, Vito Pistoia, AL Horenstein and F Malavasi, unpublished data) (67). toplasmic side of the membrane (5). One cDL06 was stabilized from cells obtained from a pleural effusion of an aggressive, therapy- function initially attributed to CD38 is refractory plasma cell leukemia patient. These cells maintain a high secretion in vitro of the the regulation of activation and prolifera- monoclonal protein seen in patient blood (namely, IgAλ). tion of human T lymphocytes (6,7). CD38 dLP-1 cell line was produced in collaboration with the lab of L Pegoraro (University of ligation by agonistic mAbs induces rapid Torino) (66). e Ca2+ fluxes and triggers the phosphoryla- JJN3, U266, OPM-2, IM9 and NCI-H929 cell lines were obtained from ATCC (Manassas, VA, USA). tion of a cascade of intracellular sub- strates, leading to activation of the levels of the molecule. CD38 also is different environments. Immunopheno- NF-κB complex (8,9). Protracted effects found in soluble form in normal and typic and genetic analyses of several neo- include initiation of genetic programs pathological fluids (15) and in exosomes, plastic clones led to the identification of causing cytokine secretion and prolifera- which are membrane vesicles secreted by a number of molecular markers, some of tion of T lymphocytes (10). CD31 (also B cells and likely a component of an in- which have been adopted in clinics to known as platelet endothelial cell adhe- tercellular communication network (16). predict disease outcome. Cell surface sion molecule-1 [PECAM-1]) is a CD38 Clinical routine confirms that the cells CD38 is one of these. Association be- nonsubstrate ligand that can start the sig- of the myeloma clone do express CD38 tween CD38 expression by CLL cells and naling cascade and that recapitulates the in the overwhelming majority of pa- a more aggressive clinical behavior was biological events observed in vitro using tients, although at varying surface densi- first reported in 1999 (17) and later con- surrogate agonistic mAbs (11,12). ties. A similar analysis has been con- firmed by several studies (18). It is now The transition from monomers to ducted on a vast panel of human cell generally accepted that CD38+ patients dimers (or multimers) modulates the lines derived from myeloma and plasma will have a shorter progression-free in- functions of the molecule (13). CD38 dis- cell leukemia patients. These cell lines terval, require earlier and more frequent plays preferential localizations in mi- are usually used for in vitro and animal treatments, and ultimately die sooner. It crodomains of the plasma membrane, in in vivo tests to confirm the validity of the remains undeniable that CD38 marks the close contact with the BCR complex and working hypothesis (Table 1). majority of clinically more aggressive with other molecules regulating signal- leukemic clones requiring treatment (19). ing, homing and adhesion (14). CD38 in Chronic Lymphocytic Leukemia Interaction between Specific mAbs CD38 in Myeloma CLL is a disease characterized by a dy- and Surface CD38 The first question regarding use of namic balance between cells circulating The events taking place between a CD38 as a model target concerns its dis- in the blood and cells located in permis- mAb and its target are of key relevance tribution in normal and pathological sive niches in lymphoid organs. The for- for in vivo use. The results obtained in samples. Within the B-cell compartment, mer are primarily mature-appearing normal and tumoral cells show that CD38 CD38 is expressed at high levels only by small lymphocytes resistant to apoptosis, endocytosis is a reproducible event which committed progenitor bone marrow whereas the latter are composed of cells follows CD38 ligation with specific mAbs (early BM cells are CD38–) and by B lym- that undergo either proliferation or apo- and involves significant fractions of the phocytes in germinal centers, by termi- ptosis according to the microenviron- entire amount of surface CD38 molecules. nally differentiated plasma cells and in ment. The heterogeneous clinical out- It is independent of any signal transduc- activated tonsils. Instead, mature virgin come of CLL patients is determined, at tion implemented by mAb ligation, as and memory B lymphocytes express low least in part, by signals coming from the can be inferred from the observations that 100 | CHILLEMI ET AL. | MOL MED 19:99-108, 2013 REVIEW ARTICLE flop mechanism of membrane positioning has been proposed recently, with a type III form of CD38 displaying its catalytic site in the cytoplasm (5).