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REVIEW Anti-CD20-Based Therapy of B Cell Lymphoma: State of The Leukemia (2002) 16, 2004–2015 2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu REVIEW Anti-CD20-based therapy of B cell lymphoma: state of the art C Kosmas1, K Stamatopoulos2, N Stavroyianni2, N Tsavaris3 and T Papadaki4 1Department of Medicine, 2nd Division of Medical Oncology, ‘Metaxa’ Cancer Hospital, Piraeus, Greece; 2Department of Hematology, G Papanicolaou General Hospital, Thessaloniki, Greece; 3Oncology Unit, Department of Pathophysiology, Athens University School of Medicine, Laikon General Hospital, Athens, Greece; and 4Hemopathology Department, Evangelismos Hospital, Athens, Greece Over the last 5 years, studies applying the chimeric anti-CD20 ficulties in identifying a completely tumor-specific target; (2) MAb have renewed enthusiasm and triggered world-wide appli- the impracticality of constructing a unique antibody for each cation of anti-CD20 MAb-based therapies in B cell non-Hodg- kin’s lymphoma (NHL). Native chimeric anti-CD20 and isotope- patient; (3) the development of an immune response to murine 6 labeled murine anti-CD20 MAbs are currently employed with immunoglobulins (human anti-mouse antibodies, HAMA). By encouraging results as monotherapy or in combination with the end of the 1980s enthusiasm for therapeutic MAbs was conventional chemotherapy and in consolidation of remission waning; murine native (unconjugated), radioactively labeled after treatments with curative intent (ie after/ in combination or toxin-conjugated MAbs failed to yield significant clinical with high-dose chemotherapy and hematopoietic stem cell responses; moreover, they were not uncommonly associated rescue). On the available experience, anti-CD20 MAb-based therapeutic strategies will be increasingly integrated in the with toxicities, predominantly in the form of serum sickness treatment of B cell NHL and related malignancies. from repeated administrations as a result of HAMA develop- Leukemia (2002) 16, 2004–2015. doi:10.1038/sj.leu.2402639 ment, hematological or other toxicity (pulmonary toxicity and Keywords: monoclonal antibodies; B cell lymphoma; rituximab; encephalopathy). Therefore, refinement of the antibody mol- tositumomab; ibritumomab ecule itself in order to avoid immunogenicity – HAMA by chi- merization or ‘humanization’, optimization of the method- ology to obtain more stable radioactively labeled MAbs and Introduction better understanding of the biology of antigenic epitopes expressed on developing lymphocytes – the counterparts of Over the last 25 years, since Kohler and Milstein1 first lymphoma cells – appeared the major prerequisites to enter described making monoclonal antibodies (MAbs), much time into the novel rapidly progressing era of Mab therapy of NHL. has been spent trying to develop these reagents in order to The most widely selected target for MAb-based therapeutic treat human disease. Until recently, progress has been notori- modalities in B cell NHL was the CD20 antigen for reasons ously slow and by 1994 only one MAb, anti-CD3 (OKT3), had that will be analyzed in the present report. been licensed for clinical use in treating renal and cardiac allograft rejection. In the past 5 years, however, the situation has changed dramatically, with numerous MAbs now having The CD20 target clinical potential, of which seven have been approved for tre- ating human disease. Furthermore, all indications are that this The CD20 antigen is restricted to B cells:7 its expression starts upward trend will continue, with a quarter of all new biologi- at the pre-B stage of B cell ontogeny and continues until the cal products currently undergoing clinical development being immunoblast stage; importantly, CD20 is not expressed on antibody based. either precursor lymphoid cells or in the vast majority of The first indication that MAbs might have significant thera- plasma cells. CD20 antigen expression on malignant B cells peutic potential came in the early 1980s, when Nadler and corresponds to the ontogenetic stage at which the malignancy colleagues,2 soon to be followed by Levy et al3 reported the is assigned: thus, non-Hodgkin’s lymphomas (NHL) are CD20- first two cases of lymphoma patients experiencing a complete positive in over 90% of cases, contrasting with B cell acute response (CR) to a brief course of treatment with a ‘tailor- lymphoblastic leukemia which is positive in about half the made’ mouse anti-idiotype (anti-Id) MAb. This notable suc- cases and neoplastic plasma cells of multiple myeloma which cess, together with (limited) animal data, sparked widespread are usually CD20-negative.8 academic and commercial interest, followed by a period of Although the function of CD20 has not yet been fully unrav- extreme enthusiasm in applying Mab-based therapeutic eled and CD20-knockout mice do not show a prominent approaches to treat human cancer.4 It was anticipated that the phenotype,9 CD20 does appear to play a role in Ca2+ transport progress MAbs had brought to biomedical research and clini- as cells transfected with CD20 increase their resting levels of cal diagnostics would be repeated for therapeutics. Unfortu- intracellular Ca2+.10–12 Some of the most interesting data on nately, this did not materialize: subsequent trials with different CD20 signalling comes from work showing that when types of murine and human-mouse chimeric MAbs in various crosslinked with MAb, CD20 is rapidly reorganized in the cancers failed to meet the success of the first anti-Id Mab case. lipid bilayer membrane.13 CD20 might be one of many signal- A number of limitations emerged from these studies:4,5 (1) dif- ling molecules (including the kinases Lyn, Fyn and Lck) able to divide into the sphingolipid and cholesterol-rich micro- domains so important in antigen receptor signalling in lymphocytes.14 Correspondence: C Kosmas, Consultant Medical Oncologist, 2nd Division of Medical Oncology, ‘Metaxa’ Cancer Hospital, 21 Apol- Certain characteristics make the CD20 antigen an appealing loniou Street, 16341 Athens, Greece; Fax: +3010-9962917 target for monoclonal antibody therapy; it is present on the Received 20 March 2002; accepted 7 May 2002 surface of mature B cells8 and has been noted in approxi- Anti-CD20 MAbs in B cell NHL C Kosmas et al 2005 mately 93% of patients with B cell lymphoma,15 but is not to moderate infusion-related toxic effects (fever, chills, present on B cell precursors, mature plasma cells, or other asthenia, nausea, rash, and urticaria). In the initial phase I nonlymphoid normal tissues.8,15 Additionally, it does not cir- trial, Rituximab produced rapid depletion of circulating B cells culate in the plasma as free protein that could competitively that slowly recovered during 3–6 months. Tumor biopsies per- inhibit MAb binding to lymphoma cells, does not shed from formed 2 weeks after a single infusion showed antibody the surface of CD20+ cells after antibody binding and does bound to tumor cells and a decrease in the percentage of B not seem to be internalized or, subsequently, downregulated cells in the tumor. In a multiple-dose study, 375 mg/m2 was on antibody binding.16,17 well tolerated and thus selected for further phase II trials.27,28 Crosslinking of CD20 with various Mabs induces a number In a seminal paper, McLaughlin et al31 reported the results of signalling events, including increased protein tyrosine phos- of a large multi-institutional trial. In that study, 166 patients phorylation, activation of protein kinase C and upregulation with relapsed or refractory low-grade or follicular B cell lym- of C-MYC.18 In vitro, these changes can regulate B cell growth phoma were studied. The overall response rate (RR) in the and appear to depend upon the association of CD20 with an intent-to-treat analysis was 48% (CRs: 6%): with a median ill-defined factor that couples it to the Src-kinases Lyn, Fyn time of follow-up of 11.8 months, the projected median time and Lck.19 There is a growing body of evidence confirming to progession (TTP) was 12.5 months. A detailed pharmacoki- that anti-CD20 Mabs are able to recruit immune effector netic analysis performed on a subset of patients revealed that mechanisms, such as complement-mediated lysis and anti- there was a stepwise increase of peak levels and serum half- body-dependent cellular cytotoxicity (ADCC);17 furthermore, life after each course. A significant correlation was noted they might also employ other intracellular signalling mech- between the number of circulating B cells at baseline and the anisms to achieve direct cytotoxic and/or apoptotic effects. rapidity of antibody clearance from the systemic circulation after the first infusion. Importantly, only one patient (Ͻ1%) developed human anti-chimeric antibodies (HACA). Rituximab: general features The results of the above two trials provided the basis for the fast-track approval of Rituximab by the FDA for the treatment Rituximab (IDEC-C2B8) is a highly specific mouse/human of relapsed or refractory indolent lymphoma. Since then, chimeric antibody engineered by grafting the variable regions many studies have contributed in better defining the thera- targeting the CD20 antigen from a murine anti-CD20 antibody peutic role of Rituximab as monotherapy or in combination (2B8) on to human constant regions.15 Rituximab has a longer with standard chemotherapy for management of indolent half-life than the parent murine antibody and is less immuno- lymphoma. genic, essentially eliciting no HAMA response.17,20 In an important recent paper, Colombat et al reported the The reactivity of Rituximab is restricted to B cells: Rituximab results of a multi-institutional trial of a 4-dose course of Rituxi- binds complement (C1q) and induces antibody-dependent mab in previously untreated follicular lymphoma patients with cellular cytotoxicity:17,20 in vitro, follicular lymphoma cell a low tumor burden (32). Of the fifty patients enrolled in the lines are lysed with Rituximab and human complement, albeit study, 36 responded within a month of treatment, with 10 with marked heterogeneity in the extent of the response. patients in CR, 3 in CR/unconfirmed (CRu) and 23 in PR.
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