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Journal of Cancer Research and Therapeutics, Vol. 7, No. 4, October-December, 2011, pp. 399-407 Review Article Monoclonal antibodies in hematological malignancies: Past, present and future I Tazi, H Nafil, L Mahmal Department of Hematology, Chu Mohamed VI, Cadi Ayyad University, Marrakech, Morocco Code Number: cr11110 DOI: 10.4103/0973-1482.91999 Abstract Much progress has been made during the last few decades in the treatment of hematological malignancies. Monoclonal antibodies (MoAbs) represent a major advance toward a targeted therapy that can dramatically improve the antitumor effect with a substantial reduction of toxicity derived from therapy. Unlike many small molecules, MoAbs offer unique target specificity. Several MoAbs are now in clinical use for hematologic malignancies therapy, and many others are currently undergoing clinical evaluation. This review summarizes the state-of-the-art MoAbs treatment, beginning with an overview of the scientific background to their synthesis, mechanism of action and choice of target antigen, mainly focusing on those antibodies that are currently in use in clinical practice. Despite these advances, significant challenges remain in the identification of optimal cellular targets, antibody forms and treatment schedules for therapeutic applications. Keywords: Hematological malignancies, monoclonal antibodies, review, therapy Introduction In recent years, several studies on monoclonal antibodies (MoAbs) in the treatment of cancer have been published. Several products are the avant-garde of a new family of anticancer drugs, called 'targeted therapy' which brings new hopes: more efficacy and less toxicity. Among the best-studied examples, the MoAbs trastuzumab, rituximab and bevacizumab, are now approved as part of the standard therapy for appropriate forms of breast cancer, [1],[2] B-cell lymphoma and colorectal cancer, [3],[4] respectively, as well as other types of cancer. [5],[6] Since the seminal description of murine hybridoma methodology in 1975, [7] MoAbs have been developed as diagnostic tools and therapeutic agents for hematological malignancies: initially from murine origin, later chimeric between murine and humanized, and now fully human antibodies. [8],[9] MoAbs, either as single agents or in combination with cytotoxic agents, have changed the treatment of hematological malignancies, eventually leading to a longer time to progression, longer overall survival time, and superior quality of life. MoAbs kill neoplastic cells by multiple mechanisms including induction of apoptosis, inhibition of cell growth, complement-mediated cytotoxicity, antibody-dependent cellular cytotoxicity, and sensitization to chemotherapy or radiation. Several MoAbs are now in clinical use for hematologic malignancies therapy, and many others are currently undergoing clinical evaluation. The purpose of this review is to summarize the state-of-the-art MoAbs treatment, beginning with an overview of the scientific background to their synthesis, mechanism of action, initial experience with novel MoAbs, new therapeutic approaches with already approved agents. Synthesis of Monoclonal Antibodies MoAbs are synthesized using a process developed in the 1970s. [7] Producing MoAbs requires immunizing an animal, usually a mouse; obtaining immune cells from its spleen; and fusing the cells with a cancer cell (such as cells from a myeloma) to make them immortal, which means that they will grow and divide indefinitely. A tumor of the fused cells is called a hybridoma, and these cells secrete MoAbs. The development of the immortal hybridoma requires the use of animals; no commonly accepted nonanimal alternatives are available. The earliest use of a MoAb for treatment of lymphoma was 1980, when an antibody against a lymphoma antigen was given to a patient with relapsed lymphoma. [10] Thus, the major impetus of MoAb therapy in the last 20 years has been to target lymphoma-specific antigens. The ideal antigen is one which is densely expressed on malignant cells, but not on normal cells, and one which is not internalized or shed from the cell surface upon antibody binding. [11] Mechanism of Action The mechanisms of action of MoAbs differ with the antibody, the antigen it targets, and its use: alone, in combination with chemotherapy, or conjugated to a toxin or a radionuclide. Different antigens can be targeted of MoAbs in lymphomas and leukemias. When designing a therapeutic approach for lymphomas, cancer immunologists face the issue of selecting the best target antigen. Tumor antigens are traditionally divided in tumor-specific antigens (proteins that are uniquely expressed by cancer cells) and tumor-associated antigens (molecules that are expressed by cancer cells, although their expression is also found on normal cells). [12] Ideally, an immune response against tumor antigens should destroy tumor cells without damaging normal cells. MoAbs have been the most successful therapeutics ever brought to cancer treatment by immune technologies. The use of MoAbs in B-cell Non-Hodgkin's lymphomas (NHL) represents the greatest example of these advances, as the introduction of the anti-CD20 antibody rituximab has had a dramatic impact on how we treat this group of diseases today. Moreover, due to its capacity to eliminate B-lymphocytes, it has recently been applied in immune-mediated disorders. [13] The optimal target for MoAbs therapy would be a specific antigen present at high density on tumor cells, absent or present at low concentrations on normal cells (or present in noncritical host cells), with stable expression and with no modulation or internalization. CD20 antigen, present in most B-cell neoplasias, has all of these requisites and is the paradigm of the target molecules. [11],[14],[15] The cell surface protein CD20 is a 33-kDa protein expressed by mature B cells and most malignant B cells, but not by pre-B cells or differentiated plasma cells. [10],[16],[17],[18] In vitro studies have revealed that CD20 acts as a calcium ion channel, [19] and may also activate intracellular signaling through its ability to associate with the B-cell receptor. [20] Humanized MoAbs have a greater efficiency than mouse MoAbs for activating these immunological mechanisms. Antigen density and MoAbs binding affinity may influence the cytotoxic efficacy. [21] The affinity of the Fc receptor on effector cells seems to be related to the in vivo activity, at least in indolent lymphomas when rituximab is used alone. [21],[22] Although the exact in vivo mechanisms of action for rituximab are not fully understood, the mechanisms of B cell killing by this MoAbs have been exhaustively analyzed. [23] Briefly, the major mechanism of rituximab-induced B cell depletion involves antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity. [24] Additionally rituximab was reported to directly induce apoptosis, inhibit B-cell proliferation and to enhance the cytotoxic activity of chemotherapeutic agents. [25] An alternative approach to increase the activity of MoAbs has been the development of immunotoxin, a construct conjugating the antibody to cytotoxic plant, bacterial toxic proteins, or chemotherapy drugs (doxorubicin). [20] The commonly used toxins, ricin or diphtheria toxin are highly potent natural products that disrupt protein synthesis. More recently, in order to increase the antitumor effect, MoAbs have been conjugated either with radiation emitters or with cytotoxins. [26],[27],[28] The latter could substantially increase the cytotoxic capability, but also the toxicity for the patient. Radioimmunotherapy with β-emitting isotopes, such 131I or 90Y, has the advantage of making a 'crossfire effect' eliminating tumor cells to which the MoAbs is not directly bound, although of course, the dose-limiting toxicity to normal cells is important. [28] Monoclonal Antibodies Applications in Hematological Malignancies Acute leukemias Gemtuzumab ozogamicin Gemtuzumab ozogamicin (GO), a recombinant humanized anti-CD33 antibody linked to a derivate of the antitumor antibiotic calicheamicin, is the only antibody-drug conjugate approved by the Food and Drug Administration (FDA). It is indicated for the treatment of relapsed acute myeloid leukemia (AML) in elderly patients. [29] GO consists of an IgG4 anti-CD33 MoAbs, bound to N-acetyl-g-calicheamicin dimethyl hydrazide. [30] In general terms, it is accepted that GO binds the CD33 molecule and is then internalized and allocated into lysosomes, where calicheamicin is released and generates oxidative damage of DNA and mitochondrial damage leading to apoptosis. [31],[32] A phase II study of 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years has been performed. All patients received GO as a 2-h infusion (9 mg/m2 intravenously) with intervals of 2 weeks for two doses. Thirty percent of patients achieved complete remission and median relapse-free survival for these patients was 7.2 months. [29],[33] Side-effects of treatment with GO consisted of infusion reactions and nearly all patients had grade 3 or 4 neutropenia thrombocytopenia; 28% had grade 3-4 infections. Transient and reversible hepatic toxic effects (hyperbilirubinemia and high concentrations of transaminases) occurred in some patients. GO has been combined with standard cytotoxic chemotherapy in AML in numerous small clinical trials involving various age groups. [34],[35] Kell et al., added Mylotarg® (GO for injection) to an induction regimen of cytosine arabinoside, daunorubicin, and 6-thioguanine or fludarabine, cytosine arabinoside and granulocyte colony factor (G-CSF) and idarubicin (Flag-Ida) in patients ages 17-59-years old. [34] The complete remission (CR) rate was 91%. Patients were only able to tolerate GO at the reduced dose of 3 mg/m2 due to liver toxicity-limiting escalation beyond this dose. Nand recently reported favorable early results using hydroxyurea, 5-azacytidine, and low dose Mylotarg in a small group of elderly AML patients. [35] Twenty elderly patients (median age=76 years) with AML and high-risk myelodysplastic syndrome (MDS) were treated with azacytidine for 7 days followed by GO at 3 mg/m2 on day 8. Hydoxyurea was used to lower the WBC<10,000. Fourteen (70%) achieved a CR (three iCR). Median duration of remission and survival was 8 and 10 months, respectively. GO appears to be poorly tolerated in patients older than 75 years, and a dosage reduction has been proposed for these patients. GO used in combination with chemotherapy. In patients with untreated AML, GO has been used followed by mitoxantrone, etoposide, and cytarabine. [36] This combination showed a response of 54%. GO in acute promyelocytic leukemia. Acute promyelocytic leukemia (APL) is a disctinct subtype of AML characterized cytogenetically by t (15;17), which transcribes PML/RAR-α, molecule involved in myeloid differentiation and apoptosis. The APL blasts express high levels of CD33. Single-agent GO showed to be very active in APL. In patients with molecularly relapsed APL, GO achieved molecular remission in 91% of patients after two doses and 100% of patients after three doses. [37] Estey et al., evaluated the combination of GO and alltransretinoic acid in 19 untreated APL patients and reported a CR rate of 84% without increased hepatotoxicity. [38] Twelve patients achieved a PCR-negative response. The combination of GO, all-trans-retinoic acid and arsenic trioxide was tried in APL patients in first relapse; [39] most of the patients achieved molecular remission and remained in a second response that was longer than their first response. Ongoing trials are similarly addressing the efficacy and safety of GO in combination with standard antileukemic agents and in stem cell transplant regimens. Actually, FDA notified health care professionals that result from a recent clinical trial raised new concerns about the product's safety, and the drug failed to demonstrate clinical benefit to patients enrolled in trials. So Mylotarg will not be commercially available to new patients with AML. Lintuzumab Another MoAbs directed to CD33 has been developed. Lintuzumab is a humanized MoAbs developed from the original murine M195. [40] Studies with this antibody have shown mixed results. Lintuzumab has been used of the treatment of AML, both as an unmodified and radiolabeled MoAbs. [41],[42] In acute promyelocytic leukemia, lintuzumab converted patients with minimal residual disease into molecular remission. [43] However, a randomized phase III study of lintuzumab used with chemotherapy (MEC) compared to MEC alone failed to show a clinical benefit of lintuzumab. [44] Lymphoproliferative disorders Rituximab Rituximab, a chimeric MoAb that binds to CD20, was the first MoAb to be approved for clinical use in the therapy of cancer. The key features of the cytotoxic mechanism of rituximab were demonstrated in 1994; rituximab promoted antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of a human lymphoid cell line expressing CD20, and was found to be very effective at depleting B-cells from peripheral blood and moderately effective at clearing B-cells from lymph nodes and bone marrow. [45] Importantly, rituximab does not compromise humoral immunity: despite B-lymphopenia and a significant drop of plasma IgM levels, the incidence of infections is not increased even after prolonged treatment with the antibody. [43] Animal models have demonstrated that infusion of rituximab promotes rapid opsonization of circulating B cells followed by phagocytosis by FcgR-expressing fixed tissue macrophages in liver (and possibly spleen). [46],[47] Apoptosis was proposed as a rituximab cytotoxic mechanism, but in the absence of cross-linking with nonphysiological reagents, the ability of rituximab to induce apoptosis is marginal. [48],[49],[50],[51] Follicular lymphoma (FL): Rituximab was first assayed as monotherapy in FL. In the pivotal study performed in previously treated patients with low-grade lymphomas, [52] a response rate of 48% was observed, including 6% of complete response (CR). The response duration lasted for a median of 12 months. Patients relapsing after rituximab were re-treated with the same drug with similar responses and a few side effects. Recent reports have pointed out that patients treated with rituximab containing regimens had better overall survival than those treated without rituximab. [53] A new role for rituximab in patients with FL is as maintenance treatment after achieving a response with any rituximab-containing regimen. [43],[54] Although rituximab is considered to be relatively well tolerated, more than 90% of patients experience some infusion-related reaction, which is generally mild to moderate in severity. [52],[55] Diffuse large B-cell lymphoma (DLBCL) : The addition of rituximab to CHOP or CHOP like regimens has reduced the DLBCL-associated deaths of young and old patients to less than half of what was reported 10 years ago without a relevant increase of toxic effects. [52],[56] The toxic effects of rituximab are mild and usually limited to the first application when there might be dyspnea and fever, which are usually self-limited and resolve upon the reduction of infusion velocity. Other side effects of rituximab include herpes simplex virus stomatitis and an increase in herpes zoster. Unsurprisingly, initial reports showed clearly inferior response rates: 32% responses, most of then short-lived, were reported by Coiffier in 1998, [57] using rituximab as single agent. However, a later phase III trial where rituximab was added to standard CHOP and compared with CHOP alone, showed patients receiving rituximab had a higher CR rate (76% versus 63%) and overall survival (62% versus 51%). [56] In a series of patients between 60 and 80 years of age diagnosed with DLBCL, R-CHOP demonstrated superiority over CHOP in terms of CR rate, primary resistance, event-free, progression-free, disease-free and overall survival. [57],[58] The addition of rituximab to standard chemotherapy appears to improve the CR rate in mantle cell lymphoma although, again, this is short-lived. [59],[60] In an attempt to overcome this, aggressive regimens where rituximab is administered prior to or after autologous transplants are being developed. [61] There are several ongoing studies on the role of rituximab in combination with other chemotherapy regimens, with autologous stem-cell transplantation, as well as the combination of different MoAbs plus rituximab-containing chemotherapy. Thus, the role of various resistance pathways, some documented in experimental systems and others still hypothetical, remains uncertain. Resistance could potentially be mediated by alterations in CD20 expression or signaling, elevated apoptotic threshold, modulation of complement activity or complement activity or diminished cellular cytotoxicity. Chronic lymphocytic leukemia (CLL): Early reports with discouraging response rates (as low as 12% in CLL) led to dose-escalation studies under the belief that the low density of expression of CD20 in these cells might be partly responsible for these results. [62],[63] Following this strategy, higher responses of up to 51% were seen with high-dose rituximab used as first-line treatment for CLL. [64] The combination of chemotherapy with rituximab appears to be well-tolerated and effective in CLL. Studies of rituximab with fludarabine-containing regimens, based on previous data showing an in vitro synergy between fludarabine and rituximab, reported high response rates of 90-95% (CR of 33-67%). [65] The combination of fludarabine, cyclophosphamide, and rituximab (FCR) is considered by many the standard of care in previously treated or untreated CLL. In relapsed CLL, FCR achieved an ORR of 37% with complete response (CR) rate of 25% and a nodular PR of 12%. [66] Furthermore, FCR reached an ORR of 94% with a 72% CR rate and a 4-year OS of 83% in patients with untreated CLL. [67] Other promising combinations is fludarabine and rituximab (FR); in untreated CLL patients, FR has shown an ORR of 90% with a 47% CR rate in the CALGB 9712 study. [68] Alemtuzumab Alemtuzumab is a fully humanized IgG1-type MoAb directed against CD52, a glycosylphosphatidylinositoal-anchored cell surface glycoprotein expressed on human B- and T-cells, natural killer cells, eosinophils and macrophages. [69],[70] The antibody kills target cells by complement-and/or antibody-dependent cellular cytotoxicity, but seems also to be capable of inducing direct apoptosis via caspase-dependent and -independent mechanisms. [71],[72] Based on the activity of alemtuzumab in patients with CLL, [73],[74] the US FDA initially approved alemtuzumab for the treatment of relapsed and refractory CLL. Clinically, the antibody reduces normal lymphocytes of both B- and T-lineage, resulting in a profound and occasionally long-lasting lymphopenia with concomitant immunosuppression. An anti-infective prophylaxis with cotrimoxazole and acyclovir or equivalent is mandatory during therapy and should be coutinued for at least 6 months after cessation of alemtuzumab. [75] Intravenous administration of alemtuzumab has been correlated with a higher rate of first-dose side effects (e.g., flu-like' symptoms, chills, rigor, hypotension, nausea, vomiting, rash, urticaria, bronchospasm) compared to subcutaneous application, which on the other hand entails more convenience and the possibility of self-administration in an outpatient setting. [74],[76] In general, treatment using this antibody should not be employed too late in the disease course, since the additional disease- or age/comorbidity- related impairment of the immune system might increase the risk of infections complications. One of the pivotal phase II trials attracting major attention to the efficacy of alemtuzumab was performed as salvage monotherapy in 93 CLL patients with inferior prognosis, who were refractory to fludarabine and had only few treatment options. [77] After 12 weeks of 30 mg alemtuzumab intravenous, the ORR reached 33% with 2% complete and 31% partial remissions (PR). [77] Corresponding to its activity in fludarabine-refractory patients, early studies with alemtuzumab also demonstrated unexpected activity in patients with high-risk genetic features, particularly in chemotherapy-refractory patients presenting with 17p-deletions by FISH or TP53 mutations. [78],[79] In this group, ORR of 39% to 50% have been reported. High-risk CLL patients with 17p/TP53 abnormalities have the worst prognosis, even after FCR induction. They seem to benefit particularly from the p53 independent activity of alemtuzumab treatment. Moreton el al were the first, who administered alemtuzumab monotherapy in a phase II study cohort of 91 heavily pretreated (44 fludarabine refractory) CLL patients not according to a fixed treatment schedule, but until the maximal possible response including MRD negativity was reached. [80] The ORR was 55% (36% CR and 19% PR). Eighteen of 49 complete responders (36.7%) achieved MRD negativity in bone marrow. Radioimmunotherapy Ibritumomab 90Y-Ibritumomab tiuxetan (90Y-IT) is a conjugate of an anti-CD20 MoAbs and the radionucleotide yttrium. The main toxicity is myélosuppression, especially when bone marrow is involved by the lymphoma. For this reason, patients with platelet count <100.109/l and/or bone marrow involvement>25% should not receive 90Y-IT. Several studies in humans have been performed, one of them showing 67% responses in patients with DLBCL, with 26% patients achieving CR. [81],[82] In a randomized controlled trial, 143 patients with relapsed or refractory low-grade lymphoma were treated with either 90Y-IT as described above or with four weekly administrations of rituximab. Overall response rate was 80% for patients treated with 90Y-ibritumomab (CR=30%) compared to 56% overall response (CR=16%) in the rituximab arm (P=0.002). However, the median response duration was statistically equivalent in both arms (14.2 and 12.1 months, respectively), [83] and the increase in response rate and duration did not prolong the survival of patients treated with radiolabeled antibody as compared to standard rituximab treatment. Tositumomab The FDA-approved 131I-tositumomab in June, 2003, for the treatment of CD20-positive follicular NHL (with or without malignant transformation to a higher grade) in patients refractory to rituximab treatment who relapsed after chemotherapy. 131I-tositumomab combines an anti-CD20 MoAbs with 131I. Myélosuppression is the main limitation toxicity of 131I-Tositumomab. [84] Use of 131I-tositumomab in patients with untreated low-grade lymphoma has also achieved a response in 100% of patients, with 56% having a complete response. [85] Currently, it is approved for use in patients whose disease has relapsed after chemotherapy and is refractory to rituximab, including patients whose tumors have transformed to a higher histologic grade. Ofatumumab Ofatumumab is a second-generation, fully-human, anti-CD20 MoAbs with enhanced Fc effector function based on an IgG1kappa immunoglobulin framework. [86] This newer antibody interacts with a different epitope than rituximab, which is located in the smaller extracellular loop of CD20, [24] giving it a higher binding affinity. The antibody is generated via transgenic mouse and hybridoma technology and produced in a recombinant murine cell line using standard mammalian cell cultivation and purification technologies. Initial phase I/II clinical data in relapsed/refractory FL was presented by Hagenbeek et al. [87] Forty patients were given escalated doses of ofatumumab from 300 to 1000 mg intravenously weekly for 4 weeks, obtaining an ORR of 63% with 57% response in patients previously treated with rituximab without reported dose-limiting toxicity. In 2009, the FDA approved ofatumumab for patients with CLL that is no longer being controlled by other forms of chemotherapy. Currently, NCCN guidelines provide the recommendation for use of ofatumumab in previously treated CLL patients. [88] At present, the combination of ofatumumab (500 mg and 1000 mg, respectively) with Fludarabine and cyclophosphamide (FC) in previously untreated CLL patients is investigated in a phase II trial. Preliminary data show an overall response rate of 77%, including a CR rate of 32% in the 500 mg dosing arm and an ORR of 73%, including a CR rate of 50% in the 1000 mg dosing arm. [89] Brentuximab vedotin (SGN-35) The anti-CD30 antibody cAC10 was conjugated to a synthetic antimicrotubule agent, monomethyl auristatin E (MMAE), resulting in a novel immunotoxin conjugate brentuximab vedotin (SGN-35). [90] Brentuximab vedotin was recently evaluated in two phase I clinical trials in patients with relapsed Hodgkin lymphoma and anaplastic large cell lymphoma. The first phase I study, 45 patients with relapsed Hodgkin's lymphoma and anaplastic large cell lymphoma were treated with escalating doses (0.1-3.6 mg/kg) by intravenous infusions every 3 weeks. Remarkably, 88% of the patients demonstrated tumor reductions, of whom 17 (37%) achieved partial or complete remissions. [91] In a second phase I study, 37 patients (31 with Hodgkin lymphoma) were treated with brentuximab vedotin that was administered on a weekly schedule for 3 consecutive weeks in four week cycles. The overall response rate was 46%. [92] Other Monoclonal Antibodies Milatuzumab is a novel humanized MoAb targeting CD74, a membrane protein preferentially expression in hematopoietic cancers and some solid tumors. [93] Milatuzumab demonstrated antiproliferative activity in transformed B-cell lines, improved survival in preclinical models. [94] Moreover; it was shown to have therapeutic activity in a xenograft model of multiple myeloma, perhaps by inhibiting the high level of CD74 expression in plasma cell malignancy. [95] Based on the preclinical evidence of activity, it is currently in clinical evaluation for therapy of multiple myeloma, NHL and CLL. This effect is also synergistic with other MoAbs such as rituximab. [94],[96] Milatuzumab and rituximab could potentially represent an active therapeutic strategy for the treatment of mantle cell lymphoma patients. [97] Apolizumab is a humanized IgG1 anti-HLA class II MoAb, which binds to 1D10. HLA-DR is expressed in normal and malignant cells, mainly in the B-cell population. [98] Apolizumab was used in a phase I dose-escalation trial in patients with relapsed 1D10 NHL. The trial investigated five different dose levels. The drug was well tolerated with no long term toxicities. [99] A phase I/II dose-escalation study of thrice-weekly (1.5, 3.0, 5.0 mg/kg/dose) apolizumab for 4 weeks in relapsed CLL has been performed. Two of six patients at 5.0 mg/kg/dose developed treatment-related dose-limiting toxicity. Eleven patients were enrolled in a phase I/II expansion to evaluate the maximum tolerated dose (MTD) of 3.0 mg/kg/dose. In total, 23 patients were enrolled: Nineteen patients with CLL were treated at or above the MTD. One partial response was observed, and three patients had stable disease exceeding 6 months. [100] Epratuzumab is an IgG1 humanized MoAb that in vitro has shown to bind to CD22 and internalize into the target cell. [101] It is believed to exert its anticancer effect through multiple mechanisms including apoptosis, antibody-dependent cell-mediated cytotoxicity, and alteration of signal transduction. [102] In a recent international, multicentre trial evaluating rituximab plus epratuzumab in patients with postchemotherapy relapsed/refractory, indolent NHL, an objective response was seen in 54% FL patients. [103] A pilot combination study of epratuzumab (360 mg/m2) with R-CHOP in previously untreated DLBCL (or ERCHOP) showed 87% ORR (13 on 15 patients, including 10 CR), with observed grade 3 or 4 neutropenia in 93 and 73% patients requiring dose reduction. [104] Future The discovery of MoAbs and the realization of their therapeutic potential was a key milestone in the evolution of the biotech industry. Rituximab, the first antibody approved for use in hematological malignancies, has often been help up as a model for the development of subsequent biological therapies in cancer. Since then, a myriad of academic groups and companies have ploughed vast sums of money into refining antibody technologies and developing new generations of affinity molecules designed to more effectively diagnose, monitor and treat a wide range of hematological malignancies. The approved use of MoAbs for is currently limited to NHL and leukemia, but there is reason to believe that the use of these remarkable molecules will expand in the near future. MoAbs have already transformed the treatment of many hematological malignancies; their future potential will depend on how successful new technologies are at addressing issues such as the need for parenteral administration and manufacturing costs. However, promising developments in the area of tumor-targeted antibodies have taken place in recent years. The treatment of lymphoid malignancies has experienced radical changes, as MoAbs have been accepted as components of standard therapeutic schemes. Interaction between the MoAbs effector cells mostly depends on Fc binding, so research is focusing on improving the quality of that Fc binding through protein engineering. [105],[106] Another approach to improving the effector cell/MoAbs therapy interaction is to improve the quality of the effector cells through expansion and/or activation. [107] The future in management of hematological malignancies likely will imply the ability of institute personalized therapeutic approaches. Nonetheless, there is an imperative need of more effective therapeutic strategies using combinations of chemotherapeutic agents, naked and radiolabeled MoAbs, anti-idiotype vaccines, and the new-coming antiangiogenic and immunomodulatory agents (i.e., thalidomide). Radioimmunotherapy approaches and vaccines will help eradicate MRD (minimal residual disease) and consolidate the benefits obtained by induction regimens while maintenance regimens will keep malignant progression at bay, allowing, hopeful, for prolonged drug-free and relapse-free periods of time. Conclusions In the past decade, the role of MoAbs in the treatment of hematological malignancies has become well established. Apart from these indications, some of these molecules also show promising results in the treatment of hematological and nonhematological immune-mediated disorders. Acknowledgment The authors indicated no potential conflict of interests. References
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