Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma

Non-Hodgkin's lymphoma is the most common hematologic cancer in adults, with more than 66,000 incident cases anticipated in the United States in 2008.1 Approximately 85% of non-Hodgkin's lymphomas in adults are of B cell origin.2 Some B-cell non-Hodgkin's lymphomas are indolent, or slow-growing, yet incurable. In contrast, others are aggressive or very aggressive, and may be rapidly fatal, yet are often curable.
There has been a revolution in the treatment of B-cell non-Hodgkin's lymphomas, owing largely to the availability of therapeutic monoclonal antibodies. The concept that antibodies might be effective for the treatment of cancers originated more than a century ago with Paul Ehrlich's hypothesis that it would someday be feasible to develop a "magic bullet" that has an affinity for "parasites" but that spares normal tissues3; 100 years elapsed, however, before antibodies were developed as effective agents for the treatment of cancer. The first step was the development of hybridoma technology capable of producing adequate quantities of monoclonal antibodies for clinical use.4 The next step was to identify tumor-specific cell antigens as targets.5 Finally, on November 26, 1997, rituximab became the first monoclonal antibody approved by the Food and Drug Administration (FDA) for the treatment of a human cancer — relapsed or refractory, low-grade (indolent) or follicular, CD20+ non-Hodgkin's lymphoma. In the ensuing decade, considerable effort has been focused on improving the effectiveness of this agent, identifying other therapeutic monoclonal antibodies (Table 1), and integrating antibodies into standard treatment regimens.

Rituximab for Follicular and Low-Grade Lymphoma

Rituximab is a chimeric monoclonal antibody composed of murine variable regions from the anti-CD20 antibody 2B8 that are linked to a human Fc component directed against CD20 on B cells. Unfortunately, the optimal dose of rituximab has never been defined. Phase 1 studies of doses ranging from 10 to 500 mg per square meter of body-surface area, administered once, and of doses ranging from 125 to 375 mg per square meter, administered weekly for 4 weeks, identified no dose-limiting toxic effects.21,22 Athough fever, chills, nausea, vomiting, urticaria, orthostatic hypotension, and bronchospasm occur in more than 80% of patients and are moderate to severe in about 15% of patients, these problems are generally limited to the infusion period. The regimen of 375 mg per square meter weekly for 4 weeks was selected for further testing on the basis of pharmacokinetic and pharmacodynamic data, the supply of the drug, and the feasibility of outpatient administration of the drug.23,24,25

Rituximab was initially approved by the FDA largely on the basis of a study involving 166 patients with relapsed or refractory, follicular or low-grade non-Hodgkin's lymphoma.24 The overall response rate was 48%, with 6% of the patients having complete remissions; better response rates correlated with fewer previous treatments. The median duration of the response was about a year. The response rate among patients with bulky disease (nodes larger than 10 cm in diameter) was 43%, with 4% having complete remissions that lasted for a median of 5.9 months; the median time to progression among patients with a response was 8.1 months.26 Responses lasting from 1 to 2.5 years have been reported in about 70% of patients with previously untreated, indolent non-Hodgkin's lymphoma and a low tumor burden.27,28,29

Until recently, no chemotherapeutic regimen provided a survival benefit superior to that of chlorambucil and prednisone in patients with indolent lymphomas.30 However, single-group trials have suggested that adding rituximab to chemotherapy improves the rate and the duration of the response.31,32 Several randomized studies in which rituximab was added to various chemotherapy regimens showed not only increased rates of complete response but also prolonged survival as compared with chemotherapy alone (Table 2).33,34,41 Such results supported broadening the indications for rituximab in combination with chemotherapy to include its use as an initial treatment.

Ongoing attempts to improve on the rituximab molecule include modifications that permit binding to a better epitope, binding more tightly to CD20, increasing activation of antibody-dependent cellular cytotoxicity, and facilitating apoptosis (Figure 2). The product furthest along in clinical development is ofatumumab (HuMax-CD20, Genmab), a fully human IgG1{kappa} monoclonal antibody that targets a novel epitope of CD20. Preclinical studies indicate that ofatumumab is associated with greater complement-dependent cytotoxicity than rituximab, presumably because of a slower rate of dissociation from its antigen ("off rate") and greater interaction with the complement component C1q. In clinical trials, patients with follicular lymphoma and chronic lymphocytic leukemia had responses to ofatumumab, which profoundly depleted CD19+CD5+ B cells and had a toxicity profile similar to that of rituximab.88,89,90

Another humanized antibody, hA20 (IMMU-106), induces apoptosis of B cells in vitro and mediates antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.91 Early clinical trials suggest that patients have objective responses to this antibody.91,92 PRO131921, a third-generation rituximab product, is also being investigated in early clinical trials. Additional anti-CD20 antibodies under development include some with enhanced binding to Fc receptors and augmented antibody-dependent cellular cytotoxicity. Given the substantial activity and relative safety of rituximab, it will be challenging to show whether other anti-CD20 antibodies have an advantage when they are compared with rituximab and whether they will be effective in patients whose lymphoma is resistant to rituximab.

Alemtuzumab

Alemtuzumab (Campath, Bayer HealthCare Pharmaceuticals) is a humanized anti-CD52 monoclonal antibody that has been approved by the FDA for the treatment of chronic lymphocytic leukemia. The recommended schedule for the administration of alemtuzumab is a dose of 3 mg on day 1 and 10 mg on day 2, followed by 30 mg three times weekly, as tolerated, for up to 12 weeks. About 30% of patients with chronic lymphocytic leukemia whose disease progressed after they received alkylating agents and fludarabine have had a response to alemtuzumab.93,94,95 When alemtuzumab is used as the initial therapy, the response rate is about 80%.93,94,95 Infusion-related rigors occur in about 90% of patients (14% of whom have moderate-to-severe reactions), fever in 85% (moderate to severe in 20%), mild-to-moderate nausea in 53%, vomiting in 38%, and rash in approximately 33%. These adverse events generally decrease in frequency and severity over the course of treatments. Subcutaneous administration has fewer toxic effects than intravenous administration but has similar efficacy and is now more widely used.96

Infections develop in more than 50% of patients who receive alemtuzumab; these infections are severe to life-threatening in 25% of the patients. Alemtuzumab has been associated with an increased risk of Pneumocystis jiroveci and herpesvirus infections; thus, antimicrobial prophylaxis and close monitoring for infection are essential. A reactivation of cytomegalovirus occurs in approximately 25% of patients, necessitating weekly polymerase-chain-reaction monitoring.

Galiximab

CD80 is an immune costimulatory molecule that is present on B cells.97 Galiximab (Biogen Idec) is a macaque–human chimeric anti-CD80 antibody with antilymphoma properties in vivo. About 15% of patients with recurrent follicular non-Hodgkin's lymphoma appear to have positive responses with galiximab, some of which occur as late as a year after treatment. Galiximab is reported to cause minimal adverse events — primarily mild fatigue, nausea, and headaches.98 On the basis of preclinical data suggesting synergy, a phase 1–2 study of galiximab together with rituximab was performed, and the results suggested that the combination therapy was superior to therapy with the single agents99; a randomized trial of rituximab as compared with galiximab plus rituximab in patients who have had a relapse is under way. The Cancer and Leukemia Group B (CALGB) recently studied the combination of galiximab and rituximab as the initial therapy for follicular lymphoma and reported a response in 69% of the study participants, including 41% with complete remissions.100

Anti-CD40 Antibodies

CD40, a member of the tumor necrosis factor–receptor family, is expressed on the surface of B cells from the pro-B stage to plasma cells. Preclinical studies of two anti-CD40 antibodies (SGN-40 [Seattle Genetics] and CHIR-12.12 [Novartis]) showed apoptotic effects and antibody-dependent cellular cytotoxicity. Durable, complete responses in patients with diffuse large-B-cell lymphoma in a phase 1 trial with SGN-40 stimulated further study of SGN-40 as a single agent and in combination with chemotherapy.101

Epratuzumab

CD22 is widely expressed on B cells and may be important in B-cell activation, modulation of antigen-receptor signaling, and cell-surface–receptor circlulation. Epratuzumab (Immunomedics), a humanized IgG1 anti-CD22 monoclonal antibody, has induced responses in 24% of patients with follicular lymphoma and in 15% of patients with recurrent diffuse large-B-cell lymphoma, without dose-limiting toxic effects.102,103 Results of treatment with a combination of rituximab and epratuzumab suggested at least an additive benefit, a finding that requires confirmation in a randomized study.104 Epratuzumab is also being evaluated as a treatment in combination with rituximab plus CHOP and as a therapy in other B-cell cancers and autoimmune disease.105

Lumiliximab

Chronic lymphocytic leukemia cells express the CD23 antigen, a target for the anti-CD23 antibody, lumiliximab (Biogen Idec), a macaque–human chimeric monoclonal antibody that inhibits IgE secretion in vitro and induces apoptosis of lymphoma cell lines. Lumiliximab binds complement and mediates antibody-dependent cellular cytotoxicity by binding Fc{gamma}RI and RII receptors. It appears to have limited effectiveness as a single agent among patients with chronic lymphocytic leukemia.106 However, in vitro data suggest that it has synergy with fludarabine and rituximab.107 When lumiliximab is added to the combination therapy of fludarabine, cyclophosphamide, and rituximab, the rates of response appear to be similar to those seen with the combination therapy without lumiliximab, but the proportion of complete responses is higher when lumiliximab is added.108 An international randomized study comparing fludarabine, cyclophosphamide, and rituximab with and without lumiliximab is under way.

Hu1D10

HLA class II antigens are expressed on B cells throughout differentiation and play a key role in cell cycling and proliferation. Anti-class II antibodies inhibit B-cell proliferation and induce apoptosis, at least in part through induction of the Fas–Fas ligand pathway or activation of Akt. Apolizumab (Hu1D10), a humanized anti-HLA-DR antibody capable of inducing complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and programmed cell death, has limited activity.109 Nevertheless, other anti–HLA-DR antibodies, including the anti-CD74 antibody milatuzumab (Immunomedics), are currently being studied for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and multiple myeloma.110

Related Posts