Ofatumumab, a Second- Generation Anti-CD20 Monoclonal Antibody, For
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Drug Evaluation 1 2 Ofatumumab, a second- 3 4 generation anti-CD20 monoclonal 5 6 antibody, for the treatment 7 1. Introduction 8 of lymphoproliferative and 9 2. Synthesis 10 3. Preclinical development autoimmune disorders 11 4. Clinical development † 12 Jorge Castillo , Cannon Milani & Daniel Mendez-Allwood 5. Adverse events and † 13 Brown University Warren Alpert Medical School, The Miriam Hospital, Division of Hematology and contraindications 14 Oncology, Providence, RI, USA 15 6. Conclusions Background: Lymphoproliferative and autoimmune disorders share monoclonal 16 7. Expert opinion dysregulation and survival advantage of B-lymphocytes. Thus, therapies 17 18 directed towards eliminating B-cells will play an important role as CD20 is 19 exclusively expressed in B-lymphocytes and its modulation by monoclonal 20 antibodies such as rituximab has improved outcomes in lymphoproliferative 21 and autoimmune disorders. Ofatumumab is a new, fully human anti-CD20 22 antibody and has been shown to be effective and safe, but its role in these 23 conditions is still unclear. Objectives: To describe the preclinical and clinical 24 data available on ofatumumab for the treatment of lymphoproliferative 25 and autoimmune disorders. Methods: An extensive search of published 26 articles and abstracts on preclinical and clinical studies with ofatumumab 27 was undertaken. Conclusions: Ofatumumab is a second-generation anti- 28 CD20 antibody that has been demonstrated to be safe and efficacious in 29 patients with lymphoproliferative and autoimmune disorders. Ofatumumab 30 is fully human, attaches to a newly identified epitope and shows lower off- 31 rates and improved complement-dependent cytotoxicity. Initial data present 32 ofatumumab as an attractive agent with lower rates of infusion-related 33 events than rituximab. Ongoing Phase III trials in patients with follicular 34 lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis are 35 ongoing, and Phase II trials in patients with aggressive lymphoma and multiple 36 sclerosis are also under development. 37 38 Keywords: autoimmune disorders, CD20, chronic lymphocytic leukemia, lymphoma, monoclonal 39 antibody, multiple sclerosis, non-Hodgkin’s lymphoma, ofatumumab, rheumatoid arthritis 40 41 Expert Opin. Investig. Drugs (2009) 18(4):1-10 42 43 1. Introduction 44 45 B-lymphocytes play an important role in the development of lymphoproliferative 46 and autoimmune disorders (LPDs and AIDs, respectively). Briefly, LPDs are 47 characterized by a monoclonal proliferation of malignant B- or T-lymphocytes, in 48 which a combination of increased proliferation, survival advantage and/or 49 decreased apoptosis can be observed [1]. In a similar fashion, AIDs are character- 50 ized by B-lymphocyte dysregulation, which translates into increased activation 51 and development of uncontrolled self-recognition properties [2]. Furthermore, 52 there is a bidirectional association between these disorders, since patients with 53 LPDs often present with AIDs (e.g, lymphoma patients can develop autoimmune 54 hemolytic anemia) [3] and patients who suffer from AIDs have an increased risk 55 of developing LPDs (e.g., the risk of developing lymphoma in patients with 10.1517/13543780902832679 © 2009 Informa UK Ltd ISSN 1354-3784 1 All rights reserved: reproduction in whole or in part not permitted Ofatumumab 56 systemic lupus erythematosus is 7 times higher than in the anti-TNFα failure in 2006 based on a Phase III study 111 57 general population) [4]. Based on this evidence, drugs directed showing that the combination of rituximab and MTX 112 58 towards eliminating the malignant or autoimmune clones of improved responses in comparison to MTX alone based on 113 59 B-lymphocytes, such as anti-CD20 monoclonal antibodies, American College of Rheumatology (ACR) and European 114 60 can be of great therapeutic value in these disorders. League Against Rheumatism (EULAR) response criteria [17]. 115 61 Non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic The dosing regimen for RA is different than those used to 116 62 leukemia (CLL) represent two distinct subcategories of treat lymphoma. For MS, multiple therapies are available, 117 63 malignant LPD, which originate from clonal proliferation of such as interferon, glatiramer acetate, mitoxantrone and natali- 118 64 malignant lymphocytes. NHL is the most predominant zumab, a humanized anti-CD74 MAb. The use of rituximab 119 65 adult hematologic malignancy in the USA with 66,000 in MS is limited to small trials but with hopeful results [18]. 120 66 anticipated cases in 2008 [5]; 85% of these cases will arise The premise of MAb activity centers upon modulating 121 67 from a malignant B-lymphocyte. The most common subtypes new functional receptors in malignant or autoimmune cells 122 68 are diffuse large B-cell (DLBCL) and follicular lymphoma to augment therapeutic efficacy. The actual mechanisms of 123 69 (FL). CLL, on the other hand, is the most prevalent LPD in action of MAb are unknown but, theoretically, their func- 124 70 the USA with 95,000 cases [6]. CLL is characterized by the tion is elicited by inducing complement-dependent cytotox- 125 71 accumulation of neoplastic CD5+/CD19+ B-lymphocytes. icity (CDC), antibody-dependent cellular cytotoxicity 126 72 Fifty per cent of cases will be largely asymptomatic and will (ADCC) and/or direct apoptosis [19]. Nonetheless, inherent 127 73 not need therapy. DLBCL is considered a curable disease; limitations arise with rituximab as resistance ensues in 128 74 but FL and CLL are incurable with current standard therapies. patients with low-grade NHL and CLL and responses are 129 75 AIDs comprise a constellation of conditions, such as rheu- less potent and shorter in duration [20,21]. Similarly, the effi- 130 76 matoid arthritis (RA) and multiple sclerosis (MS). RA has cacy of second-line therapy with rituximab is unclear in 131 77 an annual incidence of 30 cases per 100,000 population; DLBCL patients who failed rituximab as front-line ther- 132 78 more than a million Americans live with RA [7]. This condi- apy [10]. Moreover, rituximab has been linked to life-threat- 133 79 tion, which is characterized by the development of painful, ening infusion reactions, hepatitis B reactivation, tumor lysis 134 80 swollen joints and the presence of anticyclic citrullinated syndrome, severe mucocutaneous reactions and progressive 135 81 peptide antibodies, can be disabling and has a great impact multifocal encephalopathy [22,23]. Thus, it is paramount to 136 82 on quality of life and productivity as the joint damage discover and implement a new generation of MAb as a viable 137 83 becomes permanent with time, decreasing mobility. MS is treatment entity to achieve long-term remission while 138 84 the most common autoimmune demyelinating disease of the decreasing the rate of therapy-related adverse events. 139 85 central nervous system, affecting more than 300,000 people 140 86 in the USA [8]. It is twice as common in females as in 2. Synthesis 141 87 males, with a peak incidence at the age of 35 years but does 142 88 not affect lifespan substantially [9]. The most common form Ofatumumab (HuMax-CD20; GlaxoSmithKline, Collegeville, 143 89 of MS is relapsing-remitting MS (RRMS), characterized by PA, USA and Genmab, Copenhagen, Denmark) is an IgG1, 144 90 unpredictable relapses followed by either complete, partial fully human, second-generation anti-CD20 MAb with a 145 91 or no neurological recovery. molecular weight of approximately 150 kDa. Ofatumumab 146 92 In 1997, the advent of rituximab (Rituxan®, Genentech, was produced by immunizing HCo7 and KM mice with a 147 93 South San Francisco, CA, USA), a chimeric anti-CD20 murine cell line (NS/0) transfected with human heavy- and 148 94 monoclonal antibody (MAb), dramatically altered the foun- light-chain genes. The hybridoma was created by fusing 149 95 dation for the treatment of NHL. Rituximab is approved as B-cells from immunized mice and NS/0 cells. CD20-specific 150 96 both first-line treatment for aggressive and indolent subtypes IgG1-producing hybridomas were then sequenced and sub- 151 97 of NHL (DLBCL and FL, respectively), and for relapsed or cloned. Unique features to ofatumumab compared with 152 98 refractory, indolent or follicular, CD20-positive NHL. Clinical rituximab are a different binding site, prolonged release time 153 99 data reported by multiple investigators demonstrated from the target site and stronger CDC activity. Ofatumumab 154 100 increased response rates and prolonged survival times with is now under clinical development for indolent and aggressive 155 101 rituximab in combination with chemotherapy in patients NHL, CLL, RA and MS with promising results. 156 102 with DLBCL [10-12] and FL [13,14]. Similarly, the clinical 157 103 benefits of rituximab can be seen in patients with CLL 3. Preclinical development 158 104 when added to other chemotherapeutic agents or, to a lesser 159 105 degree, as single agent [15,16]. Of note, rituximab is not yet Elegant work from Teeling and colleagues [24] defined a series 160 106 approved by the FDA to treat CLL but it is the most com- of three fully human anti-CD20 MAbs (ofatumumab, 7B8 and 161 107 monly used MAb for this condition. The treatment for RA 11B8) with distinct characteristics. The first two were desig- 162 108 is based in nonspecific modulation of B-cells by corticoster- nated as type I anti-CD20 MAbs (rituximab-like), given their 163 109 oids, methotrexate (MTX) and anti-TNFα MAb. Rituximab ability of translocating and concentrating CD20 molecules 164 110 obtained FDA approval for the treatment of RA after into detergent-insoluble lipid rafts and inducing CDC. The 165 2 Expert Opin. Investig. Drugs (2009) 18(4) Castillo, Milani & Mendez-Allwood 166 MAb 11B8 was designated as type II (tositumomab-like) epitope to the cellular membrane plays a role in achieving 221 167 given its greater ability of eliciting ADCC and apoptosis. By stronger CDC activity.