Ofatumumab,a human anti-CD20 monoclonal antibody

Importance of the field: Since relapse of chronic lymphocytic leukemia (CLL), and refractoriness to treatment following relapse, is inevitable after initial treatment, development of novel treatment strategies is necessary.

Areas covered in this review: CD20 as a therapeutic target for CLL, successes and limitations of current anti-CD20 monoclonal antibody (mAb) therapy, and implications of preclinical and clinical developments of novel alternatives, including ofatumumab, that may enhance anti-CD20 mAb therapy are reviewed. The literature reviewed encompasses papers and congress abstracts from the past 13 years.

What the reader will gain: While rituximab combined with chemotherapy has considerably improved outcomes for some but not all CLL patients, single-agent use is limited in relapsed/refractory CLL. Novel anti-CD20 mAbs in development, such as ofatumumab, may bypass some limitations by virtue of alternative epitope binding and modified effector functions. Ofatumumab induces significant complement-dependent cell lysis in vitro, particularly in cells with low CD20 expression. The FDA recently approved ofatumumab for treatment of CLL refractory to fludarabine and alemtuzumab.

Take home message: CD20-targetting chemoimmunotherapeutic options have advanced treatment of CLL. Results for single-agent ofatumumab and other new CD20 mAbs, in different lines of therapy and in combination with chemotherapy, will guide optimal use of these alternative therapies for B-cell malignancies.     

Anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia

Introduction: The last decade has witnesd immense progress in the treatment of chronic lymphocytic leukemia (CLL). Chemoimmunotherapy (CIT) combining rituximab and fludarabine with cyclophosphamide (FCR) in the frontline setting has clearly been shown to improve outcomes in patients with CLL. Building on the success achieved with rituximab, other anti-CD20 monoclonal antibodies (mAbs) are being investigated. Novel bioengineering techniques have helped in the development of anti-CD20 mAbs. One antibody, ofatumumab, was recently approved for the treatment of refractory CLL. A type II anti-CD20 mAb, GA-101 (obinutuzumab), is currently in clinical trials. This short review focuses on ongoing clinical trials of anti-CD20 mAbs in CLL.

Areas covered: Literature search was performed using PubMed (www.clinicaltrials.gov (till August 2012)), and recent American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), European Hematology association (EHA), International workshop on CLL (iwCLL) abstracts, using the primary search terms ‘anti-CD20 monoclonal antibody' with/without CLL. Articles were chosen on the basis of relevance of anti-CD20 mAbs to CLL therapy.

Expert opinion: Rituximab, the prototype anti-CD20 mAb, forms the core of CIT in CLL. The success of rituximab and ofatumumab has led investigators to evaluate other anti-CD20 mAbs in the treatment of CLL.     

Alemtuzumab and multiple sclerosis: therapeutic application

Importance of the field: The cause and cure for multiple sclerosis (MS) remain unknown. Immunomodulatory agents are only partially effective and many patients do not tolerate the side effects or fail them. Immunosuppressive agents act non-specifically and are associated with serious complications. An emerging group of biologic agents with great potential for treatment of immune-mediated disorders such as MS are monoclonal antibodies. A review of alemtuzumab in MS is presented.

Areas covered in this review: Mechanisms of action of alemtuzumab and the results of Phase II clinical trials in MS.

What the reader will gain: Alemtuzumab is a humanized mAb, which targets the surface molecule CD52 on all T cell populations and other cellular components of the immune system such as thymocytes, B cells, and monocytes. Alemtuzumab, which is administered intravenously, depletes T as well as B lymphocyte populations for extended periods. Adverse effects in MS patients such as thyroid disorders and idiopathic thrombocytopenic purpura are discussed.

Take home message: Alemtuzumab may hold great promise for treatment of MS patients and serve as an option for patients refractory to immunomodulatory therapies. Due to its unique mechanism of action and profound effect on MS disease activity it enhances our knowledge about pathogenic mechanisms of MS.     

Monoclonal antibodies for renal diseases: current concepts and ongoing treatments

Introduction: In recent years, technological innovations in the field of molecular biology have provided new therapeutic options. In particular, human monoclonal antibodies (mAbs), initially used in the treatment of malignancies, have become a therapeutic tool for many other diseases. Most of the application of mAbs revealed encouraging findings to treat patients with immune-mediated glomerular diseases, for whom the standard protocols based on corticosteroids and non-specific immunosuppressants with heavy side effects have for decades been the only therapies.

Area covered: Rituximab, an mAb directed against a specific antigen expressed on B lymphocytes, CD20 antigen, inducing a premature cell apoptosis became very important in the treatment of membranous glomerulonephritis, steroid-resistant nephrotic syndromes and membranoproliferative glomerulonephritis (MPGN). Another important mAb, eculizumab, is used successfully for treatment of atypical hemolytic uremic syndrome, C3 nephropathy and MPGN. Many other mAbs are now under premarketing investigation, such as adalimumab, daclizumab, fresolimumab, belimumab, tocilizumab, although some of these mAbs are already approved for different medical applications.

Expert opinion: The availability of novel mAb may therefore constitute the basis for a revolution in the treatment of immune-mediated renal diseases. However, the cost for this therapy remains very high and represents a barrier for its widespread use.     

Anti-CD37 antibodies for chronic lymphocytic leukemia

Introduction: Immunotherapy using mAbs is a safe and effective method for the treatment of chronic lymphocytic leukemia (CLL) and other lymphoid malignancies. In recent years, mAbs based on selective B-cell depletion – rituximab, ofatumumab and obinutuzumab – have been approved for use in CLL therapy. More recently, CD37, a member of the tetraspanin superfamily of cell surface antigens, has been considered as a target for B-cell malignancies.

Areas covered: The results of preclinical and early clinical studies suggest that in patients with CLL, newer anti-CD37 agents, otlertuzumab (formerly known as TRU-016), BI 836826, IMGN529 and ¹⁷⁷Lu-tetulomab can be useful in the treatment of this disease.

Expert opinion: CD37 may offer advantages over CD20 as a target for CLL cells. It is selectively expressed on normal mature B cells and by most B-cell malignancies. Anti-CD37 antibodies may be useful for patients resistant or refractory to anti-CD20 mAb therapy or relapsing after such treatment. The development of these agents into a clinically useful therapy for CLL is probably many years away and will be followed with great interest by laboratory investigators and clinicians.     

The use of monoclonal antibodies for the treatment of graft-versus-host disease following allogeneic stem cell transplantation

Introduction: Graft-versus-host disease (GVHD) remains the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Steroids along with calcineurin inhibitors remain the standard initial therapy, however, less than half of the patients completely respond and there is no uniformly accepted therapy for patients with steroid-resistant GVHD.

Areas covered: This paper reviews the current role and ongoing development of mAbs in the treatment of GVHD. Various mAbs to cell surface antigens on GVHD effector cells have been investigated for the treatment of acute GVHD: these include anti-TNF-α antibodies, IL-2 receptor antagonists, anti-CD3 and anti-CD52 mAbs, while anti-CD20 mAb has been extensively investigated in the setting of chronic GVHD. Overall, response rates have been reported to be greater than 60%, although it should be emphasized that the long-term survival still remains suboptimal, mainly due to the detrimental side effects of infectious complications, progressive GVHD and relapse of underlying malignancy.

Expert opinion: Future challenges will include more appropriate definition of these agents in the therapeutic scenario of GVHD. Combinations of mAbs or mAb combined with newer immunosuppressive drugs might potentially achieve greater success, especially if used early in the disease process.     

Alemtuzumab for the treatment of multiple sclerosis

Introduction: Alemtuzumab is a monoclonal antibody that targets for the destruction CD52+ cells, particularly B and T cells. Alemtuzumab is approved in more than 50 countries around the world for the treatment of adult patients with relapsing remitting multiple sclerosis (MS).

Areas covered: In this review, the authors summarize biological, clinical and safety data related to the use of alemtuzumab in patients with MS. The authors then provide their expert opinion on alemtuzumab and the field as of whole before providing their perspectives for the future.

Expert opinion: Alemtuzumab is highly efficacious; more so than first line treatments but comparable to natalizumab. Treatment schedule makes alemtuzumab administration easy and attractive to patients. However, its safety profile makes it a choice for a very limited number of patients, in a specific disease window. As of now, a cure for MS remains elusive and there is an unmet need for a safe and highly potent agent at the level of and beyond the blood brain barrier.     

Clinical evaluation of natalizumab for formulary consideration

Importance of the field: Natalizumab is a monotherapy for relapsing forms of multiple sclerosis (MS) and maintaining remission in Crohn's disease (CD). Evaluation of natalizumab's clinical relevance must be performed before considering its place in treatment of these diseases.

Areas covered in this review: MEDLINE and PubMed searches were performed using the keywords multiple sclerosis, Crohn's disease, natalizumab and clinical trials. The manufacturer's product information was consulted to extract additional data. Pivotal clinical trials included: Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM), Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL), Efficacy of Natalizumab as Active Crohn's Therapy (ENACT)-1 and 2 and Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE).

What the reader will gain: AFFIRM and SENTINEL showed improvements in progression of MS. ENACT-1 failed to show a significant effect, but the follow-up trials ENACT-2 and ENCORE were able to demonstrate a response to natalizumab.

Take home message: Two trials on efficacy of Tysabri for treatment of MS demonstrated positive results. Efficacy for CD was mixed. More research demonstrating head-to-head evidence against other agents is necessary to determine if Tysabri's benefits are significant.     

Complement and cellular cytotoxicity in antibody therapy of cancer

The effective and practical use of mAbs in cancer therapy became a reality with the development of the chimeric anti-CD20 mAb, rituximab. Several additional mAbs have since been approved for clinical use. Despite these successes, the mechanisms by which mAbs mediate antitumor activity are still unclear. Preclinical studies indicate complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) both can contribute to mAb-induced tumor cell lysis. However, evidence related to the relative clinical importance of each mechanism, and whether they are synergistic or antagonistic, is conflicting. New ways to enhance both CDC and ADCC are being developed in attempt to develop a more effective anticancer mAb. Continued research on the mechanisms of mAb therapy will be necessary if we are to take optimal advantage of the current mAbs and develop more effective mAbs in the future.     

Use of natalizumab in multiple sclerosis: current perspectives

ABSTRACT

Introduction: Natalizumab is an efficacious monoclonal antibody approved for use in relapsing-remitting multiple sclerosis (RRMS). Multiple studies have demonstrated reduced relapse rate, decreased disability progression and prolonged disease-free intervals with natalizumab use. However, natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), thus restricting its widespread use with populations at high risk for developing PML. Recently, the effect of natalizumab in secondary-progressive (SPMS) population has been explored.

Areas covered: This review highlights the pathophysiology behind disease progression in MS and summarizes various attributes of natalizumab including: its pharmacological properties and global economic impact, results of clinical efficacy studies, its role in SPMS, pregnancy and its adverse events profile including PML and discontinuation protocols.

Expert opinion: Despite an established role in reducing RRMS disease activity, natalizumab has found limited use in SPMS due to insufficient evidence of efficacy. Current disease-modifying therapies exert modest overall benefit in SPMS owing to its complex pathophysiology, higher prevalence of comorbidities and increased PML risk with age and lack of reliable outcome measures. Finding more appropriate MRI and clinical outcome measures is quintessential for designing future randomized trials and possibly exploring primary neuroprotective agents for treating SPMS.     

Monoclonal antibodies for the treatment of osteoarthritis

ABSTRACT

Introduction: Osteoarthritis (OA) is a multifactorial chronic joint disease, and so far, there are no approved disease-modifying anti-OA drugs (DMOADs). There is an urgent need to develop therapies for different phenotypes of OA. Monoclonal antibodies (mAb) may slow structural progression, control inflammation and relieve pain, and thus have the potential to be DMOADs.

Areas covered: In this review, the authors searched the literature on PubMed, EMBASE and the Cochrane Library using keywords, including mAbs, biological agents, OA and osteoarthritis, electronically up to May 2016. They also included abstracts of international conferences. Furthermore, they reviewed experimental and clinical studies of various mAbs targeting different pathological mechanisms of OA, including ADAMTS, Interleukine-1, tumour necrosis factor, never growth factor and vascular endothelial growth factor.

Expert opinion: MAbs for the treatment of OA are under intense investigation and the results for some mAbs (e.g., anti-nerve growth factor mAbs, anti- vascular endothelial growth factor mAbs) are promising. The authors believe that mAb therapy can be a targeted therapeutic approach for the treatment of OA. Future clinical trials are required to evaluate the therapeutic efficacy of these agents by the appropriate selection of specific phenotype for targeted therapy based on the mechanism of drug action.     

Optimizing treatment of metastatic colorectal cancer patients with anti-EGFR antibodies: overcoming the mechanisms of cancer cell resistance

Introduction: A number of anti-EGFR monoclonal antibodies (mAbs) have been recently developed for the treatment of refractory metastatic colorectal cancer (mCRC). These mAbs, blocking ligand/receptor interactions, exert their biological activity via multiple mechanisms, including inhibition of cell cycle progression, potentiation of cell apoptosis, inhibition of angiogenesis, tumor cell invasion and metastasis and, potentially, induction of immunological effector mechanisms.

Areas covered: Cetuximab is an anti-EGFR mAb currently used in mCRC treatment. Despite the evidence of efficacy of cetuximab in the treatment of mCRC patients, the observation of low response rates was the proof of concept of resistance to anti-EGFR mAbs treatment. An increasing number of molecular alterations have been more recently hypothesized to be involved in resistance to anti-EGFR mAbs in CRC: mutations in BRAF, NRAS and PIK3CA, loss of expression of PTEN and, now, activation of HER2 signaling through HER2 gene amplification and/or increased heregulin stimulation.

Expert opinion: This review focuses on the development of new strategies such as combination with other agents blocking alternative escape pathways, cancer cell prioritization hyperactivating EGFR pathway, combination with immune system, development of nanotech devices to increase efficacy of antibody-based therapy and overcome the mechanisms of cancer cell resistance.     

Monoclonal antibody therapy of B cell lymphoma

Studies in the early 1980s with anti-idiotype mAbs provided clinical proof that mAbs could be safe and effective antilymphoma agents; however, mAb therapy of lymphoma did not become practical until the chimaeric anti-CD20 mAb rituximab was developed. As a single agent, rituximab is well-tolerated and has clinical efficacy in select patient populations. A number of mechanisms of action have been identified that appear to contribute to the observed antilymphoma effects of mAb. Growing evidence suggests that multiple interacting mechanisms are likely to be involved. Anti-CD20-based radioimmunotherapy and combinations of mAb and chemotherapy are showing promise. mAbs that recognise other target antigens and immunotoxins have been evaluated clinically. It remains unclear whether these other mAbs provide value added beyond rituximab. Research geared towards understanding mAb mechanisms of action and the rational design of the next generation of mAb-based regimens will allow us to take full advantage of this exciting new mode of therapy.     

Bococizumab for the treatment of hypercholesterolaemia

Introduction: Low-density lipoprotein cholesterol (LDL-C) remains a well-established risk factor for cardiovascular disease (CVD). LDL-C levels are considered primary targets of therapy. A new series of systemic biomolecules, the monoclonal antibodies (mAbs) of proprotein convertase subtilisin/kexin type 9 (PCSK9), have a higher activity in reducing LDL-C.

Areas covered: The authors critically review the current evidence on the efficacy and safety of bococizumab, a humanized mAb against PCSK9, which was surprisingly discontinued in November 2016. The pharmacokinetic profile and the biological features of bococizumab vs others mAbs are also discussed. As of now, in adjunct to diet, alirocumab and evolocumab are the only approved PCSK9 mAbs for the treatment of adult patients with severe clinical atherosclerotic CVD already at maximally-tolerated statin therapy and require additional LDL-C lowering.

Expert opinion: Although discontinued, data from a phase 2b trial show the effectiveness of bococizumab in lowering LDL-C in a similar way to the two available PCSK9 antagonists. However, some peculiar biological characteristics of bococizumab may explain the attenuation of LDL-C lowering over time, as well as a higher rate of immunogenicity and of injection-site reactions.     

Applications of monoclonal antibodies for the treatment of hematological malignancies

Background: The introduction of mAbs has changed the clinical approach to patients with lymphoma and leukemia. Objective: To summarize the most significant applications of mAb-based regimens in the treatment of hematological malignancies and explore their possible role in the future management of these patients. Results: Rituximab (anti-CD20) was the first mAb developed for the treatment of B-cell lymphomas. Several randomized studies have demonstrated its efficacy in lymphomas and low toxicity profile; rituximab also has significant activity in chronic lymphocytic leukemia (CLL). Alemtuzumab (anti-CD52) has shown efficacy in previously untreated or refractory CLL patients, while gemtuzumab ozogamicin (anti-CD33) appears to have significant activity in acute myeloid leukemias and myelodysplastic syndromes. Conclusions: In the next few years, investigations will be concentrated on the improvement of the older mAbs, and the development of new mAbs, targeting molecules important for malignant cell cycle and survival in an attempt to further improve patient survival.     

Monoclonal antibody-based therapeutics for leukemia

Monoclonal antibodies (mAbs) represent a unique class of therapeutics because of their exquisite antigen specificity and effector mechanisms. Clinically, antibody-based therapy has increasingly become an established modality for the treatment of cancer. Among the nine mAbs and immunoconjugates approved by the FDA for therapeutic indications in oncological diseases, five are for use in hematological malignancies. Alemtuzumab is approved for B cell chronic lymphocytic leukemia; rituximab, an anti-CD20 antibody approved for the treatment of B cell non-Hodgkin's lymphoma, is being tested in patients with chronic lymphocytic leukemia; and gemtuzumab ozogamicin is marketed for relapsed acute myelogenous leukemia in patients of > 60 years of age. A number of other mAbs are in different stages of clinical development for antileukemia therapy. This article discusses the general aspects and mechanisms of action of therapeutic mAbs, and highlights the development of antibody-based therapies in leukemia.     

New antibody drug treatments for lymphoma

Introduction: The advent of anti-CD20 monoclonal antibody (mAb) rituximab heralded a new era in the treatment of non-Hodgkin's lymphoma leading to significant improvements in outcome for patients. This unprecedented success has changed the mindset of the clinical community and catalyzed the interest in the pharmaceutical industry to develop the next-generation of antibodies and antibody conjugates in cancer.

Areas covered: There are an ever increasing number of newer generation anti-CD20 and rituximab ‘bio-similars’ undergoing early phase clinical development. In addition emerging novel therapies including antibody drug conjugates (brentuximab vedotin, SGN-35) and mAb against T-cell lymphomas antigens (e.g., zanolimumab) offer hope of improved outcome for other lymphomas. Bispecific T-cell-engaging antibodies and combination immunotherapy, also provide the promise of further improvements. Radiolabelled antibodies or radioimmunotherapy (RIT) has also demonstrated high clinical activity and two drugs namely ¹³¹I-tositumomab (Bexxar) and ⁹⁰Y-ibritumomab (Zevalin) are licensed.

Expert opinion: Despite the large numbers of new anti-CD20 mAb currently undergoing clinical testing, improving on clinical efficacy of rituximab is a substantial challenge. Further improvements in outcome for patients will require rigorous testing in well designed clinical trials alongside the translation of new insights into mechanism of mAb action that lead to improvements in clinical efficacy.     

Galiximab: a review

Importance of the field: A significant number of patients relapse or do not respond to rituximab due to intrinsic or acquired resistance. Hence, mAbs targeting other cell surface antigens on B-cell lymphomas are being studied. CD80 is a glycoprotein expressed on Hodgkin's lymphoma, mature B-cell lymphomas and immunoeffector cells which may have T-regulatory, in addition to direct antitumor activity. CD80 serves as an attractive target in the continued development of mAbs against lymphoma.

Areas covered in this review: Preclinical studies with galiximab, an anti-CD80 primatized mAb, have been encouraging and have demonstrated antitumor activity against various B-cell lymphoma models, both as a single agent as well as in combination with rituximab. Data were reviewed from a PubMed literature search from 1975 to 2009 and also included a review of abstracts from published proceedings of annual meetings from the American Society of Hematology and International Conference of Malignant Lymphoma, Lugano.

What the reader will gain: Readers will gain a better understanding of mechanisms of action (both documented and proposed) of galiximab. An update of currently available clinical data will be presented.

Take home message: Data from completed clinical trials are promising and galiximab is being studied in both upfront and relapsed settings with the potential of being incorporated into the future treatment of B-cell lymphoma.     

Emerging role of Alemtuzumab in renal and renal–pancreas transplantation

Background: Alemtuzumab is a humanized anti-CD52 monoclonal antibody that is increasingly used in solid organ transplantation. Objective: The novel mechanism by which alemtuzumab works was used to provide an understanding of its clinical efficacy and adverse effects. Methods: Human studies of alemtuzumab in adult renal and pancreas transplantation were reviewed. These studies looked at the role of alemtuzumab as a tolerogenic and induction agent as well as its role in the treatment of acute rejection. Results/conclusions: Overall, alemtuzumab induction resulted in patient and graft outcomes comparable to other induction strategies but studies failed to show development of true tolerance. Economic benefit is a major attraction for alemtuzumab use. Future studies will further identify the optimal use of alemtuzumab.     

Novel approaches to biological therapy for psoriatic arthritis

ABSTRACT

Introduction: Improved understanding of the immunopathogenic mechanisms in psoriatic arthritis (PsA) has led to the development of targeted biological therapies, which demonstrate superior clinical efficacy to traditional disease-modifying antirheumatic drugs (DMARDs). There are currently 3 classes of biological agents that are approved for the treatment of psoriatic disease: tumor necrosis factor alpha inhibitors (TNFi), including etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol; ustekinumab, a monoclonal antibody (mAb) directed against interleukin (IL)-12 and IL-23; and secukinumab, a human anti-IL-17A mAb. Other agents are in development. Our growing experience with these medications has revolutionized the approach to disease management in PsA.

Areas covered: This article discusses the rationale for using biological therapies in PsA, highlighting clinical trial evidence that supports the use of these agents. We summarize novel treatment approaches using biological therapies in the management of PsA, including early intervention, targeted therapy, TNFi switching, combination therapy, and tapering or discontinuation of biological therapy. We conclude with a discussion of the importance comorbidities have on selection of therapy.

Expert opinion: The advent of highly effective biological therapies has revolutionized the management of patients with PsA. Growing experience with these agents has led to novel treatment approaches that may improve clinical outcomes for PsA patients.