Anti-infective monoclonal antibodies: perils and promise of development

So far, most monoclonal antibodies have been developed for treating cancer or immunological diseases. However, the global spread of infections such as West Nile and corona viruses, and the need to address the potential threat of bioterrorism, has boosted public interest in, and government support of, counter-measures for infectious diseases. The attractive features of monoclonal antibodies, such as high specificity and effective recruitment of the immune system, would seem to make them excellent candidates as anti-infective agents. Here, we analyse trends in the development and approval of anti-infective monoclonal antibodies, and discuss factors that influence their success.     

Antibody‐Drug Conjugates: A Clinical Pharmacy Perspective on an Emerging Cancer Therapy

Antibody‐drug conjugates (ADCs) combine highly specific monoclonal antibodies with potent cytotoxic drugs. Their synergy allows for targeted delivery of toxic drugs to cancer cells while sparing systemic exposure. In this review, we focus on the history and clinical applications of ADCs approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer and highlight new ADCs in the drug development pipeline. Three ADCs have received FDA approval thus far. Gemtuzumab ozogamicin, although withdrawn from the U.S. market, may still be an effective treatment modality in subsets of patients with acute myeloid leukemia. Brentuximab vedotin and ado‐trastuzumab emtansine have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of advanced lymphoma and breast cancer, respectively. With a number of ADCs with promising preliminary data in the clinical trial pipeline, cancer therapy is moving forward from traditional chemotherapy to targeted treatment modalities driven by the specificity of monoclonal antibodies and advancing biotechnology.     

Development trends for monoclonal antibody cancer therapeutics

Monoclonal antibodies are now established as a key therapeutic modality for a range of diseases. Owing to the ability of these agents to selectively target tumour cells, cancer has been a major focus of development programmes for monoclonal antibodies so far. Here, we overview trends in the clinical development and regulatory approval of monoclonal antibodies for cancer since 1980, with the aim of informing future research and development for this class of therapeutics.     

Infliximab

Infliximab (Remicade, Centocor, Inc.) is an intravenously administered monoclonal antibody to TNF proven effective in the treatment of moderate to severe Crohn's disease (CD). Its introduction in October 1998 was heralded by some as the most important addition to therapy for this condition in 50 years. Since then, additional indications have been added as efficacy has been proven in fistulising CD and in rheumatoid arthritis. Even though the costs associated with a single dose are several thousand US dollars, more than 150,000 patients have received infusions since its approval.     

Novel antibodies targeting immune regulatory checkpoints for cancer therapy

Cancers must evade or suppress the immune system in order to develop. Better understanding of the molecular regulation governing tumour detection and effective activation of the immune system (so called immune regulatory checkpoints) has provided new targets for cancer immunotherapy. Therapeutic monoclonal antibodies against these targets are currently undergoing clinical evaluation with more in pre-clinical development; buoyed by the recent licence approval of the anti-CTLA-4 antibody, ipilumumab, for use in melanoma. This article will review the current status of the various antibodies and target molecules being investigated.     

Therapeutic antibodies against CGRP or its receptor

CGRP is an extensively studied neuropeptide that has been implicated in the pathophysiology of migraine. While a number of small molecule antagonists against the CGRP receptor have demonstrated that targeting this pathway is a valid and effective way of treating migraine, off-target hepatoxicity and formulation issues have hampered the development for regulatory approval of any therapeutic in this class. The development of monoclonal antibodies to CGRP or its receptor as therapeutic agents has allowed this pathway to be re-investigated. Herein we review why CGRP is an ideal target for the prevention of migraine and describe four monoclonal antibodies against either CGRP or its receptor that are in clinical development for the treatment of both episodic and chronic migraine. We describe what has been publically disclosed about their clinical trials and future clinical development plans.     

Drug-conjugated monoclonal antibodies for the treatment of cancer

Early clinical development in the field of targeted delivery of cytotoxic drugs to tumors was not successful because the limitations imposed by the pharmacokinetic and pharmacodynamic properties of monoclonal antibodies were not fully appreciated. Recently, development of this concept has been reinvigorated by the approval of gemtuzumab ozogamicin for treatment of acute myeloid leukemia. Other conjugates of calicheamicin and conjugates of potent tubulin poisons (maytansinoids auristatins and taxoids) are undergoing clinical evaluation or are in preclinical development. What all of these drugs have in common is that their cytotoxic potencies are in the picomolar range. Thirty years after the discovery of monoclonal antibodies, this new generation of highly potent compounds could yield targeted cytotoxic agents that are effective treatments for many cancers.     

Hybridoma technology a versatile method for isolation of monoclonal antibodies,its applicability across species,limitations, advancement and future perspectives

The advancements in technology and manufacturing processes have allowed the development of new derivatives, biosimilar or advanced improved versions for approved antibodies each year for treatment regimen. There are more than 700 antibody-based molecules that are in different stages of phase I/II/ III clinical trials targeting new unique targets. To date, approximately more than 80 monoclonal antibodies (mAbs) have been approved. A total of 7 novel antibody therapeutics had been granted the first approval either in the United States or European Union in the year 2019, representing approximately 20% of the total number of approved drugs. Most of these licenced mAbs or their derivatives are either of hybridoma origin or their improvised engineered versions. Even with the recent development of high throughput mAb generation technologies, hybridoma is the most favoured method due to its indigenous nature to preserve natural cognate antibody pairing information and preserves innate functions of immune cells. The recent advent of antibody engineering technology has superseded the species level barriers and has shown success in isolation of hybridoma across phylogenetically distinct species. This has led to the isolation of monoclonal antibodies against human targets that are conserved and non-immunogenic in the rodent. In this review, we have discussed in detail about hybridoma technology, its expansion towards different animal species, the importance of antibodies isolated from different animal sources that are useful in biological applications, advantages, and limitations. This review also summarizes the challenges and recent progress associated with hybridoma development, and how it has been overcome in these years to provide new insights for the isolation of mAbs.     

EGFR-targeting monoclonal antibodies in head and neck cancer

The epidermal growth factor (EGF) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides the reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locoregionally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.     

Application of monoclonal antibodies as cancer therapy in solid tumors

Monoclonal antibodies have become an important new class of therapeutic agents approved for use in solid tumors. They function through several different mechanisms including inhibition of tumor-related signal transduction, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of cytotoxic agents to the tumor site. Several monoclonal antibodies have now received regulatory approval--trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab--across multiple solid tumor types, including breast, colorectal, head and neck, non-small cell lung cancers and melanomas, amongst others. These agents are employed clinically in some neoadjuvant/adjuvant and radical treatment settings, as well as more extensively in the metastatic and palliative settings. Current research is focused on innovative compound design, novel targets, predictive biomarker discovery, enriched patient populations, and combination strategies in order to overcome resistance and prolong disease control. Here we provide an overview of monoclonal antibodies approved for use in clinical oncology and those currently in clinical development.     

EGFR-targeting monoclonal antibodies in head and neck cancer

The epidermal growth factor (EGFR) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, profoundly radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides a reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.     

Monoclonal antibodies in the treatment of cancer, Part 1.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies--rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan--are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab. Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.     

Monoclonal antibodies in the treatment of cancer, Part 2.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies--rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan--are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab. Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.     

Trends in therapeutic monoclonal antibodies of cancer

Therapeutic monoclonal antibodies are increasingly applied in clinical application with great success. A variety of antibody products have been approved by the FDA since 1997. Furthermore, the industries have been paying more attention to and efforts in the field of antibody development than ever, suggesting the grand potential of the market and benefits. At present, many monoclonal antibodies have proven their therapeutic value in combination with established treatment for many diseases, as shown in FDA approved expanded indications. This old-fashioned immunotherapy exerts profound effects in many refractory and formidable diseases, especially cancers. With further understanding of the interaction between immune system and cancer, more target molecules were discovered and more promising therapeutic antibodies with improved effects will be feasible in the future. Regardless of initial development or ultimate approved drug, therapeutic monoclonal antibodies have always been associated with numerous patent applications. This review mainly focuses on potential therapeutic monoclonal antibodies in oncology and related antibody patents, and discusses the trend for antibody development and therapeutic applications in humans.     

Trends in development and approval times for new therapeutics in the United States

The process of clinical development and regulatory review of new therapeutics in the United States was significantly changed by a number of legislative acts passed in the 1980s and 1990s. These acts were designed to encourage the development of innovative products, especially for rare, serious or life-threatening diseases, and to ensure that patients had timely access to these treatments. To assess the effects of the various modifications to the process, the Tufts Center for the Study of Drug Development analysed clinical development and approval data for 554 therapeutics (504 small molecules, 40 recombinant proteins and 10 monoclonal antibodies) approved in the United States from 1980-2001. Trends in the number of approved products and the clinical development and approval times indicated that the effects of these changes were generally beneficial as of the mid- to late-1990s, but that the gains have not been sustained in the early 2000s. Current efforts by the FDA, and the pharmaceutical and biopharmaceutical industry, to reverse the recent tendency toward fewer new approvals and longer approval times are discussed.     

Preclinical and clinical safety of monoclonal antibodies

Owing to their unique specificity, monoclonal antibodies have provided a novel approach to the treatment of human diseases. Several types of antibodies against a diverse array of pharmacological targets have been marketed and many more are currently in clinical trials. Factors related to antigen expression, target pharmacology, and antibody effector functions can contribute to the adverse event profiles observed with monoclonal antibodies. Effective translation of information gained from preclinical research and safety studies into clinical development is a crucial step for successful development of monoclonal antibodies.     

Monoclonal antibody "gold rush"

The market, sales and regulatory approval of new human medicines, during the past few years, indicates increasing number and share of new biologics and emergence of new multibillion dollar molecules. The global sale of monoclonal antibodies in 2006 were $20.6 billion. Remicade had annual sales gain of $1 billion during the past 3 years and five brands had similar increase in 2006. Rituxan with 2006 sales of $4.7 billion was the best selling monoclonal antibody and biological product and the 6th among the top selling medicinal brand. It may be the first biologic and monoclonal antibody to reach $10 billion annual sales in the near future. The strong demand from cancer and arthritis patients has surpassed almost all commercial market research reports and sales forecast. Seven monoclonal antibody brands in 2006 had sales exceeding $1 billion. Humanized or fully human monoclonal antibodies with low immunogenicity, enhanced antigen binding and reduced cellular toxicity provide better clinical efficacy. The higher technical and clinical success rate, overcoming of technical hurdles in large scale manufacturing, low cost of market entry and IND filing, use of fully human and humanized monoclonal antibodies has attracted funds and resources towards R&D. Review of industry research pipeline and sales data during the past 3 years indicate a real paradigm shift in industrial R&D from pharmaceutical to biologics and monoclonal antibodies. The antibody bandwagon has been joined by 200 companies with hundreds of new projects and targets and has attracted billions of dollars in R&D investment, acquisitions and licensing deals leading to the current Monoclonal Antibody Gold Rush.     

Comparability and biosimilarity: considerations for the healthcare provider

Abstract

Background:

Healthcare providers use recombinant biologics such as monoclonal antibodies to treat a variety of serious illnesses. Manufacturing of approved biotechnology products is complex, and the quality of the resulting biologic is dependent on careful control of process inputs and operating conditions. Biosimilars, which are similar but not identical to innovator biologics, are entering regulatory evaluation, approval, and marketing in regions with biosimilar approval pathways.     

Novel therapeutic approaches to autoimmune demyelinating disorders

Multiple Sclerosis (MS) is the most common autoimmune demyelinating disorder in Western countries and can lead to permanent disability. Over the past decades remarkable progress has been made in providing new therapeutic strategies to tackle the burden of the disease. Oral drugs and monoclonal antibodies are the main innovative approaches that have been tested in advanced stage clinical trials. Several new drugs have been shown to be superior to traditional disease modifying treatments (DMTs), in terms of both clinical and imaging outcome measures. Oral drugs have the advantage of offering a convenient route of administration. Recently fingolimod has received approval for the treatment of relapsing remitting (RR)-MS in several countries, becoming the first oral drug available to patients. Whilst the majority of the current studies focus on RR-MS, some trials investigate the primary or secondary progressive subtypes as well as the early forms of the disease aiming at delaying the conversion to clinically definite MS. Overall the future of the treatment options looks promising, although the occurrence of significant adverse events in some instances points to cautious evaluation of risks and benefits. Extension studies for most of the new drugs are under way and will provide evidence on the efficacy and long term effects of the new treatment strategies.