Monoclonal antibodies specific for differentiation antigens of human myelomonocytic cells

Several monoclonal antibodies specific for human cells of the myelomonocytic lineage at discrete stages of differentiation have been described. In this review I briefly summarize the results obtained with these reagents and discuss their possible use for the study of cell lineage and functional activities of normal peripheral blood leukocytes, for the analysis of myelomonocytic cell differentiation in vivo and in vitro and for the antigenic phenotyping of leukemia cells.     

Monoclonal antibodies reactive with the mouse interleukin 5 receptor

The rat mAbs R52.120 and R52.625 inhibit the action of IL-5 on both IL-5-sensitive cell lines and freshly isolated splenic B lymphocytes. Neither antibody inhibits the proliferative cell responses promoted by IL-2, IL-3, or IL-4. Purified R52.120+ lymphoid spleen cells contain 15-20-fold higher numbers of B lymphocytes responding to IL-5 in the form of maturation into antibody-producing cells. By immunofluorescence staining and flow fluorocytometry, the R52.120 and R52.625 antibodies bound to all 12 IL-5-sensitive cell lines tested. Both antibodies react with 2-4% cells in the spleen, 5% lymphoid cells, and 10-15% myeloid cells in the bone marrow, and 10-14% in the peritoneum of C57BL/6, DBA/2, and BALB/c adult mice. No positive cells for either antibody were detected in the thymus and lymph nodes of these mice. Both R52.120 and R52.625 antibodies specifically inhibit the binding of radiolabeled IL-5 to its receptor. Finally, R52.120 and R52.625 antibodies precipitate from 35S-methionine-labeled IL-5-R+ cell lysates three proteins with Mr 46,000, 130,000, and 140,000. Taken together from these results, we conclude that the R52.120 and R52.625 mAbs recognize epitopes on the IL-5-R complex very close or identical to the IL-5 binding sites.     

Monoclonal antibodies with specificity for hairy cell leukemia cells.

Hairy cell leukemia is a well described clinical entity, but the cell of origin for this leukemic cell and its function are still unknown. There are no totally specific markers for this cell, although tartrate-resistant acid phosphatase staining has been used extensively as a diagnostic test. This study describes three monoclonal murine antibodies with variable specificity for hairy cells. Antibody 1 was highly specific for hairy cells and was not found to react with normal or leukemic cells in this limited study. It did not react with the cells of all patients. It also did not react with all of the hairy cells of some of the positive cases. Antibodies 2 and 3 reacted with virtually all hairy cells but not with normal peripheral blood cells. However, reactions were obtained with certain leukemic myelomonoblasts and some activated B cells. The most obvious use for these three antibodies is for diagnostic purposes. They should also be helpful reagents to investigate the origin of the leukemic hairy cell. The possibility that antibody 1 detects a tumor-specific antigen is discussed.     

Monoclonal antibodies for treating osteoporosis

Introduction: Osteoporosis is the most widespread skeletal disease requiring innovative therapeutic strategies for its management. The understanding of receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin’s role in bone cell biology is completely changing the therapeutic landscape. RANKL supports osteoclast formation and activity and is mainly produced by cells of osteoblastic lineage. Sclerostin, an antagonist of the Wnt pathway, has a key role in bone formation and is mainly secreted by osteocytes. High levels of RANKL and sclerostin have been detected in osteoporosis, leading to the production of antibodies able to neutralize their activity.

Areas covered: In this review, the authors give an overview and discuss the literature and data on denosumab and romosozumab to treat osteoporosis. Clinical studies indicate that long-term treatment with denosumab causes a continuous increase in bone mineral density with low incidence of adverse effects. Romosozumab treatment gives increases bone formation and improves bone mineral density (BMD) though further studies are needed to better evaluate the adverse effects.

Expert opinion: Denosumab and romosozumab show promise in the treatment of osteoporosis. Furthermore, their different mechanisms of action compared to existing anti-osteoporotic drugs may permit alternative strategies for osteoporosis treatment down the line.     

Monoclonal antibodies for malaria prevention

Monoclonal antibodies are highly specific proteins that are cloned from a single B cell and bind to a single epitope on a pathogen. These laboratory-made molecules can serve as prophylactics or therapeutics for infectious diseases and have an impressive capacity to modulate the progression of disease, as demonstrated for the first time on a large scale during the COVID-19 pandemic. The high specificity and natural starting point of monoclonal antibodies afford an encouraging safety profile, yet the high cost of production remains a major limitation to their widespread use. While a monoclonal antibody approach to abrogating malaria infection is not yet available, the unique life cycle of the malaria parasite affords many opportunities for such proteins to act, and preliminary research into the efficacy of monoclonal antibodies in preventing malaria infection, disease, and transmission is encouraging. This review examines the current status and future outlook for monoclonal antibodies against malaria in the context of the complex life cycle and varied antigenic targets expressed in the human and mosquito hosts, and provides insight into the strengths and limitations of this approach to curtailing one of humanity’s oldest and deadliest diseases.

This review discusses the use of monoclonal antibodies for the prevention of malaria, describing the prospects and challenges of this strategy in the context of the complex Plasmodium life cycle. Several antibodies are discussed in detail, providing a thorough overview of this approach to malaria prevention.     

Monoclonal antibodies specific for murine p55 and p75 tumor necrosis factor receptors: identification of a novel in vivo role for p75

Monoclonal antibodies (mAbs) specific for the murine p55 and p75 tumor necrosis factor (TNF) receptors were produced after immunization of Armenian hamsters with the purified soluble extracellular domains of each receptor protein. Four p55- (55R) and five p75 (TR75)-reactive mAbs immunoprecipitated the appropriate receptor from the surface of L929 cells. None of the mAbs cross-reacted with the other TNF receptor form. The mAbs were functionally characterized by their ability to inhibit ligand binding and influence TNF-dependent L cell cytolytic activity or proliferation of the murine cytolytic T cell clone CT6. One p55-specific mAb, 55R-593, displayed agonist activity, while two other p55-specific mAbs (55R-170 and -176) were found to be TNF antagonists. The fourth mAb (55R-286) had no functional effects on cells. Several antibodies specific for the p75 TNF receptor partially inhibited recombinant murine TNF-alpha-dependent cytolytic activity (60%). Blocking mAbs specific for p75 but not anti-p55 inhibited TNF-mediated proliferation of CT6 T cells. When used in vivo, p55- but not p75- specific mAbs protected mice from lethal endotoxin shock and blocked development of a protective response against Listeria monocytogenes infection. In contrast, both p55 and p75 mAbs individually blocked development of skin necrosis in mice treated with murine TNF-alpha. These data thus demonstrate the utility of the two families of murine TNF receptor-specific mAbs and identify a novel function of the p75 TNF receptor in vivo.     

Monoclonal antibodies to polioviruses. Production of specific monoclonal antibodies to the Sabin vaccine strains

Murine lymphocyte hybridomas which produce neutralizing or non-neutralizing monoclonal antibodies to different type 1, 2 or 3 poliovirus strains were isolated. The majority of these monoclonal antibodies reacted with antigenic determinants present on different poliovirus strains of the same type. However, hybridomas producing monoclonal antibodies specific for each of the three Sabin vaccine strains were also generated.     

Monoclonal antibodies for brain tumour treatment

Conventional treatment of brain tumours includes surgical, radiotherapeutic and chemotherapeutic modalities. Nonetheless, the outcome of patients with brain tumours, in particular glioblastoma, remains poor. Immunotherapy with armed or unarmed monoclonal antibodies targeting tumour-specific antigens has emerged in the last two decades as a novel potential adjuvant treatment for all types of neoplasia. Many challenges to its implementation as a safe and viable therapy for brain tumours still need to be addressed; nevertheless, results from ongoing Phase I/II clinical trials are encouraging, as disease stabilisation and patient survival prolongation have been observed. Advances in preclinical and clinical research indicate that treatment of brain tumours with monoclonal antibodies can be increasingly adjusted to the characteristics of the targeted tumour and its environment. This aspect relies on the careful selection of the target antigen and corresponding specific monoclonal antibody, and antibody format (size, class, affinity), conjugation to the appropriate toxin or radioactive isotope (half-life, range), and proper compartmental administration.     

Monoclonal antibodies for brain tumour treatment

Conventional treatment of brain tumours includes surgical, radiotherapeutic and chemotherapeutic modalities. Nonetheless, the outcome of patients with brain tumours, in particular glioblastoma, remains poor. Immunotherapy with armed or unarmed monoclonal antibodies targeting tumour-specific antigens has emerged in the last two decades as a novel potential adjuvant treatment for all types of neoplasia. Many challenges to its implementation as a safe and viable therapy for brain tumours still need to be addressed; nevertheless, results from ongoing Phase I/II clinical trials are encouraging, as disease stabilisation and patient survival prolongation have been observed. Advances in preclinical and clinical research indicate that treatment of brain tumours with monoclonal antibodies can be increasingly adjusted to the characteristics of the targeted tumour and its environment. This aspect relies on the careful selection of the target antigen and corresponding specific monoclonal antibody, and antibody format (size, class, affinity), conjugation to the appropriate toxin or radioactive isotope (half-life, range), and proper compartmental administration.     

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.     

Monoclonal antibodies for the treatment of osteoporosis

Introduction: Osteoporosis is a systemic skeletal disorder that weakens bones and increases the risk of fractures. It is caused by perturbations of bone remodeling, the coupled process whereby bone is continually resorbed and formed in small discrete units. Despite the availability of cost-effective pharmacological agents that reduce fracture risk, many patients who could benefit from treatment are not receiving it. Advances in the understanding of the molecular regulators of bone remodeling have led to the identification of new targets for therapeutic intervention. Monoclonal antibodies directed to these targets have recently been developed, providing new ways of modulating bone remodeling that may provide additional benefits beyond previously available therapy.

Areas covered: An approved fully human monoclonal antibody to receptor activator of nuclear factor-κB ligand, the principal regulator of osteoclastic bone resorption, reduces the risk of fractures in postmenopausal women with osteoporosis. Monoclonal antibodies in development include inhibitors of sclerostin and Dickhopf1, with osteoanabolic activity that may be beneficial in the treatment of osteoporosis.

Expert opinion: Monoclonal antibodies to molecular regulators of bone remodeling represent a new class of compounds for the management of osteoporosis and other skeletal disorders associated with an imbalance of bone resorption and formation.     

Monoclonal antibodies for the treatment of asthma

Asthma is a chronic inflammatory disease of the airways which can have a detrimental effect on quality of life and in extreme cases cause death. Although the majority of patients can control their asthma symptoms with a combination of steroids and beta agonists there is still a group of patients whose asthma remains symptomatic despite the best available treatment. These severe asthmatic patients represent the unmet medical need in asthma and are the focus of those developing novel monoclonal antibody based drugs. The complex networks of cytokines and cells involved in the pathology of asthma provide plenty of scope for intervention with monoclonal antibody based drugs which are able to block cytokine or chemokine receptor interactions, deplete cells expressing a specific receptor or block cell/cell interactions. At present anti-IgE (Xolair©) is the only monoclonal antibody based drug approved for the treatment of asthma. However, a number of other antibody based drugs have been clinically tested in asthma including anti-IL-5, anti-IL-4, anti-IL-13, anti-TNFα, anti-CCR3, anti-CCR4 and anti-OX40L. This review will examine the development of these monoclonal antibody based therapies. Since many of these therapies have targeted key pathways in asthma pathology these studies provide information on patient stratification and asthma pathology.     

Monoclonal antibodies to transthyretin

Monoclonal antibodies (mabs) have been raised against human transthyretin (hTTR). The protein was isolated by an affinity chromatography procedure using Sepharose-hRBP and BALB/c mice were immunized. Following fusion with SP 2/0 myeloma cells, 26 single cell clones producing antibodies against hTTR were isolated. These mabs have been characterized and efforts have been made to establish the epitopes that they recognize. So far at least two different epitopes have been identified both residing in a mid-region fragment corresponding to the amino acid sequence 35-103 of the hTTR subunit. All mabs have been found suitable for immunohistochemical localization of hTTR even in formaldehyde fixed and paraffin embedded tissues.     

Monoclonal antibodies to enzymes

The production, identification, and utilisation of monoclonal antibodies to enzymes are reviewed. Such antibodies may be produced in vitro by the mouse-hybridoma technique, may occur naturally in vivo as enzyme-binding immunoglobulins and may be produced in the laboratory from the lymphocytes of patients whose sera contains such immunoglobulins. The diagnostic application of monoclonal antibodies to enzymes is considered, with special reference to their use in the measurement of the MB-isoenzyme of creatine kinase, pancreatic isoamylase, prostatic acid phosphatase, and the isoenzymes of alkaline phosphatase.