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Concept: Nomenclature of monoclonal antibodies


Malignant Mesothelioma (MM) is a highly aggressive tumor with poor prognosis. Multimodal treatments and novel molecular targeted therapies against MM are in high demand in order treat this disease effectively. We have developed a humanized monoclonal antibody YS110 against CD26 expressed in 85 % of MM cases. CD26 is thought to be involved in tumor growth and invasion by interacting with collagen and fibronectin, or affecting signal transduction processes.

Concepts: Immune system, Protein, Cancer, Bacteria, Cell division, Monoclonal antibodies, Integrin, Nomenclature of monoclonal antibodies


The experience from clinical trials indicates that anti-Aβ immunotherapy could be effective in early/pre-clinical stages of AD, whereas at the late stages promoting the clearing of Aβ alone may be insufficient to halt the disease progression. At the same time, pathological tau correlates much better with the degree of dementia than Aβ deposition. Therefore, targeting pathological tau may provide a more promising approach for the treatment of advanced stages of AD. Recent data demonstrates that the N-terminal region of tau spanning aa 2-18 termed “phosphatase activation domain” that is normally hidden in the native protein in ‘paperclip’-like conformation, becomes exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and in aggregation of tau. Hence, we hypothesized that anti-Tau2-18 monoclonal antibodies (mAb) may recognize pathological, but not normal tau at very early stages of tauopathy and prevent or decrease the aggregation of this molecule.

Concepts: Immune system, Protein, Monoclonal antibodies, Immunology, Immunohistochemistry, Nomenclature of monoclonal antibodies


Fremanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being investigated as a preventive treatment for migraine. We compared two fremanezumab dose regimens with placebo for the prevention of chronic migraine.

Concepts: Immune system, Protein, Calcitonin, Calcitonin gene-related peptide, Monoclonal antibodies, Immunohistochemistry, Nomenclature of monoclonal antibodies, Telcagepant


Countermeasures against potential biothreat agents remain important to US Homeland Security, and many of these pharmaceuticals could have dual use in the improvement of global public health. Junin virus, the causative agent of Argentine hemorrhagic fever (AHF), is an arenavirus identified as a category A high-priority agent. There are no Food and Drug Administration (FDA) approved drugs available for preventing or treating AHF, and the current treatment option is limited to administration of immune plasma. Whereas immune plasma demonstrates the feasibility of passive immunotherapy, it is limited in quantity, variable in quality, and poses safety risks such as transmission of transfusion-borne diseases. In an effort to develop a monoclonal antibody (mAb)-based alternative to plasma, three previously described neutralizing murine mAbs were expressed as mouse-human chimeric antibodies and evaluated in the guinea pig model of AHF. These mAbs provided 100% protection against lethal challenge when administered 2 d after infection (dpi), and one of them (J199) was capable of providing 100% protection when treatment was initiated 6 dpi and 92% protection when initiated 7 dpi. The efficacy of J199 is superior to that previously described for all other evaluated drugs, and its high potency suggests that mAbs like J199 offer an economical alternative to immune plasma and an effective dual use (bioterrorism/public health) therapeutic.

Concepts: Immune system, Antibody, Monoclonal antibodies, Immunology, Monoclonal antibody therapy, Viral hemorrhagic fever, Arenavirus, Nomenclature of monoclonal antibodies


From the development of the first transgenic mouse model of brain amyloidosis, and the remarkable report on the dramatic effect of active immunization against aggregated amyloid peptide on this model, anti-amyloid immunotherapy has been the leading strategy for disease-modifying drug development. But progress has been devastatingly slow. Development of the active vaccine for human AD was halted because of meningoencephalitis in a small percentage of treated individuals. While efforts turned to the development of safer active vaccines, using short sequence antigens to minimize toxicity mediated by cellular immunity, many companies sought development of passive immunotherapy. This approach affords much greater control- a monoclonal antibody, free of risk of cellular immune response, with controllable dose and frequency. Four monoclonal anti-amyloid antibodies have advanced into mid- and late-phase trials. Bapineuzumab is a humanized monoclonal antibody directed against the N-terminal sequence of the amyloid peptide. It is based on the most prevalent type of antibody induced by the failed active vaccination program. N-terminal epitopes are displayed in aggregated forms of amyloid, so these antibodies recognize aggregates including deposited fibrils. Animal studies indicate brain amyloid reduction, and suggest enhanced microglial phagocytosis as a mechanism. Bapineuzumab carries a risk of vasogenic edema and microhemmorhage (ARIA-E and ARIA-H), with risk related to drug dose and number of apolipoprotein E alleles. A phase II amyloid PET study indicated that bapineuzumab treatment reduces fibrillar amyloid in brain in individuals with AD. Topline results announced by the sponsors indicate that bapineuzumab treatment did not improve cognition or function in the pivotal trials in mild to moderate AD. In contrast to bapineuzumab, solanezumab is a humanized monoclonal antibody that targets a mid-sequence amyloid peptide epitope. This antibody binds tightly to monomeric amyloid peptides, but not to aggregated or fibrillar forms. Solanezumab is also effective in reducing amyloid in transgenic mice. The proposed mechanism involves peripheral sequestration of monomeric amyloid peptide, reducing the central amyloid pool. Solanezumab does not carry the same risk of ARIA as bapineuzumab. Topline results from the recently completed pivotal trials in mild to moderate AD indicate that primary efficacy goals were not met, though pooled analyses suggest cognitive benefits. Crenezumab also binds to a mid-sequence epitope, but differs from solenazumab in that it possesses an IgG4 (rather than IgG1) backbone, so that it triggers less cytokine production from microglia while maintaining phagocytosis towards amyloid. In vitro studies indicate that crenezumab binds to Aβ fibrils and oligomers, and to some extent monomers. Crenezumab treatment reduces brain amyloid plaque burden in transgenic mice. Phase 1 studies suggest that crenezumab may not cause vasogenic edema, though sample sizes were small. Crenezumab has been selected for the coming trial in familial autosomal dominant AD conducted by the Alzheimer’s Prevention Initiative group. Gantenerumab is a fully human monoclonal antibody that binds to both N-terminus and mid-sequence epitopes, and shows high affinity for fibrils. Like bapineuzumab, early studies demonstrated that treatment reduced brain amyloid as indicated by PET imaging, supporting target engagement. Trials in mild to moderate AD and prodromal AD are under way. SAR228810 is a humanized antibody that recognizes a particular conformational epitope that allows it to bind specifically protofibrils and fibrils. A phase 1 single and multiple dose administration clinical study in patients with Alzheimers Disease is ongoing. Ongoing analyses of the data from the two most advanced monoclonal antibody programs will address critical issues beyond the primary efficacy results. To optimize the development of disease-modifiers, careful attention must be directed to lessons from these studies. What characteristics of antibodies (eg, epitope specificity, tightness of binding, inflammatory potential) relate to biomarker, cognitive and adverse effects? How robust is reduction in amyloid PET signal? What is the impact on biomarkers of AD neurodegeneration such as cerebrospinal fluid tau and p-tau? How does immunotherapy alter regional atrophy rates as indicated by volumetric magnetic resonance imaging? Is there evidence relating bioomarker effects to impact on cognition? Which cognitive assessments are most sensitive to immunotherapy effects? How do subject characteristics such as disease severity and genotype influence immunotherapy effects? Does the timing of biomarker effects support their use in early futility analyses? How are adverse effects best minimized and managed? The details of trial design must be based on the best available answers to these questions. Pre-competitive collaboration and data-sharing will accelerate progress. Most industry and academic scientists believe that anti-amyloid therapy will be most effective early in the disease process, before there is substantial irreversible neurodegeneration and synaptic failure. Several companies are now pursuing pre-dementia trials, using biomarkers to select individuals with mild cognitive impairment and biomarker evidence of AD. Several academic consortia will soon launch anti-amyloid trials in preclinical (asymptomatic) disease, in sporadic and genetically-determined populations; these groups are pooling data, ideas and resources to increase the likelihood of success. The putative importance of stage of disease on therapeutic effect must be considered in planning further studies; an agent that has minimal or no clinical efficacy in AD dementia could prove enormously beneficial if administered at the preclinical stage of AD. We cannot afford to prematurely abandon anti-amyloid interventions. It is essential that we utilize the lessons of completed trials, but continue to pursue trial designs to reveal disease-modification at the earliest possible stage. Indeed, we should work toward sufficient understanding of the onset of AD neurobiology to support the design of primary prevention studies, aiming to control amyloid dysregulation with single or combination anti-amyloid therapy before there is measurable brain amyloid accumulation.

Concepts: Alzheimer's disease, Immune system, Antibody, Clinical trial, Monoclonal antibodies, Antigen, Epitope, Nomenclature of monoclonal antibodies


An American Society of Clinical Oncology Provisional Clinical Opinion (PCO) offers timely clinical direction after publication or presentation of potentially practice-changing data from major studies. This PCO update addresses the utility of extended RAS gene mutation testing in patients with metastatic colorectal cancer (mCRC) to detect resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) therapy.

Concepts: Immune system, DNA, Cancer, Epidermal growth factor receptor, Monoclonal antibodies, Monoclonal antibody therapy, Colorectal cancer, Nomenclature of monoclonal antibodies


Dengue virus (DENV) infection imposes enormous health and economic burden worldwide with no approved treatment. Several small molecules, including lovastatin, celgosivir, balapiravir and chloroquine have been tested for potential anti-dengue activity in clinical trials; none of these have demonstrated a protective effect. Recently, based on identification and characterization of cross-serotype neutralizing antibodies, there is increasing attention on the potential for dengue immunotherapy. Here, we tested the ability of VIS513, an engineered cross-neutralizing humanized antibody targeting the DENV E protein domain III, to overcome antibody-enhanced infection and high but brief viremia, which are commonly encountered in dengue patients, in various in vitro and in vivo models. We observed that VIS513 efficiently neutralizes DENV at clinically relevant viral loads or in the presence of enhancing levels of DENV immune sera. Single therapeutic administration of VIS513 in mouse models of primary infection or lethal secondary antibody-enhanced infection, reduces DENV titers and protects from lethal infection. Finally, VIS513 administration does not readily lead to resistance, either in cell culture systems or in animal models of dengue infection. The findings suggest that rapid viral reduction during acute DENV infection with a monoclonal antibody is feasible.

Concepts: Immune system, Antibody, Protein, Monoclonal antibodies, In vivo, Immunity, In vitro, Nomenclature of monoclonal antibodies


Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders.

Concepts: Immune system, Monoclonal antibodies, Immunology, Cytokines, Multiple sclerosis, IL-2 receptor, Nomenclature of monoclonal antibodies


Therapeutic monoclonal antibodies (mAbs) such as the superagonistic, CD28-specific antibody TGN1412, or OKT3, an anti-CD3 mAb, can cause severe adverse events including cytokine release syndrome. A predictive model for mAb-mediated adverse effects, for which no previous knowledge on severe adverse events to be expected or on molecular mechanisms underlying is prerequisite, is not available yet. We used a humanized mouse model of human peripheral blood mononuclear cell-reconstituted NOD-RAG1-/-Aβ-/-HLADQ(tg+ or tg-)IL-2Rγc-/- mice to evaluate its predictive value for preclinical testing of mAbs. 2-6 hours after TGN1412 treatment, mice showed a loss of human CD45+ cells from the peripheral blood and loss of only human T cells after OKT3 injection, reminiscent of effects observed in mAb-treated humans. Moreover, upon OKT3 injection we detected selective CD3 downmodulation on T cells, a typical effect of OKT3. Importantly, we detected release of human cytokines in humanized mice upon both OKT3 and TGN1412 application. Finally, humanized mice showed severe signs of illness, a rapid drop of body temperature, and succumbed to antibody application 2-6 hours after administration. Hence, the humanized mouse model used here reproduces several effects and adverse events induced in humans upon application of the therapeutic mAbs OKT3 and TGN1412.

Concepts: Immune system, Antibody, Cytokine, Monoclonal antibodies, Immunology, Monoclonal antibody therapy, TGN1412, Nomenclature of monoclonal antibodies


Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.

Concepts: AIDS, Immune system, Antibody, Bacteria, Blood, Monoclonal antibodies, Immunology, Nomenclature of monoclonal antibodies