Monoclonal antibody

Summary

A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies can have monovalent affinity, binding only to the same epitope (the part of an antigen that is recognized by the antibody). In contrast, polyclonal antibodies bind to multiple epitopes and are usually made by several different antibody-secreting plasma cell lineages. Bispecific monoclonal antibodies can also be engineered, by increasing the therapeutic targets of one monoclonal antibody to two epitopes. It is possible to produce monoclonal antibodies that specifically bind to almost any suitable substance; they can then serve to detect or purify it. This capability has become an investigative tool in biochemistry, molecular biology, and medicine. Monoclonal antibodies are being used on a clinical level for both the diagnosis and therapy of sever

Official source

https://en.wikipedia.org/wiki/Monoclonal_antibody

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Vaccines currently represent one of the most effective means to control and prevent infectious diseases affecting humans and animals and have dramatically improved public health, quality of life, and life expectancy. Over the last years several conceptual and technological advances in the field of bioengineering and immunology have allowed the development of new vaccines designs. Expanding novel domains such as structural biology, human monoclonal antibody isolation, high throughput sequencing, and design of new nanocarrier delivery platforms have changed the landscape of vaccinology. These new vaccine formulations allow the design of tailor-made antigens and particulate vehicles which allow better and fine-tuned protective immune responses against known and newly emerging pathogens. Over the past decades emerging human pathogens with the potential to cause severe epidemics have become a major public health problem. The last Ebola and Zika virus epidemics demonstrated in a dramatic manner that there is an urgent need to develop prophylactic and therapeutic approaches against pathogenic emerging viruses. Most successful vaccines rely on attenuated live microorganisms to induce protective immunity. However, changed demographics and associated safety concerns makes the development of a safer alternative a priority. Subunit vaccines composed of microbial components and proteins have emerged as a suitable alternative, however they are generally less immunogenic. To address this problematic our laboratory works on the development of immunization platforms which allow 1) the development of safe recombinant subunit vaccines and 2) the rapid generation of specific monoclonal antibodies using biosynthetic immunogens without the need for prior isolation and culture of the agent. The approach evaluated in the present studies is based on a novel polymersome (PS) platform serving as nanocarrier for efficient antigen delivery and the induction of humoral immunity. The potential of PS was assessed in the context of two important human emerging pathogens form the arenavirus family that cause severe hemorrhagic fevers and of which there are neither FDA-approved vaccines not prophylactic treatments: Lassa virus (LASV), endemic in Western Africa, and Machupo virus (MACV), the causative agent of Bolivian hemorrhagic fever. In a first part, we evaluated the PS platformâs capacity to enhance humoral immunity against the envelope glycoprotein 1 of LASV, (LASV GP1) that is notorious for its weak immunogenicity and poor antibody response. Immunization of mice with adjuvanted PS (LASV GP1) enhanced the quality of the humoral response to LASV GP1, eliciting antibodies with higher binding affinity to virion GP1, increased levels of polyfunctional anti-viral CD4 T cells, and the frequency of IgG-secreting B cells. PS (LASV GP1) elicited a more diverse epitope repertoire of anti-viral IgG. In a second part, we employed the PS platform in combination with single cell B cell sorting and cloning of recombinant IgG to generate a first set of species-specific mAbs against MACV. These new mAbs show exquisite specificity and negligible cross-reactivity to closely related arenaviruses in relevant techniques making them a unique and powerful tool for research and diagnostics purposes.

EPFL2017

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

Malignant gliomas represent 80% of tumors developing in the central nervous system, with 50% being glioblastomas (GBM), the most aggressive form of the disease. The benefit from current therapies is very limited, the overall 5-year survival rate of patients with GBM being less than 5%. Thus, there is an urgent need for better therapies. It has been reported that the use of tricyclic antidepressants (TCAs) is linked with reduced incidence of gliomas. In line with these observations, our lab previously demonstrated that combining imipramine (IM), a TCA that activates adenylate cyclase and elevates production of cAMP, with ticlopidine (TIC), an inhibitor of the purinergic receptor P2Y12 that otherwise suppresses cAMP, results in a concerted increase in the levels of intracellular cAMP, which consequently stimulates increased autophagy in glioma cells, leading to autophagy-associated cell death (AACD) in culture and during orthotopic tumor growth. In several mouse models of glioma, the combination improved survival and reduced malignant grade. Seeking to assess the therapeutic translational potential of these repurposed drugs, particularly IM, we performed pre-clinical trials combining IM+/-TIC with anti-VEGF therapy, which is commonly used in patients with GBM; such anti-angiogenic therapy is associated with a transitory improvement in progression-free survival and quality of life, but does not translate into an overall survival benefit. Using genetic mouse models with enabling bioluminescent monitoring of the cancer cells, we treated established GBMs with imipramine, ticlopidine, and B20S, an anti-mouse VEGF monoclonal antibody. We observed transient stabilization of tumor growth, and the overall survival was significantly extended in the regimens combining B20S with IM +/- TIC compared to control and single treatments. Similar to clinical observations in GBM patients treated with anti-angiogenic therapy, mice treated with B20S alone had no survival benefit, implicating a synergetic effect for the combination of anti-VEGF treatment with imipramine and ticlopidine. We found that the combinatorial therapy elicited further increases in autophagy and displayed some indication of blood vessel normalization, concomitant with an elevation of CD8+T lymphocyte infiltration into the orthotopic tumors. Notably, we could partially reverse the beneficial effect of the combinations using a CD8+T cell-depleting antibody, revealing the involvement of the recruited CD8+T cells in the efficacy of the combinatorial treatment, in addition to the cell-intrinsic autophagy-associated death that is demonstrable in culture and in tumors. Together, these results suggest a strategy to improve anti-angiogenic therapy in patients with glioblastoma, by using repurposed FDA-approved drugs that markedly elevate autophagy in concert with anti-VEGF therapy. The recruitment of CD8+ T cells into the treated tumors and their evident contribution to therapeutic efficacy motivates ongoing experiments aimed to heighten and sustain the induced anti-tumor immune response.

EPFL2018

Introducing tolerance to foreign and partly foreign proteins by erythrocyte binding and artificial glycosylations

Kym Lorenz Brünggel

Over the last few years, protein drugs have steadily gained importance in the clinic. Compared to small molecule drugs, protein drugs are taken up by antigen presenting cells, which degrade the proteins into peptides that are then presented on major histocompatability complex I and II to CD8+ respectively CD4+ T-cells. CD4+ T-cells are then able to activate B-cells, which upon activation will produce anti-drug antibodies. While anti-drug antibodies have mostly been viewed as a safety risk leading to drug injection related side effects, they have recently been proven to diminish the efficacy of the treatment. High antibody titers against Humira, a clinically approved monoclonal antibody used to treat rheumatoid arthritis, have been associated with low serum drug concentration and high disease activity score, ultimately leading to treatment failure. Two approaches to induce tolerance were developed in the Hubbell lab. One approach utilizes protein variants that are designed to bind to circulating erythrocytes. As 1 % of erythrocytes undergo apoptosis each day and are taken up by antigen presenting cells, along with the bound protein, they are presented to the immune system in a non-inflammatory tolerogenic fashion. Immunological tolerance is thereby induced against the apoptotic erythrocyte debris and the associated bound protein. The second approach uses synthetic glucose, galactose or mannose polymers conjugated to the target protein. The polymers target C-type lectins, which are known to clear apoptotic debris, leading to presentation of the protein by hepatic antigen presenting cells in a tolerogenic liver microenvironment. This thesis investigates the potential of these approaches to induce tolerance towards protein drugs. Arylsulfatase B was used as a model protein to investigate the potential of tolerance induction by targeting circulating erythrocytes, as 97% of patients receiving arylsulfatase B develop anti-drug antibodies. An erythrocyte binding variant of arylsufatase B was created by chemically conjugating the erythrocyte binding peptide ERY1 to arylsulfatse B. In mice receiving two doses of ERY1-arylsulfatase B one week apart followed by weekly doses of arylsulfatase B a significant delay of four week in the production of anti-drug Antibodies was found when compared to mice receiving weekly doses of only arylsulfatase B. To investigate the ability of synthetic glyco-polymers to induce tolerance towards protein drugs we used asparaginase as model protein. Between 37.5 % to 75% of patients treated with asparaginase develop anti-drug antibodies. Administering three intravenous injections of asparaginase-conjugated to glucose polymers before eight weeks of treatment with asparaginase significantly reduced anti-drug antibody titers by a factor of 125 when compared to animals only receiving eight weeks of treatment with asparaginase. Three pre-injections with asparaginase conjugated to the galactose or mannose polymer led to a reduction in anti-drug antibody titers by a factor of 12 respectively 400 after 5 weeks of treatment with asparaginase when compared to mice receiving only asparaginase for 5 weeks. These results indicates that synthetic glyco polymers, especially mannose and glucose based ones, are able to induce long term tolerance towards asparaginase. Synthetic glucose and mannose polymers therefore represent an excellent molecular approach to induce tolerance towards protein drugs.

EPFL2018

Introducing tolerance to foreign and partly foreign proteins by erythrocyte binding and artificial glycosylations

Kym Lorenz Brünggel

EPFL2018

Combinatorial targeting of angiogenesis with inducers of autophagy in the treatment of glioblastoma multiforme

Julie Laetitia Scotton

EPFL2018

EPFL2017