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Baker M.P.,Antitope Ltd. | Carr F.J.,Antitope Ltd.
Current Drug Safety | Year: 2010

Protein therapeutics offer distinct advantages over other classes of drugs largely due to the high level of target specificity and generally low toxicity. Problems have, however, been encountered with some protein therapeutics inducing undesirable immune responses in patients. This immunogenicity can produce pleiotropic effects including the development of a high affinity B cell-mediated humoral response that is often directed against the therapeutic. Opinions are divided as to the principal causes of clinical immunogenicity and, as a result, this area has been the subject of much research. One thing that has emerged as a result of this intense activity is the development of pre-clinical models that can provide a level of prediction of the immunogenic potential of novel protein therapeutics before administration in man. © 2010 Bentham Science Publishers Ltd.


Brinks V.,University Utrecht | Weinbuch D.,Leiden University | Baker M.,Antitope Ltd | Dean Y.,Eclosion SA | And 4 more authors.
Pharmaceutical Research | Year: 2013

All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models. © 2013 Springer Science+Business Media New York.


Bryson C.J.,Antitope Ltd. | Jones T.D.,Antitope Ltd. | Baker M.P.,Antitope Ltd.
BioDrugs | Year: 2010

Most protein therapeutics have the potential to induce undesirable immune responses in patients. Many patients develop anti-therapeutic antibodies, which can affect the safety and efficacy of the therapeutic protein, particularly if the response is neutralizing. There are a variety of factors that influence the immunogenicity of protein therapeutics and, in particular, the presence of B- and T-cell epitopes is considered to be of importance. In silico tools to identify the location of both B- and T-cell epitopes and to assess the potential for immunogenicity have been developed, and such tools provide an alternative to more complex in vitro or in vivo immunogenicity assays. This article reviews computational epitope prediction methods and also the use of manually curated databases containing experimentally derived epitope data. However, due to the complexities of the molecular interactions involved in epitope recognition by the immune system, the heterogeneity of key proteins in human populations and the adaptive nature of the immune response, in silico methods have not yet achieved a level of accuracy that enables them to be used as stand-alone tools for predicting clinical immunogenicity. Computational methods, particularly with regard to T-cell epitopes, only consider a limited number of events in the process of epitope formation and therefore routinely over-predict the number of epitopes within a molecule. Epitope databases such as the Immune Epitope Database (IEDB) and the proprietary T Cell Epitope Database™ (TCED™) have reached a size and level of organization that increases their utility; however, they are not exhaustive. These methods have greatest utility as an adjunct to in vitro assays where they can be used either to reduce the amount and complexity of the in vitro screening, or they can be used as tools to analyze the sequence of the identified epitope in order to locate amino acids critical for its properties. © 2010 Adis Data Information BV.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: European | Award Amount: 173.82K | Year: 2016

Awaiting Public Project Summary


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: European | Award Amount: 193.26K | Year: 2012

The aim of this project is to develop a novel and improved anticoagulant drug for the treatment of blood clotting, using the niche indication vascular access thrombosis as a model for development. It will also offer great blockbuster potential


Patent
ANTITOPE Ltd | Date: 2012-07-31

The invention relates to databases of T cell epitopes, especially helper T cell epitopes, for rapid interrogation of protein sequences for the presence of T cell epitopes. The invention includes full or partial databases and data structures of T cell epitopes including epitopes identified especially by ex vivo T cell assays with test peptides and includes T cell epitopes identified by extrapolation of data from test peptides. The present invention also includes high throughput methods for determining the T cell epitope activity of peptides for subsequent inclusion in databases and data structures including methods where subsets of T cell especially regulatory T cells are removed or inhibited from T cell assays in order to maximize the sensitivity of detection of T cell epitope activity.


Patent
ANTITOPE Ltd | Date: 2012-03-09

The invention provides an anti-CTLA4 antibody which inhibits the binding of CTLA4 to human B7, in particular, it inhibits binding of CTLA4 to human B7.1 and/or human B7.2. Specific antibodies are provided with specific variable region sequences as well as compositions comprising such antibodies for use in treating disease.


Patent
ANTITOPE Ltd | Date: 2012-06-01

The present invention relates to novel humanised antibodies against human CD52 and their use in methods of treating or preventing human diseases.


Patent
Antitope Ltd | Date: 2011-11-23

The present invention provides composite antibody variable regions or fragments thereof, which show reduced immunogenicity. In particular, composite antibody variable regions for use in humans are provided, in particular variable regions which have been modified to remove one or more T-cell epitopes. Methods for generating such variable regions are also provided.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.1.4-3 | Award Amount: 8.73M | Year: 2011

The consortium aims to develop and produce an Anticalin, a member of a novel high-affinity scaffold derived from the lipocalin protein family. The Anticalin is specific for hepcidin which is a central regulator of iron homeostasis, and will be used to antagonize hepcidin for the treatment of anemia of chronic disease (ACD). Anticalins are genetically modified lipocalins that can target almost any desired molecule. Unlike Immunoglobulins, they can be produced at low cost in microbial expression systems, are expected to be non immunogenic and offer therapeutic advantages where antibody effector functions are not desired. ACD, the most frequent anemia in hospitalized patients, develops in subjects suffering from infections, inflammatory and auto-immune disease, cancer and chronic kidney disease. It is often successfully treated by administering Erythropoiesis-Stimulating Agents. However, a significant number of patients are hypo- or non-responsive to ESA. Anti-hepcidin therapies, alone or together with ESAs, may improve anemia and the patients erythropoietic response and enable the use of no or even much lower ESA doses, avoiding the potential detrimental effects of high doses of ESA. The Consortium has already generated proof-of-concept data in an animal model with early candidates. The project aims at identifying, validating, and developing a specific, high affinity drug candidate based on the lipocalin scaffold as promising alternatives to immunoglobulins and a therapeutic approach based on the neutralization of hepcidin. Animal models will be developed and utilized to characterize pharmacokinetic and pharmacodynamic relationships, optimize dosing, to determine safety, biomarker responses and potential synergy with ESAs. Furthermore, production processes will be optimized leading to a scalable GMP process which provides material for preclinical and clinical studies to establish the safety, tolerability, and PK/PD of an Anticalin hepcidin blocker (Phase Ia/b).

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