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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.


Gahan P.B.,King's College London | Stroun M.,Eclosion SA
Cell Biochemistry and Function | Year: 2010

Studies on a range of prokaryote and eukaryote cells and tissues have shown that a newly synthesized DNA/RNA-lipoprotein complex is released in a regulated manner. This complex, termed a virtosome, is a novel cytosolic component of eukaryote cells. The released virtosomes can readily enter other cells where they can modify the biology of the recipient cells. Such modifications include immunological changes and transformation from normal to cancer cells. The virtosomes form a normal component of the circulating nucleic acids in plasma and serum currently used for clinical diagnostic purposes. Given the transformative powers of virtosomes released from tumour cells, the presence of such a complex in human plasma could readily offer the basis of an alternative mechanism for the initiation of metastases. © 2010 John Wiley & Sons, Ltd.


Wouters J.,Catholic University of Leuven | Hunger R.E.,Inselspital | Garrod T.,Catholic University of Leuven | Dubuis B.,Eclosion SA | And 3 more authors.
Oncologist | Year: 2015

Background. This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients. Methods. Three patients received a single intralesional BQ788 application of 3 mg. After 3–7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0–3, lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10, lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings. Results. No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement. Conclusion. The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells. © AlphaMed Press 2015.


PubMed | Inselspital, Catholic University of Leuven and Eclosion SA
Type: Clinical Trial, Phase I | Journal: The oncologist | Year: 2015

This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients.Three patients received a single intralesional BQ788 application of 3 mg. After 3-7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 2.0 mg, days 0-3; lesion removed on day 4) and to 10 mg in patient 5 (3 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings.No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement.The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.


Anker P.,Eclosion SA | Stroun M.,OncoXL
Expert Opinion on Biological Therapy | Year: 2012

Introduction: J.B. Lamarck in 1809 was the first to present a theory of evolution. He proposed it was due to the adaptation of species to environmental changes, this adaptation being acquired by the offspring. In 1868, Darwin suggested that cells excrete gemmules, which circulate through the body and reach the gonads where they are transmitted to the next generation. His main argument came from graft hybrids. Areas covered: In the fifties and sixties, Russian geneticists, rejecting neo-Darwinism, said that acquired characteristics were the basis of evolution. The main experiments on which they based their theory were the transmission of hereditary characteristics by a special technique of grafting between two varieties of plants. We repeated this kind of experiment and also succeeded in obtaining hereditary modifications of the pupil plants that acquired some characteristics of the mentor variety. Rather than adopting the views of the Russian scientists, we suggested that DNA was circulating between the mentor and pupil plants. Hirata's group have shown recently, by using molecular techniques such as cloning, RFLP PCR and sequencing some genes of their graft hybrids of pepper plants, that transfer of informative molecules from the mentor to the pupil plant does exist. Nucleic acids are actively released by cells; they circulate in the body. They can transform oncogenically or trigger antibody response but the only genetic transformation showing that DNA can go from the soma to the germen comes from graft hybrids. Expert opinion: This suggests that circulating nucleic acids, in this case DNA, like Darwin's gemmules, play a role in the mechanism of evolution. © 2012 Informa UK, Ltd.


PubMed | Eclosion SA
Type: | Journal: Expert opinion on biological therapy | Year: 2012

J.B. Lamarck in 1809 was the first to present a theory of evolution. He proposed it was due to the adaptation of species to environmental changes, this adaptation being acquired by the offspring. In 1868, Darwin suggested that cells excrete gemmules, which circulate through the body and reach the gonads where they are transmitted to the next generation. His main argument came from graft hybrids.In the fifties and sixties, Russian geneticists, rejecting neo-Darwinism, said that acquired characteristics were the basis of evolution. The main experiments on which they based their theory were the transmission of hereditary characteristics by a special technique of grafting between two varieties of plants. We repeated this kind of experiment and also succeeded in obtaining hereditary modifications of the pupil plants that acquired some characteristics of the mentor variety. Rather than adopting the views of the Russian scientists, we suggested that DNA was circulating between the mentor and pupil plants. Hiratas group have shown recently, by using molecular techniques such as cloning, RFLP PCR and sequencing some genes of their graft hybrids of pepper plants, that transfer of informative molecules from the mentor to the pupil plant does exist. Nucleic acids are actively released by cells; they circulate in the body. They can transform oncogenically or trigger antibody response but the only genetic transformation showing that DNA can go from the soma to the germen comes from graft hybrids.This suggests that circulating nucleic acids, in this case DNA, like Darwins gemmules, play a role in the mechanism of evolution.


Eclosion SA | Entity website

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Eclosion SA | Entity website

GeneuroGeNeuro dveloppe une nouvelle voie thrapeutique contre des pathologies lies aux rtrovirus endognes humains, dont la sclrose en plaque (SEP). L'inhibition par un anticorps monoclonal des effets de la protine toxique la surface de ces rtrovirus montre des rsultats pharmacologiques exceptionnels et un espoir rel d'arrt de la progression de la maladie ...


Eclosion SA | Entity website

La mission d'Eclosion est de transformer le fort potentiel d'innovation rgionale dans le domaine des sciences de la vie en valeur conomique et en emplois.La Fondation Eclosion fournit aux entrepreneurs les ressources ncessaires entre le stade de sortie du laboratoire et celui o une start-up peut raisonnablement attirer du capital-risque ...

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