Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa

Other

Istituto Di Ricerche Di Biologica Molecolare P. Angeletti S.p.a.

Merck + Co., Inc.

Instituto Di Ricerche Di Biologia Molecolare P. Angelett S.p.a.

Rocco Savino

Gennaro Ciliberto

Armin Lahm

Carlo Toniatti

Michel Perricaudet

Riccardo Cortese

Nicola La Monica

Giacomo Paonessa

Isabella Saggio

Gennaro Cillberto

Cytokines, including muteins thereof, which are biologically inactive in humans but remain immunogenic, are used in pharmaceutical compositions to promote a neutralizing immune response against native cytokines when administered to a subject in need thereof to treat homeostatic disorders and disorders associated with an overproduction of cytokines.

Compositions and methods comprising immunogenic muteins of interleukin-6

Helper dependent adenoviral vectors encoding erythropoietin (epo) provide high levels of epo to achieve a long-term therapeutically effective dosage, and allow for repeat administration to patients with disorders such as anaemia of Chronic Renal Failure (CFR), anaemias due to beta-thalassaemia, and sickle cell anaemia (SCA).

Adenoviral vectors encoding erythropoietin and their use in gene therapy

The subject matter of the present invention are recombinant defective adenoviruses comprising a heterologous DNA sequence coding for a mutein having the activity of human Interleukin 6 (hIL-6) antagonists or superantagonist. Moreover, the invention refers to therapeutical uses thereof, in particular for preparing pharmaceutical compositions for treating and/or preventing pathologies caused by hIL-6 overproduction.

Adenoviral vectors for mutants of human interleukin 6 (hIL-6) with hIL-6 antagonist activity, pharmaceutical compositions therewith and their uses

DNA encoding human IL-6 receptor antagonist and protein encoded thereby

It is known that the ligands of the group of cytokines similar to Interleuk 6 (IL-6), that is Oncostatin M (OSM), Leukemia Inhibitory Factor (LIF), Ciliary Neurotrophic Factor (CNTF) and Interleukin 11 (IL-11), induce the formation of a receptor complex of which the membrane molecule gp 130 is a part. The present invention refers to a methodology for selecting superagonists, antagonists and superantagonists of human interleukin-6 comprising the following operations: comparing the amino acid sequence of bovine granulocyte colony stimulating factor (bG-CSF) with the sequence of said hormone; and on the basis of the above comparison, formulating a three dimensional model of said hormone, which allows the identification of residues that form the site of interaction with the specific receptor (Site 1) and those that constitute the site of interaction with gp 130 (Site 2) respectively. The invention allows the identification of these sites in human interleukin-6 and the isolation of variants having, with respect to the wild type hormone, a greater affinity for the specific receptor (superagonists and superantagonists) or affinity for gp 130 reduced or abolished (antagonists and superantagonists). A scheme illustrating the methodology applied to identify site 1 and site 2 in the case of human interleukin-6 is disclosed. The invention also describes the obtaining of specific superagonists and superantagonists of interleukin-6 and the use of superantagonists as low dose inhibitors of the growth of human myeloma cells dependent on wild type interleukin-6.

Interleukin-6 receptor agonists

Disclosed are interleukin-6 receptor agonists. These receptor agonists were enerated by mutating amino acid positions 175, 176, 177, 181, and/or 183 of human interleukin-6.

Human interleukin-6 receptor antagonists

Disclosed are interleukin-6 receptor antagonists. These receptor antagonists are generated by mutating amino acid positions 31, 35, 118, 121, 175, 176 and/or 183 of human interleukin-6.

Interleukin-6 receptor antagonists

The present invention is drawn to mutant interleukin 6, which has the amino acid arginine in position 176, replacing serine in position 176 with wild-type interleukin 6. The mutant interleukin 6 of the present invention has greater biological activity than the wild-type protein. The present invention is further drawn to methods of making mutant interleukin 6, having arginine at position 176 and methods of using the same.

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Pomezia, Italy

Rocco Savino