Mutants of thyroid stimulating hormone and methods based...

C - Chemistry – Metallurgy – 12 – N

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C12N 15/16 (2006.01) A61K 38/24 (2006.01) C07K 14/59 (2006.01) G01N 33/68 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2302993

The present invention is based upon the discovery that mutant .alpha. subunits and mutant .beta. subunits each comprising amino acid substitutions relative to the wild type can be produced and assembled to form a mutant TSH heterodimer or TSH analog that possesses higher bioactivity in vitro and longer half life in vivo. Accordingly, the present invention provides methods for using mutant TSH heterodimers, TSH analogs, fragments, and derivatives thereof for treating or preventing diseases of the thyroid, in particular thyroid cancer. The invention also relates to methods of diagnosis, prognosis and monitoring for thyroid-related functions. Pharmaceutical and diagnostic compositions, methods of using mutant TSH heterodimers and TSH analogs with utility for treatment and prevention of metabolic and reproductive diseases are also provided.

L'invention repose sur la découverte que les sous-unités mutantes .alpha. et les sous-unités mutantes .beta., qui comprennent chacune des substitutions d'acides aminés par rapport au type sauvage, peuvent être assemblées pour former un hétérodimère de TSH mutant ou un analogue de TSH qui présente une bioactivité plus élevée in vitro et une demi-vie plus longue in vivo. L'invention concerne des méthodes d'utilisation de ces hétérodimères de THS mutants, de ces analogues de TSH, et des fragments et des dérivés de ces derniers, pour traiter ou prévenir les maladies thyroïdiennes, en particulier le cancer de la thyroïde. L'invention concerne également des méthodes de diagnostic, de pronostic et de surveillance des fonctions dépendant de la thyroïde. L'invention concerne en outre des compositions pharmaceutiques et diagnostiques, des méthodes d'utilisation des hétérodimères de TSH mutants et des analogues de TSH destinés au traitement et à la prévention des maladies du métabolisme et des fonctions reproductrices.

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