Novartis Ag

Novartis Pharma Gmbh

Mara Fornaro

David Jonathan Glass

Yuan Gao

Thomas Huber

Thomas Jostock

Holger Laux

Francois Legay

Mauro Zurini

Rainer Hillenbrand

Sandrine Romand

Daniela Stoellner

John Xu

This invention is in the field of IGF-1 modifications. In particular, it relates to modified IGF-polypeptides and modified IGF-1 precursor polypeptides wherein the cleavage of E-peptide is prevented. The invention also relates to the use of such polypeptides for treating muscle diseases and disorders.

Stabilized insulin-like growth factor polypeptides

The invention relates to methods for the production of therapeutic proteins in mammalian cells. In one embodiment, the method comprises producing a therapeutic protein such as IGF-1 in a mammalian cell endogenously expressing a cognate receptor of said recombinant therapeutic protein and wherein binding of said therapeutic protein to said cognate receptor results in a low titer of the therapeutic protein, the method comprising with a mammalian cell being deficient in the expression of the cognate receptor of said therapeutic protein and being transformed with an expression vector comprising a nucleic acid molecule encoding the therapeutic protein: a. Cultivating said cell under conditions allowing the expression of the therapeutic protein; and b. Harvesting the therapeutic protein from the mammalian cell cultivated in step a, wherein said mammalian cell produces at least 1.5 fold more therapeutic protein than a cell in which the expression of the cognate receptor has not been so modified.

Production of therapeutic proteins in genetically modified mammalian cells

High-specificity antibodies can distinguish between modified (e.g, hIGF-1/Ea 3mut) and endogenous wild-type human IGF-1 proteins. These antibodies have little or no cross-reactivity with hIGF-1 or hIGF-2. They also have little or no cross-reactivity with rodent IGF-1 or IGF-2. The antibodies can be used in pharmacokinetic (PK)/pharamcodynamic (PD) assessments of IGF-1/E peptides that have been administered to humans or animals. A sandwich ELISA assay, using the antibody of the invention as a capture antibody, can quantify the mutant IGF-1/E proteins in samples.

Antibodies to modified human IGF-1/E peptides

The invention relates to stabilized polypeptides having an IGF-1 sequence and an Ea peptide sequence, where the natural physiological cleavage of the Ea peptide from the IGF-1 is prevented.

The invention relates to stabilized polypeptides having an IGF-1 or IGF-2 sequence and an E-peptide sequence, where the natural physiological cleavage of the E-peptide from the IGF is prevented.

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Basel, Switzerland

Mara Fornaro