Regeneron Pharmaceuticals, Inc.

David J Glass

George D Yancopoulos

Nicholas J Papadopoulos

Thomas Daly

David M Valenzuela

David C Bowen

Trevor Stitt

Thomas H Aldrich

Mark E Furth

Esther Latres

Vivien Wong

Stephen P Squinto

Peter S DiStefano

Gregory Conn

Thomas J Daly

A fusion protein comprising at least one IGF1 variant component and a fusion component (F), and, optionally, a signal sequence, exhibits improved stability relative to the native IGF1 or IGF2 polypeptide. The fusion component (F) may be a multimerizing component, such as an immunoglobulin domain, in particular, the Fc domain of IgG or a heavy chain of IgG. IGF1 variants were shown to have improved ability to increase muscle mass in a subject suffering from muscle atrophy caused by cachexia, immobilization, aging, chronic disease, cancer, hereditary condition, an atrophy-causing agent, and the like. IGF1 variants are also effective in decreasing blood glucose in a subject suffering from diabetes or hyperglycemia.

IGF-1 fusion polypeptides and therapeutic uses thereof

A fusion protein comprising at least one IGF1 variant component and a fusion component (F), and, optionally, a signal sequence, exhibiting improved stability relative to the native IGF1 or IGF2 polypeptide. The fusion component (F) may be a multimerizing component, a targeting ligand, or another active or therapeutic compound. IGF1 variants were shown to have improved ability to induce skeletal muscle hypertrophy relative to native IGF1.

Method of increasing muscle mass with IGF-1 fusion polypeptides

Pharmaceutical compositions containing a chimeric protein comprising an IGF1 and an IGF2 component and optionally (F), a fusion component, and/or a signal sequence, are provided. The chimeric protein exhibits improved activity relative to the native IGF1 or IGF2 polypeptide. Further, therapeutic methods for treating IGF1 insufficiency diseases or conditions using the pharmaceutical compositions of the invention are also provided. The diseases or conditions treatable with the methods include muscle atrophy as a result of, for example, aging, cachexia, rheumatoid arthritis, diabetes, disuse or immobilization of muscle, and the like, as well as dwarfism and myocardial infarction.

IGF-1 and IGF-2 chimeric polypeptides and therapeutic uses thereof

A targeting fusion protein comprising a component that comprises a (i) ligand or derivative or fragment thereof that binds a pre-selected target surface protein, such as a receptor, and (ii) an active agent or therapeutic agent(s), and further optionally (iii) a multimerizing component and/or (iv) a signal sequence. In a preferred embodiment, the targeting fusion polypeptide targets muscle and is useful to treat a muscle-related disease or condition, such as muscle atrophy.

Method of treating a muscle-related condition with modified IGF1 polypeptides

A chimeric protein comprising an IGF1 and an IGF2 component and optionally a fusion component (F) and/or a signal sequence, exhibiting improved activity relative to the native IGF1 or IGF2 polypeptide. The fusion component (F) may be a multimerizing component, a targeting ligand, or another active or therapeutic compound.

IGF-I fusion polypeptides and therapeutic uses thereof

Modified IGF1 polypeptides with increased stability and potency

The present invention provides for nucleic acid sequences that encode novel mammalian intracellular signaling polypeptides, designated MINC102. The invention also provides assay systems that may be used to detect and/or measure agents that bind the MINC102 gene product. The present invention also provides for diagnostic and therapeutic methods for treating muscle atrophy by inhibiting expression or activity of MINC102.

Ion channel receptor and uses thereof

The present invention provides for a gene, designated as musk, that encodes a novel tyrosine kinase receptor expressed in high levels in denervated muscle. The invention also provides for an isolated polypeptide which activates MuSK receptor. The invention further provides for a polypeptide which is functionally equivalent to the MuSK activating polypeptide. The invention also provides assay systems that may be used to detect and/or measure ligands that bind the musk gene product. The present invention also provides for diagnostic and therapeutic methods based on molecules that activate MuSK.

Tyrosine kinase receptors and ligands

The present invention provides for a method of promoting motor neuron survival, growth or differentiation comprising treating motor neurons with an effective amount of HGF. The invention also provides for a method of promoting motor neuron survival, growth or differentiation comprising treating motor neurons with an effective amount of HGF and an effective amount of CNTF. The invention further provides for a method of alleviating the toxic effects of vincristine on motor neurons comprising treating motor neurons with an effective amount of HGF and an effective amount of CNTF. The methods may be carried out in vitro or in vivo. The invention also provides a method of treating a motor neuron disorder in a patient comprising administering to the patient an effective amount of HGF and CNTF. The invention further provides a pharmaceutical composition for treating a motor neuron disorder in a patient comprising HGF and CNTF in a pharmacologically acceptable carrier.

Methods of using hepatocyte growth factor to promote survival, growth

The present invention provides for a gene, designated as musk, that encodes a novel tyrosine kinase receptor expressed in high levels in denervated muscle. The invention also provides for an isolated and purified polypeptide which activates MuSK receptor. The invention further provides for a polypeptide which is functionally equivalent to the MuSK activating polypeptide. The invention also provides assay systems that may be used to detect and/or measure ligands that bind the musk gene product. The present invention also provides for diagnostic and therapeutic methods based on molecules that activate MuSK.

The present invention provides for assay systems that may be used to detect and/or measure neurotrophin activity or to identify agents that exhibit neurotrophin-like activity, and for methods of using such assay systems. It is based, at least in part, on the discovery that the trkB protooncogene encodes a tyrosine kinase receptor that may serve as a functional binding protein for BDNF and NT-3. Such assay systems may be of particular value in identifying new neurotrophins or agents with neurotrophin-like activity. In various embodiments, the assay systems and methods of the invention may be used to detect and/or measure the binding of neurotrophin to trkB, either using direct binding studies or the detection of the secondary affects of trkB/neurotrophin binding. The present invention also has diagnostic and therapeutic utilities. In particular embodiments of the invention, methods of detecting aberrancies in trkB function or expression may be used in the diagnosis of neurological disorders. In other embodiments, manipulation of the trkB/neurotrophin interaction may be used in the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (Lou Gehrig's disease).

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Cortlandt Manor, NY, United States of America

David J Glass