Amgen Inc.

Other

Cugene Inc.

Eaton Intelligent Power Limited

Jing M Xu

Yue-Sheng Li

Mark Leo Michaels

Randy Ira Hecht

Edward John Belouski

Murielle Marie Ellison

Jeonghoon Sun

Agnes Eva Hamburger

Lingyun Rui

Martin Wayne Mensch

Tamara Orshanskaya

Bin Wu

Kenneth William Walker

Yuan Cheng

Leslie Phillip Miranda

James Richard Falsey

Kelvin C Sham

Murielle M Veniant-Ellison

Bradley J Herberich

Jerry Ryan Holder

Colin Victor Gegg, Jr

Junming Yie

Martin Moskovits

Shu-Chen Lu

Chawita Netirojjanakul

Shanaka Stanislaus

The present invention relates to polypeptides which share primary sequence with human Interleukin 2 (IL-2), except for several amino acids that have been mutated. One panel of IL-2 variants comprise mutations with impressive manufacturability that preferentially promotes the proliferation, survival, activation and/or function of immunosuppressive regulatory T cells (Tregs) (Treg: CD4+CD25+FoxP3+) over effector T cells and Natural Killer Cells (NK). cells. Also includes therapeutic uses of such IL-2 selective agent, used alone, or in combination with immune modulating agents or disease-tissue targeting antibody, protein or peptide to treat Treg cell-deficiency, various autoimmune and inflammatory disorders, organ transplantation and graft-versus-host disease. In another aspect the present invention relates to pharmaceutical compositions comprising the polypeptides disclosed. Finally, the present invention relates to the therapeutic use of the polypeptides and pharmaceutical compositions disclosed due to their selective modulating effect of the immune system on diseases like autoimmune and inflammatory disorders.

Interleukin-2 variants and methods of uses thereof

The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.

Methods of treating non-alcoholic steatohepatitis using FGF21 mutants

The present disclosure provides a cytokine-based bioactivatable drug construct ('VitoKine') platform that aims to reduce systemic mechanism-based toxicities and lead to broader therapeutic utility for proteins and cytokines such as IL-15 and IL-2 for the treatment of cancer, autoimmune diseases, inflammatory diseases, viral infection, transplantation and various other disorders. The novel VitoKine constructs of the present invention comprise: 1) a tissue or disease site targeting moiety D1 domain ('D1'), 2) a bioactivatable moiety D2 domain (&#x201c;D2&#x201d;), and a concealing moiety D3 domain (&#x201c;D3&#x201d;). Importantly, because the &#x201c;active moiety&#x201d; of the VitoKine construct will remain inert until activated locally by proteases that are upregulated in diseased tissues, this will limit binding of the active moiety to the receptors or to the targets in the peripheral or on the cell-surface of non-diseased cells and tissue to prevent over-activation of the pathway and reduce undesirable &#x201c;on-target&#x201d; &#x201c;off tissue&#x201d; toxicities. Additionally, the inertness of the VitoKine active moiety prior to protease activation will significantly decrease the potential antigen or target sink, and thus, prolong the in vivo half-life and result in improved biodistribution, bioavailability and therapeutic efficacy.

Cytokine-based bioactivatable drugs and methods of uses thereof

A fill limit vent valve for a fuel system includes a housing assembly, an outlet port and a flow dam. The housing assembly has a main housing including a cylindrical body and an upper housing portion. The upper housing portion has a lower wall that defines an orifice and an outer cylindrical wall that defines an upper housing chamber. The outlet port is formed on the main housing and fluidly communicates fuel vapor out of the fill limit valve. The orifice is offset from a centerpoint of the lower wall in a direction away from the outlet port. The flow dam extends from the lower wall into the upper housing chamber and connects on opposite ends to the outer cylindrical wall. The flow dam and upper housing chamber cooperating to form a liquid trap that mitigates the possibility of liquid fuel from reaching the outlet port from the orifice.

Fill limit venting valve with high shut-off height

The invention provides methods for treating non-alcoholic steatohepatitis (NASH) using FGF21 mutant polypeptides.

Methods of treating metabolic diseases and disorders using a composition comprising an antigen binding protein specific for the GIPR polypeptide conjugated to a GLP-1 receptor agonist are provided. In various embodiments the metabolic disease or disorder is type 2 diabetes, obesity, dyslipidemia, elevated glucose levels, elevated insulin levels and diabetic nephropathy. In certain embodiments the composition comprises an antibody or functional fragment thereof comprising a cysteine at one or more conjugation site(s) wherein the GLP-1 receptor agonist is conjugated to the antibody or functional fragment thereof through the side-chain of the cysteine residue.

Method of treating or ameliorating metabolic disorders using GLP-1 receptor agonists conjugated to antagonists for gastric inhibitory peptide receptor (GIPR)

The invention provides methods of treating diabetes, reducing triglyceride levels, and treating obesity by administering to a subject in need there a fusion protein comprising an FGF21 mutant.

Methods of treating of diabetes and obesity using FGF21 mutants

The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions. In some embodiments, the FGF21 mutant polypeptide comprises a substitution at position 98, 171 and/or 180.

FGF21 mutants comprising a mutation at position 98, 171 and/or 180

The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides comprising extended in vivos half-lives, pharmaceutical compositions comprising FGF21 mutant polypeptides having extended in vivos half lives, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.

FGF-21 mutants comprising polyethylene glycol and uses thereof

The invention provides FGF21 mutant polypeptides with reduced proteolysis and aggregation, pharmaceutical compositions comprising the same.

FGF mutants with reduced proteolysis and aggregation

The invention provides nucleic acid molecules encoding FGF21 mutant polypeptides, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, wherein the FGF 21 mutant polypeptides comprise two or more mutations, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.

FGF21 polypeptides comprising two or more mutations and uses thereof

FGF 21 polypeptides comprising two or more mutations and uses thereof

The invention provides nucleic acid molecules encoding FGF21 mutant fusion polypeptides comprising mutations at positions 98, 171, 179, 180 or 181, FGF21 mutant polypeptides, pharmaceutical compositions comprising FGF21 mutant polypeptides, and methods for treating metabolic disorders using such nucleic acids, polypeptides, or pharmaceutical compositions.

FGF21 mutant fusion polypeptides and uses thereof

The invention provides a multimer comprising at least a first and a second chain, the first chain comprising the polypeptide of SEQ ID NO:4, wherein the leucine at position 98 is substituted with an arginine; the proline at position 171 is substituted with glycine; and the alanine at position 180 is substituted with glutamic acid; a linker sequence comprising SEQ ID NO:31; and an Fe domain comprising SEQ NO:11; and a second chain comprising the polypeptide of SEQ ID NO:4, wherein the leucine at position 98 is substituted with an arginine; the proline at position 171 is substituted with glycine; and the alanine at position 180 is substituted with glutamic acid; a linker sequence comprising SEQ ID NO:31; and an Fe domain comprising SEQ ID NO:11, nucleic acids encoding the multimer, pharmaceutical compositions comprising the multimer and methods for treating metabolic disorders using such nucleic acids, multimers or pharmaceutical compositions.

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Jing M Xu