Amgen Inc.

Cugene Inc.

Other

E. R. Squibb Sons, Inc.

Medarex Inc.

Atara Biotherapeutics, Inc.

Washington University

Yue-Sheng Li

Mark Leo Michaels

Jeonghoon Sun

Jing M Xu

Randy Ira Hecht

Edward John Belouski

Murielle Marie Ellison

Agnes Eva Hamburger

Thomas Charles Boone

Kenneth William Walker

Lingyun Rui

Taruna Arora

Frederick W Jacobsen

Lei-Ting Tony Tam

Rohini Deshpande

HoSung Min

Jane Talvenheimo

Haichun Huang

Andrew A Welcher

Huiquan Han

Hilary T Chute

George Doellgast

Colin V Gegg

Qi Huang

Benny C Askew

Chuan-Fa Liu

Derin C D'amico

Gordon Ng

Yuelie Lu

Thomas Storz

Mark A Jarosinski

Jing Xu

Hq Han

Colin Victor Gegg, Jr

Thomas F Deuel

Ho-Sung Min

George (deceased) Doellgast

Peter G Milner

Hosung Min

Murielle M Ellison

Jr Benny C Askew

Liu Chuan-Fa

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 (“D2”), and a concealing moiety D3 domain (“D3”). Importantly, because the “active moiety” 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 “on-target” “off tissue” 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

The present disclosure provides novel and improved IL-15 fusion proteins for use in the treatment of cancer and other disorders. In various embodiments, the fusion proteins of the invention have two functional domains: an IL-15/IL-15RαSushi domain (also referred to herein as an 'IL-15/IL-15RαSushi complex') and an Fc domain, each of which can take different forms, and configured such that the IL-15 is fused to the C-terminal of the Fc domain and co-expressed and non-covalently complexed with IL-15RαSushi. Importantly, the fusions proteins of the present invention address several of the limitations observed with the IL-15 therapeutics evaluated to date; specifically, the fusion proteins demonstrate extended the half-life of IL-15 in vivo, and demonstrate superior preclinical activity compared to rIL-15 or related cytokine therapeutics.

Interleukin-15 (IL-15) fusion proteins and uses thereof

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 invention provides stabilized activin IIB receptor polypeptides and proteins capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11. The present invention also provides polynucleotides, vectors and host cells capable of producing the stabilized polypeptides and proteins. Compositions and methods for treating muscle-wasting diseases and metabolic disorders are also provided.

Stabilized receptor polypeptides and uses thereof

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.

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

Isolated nucleic acid molecules encoding stabilized receptor polypeptides and uses thereof

Disclosed is an isolated antigen binding protein, such as but not limited to, an antibody or antibody fragment. Also disclosed are pharmaceutical compositions and medicaments comprising the antigen binding protein, isolated nucleic acid encoding it, vectors, host cells, and hybridomas useful in methods of making it. In some embodiments the antigen binding protein comprises one to twenty-four pharmacologically active chemical moieties conjugated thereto, such as a pharmacologically active polypeptide.

Carrier immunoglobulins

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

Growing community of inventors

Thousand Oaks, CA, United States of America

Yue-Sheng Li