Regeneron Pharmaceuticals, Inc.

Regeneran Pharmaceuticals, Inc.

Joel H Martin

Tammy T Huang

Nicholas J Papadopoulos

Jeanette L Fairhurst

Sean Stevens

Kevin J Pobursky

Eric L Smith

Ashique Rafique

Margaret Karow

Lynn Macdonald

Douglas MacDonald

Gavin Thurston

Gang Chen

James P Fandl

Marc R Morra

Joel C Reinhardt

Richard Torres

Frank Delfino

Mark W Sleeman

Joan A Windsor

Paul Tiseo

Warren R Mikulka

Thomas Nittoli

Jessica Kirshner

Allen Radin

Marcus Kelly

Katherine Cygnar

Irene Noguera-Troise

Raymond W Leidich

Diana M Ahrens

Marcela Torres

Andrew J Murphy

John R McWhirter

Li-Hsien Wang

Nithya Thambi

Erin M Allison

Gary Swergold

George D Yancopoulos

Cheng Fang Wang

William C Olson

Aris N Economides

Neil E Stahl

Christos Kyratsous

Alexander O Mujica

Eric B Smith

Jee Hwan Kim

Viktoria Gusarova

Robert C Pordy

Mark Sleeman

Cheng Wang

Ergang Shi

Julian Andreev

Tammy H Huang

William J Sasiela

John Mcwhirter

Douglas Macdonald

Terra Potocky

Warren R Mikluka

Regina Raz

Jessica R Kirshner

Eric Smith

The present invention provides multispecific antigen-binding molecules and uses thereof. The multispecific antigen-binding molecules comprise a first antigen-binding domain that specifically binds a target molecule, and a second antigen-binding domain that specifically binds an internalizing effector protein. The multispecific antigen-binding molecules of the present invention can, in some embodiments, be bispecific antibodies that are capable of binding both a target molecule and an internalizing effector protein. In certain embodiments of the invention, the simultaneous binding of the target molecule and the internalizing effector protein by the multispecific antigen-binding molecule of the present invention results in the attenuation of the activity of the target molecule to a greater extent than the binding of the target molecule alone. In other embodiments of the invention, the target molecule is a tumor associated antigen, and the simultaneous binding of the tumor associated antigen and the internalizing effector protein by the multispecific antigen-binding molecule of the present invention causes or facilitates the targeted killing of tumor cells.

Multispecific antigen-binding molecules and uses thereof

An human antibody or antigen-binding fragment of a human antibody that specifically binds and inhibits human proprotein convertase subtilisin/kexin type 9 (hPCSK9) characterized by the ability to reduce serum LDL cholesterol by 40-80% over a 24, 60 or 90 day period relative to predose levels, with little or no reduction in serum HDL cholesterol and/or with little or no measurable effect on liver function, as determined by ALT and AST measurements.

Anti-PCSK9 antibodies

The present invention provides nucleic acid molecules that encode antibodies or antigen-binding fragments thereof, which specifically bind human interleukin-4 receptor (IL-4R). Also provided are expression vectors comprising nucleic acid molecule that encode anti-IL-4R antibodies, host cells comprising the expression vectors, and methods of producing anti-IL-4R antibodies or antigen-binding fragments thereof comprising growing the host cells under conditions permitting production of the antibody or fragment, and recovering the antibody or fragment so produced.

High affinity human antibodies to human IL-4 receptor

Vascular endothelial growth factor (VEGF) traps and VEGF mini-traps that include VEGF receptor Ig-like domains, fused to a multimerizing component, are disclosed. The VEGF traps and VEGF mini-traps bind to VEGF and block its interaction with the VEGF receptor. Such molecules are useful for treating angiogenic eye disorders (e.g., age-related macular degeneration), cancer and for other undesired angiogenesis.

VEGF traps and mini-traps and methods for treating ocular disorders and cancer

The present invention provides methods of treating, ameliorating, or inhibiting tumor growth, cancer, or pathological angiogenesis by administering to a subject in need thereof a human antibody or fragment thereof that specifically binds to human delta-like ligand 4 (hDll4) and blocks hDll4 binding to a Notch receptor. The anti-hDll4 antibody or fragment thereof of the present invention have a high affinity with the Kof 500 pM or less, as measured by surface plasmon resonance.

Human antibodies to human delta like ligand 4

Non-human animal cells and non-human animals comprising a humanized Asgr1 locus and methods of using such non-human animal cells and non-human animals are provided. Non-human animal cells or non-human animals comprising a humanized Asgr1 locus express a human ASGR1 protein or an Asgr1 protein, fragments of which are from human ASGR1. Methods are provided for using such non-human animals comprising a humanized Asgr1 locus to assess in vivo efficacy of human-ASGR1-mediated delivery of therapeutic molecules or therapeutic complexes to the liver and to assess the efficacy of therapeutic molecules or therapeutic complexes acting via human-ASGR1-mediated mechanisms.

Non-human animals comprising a humanized ASGR1 locus

The present invention provides antibodies that bind to the class Ill variant of EGFR (EGFRvIII) and methods of using the same. According to certain embodiments, the antibodies of the invention bind human EGFRvIII with high affinity. The antibodies of the invention may be fully human antibodies. The invention includes anti-EGFRvIII antibodies conjugated to a cytotoxic agent, radionuclide, or other moiety detrimental to cell growth or proliferation. The antibodies of the invention are useful for the treatment of various cancers.

Anti-EGFRvIII antibodies and uses thereof

Methods are disclosed for treating osteoarthritis in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-human NGF antibody, or antigen-binding fragment thereof, wherein at least one symptom associated with osteoarthritis is prevented, ameliorated or improved.

Method of treating osteoarthritis with an antibody to NGF

A human antibody or an antigen-binding fragment which binds human IL-6 receptor (hIL-6R) with a Kof about 500 pM or less and blocks IL-6 activity with an ICof 200 pM or less, is provided. In preferred embodiments, the antibody the antibody or antigen-binding fragment binds hIL-6R with an affinity at least 2-fold higher relative to its binding monkey IL-6R.

High affinity antibodies to human IL-6 receptor

Genetically modified non-human animals are provided that express an immunoglobulin variable domain that comprises at least one histidine, wherein the at least one histidine is encoded by a substitution of a non-histidine codon in the germline of the animal with a histidine codon, or the insertion of a histidine codon in a germline immunoglobulin nucleic acid sequence. Immunoglobulin genes comprising histidines in one or more CDRs, in an N-terminal region, and/or in a loop 4 region are also provided. Immunoglobulin variable domains comprising one or more histidines (e.g., histidine clusters) substituted for non-antigen-binding non-histidine residues. Non-human animals that are progeny of animals comprising modified heavy chain variable loci (V, D, J segments), modified light chain variable loci (V, J segments), and rearranged germline light chain genes (VJ sequences) are also provided. Non-human animals that make immunoglobulin domains that bind antigens in a pH-sensitive manner are provided.

Non-human animals expressing pH-sensitive immunoglobulin sequences

The present disclosure provides multispecific antigen-binding molecules and uses thereof. The multispecific antigen-binding molecules comprise a first antigen-binding domain that specifically binds a target molecule, and a second antigen-binding domain that specifically binds an internalizing effector protein. The multispecific antigen-binding molecules of the present disclosure can, in some embodiments, be bispecific antibodies that are capable of binding both a target molecule and an internalizing effector protein. In certain embodiments of the disclosure, the simultaneous binding of the target molecule and the internalizing effector protein by the multispecific antigen-binding molecule of the present disclosure results in the attenuation of the activity of the target molecule to a greater extent than the binding of the target molecule alone. In other embodiments of the disclosure, the target molecule is a tumor associated antigen, and the simultaneous binding of the tumor associated antigen and the internalizing effector protein by the multispecific antigen-binding molecule of the present disclosure causes or facilitates the targeted killing of tumor cells.

The present invention provides antibodies that bind to the class III variant of EGFR (EGFRvIII) and methods of using the same. According to certain embodiments, the antibodies of the invention bind human EGFRvIII with high affinity. The antibodies of the invention may be fully human antibodies. The invention includes anti-EGFRvIII antibodies conjugated to a cytotoxic agent, radionuclide, or other moiety detrimental to cell growth or proliferation. The antibodies of the invention are useful for the treatment of various cancers.

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Putnam Valley, NY, United States of America

Joel H Martin