Regeneron Pharmaceuticals, Inc.

Yale University

Institute for Research in Biomedicine (irb)

Other

University of California

Max-planck-gesellschaft Zur Forderung Der Wissenschaften E.v.

University of Texas System

Regeneran Pharmaceuticals, Inc.

Univ. of Texas

Duke University

St. Jude Children's Research Hospital

Institute for Research in Biomedicine

Columbia University

Regeneron Pharmacueticals, Inc.

George D Yancopoulos

Andrew J Murphy

David M Valenzuela

Samuel H Davis

Sean Stevens

Aris N Economides

Neil E Stahl

Nicholas J Papadopoulos

Richard A Flavell

Markus G Manz

Margaret Karow

Lynn MacDonald

David Frendewey

Ka-Man Venus Lai

Wojtek Auerbach

Elizabeth Eynon

Till Strowig

Anthony Rongvaux

Gang Chen

Pamela F Jones

Thomas H Aldrich

Tim Willinger

James P Fandl

David J Glass

Thomas Daly

Nikos Panayotatos

Melanie H Cobb

Mark E Furth

Stephen P Squinto

Steven Nye

Teri G Boulton

Tammy T Huang

Jorge E Galan

Peter C Maisonpierre

Lynn Macdonald

Cagan Gurer

William C Olson

Jamie M Orengo

Christos Kyratsous

Stanley J Wiegand

Robert Babb

Dimitris Skokos

Mitchell Goldfarb

Alina Baum

Wen-Yi Lee

Hans Thoenen

Cindy Gerson

Johanna Hansen

Czeslaw Radziejewski

Marine Malbec

Yves-Alain Barde

Joachim Leibrock

Lauric Haber

Friedrich Lottspeich

Nicholas W Gale

Madhav Dhodapkar

Eric L Smith

Jesper Gromada

Alexander O Mujica

William C Smith

Gustavo Droguett

Jeffrey D Lee

Noah Palm

Richard M Harland

Aynur Hermann

Marcel De Zoete

Jocelyn Holash

Nancy Y Ip

Erica Ullman

John Rudge

John R McWhirter

Gavin Thurston

Aris I Baras

Karolina Meagher

Israel Lowy

Vera Voronina

Chia-Yang Lin

Lori C Morton

Jesse M Cedarbaum

Thomas M DeChiara

Esther Latres

Joel H Martin

Eric Steven Furfine

Peter Anthony Campochiaro

Jeanette L Fairhurst

Allen Radin

O Gavin Thurston

Alison Crawford

Namita A Gandhi

Junko Kuno

Scott Mellis

Anthony Gagliardi

Ronald M Lindsay

Garnett Kelsoe

Kara Olson

Trevor Stitt

Matthew Koss

Ana Kostic

Jeanne Allinne

The present invention provides multispecific antibodies that bind to EGFR and CD28 (EGFR×CD28) as well as anti-EGFR antibodies. Such antibodies may be combined with a further therapeutic agent such as an anti-PD1 antibody. Methods for treating cancers (e.g., EGFR-expressing cancer) by administering the antibodies (e.g., and combinations thereof with anti-PD1) are also provided. The EGFR×CD28 antibodies of the present invention embody a tumor-targeted immunotherapeutic modality combined with PD-1 inhibition. These bispecific antibodies bind a tumor-specific antigen (TSA) (EGFR) with one arm and the co-stimulatory receptor, CD28, on T-cells with the other arm. Combination therapy with PD-1 inhibitors specifically potentiated intra-tumoral T cell activation, promoting an effector memory-like T cell phenotype without systemic cytokine secretion in a variety of syngeneic and human tumor xenograft models. Combining this class of CD28-co-stimulatory bispecific antibodies with the clinically validated anti-PD-1 treatment provides a well-tolerated antibody therapy with markedly enhanced anti-tumor efficacy.

EGFR x CD28 multispecific antibodies

A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mIl2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/Il2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g.,oris described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

Genetically modified mice and engraftment

The present invention provides methods for treating angiogenic eye disorders by sequentially administering multiple doses of a VEGF antagonist to a patient. The methods of the present invention include the administration of multiple doses of a VEGF antagonist to a patient at a frequency of once every 8 or more weeks. The methods of the present invention are useful for the treatment of angiogenic eye disorders such as age related macular degeneration, diabetic retinopathy, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, and corneal neovascularization.

Use of a VEGF antagonist to treat angiogenic eye disorders

The present disclosure provides antibodies and antigen-binding fragments thereof that bind specifically to a coronavirus spike protein and methods of using such antibodies and fragments for treating or preventing viral infections (e.g., coronavirus infections).

Anti-SARS-CoV-2-spike glycoprotein antibodies and antigen-binding fragments

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

The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use.

Genetically modified non-human animals and methods of use thereof

Genetically modified mice comprising a nucleic acid sequence encoding a human M-CSF protein are provided. Also provided are genetically modified mice comprising a nucleic acid sequence encoding a human M-CSF protein that have been engrafted with human cells such as human hematopoietic cells, and methods for making such engrafted mice. These mice find use in a number of applications, such as in modeling human immune disease and pathogen infection; in in vivo screens for agents that modulate hematopoietic cell development and/or activity, e.g. in a healthy or a diseased state; in in vivo screens for agents that are toxic to hematopoietic cells; in in vivo screens for agents that prevent against, mitigate, or reverse the toxic effects of toxic agents on hematopoietic cells; in in vivo screens of human hematopoietic cells from an individual to predict the responsiveness of an individual to a disease therapy, etc.

Humanized M-CSF mice

Compositions and methods are provided for modifying a rat genomic locus of interest using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Compositions and methods for generating a genetically modified rat comprising one or more targeted genetic modifications in their germline are also provided. Compositions and methods are provided which comprise a genetically modified rat or rat cell comprising a targeted genetic modification in the rat interleukin-2 receptor gamma locus, the rat ApoE locus, the rat Rag2 locus, the rat Rag1 locus and/or the rat Rag2/Rag1 locus. The various methods and compositions provided herein allows for these modified loci to be transmitted through the germline.

Targeted modification of rat genome

The present disclosure provides methods for treating allergy comprising selecting a patient with an allergy and administering a therapeutically effective amount of an IL-4/IL-13 pathway inhibitor (e.g., an anti-IL-4 receptor antibody or antigen-binding fragment thereof) in combination with a therapeutically effective amount of an agent that depletes plasma cells (e.g., an anti-BCMA/anti-CD3 bispecific antibody). In certain embodiments, a plasma cell ablating agent such as an anti-BCMA/anti-CD3 bispecific antibody ablates the plasma cells, including IgE+ plasma cells, while the IL-4/IL-13 pathway inhibitor prevents the generation of new IgE+ plasma cells, thus eliminating allergen-specific IgE in the patient.

Combination of IL-4/IL-13 pathway inhibitors and plasma cell ablation for treating allergy

EGFR × CD28 multispecific antibodies

The present invention provides methods for treating inflammatory diseases, or conditions associated with, or resulting in part from, elevated levels of IL-33 and IL-4, in particular inflammatory lung disorders. The methods of the present invention comprise administering to a subject in need thereof one or more therapeutically effective doses of an IL-33 antagonist alone or in combination with one or more therapeutically effective doses of an IL-4R antagonist. In certain embodiments, the methods of the present invention include use of the antagonists to treat any inflammatory disease or condition mediated in part by enhanced IL-33-mediated signaling and IL-4-mediated signaling.

Methods for treating inflammatory conditions of the airway or lungs by administering antagonist monoclonal antibodies to interleukin-33 and interleukin-4 receptor

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided.

Methods and compositions for the targeted modification of a genome

Genetically modified non-human animals are provided that may be used to model human hematopoietic cell development, function, or disease. The genetically modified non-human animals comprise a nucleic acid encoding human IL-6 operably linked to an IL-6 promoter. In some instances, the genetically modified non-human animal expressing human IL-6 also expresses at least one of human M-CSF, human IL-3, human GM-CSF, human SIRPa or human TPO. In some instances, the genetically modified non-human animal is immunodeficient. In some such instances, the genetically modified non-human animal is engrafted with healthy or diseased human hematopoietic cells. Also provided are methods for using the subject genetically modified non-human animals in modeling human hematopoietic cell development, function, and/or disease, as well as reagents and kits thereof that find use in making the subject genetically modified non-human animals and/or practicing the subject methods.

Growing community of inventors

Yorktown Heights, NY, United States of America

George D Yancopoulos