Regeneron Pharmaceuticals, Inc.

Naxin Tu

Andrew J Murphy

Lynn Macdonald

Cagan Gurer

Sean Stevens

Vera Voronina

John R McWhirter

Karolina Meagher

Chunguang Guo

Faith Harris

Natasha Levenkova

Li-Hsien Wang

Margaret Karow

Corey Momont

Brinda Prasad

John Mcwhirter

John Mcwhirther

Karolina A Meagher

Non-human animals (and/or non-human cells) and methods of using and making the same are provided, which non-human animals (and/or non-human cells) have a genome comprising human antibody-encoding sequences (i.e., immunoglobulin genes). Non-human animals described herein express antibodies that contain human Igλ light chains, in whole or in part. In particular, non-human animals provided herein are, in some embodiments, characterized by expression of antibodies that contain human Igλ light chains, in whole or in part, that are encoded by human Igλ light chain-encoding sequences inserted into an endogenous Igλ light chain locus of said non-human animals. Methods for producing antibodies from non-human animals are also provided.

Non-human animals having an engineered immunoglobulin lambda light chain locus

Disclosed herein are non-human animals (e.g., rodents, e.g., mice or rats) genetically engineered to express a human or humanized T cell receptor (TCR) from a human or humanized TCR locus comprising a non-human TCR non-coding sequence, and optionally a humanized T cell co-receptor (e.g., humanized CD4 and/or CD8 (e.g., CD8α and/or CD8β)), and/or a human or humanized major histocompatibility complex that binds the humanized T cell co-receptor (e.g., human or humanized MHC II (e.g., MHC II α and/or MHC II β chains) and/or MHC I (e.g., MHC Iα) respectively, and optionally human or humanized β2 microglobulin). Also provided are embryos, tissues, and cells expressing the same. Methods for making the genetically engineered animals are also provided. Methods for using the genetically engineered animals for developing human therapeutics are also provided.

Genetically modified mice comprising humanized cellular immune system components with improved diversity of TCRB repertoire

Provided herein are methods and compositions related to non-human animals that express exogenous Terminal Deoxynucleotidyltransferase (TdT).

Non-human animals expressing exogenous terminal deoxynucleotidyltransferase

The invention provides genetically modified non-human animals that express chimeric human/non-human T cell co-receptor polypeptides (e.g., CD4, CD8α, CD8β), as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified animals and methods of making the same.

Humanized T cell co-receptor mice

Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a deletion of the endogenous low affinity FcγR locus, and wherein the mouse is capable of expressing a functional FcRγ-chain. Genetically modified mice are described, including mice that express low affinity human FcγR genes from the endogenous FcγR locus, and wherein the mice comprise a functional FcRγ-chain. Genetically modified mice that express up to five low affinity human FcγR genes on accessory cells of the host immune system are provided.

Methods of using humanized FCγR mice to assay Fc regions

Provided herein are methods and compositions related to the in vivo testing of therapeutic agents comprising a human Fc in genetically modified rodents (e.g., the testing of the pharmacokinetic and/or pharmacodynamic properties of such a therapeutic agent in genetically modified rodents). In some embodiments the genetically modified rodents express antibodies comprising a human Fc (e.g., a human IgG1 Fc, a human IgG4 Fc). In some embodiments, the rodents express fully human antibodies (i.e., antibodies having human heavy chains and human light (&#x3b3; or &#x3ba;) chains). In certain embodiments the genetically modified rodents comprise one or more Fc receptors with a human extracellular domain (e.g., a Neonatal Fc Receptor (FcRn), a &#x3b2;-2-microglobulin polypeptide (&#x3b2;2M), a Fc &#x3b5; receptor 1&#x3b1; (Fc&#x3b5;R1&#x3b1;), a Fc &#x3b3; receptor 1 alpha (Fc&#x3b3;R1a), a Fc gamma receptor 2a (Fc&#x3b3;R2a), a Fc gamma receptor 2b (Fc&#x3b3;R2b), a Fc gamma receptor 3a (Fc&#x3b3;R3a), a Fc gamma receptor 3b (Fc&#x3b3;R3b), a Fc gamma receptor 2c (Fc&#x3b3;R2c)). The transmembrane and cytoplasmic domain of such receptors can be human or non-human (e.g., rodent).

Genetically modified mouse with humanized immunoglobulin heavy chain constant region genes and method of using

The invention provides a genetically modified non-human animal that comprises in its genome unrearranged T cell receptor variable gene loci, as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified non-human animal and methods of making the same. Various methods of using the genetically modified non-human animal are also provided.

Genetically modified T cell receptor mice

Genetically modified mice and methods and compositions for making and using the same are provided, wherein the genetic modification comprises humanization of an Fc&#x3b3;RI protein.

Non-human animals having humanized Fc-gamma receptors

The invention provides genetically modified non-human animals that express a humanized MHC II protein (humanized MHC II &#x3b1; and &#x3b2; polypeptides), as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified animals and methods of making the same. Methods of using the genetically modified animals to study various aspects of human immune system are provided.

Genetically modified major histocompatibility complex mice

Disclosed herein are nucleic acids encoding for and proteins expressing chimeric C1q polypeptides, non-human animals comprising said nucleic acids, and methods of making or using said non-human animals.

Non-human animals expressing humanized C1Q complex

Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a deletion of the endogenous low affinity Fc&#x3b3;R locus, and wherein the mouse is capable of expressing a functional FcR&#x3b3;-chain. Genetically modified mice are described, including mice that express low affinity human Fc&#x3b3;R genes from the endogenous Fc&#x3b3;R locus, and wherein the mice comprise a functional FcR&#x3b3;-chain. Genetically modified mice that express up to five low affinity human Fc&#x3b3;R genes on accessory cells of the host immune system are provided.

Humanized low affinity FC&#x3b3;R mouse cells

The invention provides genetically modified non-human animals that express chimeric human/non-human T cell co-receptor polypeptides (e.g., CD4, CD8&#x3b1;, CD8&#x3b2;), as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified animals and methods of making the same.

Non-human animals (and/or non-human cells) and methods of using and making the same are provided, which non-human animals (and/or non-human cells) have a genome comprising human antibody-encoding sequences (i.e., immunoglobulin genes). Non-human animals described herein express antibodies that contain human Ig&#x3bb; light chains, in whole or in part. In particular, non-human animals provided herein are, in some embodiments, characterized by expression of antibodies that contain human Ig&#x3bb; light chains, in whole or in part, that are encoded by human Ig&#x3bb; light chain-encoding sequences inserted into an endogenous Ig&#x3bb; light chain locus of said non-human animals. Methods for producing antibodies from non-human animals are also provided.

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Pleasantville, NY, United States of America

Naxin Tu