Abstract: An adenovirus expression vector is provided. The adenovirus expression vector may include: a) one or more mutations that render the adenovirus replication incompetent and b) at least one nucleotide sequence encoding a protein or an RNA is provided. A method of synthesizing an adenovirus vector is also provided. The synthesis may include: a) producing a plurality of overlapping adenovirus sub-fragments, each sub-fragment comprising a portion of the full genome of the adenovirus; b) circularizing the sub-fragments to form plasmid structures; and c) assembling the circularized sub-fragments into a linear structure, wherein the vector comprises a combination of two or more sub-fragments. A mammalian cell line configured to replicate adenoviral vectors, wherein the cell line comprises nucleotide sequences expressing E1A and E1B gene products but is devoid of other adenovirus sequences is also provided.

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

Abstract: 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.

Abstract: Mice that comprise a replacement of endogenous mouse IL-6 and/or IL-6 receptor genes are described, and methods for making and using the mice. Mice comprising a replacement at an endogenous IL-6R? locus of mouse ectodomain-encoding sequence with human ectodomain-encoding sequence is provided. Mice comprising a human IL-6 gene under control of mouse IL-6 regulatory elements is also provided, including mice that have a replacement of mouse IL-6-encoding sequence with human IL-6-encoding sequence at an endogenous mouse IL-6 locus.

Abstract: An adenovirus expression vector is provided. The adenovirus expression vector may include: a) one or more mutations that render the adenovirus replication incompetent and b) at least one nucleotide sequence encoding a protein or an RNA is provided. A method of synthesizing an adenovirus vector is also provided. The synthesis may include: a) producing a plurality of overlapping adenovirus sub-fragments, each sub-fragment comprising a portion of the full genome of the adenovirus; b) circularizing the sub-fragments to form plasmid structures; and c) assembling the circularized sub-fragments into a linear structure, wherein the vector comprises a combination of two or more sub-fragments. A mammalian cell line configured to replicate adenoviral vectors, wherein the cell line comprises nucleotide sequences expressing E1A and E1B gene products but is devoid of other adenovirus sequences is also provided.

Abstract: Mice are provided that comprise a reduction or deletion of ADAM6 activity from an endogenous ADAM6 locus, or that lack an endogenous locus encoding a mouse ADAM6 protein, wherein the mice comprise a sequence encoding an ADAM6 or ortholog or homolog or fragment thereof that is functional in a male mouse. In one embodiment, the sequence is an ectopic ADAM6 sequence or a sequence that confers upon a male mouse the ability to generate offspring by mating. Mice and cells with genetically modified immunoglobulin heavy chain loci that comprise an ectopic nucleotide sequence encoding a mouse ADAM6 or functional fragment or homolog or ortholog thereof are also provided.

Abstract: 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?R locus, and wherein the mouse is capable of expressing a functional FcR?-chain. Genetically modified mice are described, including mice that express low affinity human Fc?R genes from the endogenous Fc?R locus, and wherein the mice comprise a functional FcR?-chain. Genetically modified mice that express up to five low affinity human Fc?R genes on accessory cells of the host immune system are provided.

Abstract: The invention provides genetically modified non-human animals that express a humanized MHC II protein (humanized MHC II ? and ? 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.

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

Abstract: 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.

Abstract: Provided are methods, polynucleotides and compositions for the generation of engineered Treg cells. The methods, polynucleotides and compositions enable the reprogramming of hematopoietic cells into Treg cells by constitutive or regulated expression of FOXP3 in engineered cells such that the engineered Treg cells can suppress the activation and proliferation of responder T cells.

Abstract: Modular synthetic receptors are provided. The synthetic receptors may include an extracellular domain capable of binding to one or more ligand molecules and may be released from the synthetic receptor after binding, a transmembrane domain derived from the Notch receptor, and an intracellular domain which may have one or more functional activities when released from the synthetic receptor. A method of use for the synthetic receptors is also provided, wherein upon binding of the extracellular domain to a specific ligand, the synthetic receptor undergoes proteolytic cleavage to release either or both the extracellular and intracellular domains. The extracellular binding domain, if released, may continue to bind to its cognate ligand and may carry one or more additional functional activities and the intracellular domain, if released, may stimulate or inhibit one or more intracellular activities.

Abstract: Genetically modified mice are provided that express human ? variable (hV?) sequences, including mice that express hV? sequences from an endogenous mouse ? light chain locus, mice that express hV? sequences from an endogenous mouse ? light chain locus, and mice that express hV? sequences from a transgene or an episome wherein the hV? sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human ? variable sequences useful for making antigen-binding proteins. Compositions and methods for making antigen-binding proteins that comprise human ? variable sequences, including human antibodies, are provided.

Abstract: The present disclosure relates to bicistronic polypeptide constructs for use in allogeneic gene therapy, for example, CAR-T cell therapy. The bicistronic constructs comprise first polynucleotide encoding a therapeutic molecule (e.g., a CAR-T or an antibody) and a second polynucleotide encoding an Immune Surveillance Masking Molecule (ISMM). The ISMM comprises a human leukocyte antigen-E genetically fused to a non-functional version, e.g., a fragment, of the protein knock-out by the insertion of the bicistronic construct, e.g., beta-2 microglobulin or B2M. Also provided are vectors comprising the bicistronic constructs, cells (e.g., CAR-T cells), and methods of use. Also provided are kits and articles of manufacture. The present disclosure also provides four novel insertion sites that can be used to insert an expression construct in the B2M gene.

Abstract: Mice are provided that comprise a reduction or deletion of ADAM6 activity from an endogenous ADAM6 locus, or that lack an endogenous locus encoding a mouse ADAM6 protein, wherein the mice comprise a sequence encoding an ADAM6 or ortholog or homolog or fragment thereof that is functional in a male mouse. In one embodiment, the sequence is an ectopic ADAM6 sequence or a sequence that confers upon a male mouse the ability to generate offspring by mating. Mice and cells with genetically modified immunoglobulin heavy chain loci that comprise an ectopic nucleotide sequence encoding a mouse ADAM6 or functional fragment or homolog or ortholog thereof are also provided.

Abstract: Modular synthetic receptors are provided. The synthetic receptors may include an extracellular domain capable of binding to one or more ligand molecules and may be released from the synthetic receptor after binding, a transmembrane domain derived from the Notch receptor, and an intracellular domain which may have one or more functional activities when released from the synthetic receptor. A method of use for the synthetic receptors is also provided, wherein upon binding of the extracellular domain to a specific ligand, the synthetic receptor undergoes proteolytic cleavage to release either or both the extracellular and intracellular domains. The extracellular binding domain, if released, may continue to bind to its cognate ligand and may carry one or more additional functional activities and the intracellular domain, if released, may stimulate or inhibit one or more intracellular activities.

Abstract: 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?R locus, and wherein the mouse is capable of expressing a functional FcR?-chain. Genetically modified mice are described, including mice that express low affinity human Fc?R genes from the endogenous Fc?R locus, and wherein the mice comprise a functional FcR?-chain. Genetically modified mice that express up to five low affinity human Fc?R genes on accessory cells of the host immune system are provided.

Abstract: A genetically modified mouse is provided, wherein the mouse expresses an immunoglobulin light chain repertoire characterized by a limited number of light chain variable domains. Mice are provided that express just one or a few immunoglobulin light chain variable domains from a limited repertoire in their germline. Methods for making bispecific antibodies having universal light chains using mice as described herein, including human light chain variable regions, are provided. Methods for making human variable regions suitable for use in multispecific binding proteins, e.g., bispecific antibodies, and host cells are provided. Bispecific antibodies capable of binding first and second antigens are provided, wherein the first and second antigens are separate epitopes of a single protein or separate epitopes on two different proteins are provided.

Abstract: Non-human animals comprising a human or humanized IL-4 and/or IL-4R? nucleic acid sequence are provided. Non-human animals that comprise a replacement of the endogenous IL-4 gene and/or IL-4R? gene with a human IL-4 gene and/or IL-4R? gene in whole or in part, and methods for making and using the non-human animals, are described. Non-human animals comprising a human or humanized IL-4 gene under control of non-human IL-4 regulatory elements is also provided, including non-human animals that have a replacement of non-human IL-4-encoding sequence with human IL-4-encoding sequence at an endogenous non-human IL-4 locus. Non-human animals comprising a human or humanized IL-4R? gene under control of non-human IL-4R? regulatory elements is also provided, including non-human animals that have a replacement of non-human IL-4R?-encoding sequence with human or humanized IL-4R?-encoding sequence at an endogenous non-human C IL-4R? locus.

Abstract: Mice are provided that comprise a reduction or deletion of ADAM6 activity from an endogenous ADAM6 locus, or that lack an endogenous locus encoding a mouse ADAM6 protein, wherein the mice comprise a sequence encoding an ADAM6 or ortholog or homolog or fragment thereof that is functional in a male mouse. In one embodiment, the sequence is an ectopic ADAM6 sequence or a sequence that confers upon a male mouse the ability to generate offspring by mating. Mice and cells with genetically modified immunoglobulin heavy chain loci that comprise an ectopic nucleotide sequence encoding a mouse ADAM6 or functional fragment or homolog or ortholog thereof are also provided.