The present invention describes transgenic animals with human(ized) immunoglobulin loci and transgenes encoding human(ized) Igα and/or Igβ sequences. Of particular interest are animals with transgenic heavy and light chain immunoglobulin loci capable of producing a diversified human(ized) antibody repertoire that have their endogenous production of Ig and/or endogenous Igα and/or Igβ sequences suppressed. Simultaneous expression of human(ized) immunoglobulin and human(ized) Igα and/or Igβ results in normal B-cell development, affinity maturation and efficient expression of human(ized) antibodies.

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, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise an immunoglobulin heavy chain locus that includes unrearranged human immunoglobulin light chain gene segments and an immunoglobulin light chain locus that includes a single rearranged human light chain variable region nucleotide sequence. The unrearranged human light chain gene segments may be operably linked to a heavy chain constant region nucleotide sequence and the rearranged human immunoglobulin light chain variable region nucleotide sequence may be operably linked to a light chain constant region nucleotide sequence. Also provided are methods for obtaining nucleic acid sequences that encode immunoglobulin light chain variable domains capable of binding an antigen in the absence of a cognate variable domain, and expressing such nucleic acid sequences in a host cell, e.g., to generate a multispecific antigen-binding protein.

The invention provides non-human cells and mammals having a genome encoding chimeric antibodies and methods of producing transgenic cells and mammals. Certain aspects of the invention include chimeric antibodies, humanized antibodies, pharmaceutical compositions and kits. Certain aspects of the invention also relate to diagnostic and treatment methods using the antibodies of the invention.

A method of producing a transgenic silkworm that spins bagworm silks and producing a large quantity of bagworm silks by transgenic technology is developed and provided. A gene encoding a modified bagworm Fib H and a transgenic silkworm in which the gene is introduced, wherein the gene is obtained by cloning a gene fragment encoding a bagworm Fib H-like polypeptide comprising a partial amino acid sequence of bagworm Fib H, and fusing the gene fragment to a gene fragment encoding silkworm-derived Fib H, are provided.

Non-human animals (and/or non-human cells) and methods of using 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 immunoglobulin (Ig) light chains characterized by the presence of human Vλ domains. Non-human animals provided herein are, in some embodiments, characterized by expression of antibodies that contain human Vλ light chains that are encoded by human Igλ light chain-encoding sequences inserted into an endogenous Igκ light chain locus of said non-human animals Methods for producing antibodies from non-human animals are also provided, which antibodies contain human variable regions and mouse constant regions.

The invention provides improved non-human vertebrates and non-vertebrate cells capable of expressing antibodies comprising human variable region sequences. The present invention is directed to the provision of long HCDR3s from non-human vertebrates and cells. The present invention is also directed to the provision of novel V, D and J pairings in immunoglobulin heavy and light chain loci. Novel, biased antibody diversities and potentially expanded diversities are provided. The invention also provides for novel and potentially expanded diversity or diversity that is biased towards variable gene usage common to antibodies useful for treating and/or preventing certain diseases or conditions, such as infectious diseases. The invention also provides methods of generating antibodies using such vertebrates, as well as the antibodies per se, therapeutic compositions thereof and uses.

Provided herein are transgenic non-human animals whose genomes comprise two or more human genes selected from CD33, Siglec-5, Siglec-7, Siglec-9, Siglec-11, Siglec-14, and Siglec-16, to methods of screening candidate agents that bind to and/or modulate the function and/or activity of at least one of the human genes in the transgenic non-human animals, and to methods of screening candidate agents to determine their effect on one or more activities and/or functions associated with expression of at least one of the human genes in the transgenic non-human animals. Further provided herein are methods of recapitulating a human Siglec immune system in a non-human animal, and methods of generating a non-human animal disease model comprising a human Siglec repertoire.

The present inventors have conducted intensive studies on an antibody which controls HIV in an administration group with a high probability over a long period of time with one or several times of single-agent administration. As a result, the present inventors have surprisingly found that, when an SW-1C10 antibody, which is obtained by producing an antibody gene reported as 1C10 in silkworms, is singly administered only a few times, the viral load in the blood is suppressed to the detection limit or lower at an early stage in all of individuals to which the antibody has been administered, and moreover, the viral RNA load in the blood is maintained at the detection limit or lower for a long time of 12 weeks. Also, the yield of the antibody in silkworms is approximately several hundreds μg per cocoon, or several μg per 1 mg of cocoon, and studies to increase the productivity more than this level have not been conducted heretofore. The present inventors have conducted studies to find an antibody having a higher yield in silk-spinning insects among a large number of anti-HIV antibodies. As a result, the present inventors have found that a 1C10 antibody and a 1D9 antibody, each of which is an anti-HIV antibody, are produced in silk threads of silk-spinning insects at a higher yield than the conventional yield.

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.