Methods and compositions are provided for making non-human animals with reduced tolerance of a foreign antigen of interest and making antigen-binding proteins against that foreign antigen of interest using such animals. The methods and compositions employ CRISPR/Cas9 systems using multiple guide RNAs to reduce or eliminate expression of a self-antigen homologous to or sharing an epitope of interest with the foreign antigen of interest or to reduce or eliminate expression of an epitope on the self-antigen that is shared with the foreign antigen of interest.

The present invention relates to transgenic mammals that express bovine-based immunoglobulins, including transgenic rodents that express bovine-based immunoglobulins for the development of bovine therapeutic antibodies.

The present invention relates to transgenic mammals that express canine-based immunoglobulins, including transgenic rodents that express canine-based immunoglobulins for the development of canine therapeutic antibodies.

Non-human animals, tissues, cells, and genetic material are provided that comprise a modification of an endogenous non-human heavy chain immunoglobulin sequence and that comprise an ADAM6 activity functional in a rodent (e.g., a mouse), wherein the non-human animals rearrange human immunoglobulin light chain gene segments in the context of heavy chain constant regions and express immunoglobulin-like molecules comprising human immunoglobulin light chain variable domains fused to heavy chain constant domains that are cognate with human immunoglobulin light chain variable domains fused to light chain constant domains.

Methods and compositions are provided for generating antigen-binding proteins against a foreign antigen of interest.

The present invention relates to transgenic mammals that express bovine-based immunoglobulins, including transgenic rodents that express bovine-based immunoglobulins for the development of bovine therapeutic antibodies.

The present invention relates to transgenic mammals that express canine-based immunoglobulins, including transgenic rodents that express canine-based immunoglobulins for the development of canine therapeutic antibodies.

The present invention relates inter alia to fertile non-human vertebrates such as mice and rats useful for producing antibodies bearing human variable regions, in which endogenous antibody chain expression has been inactivated.

The present invention relates to transgenic mammals that express canine-based immunoglobulins, including transgenic rodents that express canine-based immunoglobulins for the development of canine therapeutic antibodies.

The invention relates to a method for inhibiting an ADAM protease, comprising inhibiting binding to an integrin-binding loop of a disintegrin domain in the ADAM protease. Also provided are cyclic peptides which inhibit binding to an integrin-binding loop of an ADAM protease, as well as associated pharmaceutical compositions, uses and methods of treatment.