Abstract: The present invention provides monoclonal antibodies that bind to the Activin A type I receptor (ACVR1) protein, and methods of use thereof. In various embodiments of the invention, the antibodies are fully human antibodies that bind to ACVR1. In some embodiments, the antibodies of the invention are useful for inhibiting ACVR1-mediated bone morphogenetic protein (BMP) signal transduction, thus providing a means of treating or preventing a disease, disorder or condition associated with ACVR1.

Abstract: Provided are non-human animals comprising a mutation in the Fbn1 gene to model neonatal progeroid syndrome with congenital lipodystrophy (NPSCL). Also provided are methods of making such non-human animal models. The non-human animal models can be used for screening compounds for activity in inhibiting or reducing NPSCL or ameliorating NPSCL-like symptoms or screening compounds for activity potentially harmful in promoting or exacerbating NPSCL as well as to provide insights in to the mechanism of NPSCL and potentially new therapeutic and diagnostic targets.

Abstract: The present invention provides antibodies that bind to human gremlin-1 (GREM1), and methods of use. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to GREM1. The antibodies of the invention are useful for inhibiting or neutralizing GREM1 activity, thus providing a means of treating a GREM1-related disease or disorder such as fibrosis and cancer. In some embodiments, the antibodies of the present invention are used in treating at least one symptom or complication of fibrosis of the liver, lungs or kidney.

Abstract: The present invention provides antibodies that bind to human gremlin-1 (GREM1), and methods of use. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to GREM1. The antibodies of the invention are useful for inhibiting or neutralizing GREM1 activity, thus providing a means of treating a GREM1-related disease or disorder such as fibrosis and cancer. In some embodiments, the antibodies of the present invention are used in treating at least one symptom or complication of fibrosis of the liver, lungs or kidney.

Abstract: The present invention provides multispecific antigen-binding molecules and uses thereof. The multispecific antigen-binding molecules comprise a first antigen-binding domain that specifically binds a target molecule, and a second antigen-binding domain that specifically binds an internalizing effector protein. The multispecific antigen-binding molecules of the present invention can, in some embodiments, be bispecific antibodies that are capable of binding both a target molecule and an internalizing effector protein. In certain embodiments of the invention, the simultaneous binding of the target molecule and the internalizing effector protein by the multispecific antigen-binding molecule of the present invention results in the attenuation of the activity of the target molecule to a greater extent than the binding of the target molecule alone.

Abstract: A genetically modified rodent is provided that comprises a modified Acvr1 gene that comprises a conditional altered exon 7 encoding R258G in antisense orientation, flanked by site-specific recombinase recognition sites, wherein the altered exon is inverted to sense orientation upon action of a recombinase, resulting in ectopic bone formation.

Abstract: A genetically modified rodent is provided that comprises a modified Acvr1 gene that comprises a conditional altered exon 7 encoding R258G in anti sense orientation, flanked by site-specific recombinase recognition sites, wherein the altered exon is inverted to sense orientation upon action of a recombinase, resulting in ectopic bone formation.

Abstract: Methods for treating Fibrodysplasia Ossificans Progressiva (FOP) are provided. Such methods involve administering to a subject having FOP an effective regime of an activin receptor type 2A (ACVR2A) and/or an activin receptor type 2B (ACVR2B) antagonist or an activin receptor type 1 (ACVR1) antagonist. Antagonists include fusion proteins of one or more extracellular domains (ECDs) of ACVR2A, ACVR2B and/or ACVR1 and the Fc domain of an immunoglobulin heavy chain, and antibodies against ACVR2A, ACVR2B, ACVR1 or Activin A.

Abstract: Methods for modifying a genome are provided, wherein the modifications comprise null alleles, conditional alleles and null alleles comprising conditional by inversion elements. Methods are provided which afford the ability in a single targeting step to introduce an allele that can be used to generate a null allele, a conditional allele, or an allele that is a null allele and that further includes a conditional by inversion element. Introduced alleles comprise pairs of cognate recombinase recognition sites, an actuating sequence and/or a drug selection cassette, and a nucleotide sequence of interest, and a conditional by inversion element, wherein upon action of a recombinase a conditional allele with a conditional by inversion element is formed. In a further embodiment, action of a second recombinase forms an allele that contains only a conditional by inversion element in sense orientation.

Abstract: Nucleic acid constructs and methods for rendering modifications to a genome are provided, wherein the modifications comprise null alleles, conditional alleles and null alleles comprising COINs. Multifunctional alleles (MFA) are provided, as well as methods for making them, which afford the ability in a single targeting to introduce an allele that can be used to generate a null allele, a conditional allele, or an allele that is a null allele and that further includes a COIN. MFAs comprise pairs of cognate recombinase recognition sites, an actuating sequence and/or a drug selection cassette, and a nucleotide sequence of interest, and a COIN, wherein upon action of a recombinase a conditional allele with a COIN is formed. In a further embodiment, action of a second recombinase forms an allele that contains only a COIN in sense orientation. In a further embodiment, action by a third recombinase forms an allele that contains only the actuating sequence in sense orientation.

Abstract: The present invention provides monoclonal antibodies that bind to the Activin A type I receptor (ACVR1) protein, and methods of use thereof. In various embodiments of the invention, the antibodies are fully human antibodies that bind to ACVR1. In some embodiments, the antibodies of the invention are useful for inhibiting ACVR1-mediated bone morphogenetic protein (BMP) signal transduction, thus providing a means of treating or preventing a disease, disorder or condition associated with ACVR1.

Abstract: Methods of creating mutations in genomic exons by inserting introns into the genomic exons via homologous recombination. Also, methods are provided for introducing modifications into genomic exons by inserting introns into the genomic exons via homologous recombination such that a mature mRNA transcript produced from a genomic region of the genome comprising the genomic exon does not contain the modification are provided. The methods provide for a rapid method for introducing mutations and/or modifications of any type into a mammalian cell genome.

Abstract: The present invention provides multispecific antigen-binding molecules and uses thereof. The multispecific antigen-binding molecules comprise a first antigen-binding domain that specifically binds a target molecule, and a second antigen-binding domain that specifically binds an internalizing effector protein. The multispecific antigen-binding molecules of the present invention can, in some embodiments, be bispecific antibodies that are capable of binding both a target molecule and an internalizing effector protein. In certain embodiments of the invention, the simultaneous binding of the target molecule and the internalizing effector protein by the multispecific antigen-binding molecule of the present invention results in the attenuation of the activity of the target molecule to a greater extent than the binding of the target molecule alone.

Abstract: Methods for treating Fibrodysplasia Ossificans Progressiva (FOP) are provided in which a subject having FOP is administered an effective regime of an antibody against Activin B, BMP9 or BMP10.

Abstract: A genetically modified mouse is provided that comprises a conditional Acvr1 allele that comprises a mutated exon that, upon induction, converts to a mutant exon phenotype, wherein the mutant exon phenotype includes ectopic bone formation. Mice comprising a mutant Acvr1 exon 5 in antisense orientation, flanked by site-specific recombinase recognition sites, are provided, wherein the mice further comprise a site-specific recombinase that recognizes the site-specific recombinase recognitions sites, wherein the recombinase is induced upon exposure of the mouse to tamoxifen. Upon exposure to tamoxifen, the recombinase is expressed and acts on the RRS-flanked mutant exon 5 and places the mutant exon 5 in sense orientation and deletes the wild-type exon.

Abstract: The present invention provides antibodies that bind to human gremlin-1 (GREM1), and methods of use. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to GREM1. The antibodies of the invention are useful for inhibiting or neutralizing GREM1 activity, thus providing a means of treating a GREM1-related disease or disorder such as fibrosis and cancer. In some embodiments, the antibodies of the present invention are used in treating at least one symptom or complication of fibrosis of the liver, lungs or kidney.

Abstract: Provided herein are compositions and methods for redirecting recombinant viral capsid particles via a specific protein:protein binding pair that forms an covalent, e.g., isopeptide, bond to display a targeting ligand on the capsid protein, wherein the targeting ligand specifically binds a cell surface marker expressed on the cell of interest.

Abstract: Provided herein is a mouse that produces hybrid antibodies containing human variable regions and mouse constant regions.

Abstract: Methods for treating Fibrodysplasia Ossificans Progressiva (FOP) are provided. Such methods involve administering to a subject having FOP an effective regime of an activin receptor type 2A (ACVR2A) and/or an activin receptor type 2B (ACVR2B) antagonist or an activin receptor type 1 (ACVR1) antagonist. Antagonists include fusion proteins of one or more extracellular domains (ECDs) of ACVR2A, ACVR2B and/or ACVR1 and the Fc domain of an immunoglobulin heavy chain, and antibodies against ACVR2A, ACVR2B, ACVR1 or Activin A.

Abstract: A genetically modified mouse is provided that comprises a conditional Acvr1 allele that comprises a mutated exon that, upon induction, converts to a mutant exon phenotype, wherein the mutant exon phenotype includes ectopic bone formation. Mice comprising a mutant Acvr1 exon 5 in antisense orientation, flanked by site-specific recombinase recognition sites, are provided, wherein the mice further comprise a site-specific recombinase that recognizes the site-specific recombinase recognitions sites, wherein the recombinase is induced upon exposure of the mouse to tamoxifen. Upon exposure to tamoxifen, the recombinase is expressed and acts on the RRS-flanked mutant exon 5 and places the mutant exon 5 in sense orientation and deletes the wild-type exon.