The present disclosure relates to conjugates for delivering therapeutics across the blood brain barrier (BBB) and more particularly to conjugates comprising at least one BBB-shuttling VNAR domain operably linked to a neurotrophic agonist antibody (NAAb), with the conjugate being capable of uptake across a mammalian blood brain barrier (BBB) in a therapeutically-effective amount. These conjugates are useful for treating neurodegenerative diseases, conditions which responds to activation of a neurotrophin receptor as well as for stimulating neuronal survival, growth, repair or regeneration.

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits activity of a disease allele associated with muscle disease. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits expression or activity of DUX4. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

It is an object of the present invention to provide a therapeutic drug for polycythemia. According to the present invention, provided is a therapeutic drug for polycythemia, comprising an antibody which recognizes the amino acids at positions 629 to 633 of a human transferrin receptor.

Herein is reported an anti-transferrin receptor antibody that specifically binds to human transferrin receptor and cynomolgus transferrin receptor, which comprises i) a humanized heavy chain variable domain derived from the heavy chain variable domain of SEQ ID NO: 01, and ii) a humanized light chain variable domain derived from the light chain variable domain of SEQ ID NO: 26, wherein the antibody has an off-rate for the human transferrin receptor that is equal to or less than (i.e. at most) the off-rate of the anti-transferrin receptor antibody 128.1 for the cynomolgus transferrin receptor, whereby the off-rates are determined by surface plasmon resonance, and whereby the anti-transferrin receptor antibody 128.1 has a heavy chain variable domain of SEQ ID NO: 64 and a light chain variable domain of SEQ ID NO: 65.

Compositions and methods for delivering a therapeutic protein to the central nervous system (CNS), in order to treat diseases and disorders that impair the CNS, such as treating lysosomal storage diseases, are disclosed. Therapeutic proteins delivered via a therapeutically effective amount of a nucleotide composition encoding the therapeutic protein conjugated to a cell surface receptor-binding protein, e.g., anti-TfRCscfv:GAA, that crosses the blood brain barrier (BBB) are provided.

The present invention relates to trispecific antibodies binding to HER2 and a blood-brain barrier receptor (BBB-R), methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.

The present invention concerns binding molecules that comprise an IgM, IgA, IgG/IgM or IgG/IgA antibody with a J-chain modified to include an ADME-modulating moiety, and their uses.

Aspects of the disclosure relate to transferrin receptor 1 (TfR1)-binding proteins. In some cases, humanized TfR1-binding proteins are described. Embodiments include methods for treating one or more conditions, for example cancer, using a humanized TfR1-binding protein. In some embodiments, the disclosed methods and compositions involve one or more antibodies that are capable of binding TfR1. Certain aspects relate to humanized antibodies and antibody-like molecules comprising one or more amino acid substitutions (e.g., backmutations). Additional aspects relate to combination treatments with TfR1-binding proteins and one or more additional therapeutics.

The present disclosure provides, inter alia, methods for identifying cells undergoing non-apoptotic cell death, e.g., ferroptosis, in a subject, using anti-TfR1 antibodies such as 3F3-FMA. Methods for treating or ameliorating the effects of a cancer in a subject, methods for enhancing the anti-tumor effect of radiation in a subject with cancer undergoing radiotherapy, and compositions and kits comprising anti-TfR1 antibodies disclosed herein are also provided.