Abstract: In one aspect, bispecific proteins having the ability to specifically bind to both subdomain II of human HER2 and subdomain IV of human HER2 are provided. In another aspect, methods of treating a cancer or treating brain metastasis of a cancer using a bispecific protein that specifically binds to subdomain II and subdomain IV of human HER2 are provided.

Abstract: The present disclosure relates to anti-HER2 constructs, such as Fc polypeptide dimer-antibody variable region fusion proteins, that cross the BBB and bind to HER2 in the brain parenchyma. In some embodiments, the anti-HER2 constructs (e.g., Fc polypeptide dimer-antibody variable region fusion proteins) retain effector function upon binding to HER2, but do not substantially deplete reticulocytes in vivo. The present disclosure also relates to methods for transcytosing an anti-HER2 antibody variable region across the BBB and treating HER2-positive cancers and metastatic lesions thereof.

Abstract: The present disclosure relates generally to Fc polypeptide dimers that contain a non-native transferrin receptor (TfR) binding site, do not substantially deplete reticulocytes in vivo, but retain binding to the Fc? receptor (Fc?R). The present disclosure also relates to an Fc polypeptide dimer that contains a non-native site that specifically binds TfR on one of the Fc polypeptides; a modification or modifications on the Fc polypeptide containing the TfR-binding site that reduces Fc?R binding when bound to TfR, where the other Fc polypeptide does not contain a TfR-binding site but retains Fc?R binding.