title: Abeta targets of the biosimilar antibodies of Bapineuzumab,  Crenezumab, Solanezumab in comparison to an antibody  against N‑truncated Abeta in sporadic Alzheimer disease cases  and mouse models.
abstract: Solanezumab and Crenezumab are two humanized antibodies targeting Amyloid-β (Aβ) which are currently tested in multiple clinical trials for the prevention of Alzheimer's disease. However, there is a scientific discussion ongoing about the target engagement of these antibodies. Here, we report the immunohistochemical staining profiles of biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab in human formalin-fixed, paraffin-embedded tissue and human fresh frozen tissue. Furthermore, we performed a direct comparative immunohistochemistry analysis of the biosimilar versions of the humanized antibodies in different mouse models including 5XFAD, Tg4-42, TBA42, APP/PS1KI, 3xTg. The staining pattern with these humanized antibodies revealed a surprisingly similar profile. All three antibodies detected plaques, cerebral amyloid angiopathy and intraneuronal Aβ in a similar fashion. Remarkably, Solanezumab showed a strong binding affinity to plaques. We also reaffirmed that Bapineuzumab does not recognize N-truncated or modified Aβ, while Solanezumab and Crenezumab do detect N-terminally modified Aβ peptides Aβ4-42 and pyroglutamate Aβ3-42. In addition, we compared the results with the staining pattern of the mouse NT4X antibody that recognizes specifically Aβ4-42 and pyroglutamate Aβ3-42, but not full-length Aβ1-42. In contrast to the biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab, the murine NT4X antibody shows a unique target engagement. NT4X does barely cross-react with amyloid plaques in human tissue. It does, however, detect cerebral amyloid angiopathy in human tissue. In Alzheimer mouse models, NT4X detects intraneuronal Aβ and plaques comparable to the humanized antibodies. In conclusion, the biosimilar antibodies Solanezumab, Crenezumab and Bapineuzumab strongly react with amyloid plaques, which are in contrast to the NT4X antibody that hardly recognizes plaques in human tissue. Therefore, NT4X is the first of a new class of therapeutic antibodies.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Bouter
authors.forename: Jose Socrates
authors.initials: JS
authors.lastname: Lopez Noguerola
authors.forename: Petra
authors.initials: P
authors.lastname: Tucholla
authors.forename: Gabriela A N
authors.initials: GA
authors.lastname: Crespi
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Jens
authors.initials: J
authors.lastname: Wiltfang
authors.forename: Luke A
authors.initials: LA
authors.lastname: Miles
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D059451:Biosimilar Pharmaceuticals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D059451:Biosimilar Pharmaceuticals; D007155:Immunologic Factors; C000609698:NT4X monoclonal antibody; C550616:solanezumab; C545458:bapineuzumab; C573372:crenezumab