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.

Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier

“…This study, as well as other human and animal studies, helps to explain the marginal responses or actual failure of recent intravenous Aβ antibody (e.g., Solanezumab, Bapineuzumab, Crenezumab) infusion clinical trials. These trials appear to depend upon the Aβ antibodies enhancing efflux transport of Aβ across the BBB (Prins and Scheltens, 2013; Castello, et al 2014; Toyn, 2015; Godyn, et al 2016; Bouter, et al 2015; Fuller et al 2015). Alternatively the poor performance of Aβ antibody therapy may be the multi-morbidity of a number of pathologies seen in the brains of the AD and non-demented elderly, e.g., Lewy body disease, various tauopathies and cerebrovascular disease (Dugger et al, 2014; Attems et al 2013; Echavarri et al 2012).…”

Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot?

“…Solanezumab (Eli Lilly) is in phase III development for subjects at risk of developing AD. Studies in transgenic mice and humans suggest it recognizes soluble monomeric Aβ and also Aβ plaques . Solanezumab is one of the few anti‐Aβ antibodies shown to improve cognitive deficits in some transgenic mouse models of AD, although not in all …”

Early diagnosis and treatment of Alzheimer’s disease: new definitions and challenges

“…92 Four passive immunotherapy agents, all antiamyloid monoclonal antibodies, are now in development in phase III clinical trials of patients with early and preclinical AD and asymptomatic subjects at risk for AD. 19 The antibody solanezumab, which binds to the central region of Ab, with evidence of a preference for soluble monomeric Ab, 93 is being tested in a preventive paradigm. The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study (A4) is testing solanezumab in asymptomatic or mildly symptomatic older adults with biomarker evidence of brain amyloid deposition, 94 and the Dominantly Inherited Alzheimer Network -Trials Unit Study (DIAN-TU) is testing the compound in asymptomatic or mildly symptomatic carriers of autosomal dominant mutations in APP, PSEN1, or PSEN2.…”