ABSTRACT
Aim: Assessment of pre-existing anti-drug antibody (preADA) reactivity at early drug development stages can be beneficial for candidate selection. We investigated the applicability of a generic immune-complex anti-drug antibody (ADA) assay for early preADA assessment as an easily available alternative to the commonly used ADA bridging assay. Results: The results confirmed the expected assay difference regarding isotype detectability. Tested drug candidates were identified as preADA-reactive using the immune-complex ADA assay despite its limitation of not being able to detect IgM-type preADAs. Conclusion: We recommend a purpose-driven use of the two assay formats. For the purpose of ranking different Pro329Gly mutation-bearing drug candidates, the immune-complex ADA assay is preferred in the phase before selecting a drug for clinical development.
Subject(s)
Antibodies, Monoclonal , Antigen-Antibody ComplexABSTRACT
The role of astrocytes in the progression of Alzheimer's disease (AD) remains poorly understood. We assessed the consequences of ablating astrocytic proliferation in 9 months old double transgenic APP23/GFAP-TK mice. Treatment of these mice with the antiviral agent ganciclovir conditionally ablates proliferating reactive astrocytes. The loss of proliferating astrocytes resulted in significantly increased levels of monomeric amyloid-ß (Aß) in brain homogenates, associated with reduced enzymatic degradation and clearance mechanisms. In addition, our data revealed exacerbated memory deficits in mice lacking proliferating astrocytes concomitant with decreased levels of synaptic markers and higher expression of pro-inflammatory cytokines. Our data suggest that loss of reactive astrocytes in AD aggravates amyloid pathology and memory loss, possibly via disruption of amyloid clearance and enhanced neuroinflammation.
