Page 43 - AN-3-1

Advanced Neurology Antibodies as neurodegenerative biomarkers

Gantenerumab targets conformational epitopes pathway. 167,168 Clinical trials have demonstrated that PRX002
expressed in Aβ fibrils and requires the peptide to be folded significantly reduces free α-syn levels in serum, penetrates
near the N-terminal or middle region. 119,134 The treatment the CNS, and maintains a safe profile at evaluated doses. 167,169
with gantenerumab leads to a reduction in Aβ plaques 134-140 BIIB054 is another monoclonal antibody that focuses
with a unique mechanism of action by activating microglial on the α-syn aggregates and is directed specifically to the
cells in the brain. 134,138 Its potential to slow progression and N-terminal region. Preliminary studies have shown
170
to modify the disease in early stages may offer important that BIIB054 is well-tolerated in single doses and has an
advantages. 137,141 Nevertheless, this antibody did not acceptable safety profile, along with a high affinity for
improve cognitive function in advanced stages and may forming BIIB054/α-syn complexes, demonstrating safe
entail a significant risk of adverse effects, particularly in biological activity. 171
individuals carrying the APOE4 genetic variant. 138
This development in monoclonal antibody therapies
Aducanumab is the first approved therapy specifically offers new perspectives to address the treatment of
targeting AD through the clearance of Aβ aggregates, neurodegenerative diseases. However, the efficacy and
including oligomers and insoluble fibrils. 119,142 This safety of these therapies at various stages still require
antibody binds to the N-terminal and recognizes a further investigations.
conformational epitope present in aggregated Aβ but absent
in monomers. 119,120 Aducanumab has been demonstrated to 6. Conclusion
significantly reduce Aβ plaques 143,144 and improve cognitive
function in some cases of AD. 145,146 However, high doses of Reactive antibodies have emerged as potential biomarkers
this monoclonal antibody have been associated with events of neurodegenerative diseases, showcasing an impressive
related to cerebral inflammation. 146-148 ability to detect early changes in pathological proteins like
β-amyloid and α-syn. This unique characteristic positions
Another member of this family is lecanemab, an them as highly promising tools for early diagnosis
antibody that selectively binds to large soluble Aβ and continuous disease monitoring. Leveraging blood
protofibrils and reduces pathogenic Aβ involved in the serum samples as a source of biomarkers adds practical
pathogenesis of AD. 119,149,150 Lecanemab appears to delay advantages, simplifying sample collection and enhancing
disease progression, improve quality of life, reduce long- their application in clinical studies and long-term patient
term health-care costs, and enhance cognitive function in follow-up. Yet, the significance of reactive antibodies
patients without eliciting severe side effects. 151-154 transcends their role as biomarkers. At present, they are
Crenezumab is a humanized IgG4 monoclonal antibody, the focal point of numerous investigations, exploring their
targeting the middle domain of Aβ, that alters Aβ protein potential as candidates for passive immunotherapies aimed
structure and reduces its concentration. 119,155-158 However, at slowing or halting the progression of neurodegenerative
this biosimilar drug did not improve cognitive function diseases. This multifaceted nature of reactive antibodies
in patients or delay disease progression in preclinical highlights their pivotal role in the ongoing research and
158
carriers of the PSEN1 E280A mutation. Ponezumab is management of these diseases, holding substantial promise
159
a humanized IgG2 monoclonal antibody targeting the for both diagnostic and therapeutic applications (Figure 4).
119
C-terminal of soluble Aβ. The clinical results show that
160
the drug was able to modify Aβ levels in plasma and CSF
but did not improve plaque accumulation or cognitive
function. 161-163 No serious adverse effects or deaths were
observed following ponezumab administration. 161-163
In the context of PD, monoclonal antibodies targeting
α-syn have shown potential in reducing protein aggregation
and mitigating neurodegeneration in experimental
models. 164-166 At present, monoclonal antibodies PRX002 and
BIIB054, also known as prasinezumab and cinapanemab,
respectively, are under investigation.
PRX002 is an antibody directed to the C-terminal of
α-syn in clinical development. Preliminary studies indicate Figure 4. Summary of the multifaceted role of reactive antibodies in
neurodegenerative diseases: from their involvement as protective and
that PRX002 can target α-syn extracellular aggregates in the pathogenic agents to their potential value in passive immunotherapies
brain and promote their clearance through the lysosomal and early diagnosis.

Volume 3 Issue 1 (2024) 8 https://doi.org/10.36922/an.2058