Therapeutics
SOBIN Therapeutics
In development for use in concert with early detection to target and neutralize the α-sheet toxic soluble oligomers associated with amyloid diseases.
Unique.
Therapeutics for amyloid diseases, in development with the potential to provide:
Early treatment. Neutralization of α-sheet toxic oligomers. Elimination of downstream processes.
α-sheet, the defining feature of toxic oligomers
Highly selective, early targeting
Unique mechanism of action and clearance pathway
Potentially lower risk
α-sheet
the defining feature of toxic oligomers
AltPep’s early disease-modifying treatments and detection tools for amyloid diseases are based on the discovery of a new protein structure called α-sheet, a defining feature of toxic soluble oligomers. Toxic soluble oligomers are the earliest known molecular triggers of amyloid disease.
In Alzheimer’s disease, toxic oligomers start forming and aggregating in the brain, initiating damage 10-20 years before clinically evident disease, and continue forming through later stage disease.
De novo α-sheet peptides were designed to determine the structure of the novel protein; this information was used to verify that the amyloidogenic proteins formed α-sheet in their toxic oligomer states, and that the designed peptides selectively target the toxic species via complementary α-sheet structure.
Hopping et al. 2014 https://pubmed.ncbi.nlm.nih.gov/25027691/ was the groundbreaking publication demonstrating the existence of α-sheet and the targeting of α-sheet to inhibit amyloidogenesis.
Highly Selective,
Early Targeting
AltPep’s customized, synthetic peptides are designed to bind selectively to α-sheet toxic soluble oligomers (α-sheet) to both detect and neutralize them throughout disease progression. This highly selective approach is analogous to finding a “needle in the haystack”, as illustrated for the many structural and aggregated versions of the Amyloid-beta (Aβ) peptide in Alzheimer’s disease.
Recently approved monoclonal antibodies for Alzheimer’s disease (lecanemab and donanemab), non-selectively target downstream, extracellular amyloid plaques, fibrils and protofibrils. Selective detection of toxic oligomers is not possible with conventional antibodies. As such, they have shown to be of moderate benefit when the intervention takes place long after the damage has occurred.
Click to enlarge.
Illustrated for AD
Illustrated for AD
Unique MOA
and Clearance Pathway
TREM2 is critical in the pathogenesis of Alzheimer’s disease. Although the specific Mechanism of Action (MOA) is not fully understood, current views suggest that TREM2, located on the cell surface of microglia, is a key player in attenuating the inflammatory response in neurodegenerative diseases including Alzheimer’s disease (Neural Regen Res 2023).
SOBIN-AD clears toxic oligomers and other debris via TREM2 microglia activation and subsequent clearance. Potential stimulation of this process may slow aggregation at the earliest stages of the disease.
Potentially Lower Risk
of ARIA in AD
Amyloid-related Imaging Abnormalities (ARIA-E (edema) and ARIA- H (hemorrhage)) are a serious concern related to the use of approved antibody therapies and others in development. Initial preclinical data (unpublished) in a transgenic mouse model of AD treated chronically with SOBIN-AD showed no evidence of ARIA.
Amyloid plaque are targeted and mobilized by anti-amyloid antibodies (such as lecanemab and donanemab). The antibody-bound plaque clear through the brain’s immune cells, called microglia, by binding Fc-gamma receptors (Fc𝛾Rs). (Alzheimers Dis Rep. 2023) This binding alters the microglia resulting in inflammation and cytokine storm and thereby creating ARIA concerns (https://ajronline.org/doi/epdf/10.2214/AJR.22.28461).
SOBIN-AD binds to α-sheet toxic soluble oligomers and to TREM2 receptors on the surface of the microglia, stimulating clearance without inducing the inflammation or cytokine storm known to increase the risk of ARIA. Clinical studies will evaluate and confirm the preclinical findings.
Illustrated for AD
