Drug Development

Sabirnetug (ACU193) is a monoclonal antibody designed to selectively target toxic soluble amyloid β oligomers (AβOs). Its efficacy in mild cognitive impairment (MCI) and early Alzheimer's disease (AD) is currently being investigated in the ALTITUDE-AD phase 2 study (NCT06335173). Therapeutic targeting of AβOs in MCI/AD is challenged by the significantly higher abundance of the less toxic Aβ monomers in MCI/AD tissues and biofluids, e.g., ∼7,000-fold for Aβ_1-40/AβOs in CSF. Therefore, the therapeutic efficacy of AβO-targeting antibodies is enhanced by high selectivity for AβOs over monomeric Aβ. Here, we compare the binding affinities to AβOs and Aβ monomer of sabirnetug with other Aβ-targeting antibodies lecanemab, aducanumab, and murine donanemab.

Human lecanemab and aducanumab and murine donanemab were recombinantly produced from published sequences. Binding kinetics of these antibodies or sabirnetug to AβOs (ADDLs or Aβ_1-42 stabilized oligomers from GBS Leiden) or monomeric Aβ proteoforms (Aβ_1-28, Aβ_1-40, Aβ_1-42) was determined by surface plasmon resonance (SPR). Briefly, each Aβ test species was captured by anti-Aβ antibody 6E10 conjugated to the SPR chip and then the test antibody was titrated across the chip.

Sabirnetug showed the highest binding affinities to both AβO preparations with a correspondingly low K_D = 0.596 nM for Aβ_1-42 stabilized oligomers and 0.319 nM for ADDLs. Lecanemab had the next highest binding affinities at 0.972 nM and 0.762 nM, respectively. Sabirnetug showed the lowest binding affinities to monomeric Aβ_1-40 (sabirnetug >5.22 µM; lecanemab, 215.7 nM) and a comparable affinity to monomeric Aβ_1-28 as lecanemab (sabirnetug, 4.98 µM; lecanemab, 9.38 µM). Measurement of monomeric Aβ_1-42 binding was confounded by oligomerization within the experimental time frame. Sabirnetug had the highest selectivity for AβOs over monomeric Aβ_1-40, e.g., 8,750-fold selectivity for Aβ_1-42 stabilized oligomers over Aβ_1-40 compared to 222-fold selectivity of lecanemab, and comparable selectivity with lecanemab for AβOs over monomeric Aβ_1-28. Aducanumab and murine donanemab were less selective for AβOs over both monomeric Aβ proteoforms.

Compared to the recombinant Aβ monoclonal antibody therapeutics tested, sabirnetug showed the highest selectivity for AβOs over monomeric Aβ. Sabirnetug's observed high level of selectivity makes it well positioned to target AβOs in MCI/AD tissues and biofluids.