Background

PMN310 is a humanized IgG4 monoclonal antibody to soluble Aβ oligomers. It was raised against a constrained cyclic peptide derived from amino acids 13–16 (HHQK) of Aβ. This epitope was predicted by computer modeling to be exposed on toxic Aβ oligomers but not monomers or fibrils. The peptide was reported to accelerate Aβ aggregation in vitro, suggesting this epitope plays a role in seeding the formation of Aβ oligomers, and thus is a good target for inhibition by an antibody (Cashman et al., 2021, AAIC poster).

In preclinical work, PMN310 selectively bound to Aβ oligomers over monomers. It inhibited Aβ oligomer propagation and toxicity in vitro and in cell assays. It prevented Aβ-induced memory deficits, and lessened synaptic loss and inflammation caused by cerebroventricular Aβ-oligomer injection in mice (Kaplan et al., 2023; US Patent 9.216,217 B2).

The antibody did not bind to Aβ plaque or vascular deposits in AD brain tissue sections, but did react with soluble oligomer-enriched fractions (Gibbs et al., 2019). In a direct comparison with other Aβ antibodies, PMN310 was the least affected by high concentrations of competing monomeric Aβ, a characteristic that correlates with clinical efficacy of trialed antibodies (Kaplan et al., 2023 AD/PD poster; Kaplan et al., 2024 preprint). The ability of PMN310 to target oligomers in the presence of competing monomers and plaque suggests a potential for better target engagement in brain and a lower risk of ARIA, compared to other, less-selective antibodies.

Findings

In November 2023, Phase 1 began to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of PMN310. The placebo-controlled study plans to enroll 40 healthy adult volunteers to five sequential dose cohorts of 175, 350, 700, 1,400, and 2,800 mg. Besides safety endpoints, the study will assess serum and cerebrospinal fluid pharmacokinetics, and anti-drug antibodies. Completion is planned for July 2024.

For details on PMN310 trials, see clinicaltrials.gov.