Background

AL003 is a monoclonal antibody that was being co-developed by Alector and Abbvie. According to Alector, it counteracts the function of sialic acid binding immunoglobulin-like lectin 3, aka Siglec-3, an inhibitory microglial transmembrane receptor that reportedly interacts with TREM2 (Oct 2015 news). The gene encoding Siglec-3, CD33, has been associated with AD risk via a protective variant, expression levels, and alternative splicing (Estus et al., 2019; Katsumata et al., 2019; Bertram et al., 2008). CD33 is also expressed on peripheral blood monocytes.

Findings

In March 2019, AL003 entered the clinic with a 54-person trial being run at six sites in the United States and Melbourne, Australia (May 2019 conference news). The trial finished in May 2021, and results were presented at the November 2021 CTAD conference (poster). In a single-ascending-dose phase, 38 healthy participants received infusions of one of eight escalating doses. Outcomes included safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. In healthy volunteers, the drug was well tolerated up to the 15 mg/kg dose. One person in the 30 mg/kg dose group developed hip inflammation, and dosing in the 60 mg/kg group was stopped after one person had a severe hypersensitivity reaction. Both required hospitalization and treatment with steroids. In the subsequent multiple-ascending-dose phase, 10 participants with AD received two doses of 15 mg/kg, four weeks apart; two received placebo. All finished the study with no serious drug-related adverse events. The half-life of the antibody after multiple dosing was approximately 15 hours, and CNS levels reached 0.1-0.2 percent of plasma. Treatment lowered CD33 expression on blood monocytes, and boosted soluble CD33 in CSF, indicating target engagement.

On June 30 2022, AbbVie terminated the AL003 collaboration, according to an Alector SEC filing. No reason was given, and Alector removed AL003 from its pipeline. The companies are continuing to co-develop the TREM2 antibody AL002.

For details, see clinicaltrials.gov.