Background

ALIA-1758 is a bispecific antibody construct. It comprises an anti-Aβ antibody fused with a transferrin receptor antibody that facilitates entry into the brain. The Aβ antibody recognizes N-terminal truncated Aβ pyroglutamated at position 3, a form that is aggregated in amyloid plaques. It is similar in specificity to Lilly’s donanemab and remternetug, and ABBV-916, which are meant to remove amyloid plaques quickly and completely.

The proprietary brain delivery platform was created by Janssen scientists, and licensed to Aliada Therapeutics. It utilizes an optimized single-chain antibody to the transferrin receptor, which is fused to an Aβ antibody whose Fc sequence has reduced effector function. Binding to transferrin receptors on endothelial cells mediates transcytosis of the antibody across the blood-brain border. Once in the brain, the antibody is taken up by resident myeloid cells via receptor-mediated endocytosis through their transferrin receptors, leading to degradation of Aβ via a non-classical phagocytosis pathway. The non-functional Fc domain lessens the chance of neuroinflammation, and other changes increase antibody half-life.

According to published preclinical data, a transferrin receptor antibody shuttled β-secretase enzyme into the brain in mice, resulting in reduced production of Aβ40. A tau/transferrin bispecific antibody gained widespread entry in non-human primate brain. In a mouse model of tau seeding, the antibody reduced tau aggregates, without inducing the release of inflammatory cytokines (Edavettal et al., 2022, and commentary by Thomsen and Moos, 2022).

In October 2024, AbbVie bought Aliada (press release).

Findings

In May 2024, Aliada began Phase 1 with a single-dose trial in healthy participants. It will test the safety, tolerability, and pharmacokinetics of intravenous or subcutaneous doses of ALIA-1785 against endpoints of adverse events, pharmacokinetics, bioavailability, clearance, and volume of distribution. The trial will enroll 52 people, and is expected to finish in January 2025.

For details on ALIA-1758 trials, see clinicaltrials.gov