Na+/K+–adenosine triphosphatase (NKA) is a transmembrane protein consisting of three subunits: a, b, g. A progressive decline of NKA activity exacerbates neurodegeneration in the aging process. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region (897DVEDSYGQQWTYEQR911) of the NKAa1 subunit. It was demonstrated that DR5-12D produced therapeutic effects against neurodegenerative diseases. Therefore, DR5-12D may represent a new therapeutic strategy for neurodegenerative diseases.

Growth differentiation factor 15 (GDF-15) is a stress induced cytokine that causes anorexia and weight loss, and higher circulating levels are associated with cachexia and reduced survival in patients with cancer. Inhibition of GDF-15/GFRAL biological activity reverses cachexia in numerous preclinical tumor models, and ponsegromab (a novel, first in class humanized monoclonal anti-GDF15 antibody) is being developed as a therapeutic agent for cancer cachexia.

This talk describes the regulation of energy balance and appetite beyond traditional hormonal mechanisms. We discuss Peptide Predictor, a computational tool that identified BRINP2-Related Peptide (BRP), an anorexigenic peptide cleaved by PCSK1. BRP significantly reduces food intake and obesity through a unique central signaling pathway, without affecting other metabolic behaviors. This discovery highlights the potential of peptide prediction platforms in uncovering new metabolic regulatory mechanisms and biological pathways.

We show AAV delivery of full-length antibodies targeting GA-dipeptide proteins in C9orf72 ALS/FTD BAC-transgenic mice reduces repeat associated non-AUG (RAN) protein levels, improves behavior and neuropathology, and increases survival. AAV delivery of high-affinity antibodies is a novel strategy to achieve broad and sustained CNS expression and biodistribution of therapeutic antibodies. These data open new possibilities for developing AAV-antibody therapies as a novel approach for C9orf72 ALS/FTD and other neurodegenerative disorders.

The inability of antibodies to penetrate the blood-brain barrier is a key limitation to their use in diverse applications. We are developing bispecific antibodies that engage either CD98hc or transferrin receptor, which results in the transport of IgGs and other biologics into the CNS. We will highlight our findings related to the unique advantages of CD98hc and transferrin receptor bispecific antibodies, especially related to the impact of target engagement in the CNS on pharmacokinetics and CNS distribution. Finally, we will discuss our recent findings on applications of bispecific antibodies for targeted CNS drug delivery.

Alector is a leader in the field of Neuroimmunology - harnessing the brain's immune system to cure neurogenerative disorders. Here we describe our Neuroimmunology pipeline and our novel Blood-brain barrier crossing technology (ABC) designed to further enhance brain delivery of antibody and protein therapeutics to address neurodegenerative diseases.