The Effect of ANX005, an Anti-C1q Antibody, on Biomarkers of Target and Pathway Engagement and Neurodegeneration in ALS Patients
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motor neurons, the nerve cells in the brain and spinal cord that control voluntary muscle movement. The degeneration of motor neurons causes progressive muscle paralysis, and patients usually die within a few years of diagnosis. There are currently no drugs available that can prolong survival of ALS patients for more than a few months. A body of evidence suggests that abnormal activation of the complement protein system contributes to the development of ALS. The complement system is an arm of the immune system. One of the jobs of the complement system is to recognize microbes and bits of cellular debris that may be harmful to the body and bind to them, thereby flagging them for attack and digestion by macrophages (the scavenger cells of the immune system). In recent years, it was discovered that the complement system plays a similar role in the nervous system. When nerve cells get sick, they typically start degenerating first at their synapses (the specialized endings where nerve cells make contact with muscle cells or other nerve cells). Complement proteins speed synaptic degeneration by binding to malfunctioning synapses and recruiting microglia (the macrophages of the nervous system) to eliminate them. Overactivation of complement system may cause some synapses to be eliminated prematurely, causing the death of nerve cells that might otherwise remain functional. Overactivation of the complement system appears to be involved in many neurodegenerative diseases, including not only ALS but also Alzheimer s disease (AD), Parkinson s disease (PD), Huntington s disease (HD), and spinal muscular atrophy (SMA). Annexon Biosciences has developed an antibody drug, ANX005, that may be useful in treating ALS. This drug binds to and blocks complement protein C1q. C1q is responsible for triggering the so-called classical complement pathway--the pathway responsible for recruiting microglia to synapses. We hypothesize that blocking C1q will slow the progressive loss of motor synapses and nerve cells that occurs in ALS. In the proposed study, we will test the effects of ANX005 on complement protein levels and biomarkers of neurodegeneration in the blood and cerebrospinal fluid (CSF) of ALS patients. These studies are designed to ensure that our antibody is binding to and effectively blocking the function of C1q protein in ALS patients. They will also test how ANX005 treatment affects a biomarker of neurodegeneration. The proposed study is part of a larger clinical trial to assess the safety of ANX005, monitor its distribution and duration of action within the body, and do a preliminary test of its efficacy in ameliorating clinical symptoms of ALS. Our past research has shown that ANX-005 is effective in preventing nerve cell degeneration in mouse models of four other neurodegenerative diseases: HD, SMA, age-related macular degeneration, and Guillain-Barre Syndrome (GBS). Initial results from clinical trials of ANX-005 in GBS patients indicate that our drug (1) has no major side-effects, (2) is effective in reducing C1q levels, (3) reduces levels of a neurodegeneration marker, neurofilament protein, and (4) ameliorates neurological symptoms. These results support our hypothesis that targeting C1q with ANX-005 would be an effective treatment for ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110398
Entities
People
- Enchi Liu
Organizations
- United States Army