Preclinical Development of an Anti-CD38 Monoclonal Antibody Against ALS
Abstract
ALS is a progressive and fatal neuromuscular disease affecting several organs, including the central and peripheral nervous system, muscles, and immune system. Despite the multifactorial nature of the disease, current therapeutic approaches under development only target individual factors at the level of a single organ involved in the disease progression. However, these therapeutics have yielded weak effects on patient survival, demonstrating the need for an alternative therapeutic approach. Thus, despite hundreds of clinical trials, a safe and effective therapeutic for the treatment of ALS remains a significant unmet medical need. ENCEFA identified that the administration of antibodies that target CD38 -- an enzyme and receptor of the immune system, which is also expressed by neurons, glial, and muscle cells -- were able to simultaneously clean all these cell types from intracellular waste that accumulated over years and improve their energy supply. This resulted in strong neuronal and muscle protection as well as inflammation repression; thus, providing a multi-organ response to ALS. Our lead antibody to CD38, NC-B8, demonstrated improved functional outcomes and increased survival in the gold standard ALS mouse model, which consists in the overexpression of a mutated gene found in humans (SOD1 G93A). Moreover, NC-B8 treatment was found to impact the course of the disease in dogs suffering from CDM, the canine ALS equivalent, that also displays mutations in the SOD1 gene, an effect that was assessed using biomarkers that directly translates to the human clinic. Our goal is to treat both sporadic and familial ALS patients with NC-B8. While we observed in vivo that NC-B8 was strongly active in both SOD1 G93A mice as well as in CDM dogs bearing SOD1 mutation, both models are SOD1-linked models. Thus, one may argue that NC-B8 efficacy could be restricted to SOD1 ALS patients. We do not think this will be the case since (i) NC-B8 was found to protect neurons in vitro from toxicity induced by CSF from sporadic ALS patients, and (ii) to protect motor neurons derived from iPSC from healthy donors or ALS patients carrying the C9ORF72 mutation. Moreover, NC-B8 also demonstrated strong efficacy in vivo in mouse models where neurodegeneration was induced by oxidative stress (6-OHDA mouse model), mitochondrial impairment (MPTP mouse model), lysosomal impairment (CBE mouse model), or inflammation (EAE mouse model). Together, NC-B8 demonstrated broad neuroprotective efficacy, even when neurodegeneration is induced by CSF from sporadic ALS patients, suggesting that NC-B8 will be effective in sporadic and familial ALS patients. The ultimate applicability of this research is to provide all ALS patients with access to a safe and effective disease-modifying therapy to increase quality of life and survival. In order to advance our therapeutic to the clinical stage, we first need to produce a NC-B8 clinical batch and to perform IND-enabling studies, which is the purpose of this application. As a result of this program, the development of this innovative therapeutic for ALS will be significantly accelerated. Further, if ALS patients respond to NC-B8 the same way ALS mouse and dogs did, then we can expect NC-B8 to dose-dependently reduce neurodegeneration (as measured by reduced neurofilament levels) at the end of the first part of our clinical study (Q4 2023), and significantly impact diseases progression (as measured by ALSFRS-R) at the end of the second part of our clinical study (Q3 2024). Consequently, a first read-out of NC-B8 clinical efficacy will be available within three years. Together, these results will pave the way for approval of this disease-modifying treatment and improve the quality of life and survival of ALS patients worldwide.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210108
Entities
People
- Damien Toulorge
Organizations
- United States Army