Central nervous system-penetrant anti-C1q therapy reduces neuroinflammation and preserves neurological function in a...

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) characterized by both neuroinflammation and neurodegeneration. While significant progress has been made in the treatment of relapsing-remitting MS, with more than 20 FDA-approved therapies available as of mid-2025, effective therapeutic options for progressive forms of the disease (PMS) remain limited and largely inadequate. Among the mechanisms implicated in PMS pathogenesis is the dysregulation of the complement system, a key component of the innate immune response that also plays essential roles in CNS development and homeostasis. Hyperactivation of the classical complement cascade through C1q has been linked to chronic inflammation, synaptic pruning, and neurodegeneration. In MS, one potential trigger for sustained C1q activation is intrathecal immunoglobulin synthesis (IIgS), a hallmark of the disease that correlates with severity and progression. Persistent IIgS may provide continuous antigen-antibody complexes capable of engaging C1q, thereby perpetuating complement-mediated injury within the CNS. To investigate this mechanistic link, we used Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well-established murine model of PMS that features chronic demyelination, neurodegeneration, neuroinflammation, and robust IIgS. We tested the therapeutic potential of CNS-targeted C1q inhibition using two approaches: direct intraventricular administration of a murine anti-C1q monoclonal antibody and intraperitoneal delivery of a CNS-penetrant anti-C1q nanobody. Our results demonstrate that, regardless of the administration route, C1q blockade significantly reduces neuroinflammation, demyelination, preserves axons, and improves clinical scores. These findings support the concept that classical complement activation downstream of IIgS plays a central role in driving progressive CNS damage. By interrupting the pathological feedback loop between intrathecally produced antibodies and complement activation, C1q antagonism may represent a novel and promising therapeutic avenue for PMS. Importantly, the favorable biodistribution, brain penetration, efficacy, and less invasive route of administration of the nanobody highlight its potential as a clinically translatable treatment strategy for MS.