Safety and Activity of
 Anti‐CD14
 Antibody
 IC14
 (atibuclimab) in
 ALS
 : Experience with Expanded Access Protocol

Introduction: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody that may target T-regulatory (T-reg) cell function. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 for a single cycle of treatment. We provided longterm treatment with IC14 to 17 individuals with ALS via an expanded access protocol (EAP) and documented target engagement, safety, and disease endpoints. Method(s): Participants received intravenous IC14 every two weeks. Consistent with FDA guidelines, participants were ineligible for clinical trials and the EAP was inclusive of a broad population. Participants unable to travel to MGH due to the COVID-19 pandemic or disease progression, were transitioned to infusions in-home or local clinics. Blood samples for hematology, chemistry, and coagulation were collected to monitor safety. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) was administered monthly to track disease progression. Respiratory function was measured through slow vital capacity tests -data for this is limited due to the COVID-19 pandemic. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), soluble CD14, and antidrug antibodies (ADA). Ex vivo T regulatory functional assays were performed with five participants. Result(s): Participants received IC14 for up to 103 weeks (average: 30.1 weeks, range: 1-103 weeks). Treatmentemergent adverse events were uncommon, mild, and self-limited. There were 18 serious adverse events (SAEs) which were related to disease progression and unrelated (17) or likely unrelated (1) to IC14. Three participants died due to disease progression. Most participants achieved >80% monocyte mCD14 RO on a 14-day dosing schedule, although one individual required more frequent dosing (every 10 days) to achieve >80% RO. ADA were detected in only one participant and were transient, low titer, and non-neutralizing. Tregs were isolated from the available longitudinal samples and assayed for suppression of CD4 T cell proliferation and cytokine production versus baseline T-reg activity. Conclusion(s): IC14 administration to ALS patients was safe and well tolerated in this EAP, with no significant changes in laboratory tests and no drug-related SAEs. Measuring RO guided dosing frequency. Preliminary data suggest IC14 enhanced T-reg activity. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.