Safety and activity of anti-CD14 antibody IC14 (atibuclimab) in ALS: Experience with expanded access protocol.
IC14
amyotrophic lateral sclerosis
expanded access
motor neuron disease
regulatory T cells
Journal
Muscle & nerve
ISSN: 1097-4598
Titre abrégé: Muscle Nerve
Pays: United States
ID NLM: 7803146
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
revised:
09
12
2022
received:
04
07
2022
accepted:
13
12
2022
medline:
18
4
2023
pubmed:
20
12
2022
entrez:
19
12
2022
Statut:
ppublish
Résumé
IC14 (atibuclimab) is a monoclonal anti-CD14 antibody. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 in an acute treatment setting. We provided long-term treatment with IC14 to individuals with ALS via an expanded access protocol (EAP) and documented target engagement, biomarker, safety, and disease endpoints. Participants received intravenous IC14 every 2 weeks. Consistent with United States Food and Drug Administration guidelines, participants were not eligible for clinical trials and the EAP was inclusive of a broad population. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), IC14 levels, and antidrug antibodies. Ex vivo T-regulatory functional assays were performed in a subset of participants. Seventeen participants received IC14 for up to 103 weeks (average, 30.1 weeks; range, 1 to 103 weeks). Treatment-emergent adverse events (TEAEs) were uncommon, mild, and self-limiting. There were 18 serious adverse events (SAEs), which were related to disease progression and unrelated or likely unrelated to IC14. Three participants died due to disease progression. Monocyte CD14 RO increased for all participants after IC14 infusion. One individual required more frequent dosing (every 10 days) to achieve over 80% RO. Antidrug antibodies were detected in only one participant and were transient, low titer, and non-neutralizing. Administration of IC14 in ALS was safe and well-tolerated in this intermediate-size EAP. Measuring RO guided dosing frequency. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.
Substances chimiques
atibuclimab
0
Antibodies, Monoclonal
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
354-362Subventions
Organisme : NIH HHS
ID : 1UL1TR002541-01
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.
Références
Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994;330:585-591.
Abe K, Aoki M, Tsuji S, et al. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16:505-512.
Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. N Engl J Med. 2020;383:919-930.
Paganoni S, Hendrix S, Dickson SP, et al. Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis. Muscle Nerve. 2021;63:31-39.
Beers DR, Zhao W, Neal DW, et al. Elevated acute phase proteins reflect peripheral inflammation and disease severity in patients with amyotrophic lateral sclerosis. Sci Rep. 2020;10:15295.
Appel SH, Beers DR, Zhao W. Amyotrophic lateral sclerosis is a systemic disease: peripheral contributions to inflammation-mediated neurodegeneration. Curr Opin Neurol. 2021;34:765-772.
Giovannelli I, Heath P, Shaw PJ, Kirby J. The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential. Amyotroph Lateral Scler Frontotemporal Degener. 2020;21:435-444.
Thome AD, Atassi F, Wang J, et al. Ex vivo expansion of dysfunctional regulatory T lymphocytes restores suppressive function in Parkinson's disease. NPJ Parkinson Dis. 2021;7(41):41.
Faridar A, Thome AD, Zhao W, et al. Restoring regulatory T-cell dysfunction in Alzheimer's disease through ex vivo expansion. Brain Commun. 2020;2:fcaa112.
Thonhoff JR, Beers DR, Zhao W, et al. Expanded autologous regulatory T-lymphocyte infusions in ALS. Neurol Neuroimmunol Neuroinflamm. 2018;5:e465.
Thonhoff JR, Berry JD, Macklin EA, et al. Combined regulatory T-lymphocyte and IL-2 treatment is safe, tolerable, and biologically active for 1 year in persons with amyotrophic lateral sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022;9:e200019.
Zanoni I, Ostuni R, Capuano G, et al. CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature. 2009;460:264-268.
Ilarregui JM, Van Beelen AJ, Fehres CM, Bruijns SCM, García-Vallejo JJ, Van Kooyk Y. New roles for CD14 and IL-β linking inflammatory dendritic cells to IL-17 production in memory CD4+T cells. Immunol Cell Biol. 2016;94:907-916.
Di Gioia M, Zanoni I. Toll-like receptor co-receptors as master regulators of the immune response. Mol Immunol. 2015;63:143-152.
Henderson RD, Agosti JM, McCombe PA, et al. Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis. Medicine. 2021;100:e27421.
US Food and Drug Administration. Expanded access program report. 2018. https://www.fda.gov/media/119971/download. Accessed April 4, 2022.
Jarow JP, Lurie P, Ikenberry SC, Lemery S. Overview of FDA's expanded access program for investigational drugs. Ther Innov Regul Sci. 2017;51:177-179.
US Food and Drug Administration. Expanded access categories for drugs (including biologics). 2018. https://www.fda.gov/news-events/expanded-access/expanded-access-categories-drugs-including-biologics. Accessed April 4, 2022.
Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2000;1:293-299.
Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;169:13-21.
Andres PL, Skerry LM, Munsat TL, et al. Validation of a new strength measurement device for amyotrophic lateral sclerosis clinical trials. Muscle Nerve. 2012;45:81-85.
US Food and Drug Administration. Immunogenicity testing of therapeutic protein products---developing and validating assays for anti-drug antibody detection. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/immunogenicity-testing-therapeutic-protein-products-developing-and-validating-assays-anti-drug. Accessed September 9, 2022.
Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of Treg-mediated T cell suppression. Front Immunol. 2012;3(51):3.
Szymczak-Workman AL, Delgoffe GM, Green DR, Vignali DAA. Cutting edge: regulatory T cells do not mediate suppression via programmed cell death pathways. J Immunol. 2011;187:4416-4420.
Mercadante ER, Lorenz UM. T cells deficient in the tyrosine phosphatase SHP-1 resist suppression by regulatory T cells. J Immunol. 2017;199:129-137.
Mercadante ER, Lorenz UM. Breaking free of control: how conventional T cells overcome regulatory T cell suppression. Front Immunol. 2016;7:193.
Reinhart K, Glück T, Ligtenberg J, et al. CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14). Crit Care Med. 2004;32:1100-1108.
Axtelle T, Pribble J. IC14, a CD14 specific monoclonal antibody, is a potential treatment for patients with severe sepsis. J Endotoxin Res. 2001;7:310-314.
Verbon A, Dekkers PEP, ten Hove T, et al. IC14, an anti-CD14 antibody, inhibits endotoxin-mediated symptoms and inflammatory responses in humans. J Immunol. 2001;166:3599-3605.
Beers DR, Zhao W, Wang J, et al. ALS patients' regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight. 2017;2:e89530.
Sheean RK, McKay FC, Cretney E, et al. Association of regulatory T-cell expansion with progression of amyotrophic lateral sclerosis a study of humans and a transgenic mouse model. JAMA Neurol. 2018;75:681-689.
Schmidt A, Oberle N, Weiß EM, et al. Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-κB, and NFAT signaling in conventional T cells. Sci Signal. 2011;4:ra90.
Mempel TR, Pittet MJ, Khazaie K, et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity. 2006;25:129-141.
Sojka DK, Fowell DJ. Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10. Proc Natl Acad Sci USA. 2011;108:18336-18341.
Jin M, Günther R, Akgün K, Hermann A, Ziemssen T. Peripheral proinflammatory Th1/Th17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis. Sci Rep. 2020;10:5941.
Jin M, Akgün K, Ziemssen T, Kipp M, Günther R, Hermann A. Interleukin-17 and th17 lymphocytes directly impair motoneuron survival of wildtype and fus-als mutant human ipscs. Int J Mol Sci. 2021;22(15):8042.