Therapeutics

AL044

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Overview

Name: AL044
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Alector

Background

AL044 is an antibody targeting the MSA4 family of transmembrane cell surface proteins expressed on microglia. MS4A gene variants are associated with the risk of late-onset Alzheimer’s disease (Hollingworth et al., 2011; Antúnez  et al., 2011; Zhu et al., 2017; Ma et al., 2019). Polymorphisms have been identified that regulate MS4A expression to either increase or reduce the risk of AD. Some MSA4 family members appear to regulate TREM2 receptor activity, suggesting a role for these proteins in the microglia response to AD pathology (e.g. Ghani et al., 2016; Piccio et al., 2016; Deming et al., 2019).

No preclinical work on AL044 is published, but the company claims that this antibody modulates signaling by MS4A proteins to boost TREM2 signaling. In this way, it mimicks the activity of protective MS4A gene variants. In a presentation to investors, Alector reported that treatment of human donor monocyte-derived macrophages with AL044 resulted in several-fold increased production of the soluble extracellular fragment of TREM2, suggesting enhanced signaling and activation though this receptor (company slides #33 to 37).

Findings

In September 2022, the company announced the start of a Phase 1 study assessing safety, pharmacokinetics, and target engagement in 72 healthy adults (press release). No more details were given, and the trial does not appear in any registries. 

Last Updated: 23 Feb 2023

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References

Paper Citations

  1. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Rüther E, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Gallacher J, Hüll M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, , van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alpérovitch A, Lathrop M, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snædal J, Björnsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossù P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, Williams J. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. PubMed.
  2. Antúnez C, Boada M, González-Pérez A, Gayán J, Ramírez-Lorca R, Marín J, Hernández I, Moreno-Rey C, Morón FJ, López-Arrieta J, Mauleón A, Rosende-Roca M, Noguera-Perea F, Legaz-García A, Vivancos-Moreau L, Velasco J, Carrasco JM, Alegret M, Antequera-Torres M, Manzanares S, Romo A, Blanca I, Ruiz S, Espinosa A, Castaño S, García B, Martínez-Herrada B, Vinyes G, Lafuente A, Becker JT, Galán JJ, Serrano-Ríos M, , Vázquez E, Tárraga L, Sáez ME, López OL, Real LM, Ruiz A. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease. Genome Med. 2011;3(5):33. PubMed.
  3. Zhu R, Liu X, He Z. Association of rs610932 and rs670139 Polymorphisms in the MS4A Gene Cluster with Alzheimer's Disease: An Updated Meta-analysis. Curr Alzheimer Res. 2017;14(3):335-344. PubMed.
  4. Ma Y, Jun GR, Chung J, Zhang X, Kunkle BW, Naj AC, White CC, Bennett DA, De Jager PL, Alzheimer’s Disease Genetics Consortium, Mayeux R, Haines JL, Pericak-Vance MA, Schellenberg GD, Farrer LA, Lunetta KL. CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease. Aging Cell. 2019 Aug;18(4):e12964. Epub 2019 May 29 PubMed.
  5. Ghani M, Sato C, Kakhki EG, Gibbs JR, Traynor B, St George-Hyslop P, Rogaeva E. Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set. Neurobiol Aging. 2016 Jun;42:217.e7-217.e13. Epub 2016 Mar 21 PubMed.
  6. Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
  7. Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, Li Z, Del-Aguila JL, Dube U, Farias FG, Bradley J, Budde J, Ibanez L, Fernandez MV, Blennow K, Zetterberg H, Heslegrave A, Johansson PM, Svensson J, Nellgård B, Lleo A, Alcolea D, Clarimon J, Rami L, Molinuevo JL, Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Ewers M, Harari O, Haass C, Brett TJ, Benitez BA, Karch CM, Piccio L, Cruchaga C. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk. Sci Transl Med. 2019 Aug 14;11(505) PubMed.

External Citations

  1. press release
  2. company slides #33 to 37

Further Reading

Papers

  1. Andrews SJ, Fulton-Howard B, Goate A. Protective Variants in Alzheimer's Disease. Curr Genet Med Rep. 2019 Mar;7(1):1-12. Epub 2019 Jan 24 PubMed.
  2. Jonas LA, Jain T, Li YM. Functional insight into LOAD-associated microglial response genes. Open Biol. 2022 Jan;12(1):210280. Epub 2022 Jan 26 PubMed.
  3. Villegas-Llerena C, Phillips A, Garcia-Reitboeck P, Hardy J, Pocock JM. Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease. Curr Opin Neurobiol. 2016 Feb;36:74-81. Epub 2015 Oct 24 PubMed.
  4. Karch CM, Goate AM. Alzheimer's Disease Risk Genes and Mechanisms of Disease Pathogenesis. Biol Psychiatry. 2015 Jan 1;77(1):43-51. Epub 2014 May 17 PubMed.
  5. Ma J, Yu JT, Tan L. MS4A Cluster in Alzheimer's Disease. Mol Neurobiol. 2014 Jul 1; PubMed.
  6. Proitsi P, Lee SH, Lunnon K, Keohane A, Powell J, Troakes C, Al-Sarraj S, Furney S, Soininen H, Kłoszewska I, Mecocci P, Tsolaki M, Vellas B, Lovestone S, Hodges A, . Alzheimer's disease susceptibility variants in the MS4A6A gene are associated with altered levels of MS4A6A expression in blood. Neurobiol Aging. 2014 Feb;35(2):279-90. PubMed.
  7. Lacher SE, Alazizi A, Wang X, Bell DA, Pique-Regi R, Luca F, Slattery M. A hypermorphic antioxidant response element is associated with increased MS4A6A expression and Alzheimer's disease. Redox Biol. 2018 Apr;14:686-693. Epub 2017 Oct 27 PubMed.