Therapeutics

TB006

Overview

Name: TB006
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: TrueBinding, Inc.

Background

This humanized monoclonal antibody targets galactose-specific lectin (galectin) 3, a carbohydrate-binding protein involved in macrophage activation and antimicrobial immune responses. The rationale for targeting galectin 3 to treat Alzheimer’s disease comes from studies implicating it as a regulator of microglia activation in response to amyloid. Brain galectin 3 expression is increased in people with AD, specifically in microglia associated with amyloid plaques (Boza-Serrano et al., 2019). The same study associated variants in LGALS3, the gene encoding galectin-3, with an increased risk of AD.

In mouse studies, LGLAS3 is among the genes most upregulated genes in amyloid plaque-associated microglia, and is part of a disease-associated expression signature in those cells (Kraseman et al., 2017; Keren-Shaul et al., 2017; Butovsky and Weiner, 2018).

Galectin-3 itself activates microglia by binding to TLR-4 receptors (Burguillos et al., 2015). Galectin-3 also induces TREM2 signaling, and knocking it out in a mouse model of AD improved cognition and reduced amyloid plaque burden (Boza-Serrano et al., 2019). In the APP/PS1 mouse amyloidosis model, galectin-3 promoted Aβ aggregation and toxicity (Tao et al., 2019).

Several small human studies have associated elevated galectin-3 in blood or CSF with cognitive impairment (Wang et al., 2013; Ashraf and Baeesa, 2018; Venkatraman et al., 2018; Yazar et al., 2020).

For review, see Tan et al., 2021.

Findings

In June 2021, TrueBinding began a Phase 1, single-dose escalation study of the safety and pharmacokinetics of TB006 in healthy adults. The trial will enroll 48 participants in five dose cohorts ranging from 70 to 5,000 mg, and one cohort of people of Chinese descent. The drug is given by intravenous infusion. The study is set to run through January 2023.

A planned trial in COVID-19 was withdrawn in June 2021 due to recruitment difficulties.

For details on TB006 trials, see clinicaltrials.gov.

Last Updated: 24 Sep 2021

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References

Paper Citations

  1. Boza-Serrano A, Ruiz R, Sanchez-Varo R, García-Revilla J, Yang Y, Jimenez-Ferrer I, Paulus A, Wennström M, Vilalta A, Allendorf D, Davila JC, Stegmayr J, Jiménez S, Roca-Ceballos MA, Navarro-Garrido V, Swanberg M, Hsieh CL, Real LM, Englund E, Linse S, Leffler H, Nilsson UJ, Brown GC, Gutierrez A, Vitorica J, Venero JL, Deierborg T. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease. Acta Neuropathol. 2019 Aug;138(2):251-273. Epub 2019 Apr 20 PubMed.
  2. Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, Beckers L, O'Loughlin E, Xu Y, Fanek Z, Greco DJ, Smith ST, Tweet G, Humulock Z, Zrzavy T, Conde-Sanroman P, Gacias M, Weng Z, Chen H, Tjon E, Mazaheri F, Hartmann K, Madi A, Ulrich JD, Glatzel M, Worthmann A, Heeren J, Budnik B, Lemere C, Ikezu T, Heppner FL, Litvak V, Holtzman DM, Lassmann H, Weiner HL, Ochando J, Haass C, Butovsky O. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017 Sep 19;47(3):566-581.e9. PubMed.
  3. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.
  4. Butovsky O, Weiner HL. Microglial signatures and their role in health and disease. Nat Rev Neurosci. 2018 Oct;19(10):622-635. PubMed.
  5. Burguillos MA, Svensson M, Schulte T, Boza-Serrano A, Garcia-Quintanilla A, Kavanagh E, Santiago M, Viceconte N, Oliva-Martin MJ, Osman AM, Salomonsson E, Amar L, Persson A, Blomgren K, Achour A, Englund E, Leffler H, Venero JL, Joseph B, Deierborg T. Microglia-Secreted Galectin-3 Acts as a Toll-like Receptor 4 Ligand and Contributes to Microglial Activation. Cell Rep. 2015 Mar 4; PubMed.
  6. Tao CC, Cheng KM, Ma YL, Hsu WL, Chen YC, Fuh JL, Lee WJ, Chao CC, Lee EH. Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer's disease. Cell Death Differ. 2019 May 24; PubMed.
  7. Wang X, Zhang S, Lin F, Chu W, Yue S. Elevated Galectin-3 Levels in the Serum of Patients With Alzheimer's Disease. Am J Alzheimers Dis Other Demen. 2013 Jul 2; PubMed.
  8. Ashraf GM, Baeesa SS. Investigation of Gal-3 Expression Pattern in Serum and Cerebrospinal Fluid of Patients Suffering From Neurodegenerative Disorders. Front Neurosci. 2018;12:430. Epub 2018 Jun 29 PubMed.
  9. Venkatraman A, Callas P, McClure LA, Unverzagt F, Arora G, Howard V, Wadley VG, Cushman M, Arora P. Galectin-3 and incident cognitive impairment in REGARDS, a cohort of blacks and whites. Alzheimers Dement (N Y). 2018;4:165-172. Epub 2018 Apr 26 PubMed.
  10. Yazar T, Olgun Yazar H, Cihan M. Evaluation of serum galectin-3 levels at Alzheimer patients by stages: a preliminary report. Acta Neurol Belg. 2020 Aug 27; PubMed.
  11. Tan Y, Zheng Y, Xu D, Sun Z, Yang H, Yin Q. Galectin-3: a key player in microglia-mediated neuroinflammation and Alzheimer's disease. Cell Biosci. 2021 Apr 27;11(1):78. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Yin Q, Chen J, Ma S, Dong C, Zhang Y, Hou X, Li S, Liu B. Pharmacological Inhibition of Galectin-3 Ameliorates Diabetes-Associated Cognitive Impairment, Oxidative Stress and Neuroinflammation in vivo and in vitro. J Inflamm Res. 2020;13:533-542. Epub 2020 Sep 15 PubMed.
  2. Tan Y, Zheng Y, Xu D, Sun Z, Yang H, Yin Q. Galectin-3: a key player in microglia-mediated neuroinflammation and Alzheimer's disease. Cell Biosci. 2021 Apr 27;11(1):78. PubMed.
  3. Rahimian R, Béland LC, Sato S, Kriz J. Microglia-derived galectin-3 in neuroinflammation; a bittersweet ligand?. Med Res Rev. 2021 Jul;41(4):2582-2589. Epub 2021 Mar 18 PubMed.
  4. Sethi A, Sanam S, Alvala R, Alvala M. An updated patent review of galectin-1 and galectin-3 inhibitors and their potential therapeutic applications (2016-present). Expert Opin Ther Pat. 2021 Aug;31(8):709-721. Epub 2021 May 20 PubMed.
  5. Yazar T, Olgun Yazar H, Cihan M. Evaluation of serum galectin-3 levels at Alzheimer patients by stages: a preliminary report. Acta Neurol Belg. 2020 Aug 27; PubMed.