Therapeutics

Protollin

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Overview

Name: Protollin
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: I-MAB Biopharma Co., Ltd., Jiangsu Nhwa Pharmaceutical Co., Ltd

Background

Protollin is a nasal vaccine composed of the outer membrane proteins of bacteria complexed with lipopolysaccharides. It was developed as an adjuvant to enhance mucosal immune responses to intranasal flu and other vaccines (Jones et al., 2004). Protollin stimulates the innate immune system through toll-like receptors.

The rationale for its use as an Alzheimer’s vaccine comes from preclinical work in APP-transgenic mice, where nasal Protollin stimulated clearance of brain amyloid, apparently by activating peripheral monocytes to enter the brain and phagocytose Aβ (Frenkel et al., 2005; Frenkel et al., 2008). Removal of brain amyloid did not require an antibody response. Protollin was shown to elevate expression of the Aβ scavenger receptor Scara1 on mouse microglia (Frenkel et al., 2013); in human microglia cultures, it slightly increased phagocytosis of Aβ42 (Hjorth et al, 2010).

In a mouse model of cerebral vascular amyloidosis, nasal vaccination with Protollin reduced amyloid in blood vessels, prevented microhemorrhages, and improved cognition (Lifshitz et al., 2012).

Protollin was tested, and appeared safe, in humans as part of an experimental intranasal shigella vaccine (Fries et al., 2001).

Findings

In December 2021, I-Mab Biopharma announced dosing of the first patient in a Phase 1 Alzheimer's disease trial (press release). The study, at Brigham and Women’s Hospital in Boston, involves 16 participants between 60 and 85 years old who have early symptomatic AD (BWH press release). They will receive two doses of Protollin, one week apart. The primary outcomes are safety and tolerability, and the study will also assess immune responses.

No registration for this trial appears in clinicaltrials.gov.

Last Updated: 16 Feb 2022

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References

Paper Citations

  1. Jones T, Cyr S, Allard F, Bellerose N, Lowell GH, Burt DS. Protollin: a novel adjuvant for intranasal vaccines. Vaccine. 2004 Sep 9;22(27-28):3691-7. PubMed.
  2. Frenkel D, Maron R, Burt DS, Weiner HL. Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest. 2005 Sep;115(9):2423-33. PubMed.
  3. Frenkel D, Puckett L, Petrovic S, Xia W, Chen G, Vega J, Dembinsky-Vaknin A, Shen J, Plante M, Burt DS, Weiner HL. A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann Neurol. 2008 May;63(5):591-601. PubMed.
  4. Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, Farfara D, Kingery ND, Weiner HL, El Khoury J. Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nat Commun. 2013;4:2030. PubMed.
  5. Hjorth E, Frenkel D, Weiner H, Schultzberg M. Effects of immunomodulatory substances on phagocytosis of abeta(1-42) by human microglia. Int J Alzheimers Dis. 2010;2010 PubMed.
  6. Lifshitz V, Weiss R, Benromano T, Kfir E, Blumenfeld-Katzir T, Tempel-Brami C, Assaf Y, Xia W, Wyss-Coray T, Weiner HL, Frenkel D. Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model. Neurobiol Aging. 2012 Feb;33(2):432.e1-432.e13. PubMed.
  7. Fries LF, Montemarano AD, Mallett CP, Taylor DN, Hale TL, Lowell GH. Safety and immunogenicity of a proteosome-Shigella flexneri 2a lipopolysaccharide vaccine administered intranasally to healthy adults. Infect Immun. 2001 Jul;69(7):4545-53. PubMed.

External Citations

  1. press release
  2. BWH press release

Further Reading

No Available Further Reading