Proteopathies or proteinopathies are diseases where misfolded proteins adopt aberrant conformations that interfere with their normal functions causing organ damage, e.g. Alzheimer’s disease (AD). While many proteopathies are neurodegenerative, they also cause disorders like type 2 diabetes, which may have genetic risk factors. Yet, in AD the main risk factor is aging, with only five percent of AD cases due to genetic factors. Indeed, onset of AD and other neurodegenerative diseases correlates well with the aging associated immunodecline and increase in chronic inflammatory immunity. That since childhood the immune system using antibodies removes the aberrant proteins, an upkeep that declines with age when neurodegenerative proteopathies emerge, implies a failure of immune surveillance.
This situation suggests that maintaining an effective immunity may avert/delay these diseases, i.e. vaccination using immunogens linked to AD, like amyloid-β (Aβ) and tau protein induce in mouse models protective immunities. However, that clinical studies failed to show improvements, has fostered the belief that AD vaccines are unlikely. A conclusion that differs from the results using immunoglobulins from healthy young adults to significantly reduce AD incidence in elderly people, or those using aducanumab, a monoclonal antibody derived from elderly but cognitively competent individuals, to ameliorate AD in early-phase patients.
To prevent a damaging Th1 inflammatory immunity AD vaccines have peptides containing only Aβ B-cell epitopes as immunogens, often used with inflammatory adjuvants, which explains the disappointing results. Since antibodies against B-cell epitopes recognize monomeric but not neurotoxic oligomeric Aβ, and apparently can release toxic oligomers sequestered as plaques, they may exacerbate AD progression. Also, that adjuvants induce a systemic immunity via cytokines and other mediators, regardless of the immunogen, a Th1 immunoresponse will affect the central nervous system, worsening the disease. Therefore, AD vaccines need antigens having both B and T cell epitopes, to induce antibodies against toxic Aβ oligomers; but, to avert damaging Th1 autoimmune responses the adjuvant should induce a Th2 anti-inflammatory immunity.
However, adjuvants inducing a sole Th2 immunity are rare, and alum, the only available Th2 adjuvant, is unable to induce an effective immunity in the elderly population. Due to evolutionary reasons, sole Th2 adjuvants are different from those derived from bacteria or viruses. While inflammatory immunity was developed by multicellular organisms as a response against microorganisms, Th2 immunity occurred a few hundred million years later when metazoan parasites like helminths invaded vertebrates. Actually, helminths produce compounds mimicking those that the host makes to avert inflammatory responses that interfere with tissue healing or cause fetal rejection in mammals, compounds that besides inducing Th2 inhibit, but without abrogating Th1 immunity. Most helminth-derived immunomodulators contain fucose (Fuc) as their active group, and have fucosylated glycans mimicking the LewisX trisaccharide motif, which polarizes immunity toward Th2. Indeed, some tumors produce glycans carrying this motif to prevent an anti-tumor inflammatory immunity.
Pharmacologically, fucosylated glycans exert their Th2 immunomodulatory activity by binding to the trans-membrane C-type lectin DC-SIGN located on dendritic cells (DCs) and microglia. This receptor binds oligosaccharides carrying either mannose or fucose, biasing DCs toward Th1 or Th2 immunity respectively and to secrete the corresponding cytokines. DC-SIGN has a single binding pocket with two different sets of amino acids, which interact specifically with each sugar. That Fuc polarizes the immune system toward a sole Th2, but without abrogating Th1 immunity, explains why during pregnancy there is a “modulated immunologic condition,” but not immunosuppression. Therefore, different from other drugs that block the immunological cascade leading to Th1 immunity, creating an immunosupressed state, the Fuc based compounds could be safe and effective immunomodulatory drugs for use in proteopathies as anti-inflammatory agents, as well as vaccine adjuvants that co-administered with protein immunogens would induce a biased Th2 immunity.
The rarity of Fuc in vertebrates and pathogens, explains its role in ontogenesis and immunological functions, both biological processes requiring a high degree of specificity. Although there are no drugs exploiting Fuc immunomodulatory properties, that the plant-derived fucosylated glycoside QT-0101 is a sole Th2 immunomodulator, opens access to novel Fuc-based derived drugs that are not immunosuppressive. Paradoxically, QT-0101 is a derivative of the potent Th1 inflammatory adjuvant QS-21; analysis of their structure-activity relationships (SAR) shows that QS-21 has its single Fuc residue acylated by large fatty acids, while in QT-0101 is non-acylated. Evidently, those fatty acids interfere sterically with the Fuc binding to DC-SIGN, a hindrance that disappears upon their removal from the Fuc in QT-0101.
As degenerative proteopathies coincide with immunosenescence, it would be beneficial if Th2 immunomodulators could also amend the age-linked immunodecline to maintain an effective immunosurveillance. Since immunodecline is often caused by a loss of the receptor CD28 and its ligands CD80/86, on T-cells and DCs respectively, which leads to T-cell anergy, substitution of the lost signal by an alternative one could result in the recovery of immune competence. There is evidence that aldehyde groups deliver an alternative co-stimulatory signal to T-cells, replacing the lost one due to the absence of CD28 and CD80/86. Therefore, immunomodulators that deliver an aldehyde co-stimulatory signal may ameliorate immunosenescence;in fact , QS-21 has an aldehyde in its triterpene that delivers that co-stimulatory signal, an aldehyde that is also present in QT-0101.
QT-0101 has two different pharmacophores (Fig. 1, above), a Fuc residue (blue) that interacts with DC-SIGN on DC and an aldehyde (red) that delivers a co-stimulatory signal to T-cell’s surface receptors preventing anergy. This combination of signals, besides biasing the response to Th2-only immunity might also ameliorate immunosenescence. Since QT-0101 can be an effective Th2 vaccine’s adjuvant that can be used safely with protein immunogens having both T and B-cell epitopes; it will remove the need to modify protein antigens in ways that could render them useless or even damaging. Consequently, the availability of Fuc glycans and Fuc triterpene glycosides offer a new avenue to develop effective vaccines against proteopathies, which have been hindered by the problems associated with the use of pro-inflammatory adjuvants to induce a Th2 anti-inflammatory immunoresponse.
Filed Under: Drug Discovery