Linse S, Scheidt T, Bernfur K, Vendruscolo M, Dobson CM, Cohen SI, Sileikis E, Lundqvist M, Qian F, O'Malley T, Bussiere T, Weinreb PH, Xu CK, Meisl G, Devenish SR, Knowles TP, Hansson O. Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies. Nat Struct Mol Biol. 2020 Dec;27(12):1125-1133. Epub 2020 Sep 28 PubMed.

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  1. Linse et al. present a kinetic study of the influence of four amyloid-directed antibodies, developed to treat Alzheimer’s disease, on aspects of the complex process of amyloid-β aggregation. This is an advancement on our own efforts and those of others to develop a detailed understanding of the mechanisms of action of individual antibodies targeting Aβ in order to aid interpretation of differential outcomes from clinical trials (Miles et al., 2013; Watt et al., 2014; Crespi et al., 2015). At the heart of the matter at this time is the question of whether you can have antibodies targeting clearance or neutralization of Aβ that engage their target Aβ yet leave a pool of disease-causing amyloid, such as toxic soluble oligomers, untouched and in play. And if so, then how can we overcome this?

    The authors report data on mouse versions of four clinical antibodies, namely aducanumab, bapineuzumab, solanezumab and gantenerumab. The side-by-side comparison of these therapeutics adds weight to this study because kinetic studies of amyloid are highly susceptible to misinterpretation owing to the pleiomorphic and temperamental nature of the ligand.

    We have worked with biosimilar adu, bapi, and sola, and the authors’ general description of these antibodies is consistent with my own observations (sola, strong binder of monomers only; bapi, monomers and oligomers/fibrils; adu, oligomers/fibrils). Linse et al. show in an elegant breakdown of the complex amyloid aggregation pathway that sola readily binds monomeric Aβ and acts almost exclusively to inhibit primary aggregation of monomers. According to the study, both bapi and gant principally act to reduce fibril extension without significantly modifying fibril catalyzed (secondary) nucleation of Aβ aggregation (oligomer production). Aducanumab, which evades monomeric Aβ and binds oligomeric Aβ directly (potentially for clearance/neutralization) also significantly interferes with secondary nucleation of amyloid aggregation by interaction with fibrils. This is an important point because as noted in the papers’ introduction, above a certain level of fibrils, aggregation catalyzed at the fibril surface becomes the dominant driver of amyloid oligomer formation.

    The authors go on to show that of the antibodies studied, only the effects of aducanumab are neutralized by competition with a known secondary nucleation inhibitor.

    These findings suggest that monomer binding antibodies such as sola that make it into the brain without being inundated by Aβ in the periphery might still leave oligomeric assembly (toxicity) unaffected and where brain amyloid burden as measured by PET is stabilized but not cleared (bapi) that neuronal damage could continue unabated despite reduced brain amyloid burden. These findings also suggests that aducanumab, which is capable of robust amyloid clearance as measured by PET, acts as an inhibitor of amyloid oligomer nucleation, and should, as an early intervention or prophylaxis, result in cognitive benefit if the amyloid hypothesis holds water. These benefits if realized might well be enhanced in combination with a specific inhibitor of primary oligomer nucleation such as solanezumab.

    References:

    Miles LA, Crespi GA, Doughty L, Parker MW. Bapineuzumab captures the N-terminus of the Alzheimer's disease amyloid-beta peptide in a helical conformation. Sci Rep. 2013 Feb 18;3:1302. PubMed.

    Watt AD, Crespi GA, Down RA, Ascher DB, Gunn A, Perez KA, McLean CA, Villemagne VL, Parker MW, Barnham KJ, Miles LA. Do current therapeutic anti-Aβ antibodies for Alzheimer's disease engage the target?. Acta Neuropathol. 2014 Jun;127(6):803-10. Epub 2014 May 7 PubMed.

    Crespi GA, Hermans SJ, Parker MW, Miles LA. Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies. Sci Rep. 2015 Apr 16;5:9649. PubMed.

    View all comments by Luke A. Miles

  2. Aducanumab was first developed by Roger Nitsch and Christoph Hock of Neurimmune when they started searching for naturally occurring autoantibodies to Aβ oligomers from memory B-cells of super agers. Roger is generous in his presentations to point out that the study that inspired the Neurimmune approach was carried out by the late Rob Moir, who passed away at 58 years old in December 2019 after a short battle with glioblastoma. Rob reported auto-antibodies that recognized cross-linked Aβ oligomeric species (CAPS) in human serum, and showed that levels of those antibodies correlated with decreased risk for Alzheimer's disease.

    The final two sentences in his paper were: "We also observed that AD plasma contained lower levels of anti-CAPS antibodies compared to non-demented control subjects and that immunoreactivity to CAPS correlated with AAO of the disease. These findings may be useful for diagnosis and facilitating future designs of reagents for Aβ vaccination and antibody perfusion therapies aimed at treating and preventing AD."

    Thank you, Rob. Rest in peace.

    References:

    Moir RD, Tseitlin KA, Soscia S, Hyman BT, Irizarry MC, Tanzi RE. Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer's disease patients. J Biol Chem. 2005 Apr 29;280(17):17458-63. PubMed.

    View all comments by Rudy Tanzi

  3. This paper provides useful contributions to amyloid-β antibody characterization with respect to their isoform kinetics, potency, and selectivity prior to clinical testing. Two small additional comments on why Aβ monomer-selective antibodies like aducanumab seem to be preferential clinical candidates.

    • High selectivity versus abundant Aβ monomer is expected to contribute to a favorite pharmacokinetic profile by sparing antibody drug and thus increasing effective dose available in the CNS compartment.
    • Clinical data on Aβ-lowering drugs like γ- and β-secretase inhibitors indicate transient cognitive side effects associated with interaction of normal CNS Aβ monomer levels in sporadic AD, suggesting a physiological role for amyloid-β monomer in synaptic processes.

    View all comments by Heinz Hillen

  4. It is wonderful to see careful mechanistic characterization of these important phenomena. I believe ProMIS Neurosciences has been making a similar case regarding its PMN310 with higher selectivity and affinity for the correct target.

    Disclosure: I have made a personal investment in ProMIS Neurosciences (ARFXF).

    View all comments by Martin Page

  5. The authors claim, based on this modeling, that aducanumab selectively reduces the secondary nucleation rate, solanezumab selectively inhibits primary nucleation, and bapineuzumab and gantenerumab act by reducing elongation of fibrils. Furthermore, the effect by aducanumab is claimed to be caused by the antibody’s interaction with Aβ species involved in secondary nucleation along the surface of fibrils, leading to reduction of oligomers. This should, according to the authors, explain the clinical efficacy of aducanumab versus the other three antibodies. Moreover, the authors intriguingly suggest that aducanumab is the only antibody of the four which has the same kinetic “fingerprint” as the chaperone Brichos. Brichos has recently been proposed to act as a chaperone to prevent amyloid toxicity (Cohen et al., 2015; Nerelius et al., 2008). The definition of a molecular chaperone is to assist the conformational folding or unfolding and the assembly or disassembly of other macromolecular structures to form the active three-dimensional structure.

    We believe that the molecular details in the complex Aβ aggregation processes are still not completely understood, and different models have been proposed for Aβ aggregation. It remains to be seen if aducanumab holds these unique properties. An obvious question is why an antibody against Aβ should have chaperone activity? The main function of anti-Aβ antibodies, in our view, is to remove Aβ by microglial phagocytosis, not dissolve and thereby provide more Aβ substrate to feed into the aggregation pathway.

    We have compared aducanumab and BAN2401 with inhibition-ELISA and surface plasmon resonance (SPR). We aimed to describe the binding pattern of the two antibodies to different species of Aβ. We found that BAN2401 had a stronger binding to all forms of Aβ, including monomers, oligomers, small protofibrils, large protofibrils, and fibrils, than did aducanumab. Furthermore, BAN2401 bound strongest to small and large protofibrils, whereas aducanumab bound strongest to fibrils. In presentations at AAIC and CTAD last year we reported that BAN2401 bound stronger to small oligomers than did aducanumab. It remains to be seen if the different assays used by us and others will explain the outcome of the ongoing Phase 3 clinical trials for aducanumab, gantenerumab, and BAN2401.

    Overall, it might be premature to claim that aducanumab uniquely and dramatically reduces the flux of Aβ oligomers based only on an in vitro observation and modeling exercises. The findings by Linse et al. provide interesting new hypotheses for how different anti-Aβ antibodies might act, but ultimate translatability to the clinic and the impact on Aβ remains unclear.

    References:

    Cohen SI, Arosio P, Presto J, Kurudenkandy FR, Biverstål H, Dolfe L, Dunning C, Yang X, Frohm B, Vendruscolo M, Johansson J, Dobson CM, Fisahn A, Knowles TP, Linse S. A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers. Nat Struct Mol Biol. 2015 Mar;22(3):207-13. Epub 2015 Feb 16 PubMed.

    Nerelius C, Martin E, Peng S, Gustafsson M, Nordling K, Weaver T, Johansson J. Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C. Biochem J. 2008 Dec 1;416(2):201-9. PubMed.

    View all comments by Lars Lannfelt

  6. Linse et al. have published an excellent and elegant biophysical study characterizing the targets and therapeutic mechanisms of four clinical Aβ antibodies. The results provide yet more evidence that disease-modifying activity in AD requires targeting of toxic oligomers, directly or indirectly.

    The article demonstrates and quantifies aducanumab blockade of oligomer production by secondary nucleation in a reductionist in vitro system, using synthetic Aβ peptide. But in view of the well-established binding of aducanumab to oligomers in vitro and in vivo, these results do not rule out the possibility that aducanumab could also possess therapeutic activity by direct neutralization or clearance of toxic oligomers in Alzheimer brain, as suggested by Sevigny et al. in their publication of the PRIME trial (2016). 

    Several lines of evidence in fact indicate that direct targeting of oligomers, regardless of their origin (primary or secondary nucleation) is associated with efficacy. For example, BAN2401, which reacts with a different epitope on oligomers (and also interacts with fibrils, but to a lesser degree than aducanumab), has yielded positive results in Phase 2 trials. Moreover, approaches with greater oligomer selectivity have shown efficacy in vivo such as the PRI-002 anti-oligomer peptide (Schemmert et al., 2019) and ProMIS Neurosciences’ oligomer-selective antibodies (Silverman et al., 2018; Gibbs et al., 2019. Full disclosure: I am a co-founder and CSO of ProMIS). 

    The humanized ProMIS Neurosciences PMN310 antibody selectively binds and neutralizes toxic oligomers without interacting with Aβ monomers or insoluble fibrils. This antibody profile should promote improved safety and efficacy by focusing the dose on the toxic oligomer species of Aβ and avoiding interaction with plaque and vascular deposits which has been associated with the development of ARIA (Sperling et al., 2012; Carlson et al., 2016). 

    References:

    Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016 Aug 31;537(7618):50-6. PubMed.

    Silverman JM, Gibbs E, Peng X, Martens KM, Balducci C, Wang J, Yousefi M, Cowan CM, Lamour G, Louadi S, Ban Y, Robert J, Stukas S, Forloni G, Hsiung GR, Plotkin SS, Wellington CL, Cashman NR. A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers. ACS Chem Neurosci. 2018 Jul 18;9(7):1591-1606. Epub 2018 Apr 16 PubMed.

    Gibbs E, Silverman JM, Zhao B, Peng X, Wang J, Wellington CL, Mackenzie IR, Plotkin SS, Kaplan JM, Cashman NR. A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer's Disease. Sci Rep. 2019 Jul 8;9(1):9870. PubMed.

    Schemmert S, Schartmann E, Zafiu C, Kass B, Hartwig S, Lehr S, Bannach O, Langen KJ, Shah NJ, Kutzsche J, Willuweit A, Willbold D. Aβ Oligomer Elimination Restores Cognition in Transgenic Alzheimer's Mice with Full-blown Pathology. Mol Neurobiol. 2018 Jul 12; PubMed.

    Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012 Mar;11(3):241-9. PubMed.

    Carlson C, Siemers E, Hake A, Case M, Hayduk R, Suhy J, Oh J, Barakos J. Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease. Alzheimers Dement (Amst). 2016;2:75-85. Epub 2016 Mar 2 PubMed.

    View all comments by Neil Cashman

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  1. Of Four Aβ Antibodies, Only Aducanumab Stems Tide of Toxic Oligomers