Recombinant Antibody Fragments for Neurological Disorders: An Update

Karen      Manoutcharian; Goar      Gevorkian
Abstract

Recombinant antibody fragments are promising alternatives to full-length immunoglobulins, creating big opportunities for the pharmaceutical industry. Nowadays, antibody fragments such as antigen-binding fragments (Fab), single-chain fragment variable (scFv), single-domain antibodies (sdAbs), and bispecific antibodies (bsAbs) are being evaluated as diagnostics or therapeutics in preclinical models and in clinical trials. Immunotherapy approaches, including passive transfer of protective antibodies, have shown therapeutic efficacy in several animal models of Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), Huntington’s disease (HD), transmissible spongiform encephalopathies (TSEs) and multiple sclerosis (MS). There are various antibodies approved by the Food and Drug Administration (FDA) for treating multiple sclerosis and two amyloid beta-specific humanized antibodies, Aducanumab and Lecanemab, for AD. Our previous review summarized data on recombinant antibodies evaluated in pre-clinical models for immunotherapy of neurodegenerative diseases. Here, we explore recent studies in this fascinating research field, give an update on new preventive and therapeutic applications of recombinant antibody fragments for neurological disorders and discuss the potential of antibody fragments for developing novel approaches for crossing the blood-brain barrier (BBB) and targeting cells and molecules of interest in the brain.
Graphical Abstract

[1]
Bird, R.; Walker, B.W. Single chain antibody variable regions. Trends Biotechnol.,  1991, 9(1), 132-137.
 [http://dx.doi.org/10.1016/0167-7799(91)90044-I] [PMID: 1367550]

[2]
Morrison, S.L. In vitro antibodies: Strategies for production and application. Annu. Rev. Immunol.,  1992, 10(1), 239-265.
 [http://dx.doi.org/10.1146/annurev.iy.10.040192.001323] [PMID: 1590987]

[3]
Plückthun, A.; Pack, P. New protein engineering approaches to multivalent and bispecific antibody fragments. Immunotechnology,  1997, 3(2), 83-105.
 [http://dx.doi.org/10.1016/S1380-2933(97)00067-5] [PMID: 9237094]

[4]
Ma, H.; O’Kennedy, R. Recombinant antibody fragment production. Methods,  2017, 116, 23-33.
 [http://dx.doi.org/10.1016/j.ymeth.2016.11.008] [PMID: 27871972]

[5]
Manoutcharian, K.; Perez-Garmendia, R.; Gevorkian, G. Recombinant antibody fragments for neurodegenerative diseases. Curr. Neuropharmacol.,  2017, 15(5), 779-788.
 [http://dx.doi.org/10.2174/1570159X01666160930121647] [PMID: 27697033]

[6]
Pietersz, G.A.; Wang, X.; Yap, M.L.; Lim, B.; Peter, K. Therapeutic targeting in nanomedicine: The future lies in recombinant antibodies. Nanomedicine,  2017, 12(15), 1873-1889.
 [http://dx.doi.org/10.2217/nnm-2017-0043] [PMID: 28703636]

[7]
Bélanger, K.; Iqbal, U.; Tanha, J.; MacKenzie, R.; Moreno, M.; Stanimirovic, D. Single-domain antibodies as therapeutic and imaging agents for the treatment of CNS diseases. Antibodies,  2019, 8(2), 27.
 [http://dx.doi.org/10.3390/antib8020027] [PMID: 31544833]

[8]
Bates, A.; Power, C.A. David vs. Goliath: The structure, function, and clinical prospects of antibody fragments. Antibodies,  2019, 8(2), 28.
 [http://dx.doi.org/10.3390/antib8020028] [PMID: 31544834]

[9]
Salvador, J.P.; Vilaplana, L.; Marco, M.P. Nanobody: Outstanding features for diagnostic and therapeutic applications. Anal. Bioanal. Chem.,  2019, 411(9), 1703-1713.
 [http://dx.doi.org/10.1007/s00216-019-01633-4] [PMID: 30734854]

[10]
Pothin, E.; Lesuisse, D.; Lafaye, P. Brain delivery of single-domain antibodies: A focus on VHH and VNAR. Pharmaceutics,  2020, 12(10), 937.
 [http://dx.doi.org/10.3390/pharmaceutics12100937] [PMID: 33007904]

[11]
Gao, Y.; Zhu, J.; Lu, H. Single domain antibody-based vectors in the delivery of biologics across the blood–brain barrier: A review. Drug Deliv. Transl. Res.,  2021, 11(5), 1818-1828.
 [http://dx.doi.org/10.1007/s13346-020-00873-7] [PMID: 33155179]

[12]
Roth, K.D.R.; Wenzel, E.V.; Ruschig, M.; Steinke, S.; Langreder, N.; Heine, P.A.; Schneider, K.T.; Ballmann, R.; Fühner, V.; Kuhn, P.; Schirrmann, T.; Frenzel, A.; Dübel, S.; Schubert, M.; Moreira, G.M.S.G.; Bertoglio, F.; Russo, G.; Hust, M. Developing recombinant antibodies by phage display against infectious diseases and toxins for diagnostics and therapy. Front. Cell. Infect. Microbiol.,  2021, 11, 697876.
 [http://dx.doi.org/10.3389/fcimb.2021.697876] [PMID: 34307196]

[13]
Ruiz-López, E.; Schuhmacher, A.J. Transportation of single-domain antibodies through the blood–brain barrier. Biomolecules,  2021, 11(8), 1131.
 [http://dx.doi.org/10.3390/biom11081131] [PMID: 34439797]

[14]
Naidoo, D.B.; Chuturgoon, A.A. The potential of nanobodies for COVID-19 diagnostics and therapeutics. Mol. Diagn. Ther.,  2023, 27(2), 193-226.
 [http://dx.doi.org/10.1007/s40291-022-00634-x] [PMID: 36656511]

[15]
Fuller, J.P.; Stavenhagen, J.B.; Teeling, J.L. New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer’s Disease. Front. Neurosci.,  2014, 8, 235.
 [http://dx.doi.org/10.3389/fnins.2014.00235] [PMID: 25191216]

[16]
Sun, X.; Yu, X.; Zhu, J.; Li, L.; Zhang, L.; Huang, Y.; Liu, D.; Ji, M.; Sun, X.; Zhang, L.; Zhou, W.; Zhang, D.; Jiao, J.; Liu, R. Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model. Signal Transduct. Target. Ther.,  2023, 8(1), 30.
 [http://dx.doi.org/10.1038/s41392-022-01273-8] [PMID: 36693826]

[17]
Huang, L.; Su, X.; Federoff, H. Single-chain fragment variable passive immunotherapies for neurodegenerative diseases. Int. J. Mol. Sci.,  2013, 14(9), 19109-19127.
 [http://dx.doi.org/10.3390/ijms140919109] [PMID: 24048248]

[18]
Lulu, S.; Waubant, E. Humoral-targeted immunotherapies in multiple sclerosis. Neurotherapeutics,  2013, 10(1), 34-43.
 [http://dx.doi.org/10.1007/s13311-012-0164-3] [PMID: 23208729]

[19]
Cardinale, A.; Merlo, D.; Giunchedi, P.; Biocca, S. Therapeutic application of intrabodies against age-related neurodegenerative disorders. Curr. Pharm. Des.,  2014, 20(38), 6028-6036.
 [http://dx.doi.org/10.2174/1381612820666140314121444] [PMID: 24641233]

[20]
Wootla, B.; Watzlawik, J.O.; Stavropoulos, N.; Wittenberg, N.J.; Dasari, H.; Abdelrahim, M.A.; Henley, J.R.; Oh, S.H.; Warrington, A.E.; Rodriguez, M. Recent advances in monoclonal antibody therapies for multiple sclerosis. Expert Opin. Biol. Ther.,  2016, 16(6), 827-839.
 [http://dx.doi.org/10.1517/14712598.2016.1158809] [PMID: 26914737]

[21]
Frontzek, K.; Aguzzi, A. Recent developments in antibody therapeutics against prion disease. Emerg. Top. Life Sci.,  2020, 4(2), 169-173.
 [http://dx.doi.org/10.1042/ETLS20200002] [PMID: 32633322]

[22]
Jamwal, S.; Elsworth, J.D.; Rahi, V.; Kumar, P. Gene therapy and immunotherapy as promising strategies to combat Huntington’s disease-associated neurodegeneration: emphasis on recent updates and future perspectives. Expert Rev. Neurother.,  2020, 20(11), 1123-1141.
 [http://dx.doi.org/10.1080/14737175.2020.1801424] [PMID: 32720531]

[23]
Panza, F.; Lozupone, M.; Seripa, D.; Daniele, A.; Watling, M.; Giannelli, G.; Imbimbo, B.P. Development of disease-modifying drugs for frontotemporal dementia spectrum disorders. Nat. Rev. Neurol.,  2020, 16(4), 213-228.
 [http://dx.doi.org/10.1038/s41582-020-0330-x] [PMID: 32203398]

[24]
Haddad, H.W.; Malone, G.W.; Comardelle, N.J.; Degueure, A.E.; Poliwoda, S.; Kaye, R.J.; Murnane, K.S.; Kaye, A.M.; Kaye, A.D. Aduhelm, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer’s Disease: A comprehensive review. Health Psychol. Res.,  2022, 10(2), 37023.
 [http://dx.doi.org/10.52965/001c.37023] [PMID: 35910244]

[25]
Menon, S.; Armstrong, S.; Hamzeh, A.; Visanji, N.P.; Sardi, S.P.; Tandon, A. Alpha-synuclein targeting therapeutics for Parkinson’s Disease and related synucleinopathies. Front. Neurol.,  2022, 13, 852003.
 [http://dx.doi.org/10.3389/fneur.2022.852003] [PMID: 35614915]

[26]
Bateman, R.J.; Cummings, J.; Schobel, S.; Salloway, S.; Vellas, B.; Boada, M.; Black, S.E.; Blennow, K.; Fontoura, P.; Klein, G.; Assunção, S.S.; Smith, J.; Doody, R.S. Gantenerumab: an anti-amyloid monoclonal antibody with potential disease-modifying effects in early Alzheimer’s disease. Alzheimers Res. Ther.,  2022, 14(1), 178.
 [http://dx.doi.org/10.1186/s13195-022-01110-8] [PMID: 36447240]

[27]
De Genst, E.; Messer, A.; Dobson, C.M. Antibodies and protein misfolding: From structural research tools to therapeutic strategies. Biochim. Biophys. Acta. Proteins Proteomics,  2014, 1844(11), 1907-1919.
 [http://dx.doi.org/10.1016/j.bbapap.2014.08.016] [PMID: 25194824]

[28]
Valera, E.; Spencer, B.; Masliah, E. Immunotherapeutic approaches targeting amyloid-β, α-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics,  2016, 13(1), 179-189.
 [http://dx.doi.org/10.1007/s13311-015-0397-z] [PMID: 26494242]

[29]
Chia, K.Y.; Ng, K.Y.; Koh, R.Y.; Chye, S.M. Single-chain Fv antibodies for targeting neurodegenerative diseases. CNS Neurol. Disord. Drug Targets,  2018, 17(9), 671-679.
 [http://dx.doi.org/10.2174/1871527317666180315161626] [PMID: 29546836]

[30]
Messer, A.; Butler, D.C. Optimizing intracellular antibodies (intrabodies/nanobodies) to treat neurodegenerative disorders. Neurobiol. Dis.,  2020, 134, 104619.
 [http://dx.doi.org/10.1016/j.nbd.2019.104619] [PMID: 31669671]

[31]
Benn, J.A.; Mukadam, A.S.; McEwan, W.A. Targeted protein degradation using intracellular antibodies and its application to neurodegenerative disease. Semin. Cell Dev. Biol.,  2022, 126, 138-149.
 [http://dx.doi.org/10.1016/j.semcdb.2021.09.012] [PMID: 34654628]

[32]
Iqbal, K.; Grundke-Iqbal, I. Alzheimer’s disease, a multifactorial disorder seeking multitherapies. Alzheimers Dement.,  2010, 6(5), 420-424.
 [http://dx.doi.org/10.1016/j.jalz.2010.04.006] [PMID: 20813343]

[33]
Gong, C.X.; Liu, F.; Iqbal, K. Multifactorial hypothesis and multi-targets for Alzheimer’s Disease. J. Alzheimers Dis.,  2018, 64(s1), S107-S117.
 [http://dx.doi.org/10.3233/JAD-179921] [PMID: 29562523]

[34]
Boyd, R.J.; Avramopoulos, D.; Jantzie, L.L.; McCallion, A.S. Neuroinflammation represents a common theme amongst genetic and environmental risk factors for Alzheimer and Parkinson diseases. J. Neuroinflammation,  2022, 19(1), 223.
 [http://dx.doi.org/10.1186/s12974-022-02584-x] [PMID: 36076238]

[35]
Penke, B.; Szűcs, M.; Bogár, F. New pathways identify novel drug targets for the prevention and treatment of Alzheimer’s Disease. Int. J. Mol. Sci.,  2023, 24(6), 5383.
 [http://dx.doi.org/10.3390/ijms24065383] [PMID: 36982456]

[36]
Selkoe, D.J. Altered structural proteins in plaques and tangles: What do they tell us about the biology of Alzheimer’s disease? Neurobiol. Aging,  1986, 7(6), 425-432.
 [http://dx.doi.org/10.1016/0197-4580(86)90055-2] [PMID: 3104810]

[37]
LaFerla, F.M.; Green, K.N.; Oddo, S. Intracellular amyloid-β in Alzheimer’s disease. Nat. Rev. Neurosci.,  2007, 8(7), 499-509.
 [http://dx.doi.org/10.1038/nrn2168] [PMID: 17551515]

[38]
Montoliu-Gaya, L.; Murciano-Calles, J.; Martinez, J.C.; Villegas, S. Towards the improvement in stability of an anti-Aβ single-chain variable fragment, scFv-h3D6, as a way to enhance its therapeutic potential. Amyloid,  2017, 24(3), 167-175.
 [http://dx.doi.org/10.1080/13506129.2017.1348347] [PMID: 28699800]

[39]
Montoliu-Gaya, L.; Mulder, S.D.; Herrebout, M.A.C.; Baayen, J.C.; Villegas, S.; Veerhuis, R. Aβ-oligomer uptake and the resulting inflammatory response in adult human astrocytes are precluded by an anti-Aβ single chain variable fragment in combination with an apoE mimetic peptide. Mol. Cell. Neurosci.,  2018, 89, 49-59.
 [http://dx.doi.org/10.1016/j.mcn.2018.03.015] [PMID: 29625180]

[40]
Söllvander, S.; Nikitidou, E.; Brolin, R.; Söderberg, L.; Sehlin, D.; Lannfelt, L.; Erlandsson, A. Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons. Mol. Neurodegener.,  2016, 11(1), 38.
 [http://dx.doi.org/10.1186/s13024-016-0098-z] [PMID: 27176225]

[41]
Montoliu-Gaya, L.; Esquerda-Canals, G.; Bronsoms, S.; Villegas, S. Production of an anti-Aβ antibody fragment in Pichia pastoris and in vitro and in vivo validation of its therapeutic effect. PLoS One,  2017, 12(8), e0181480.
 [http://dx.doi.org/10.1371/journal.pone.0181480 ] [PMID: 28771492]

[42]
Esquerda-Canals, G.; Martí-Clúa, J.; Villegas, S. Pharmacokinetic parameters and mechanism of action of an efficient anti-Aβ single chain antibody fragment. PLoS One,  2019, 14(5), e0217793.
 [http://dx.doi.org/10.1371/journal.pone.0217793 ] [PMID: 31150495]

[43]
Esquerda-Canals, G.; Roda, A.R.; Martí-Clúa, J.; Montoliu-Gaya, L.; Rivera-Hernández, G.; Villegas, S. Treatment with scFv-h3D6 prevented neuronal loss and improved spatial memory in young 3xTg-AD mice by reducing the intracellular amyloid-β burden. J. Alzheimers Dis.,  2019, 70(4), 1069-1091.
 [http://dx.doi.org/10.3233/JAD-190484] [PMID: 31306135]

[44]
Güell-Bosch, J.; Lope-Piedrafita, S.; Esquerda-Canals, G.; Montoliu-Gaya, L.; Villegas, S. Progression of Alzheimer’s disease and effect of scFv-h3D6 immunotherapy in the 3xTg-AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy. NMR Biomed.,  2020, 33(5), e4263.
 [http://dx.doi.org/10.1002/nbm.4263] [PMID: 32067292]

[45]
Roda, A.R.; Montoliu-Gaya, L.; Serra-Mir, G.; Villegas, S. Both amyloid-β peptide and tau protein are affected by an anti-amyloid-β antibody fragment in elderly 3xTg-AD mice. Int. J. Mol. Sci.,  2020, 21(18), 6630.
 [http://dx.doi.org/10.3390/ijms21186630] [PMID: 32927795]

[46]
Williams, S.M.; Schulz, P.; Rosenberry, T.L.; Caselli, R.J.; Sierks, M.R. Blood-based oligomeric and other protein variant biomarkers to facilitate pre-symptomatic diagnosis and staging of Alzheimer’s disease. J. Alzheimers Dis.,  2017, 58(1), 23-35.
 [http://dx.doi.org/10.3233/JAD-161116] [PMID: 28372328]

[47]
Cho, H.J.; Schulz, P.; Venkataraman, L.; Caselli, R.J.; Sierks, M.R. Sex-specific multiparameter blood test for the early diagnosis of Alzheimer’s Disease. Int. J. Mol. Sci.,  2022, 23(24), 15670.
 [http://dx.doi.org/10.3390/ijms232415670] [PMID: 36555310]

[48]
Habiba, U.; Descallar, J.; Kreilaus, F.; Adhikari, U.K.; Kumar, S.; Morley, J.W.; Bui, B.V.; Koronyo-Hamaoui, M.; Tayebi, M. Detection of retinal and blood Aβ oligomers with nanobodies. Alzheimers Dement.,  2021, 13(1), e12193.
 [http://dx.doi.org/10.1002/dad2.12193] [PMID: 33977118]

[49]
Li, T.; Vandesquille, M.; Koukouli, F.; Dudeffant, C.; Youssef, I.; Lenormand, P.; Ganneau, C.; Maskos, U.; Czech, C.; Grueninger, F.; Duyckaerts, C.; Dhenain, M.; Bay, S.; Delatour, B.; Lafaye, P. Camelid single-domain antibodies: A versatile tool for in vivo imaging of extracellular and intracellular brain targets. J. Control. Release,  2016, 243, 1-10.
 [http://dx.doi.org/10.1016/j.jconrel.2016.09.019] [PMID: 27671875]

[50]
Vandesquille, M.; Li, T.; Po, C.; Ganneau, C.; Lenormand, P.; Dudeffant, C.; Czech, C.; Grueninger, F.; Duyckaerts, C.; Delatour, B.; Dhenain, M.; Lafaye, P.; Bay, S. Chemically-defined camelid antibody bioconjugate for the magnetic resonance imaging of Alzheimer’s disease. MAbs,  2017, 9(6), 1016-1027.
 [http://dx.doi.org/10.1080/19420862.2017.1342914] [PMID: 28657418]

[51]
Sebollela, A.; Cline, E.N.; Popova, I.; Luo, K.; Sun, X.; Ahn, J.; Barcelos, M.A.; Bezerra, V.N.; Lyra e Silva, N.M.; Patel, J.; Pinheiro, N.R.; Qin, L.A.; Kamel, J.M.; Weng, A.; DiNunno, N.; Bebenek, A.M.; Velasco, P.T.; Viola, K.L.; Lacor, P.N.; Ferreira, S.T.; Klein, W.L. A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid‐β oligomers. J. Neurochem.,  2017, 142(6), 934-947.
 [http://dx.doi.org/10.1111/jnc.14118] [PMID: 28670737]

[52]
Cline, E.N.; Bicca, M.A.; Viola, K.L.; Klein, W.L. The amyloid-β oligomer hypothesis: Beginning of the third decade. J. Alzheimers Dis.,  2018, 64(S1), S567-S610.
 [http://dx.doi.org/10.3233/JAD-179941] [PMID: 29843241]

[53]
Selles, M.C.; Fortuna, J.T.S.; Cercato, M.C.; Santos, L.E.; Domett, L.; Bitencourt, A.L.B.; Carraro, M.F.; Souza, A.S.; Janickova, H.; Azevedo, C.V.; Campos, H.C.; de Souza, J.M.; Alves-Leon, S.; Prado, V.F.; Prado, M.A.M.; Epstein, A.L.; Salvetti, A.; Longo, B.M.; Arancio, O.; Klein, W.L.; Sebollela, A.; De Felice, F.G.; Jerusalinsky, D.A.; Ferreira, S.T. AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models. Mol. Ther.,  2023, 31(2), 409-419.
 [http://dx.doi.org/10.1016/j.ymthe.2022.11.002] [PMID: 36369741]

[54]
Hu, M.; Zhang, J.; Yang, J.; Cao, Y.; Qi, J. A novel scFv Anti-Aβ antibody reduces pathological impairments in APP/PS1 transgenic mice via modulation of inflammatory cytokines and aβ-related enzymes. J. Mol. Neurosci.,  2018, 66(1), 1-9.
 [http://dx.doi.org/10.1007/s12031-018-1139-6] [PMID: 30062438]

[55]
Vitale, F.; Giliberto, L.; Ruiz, S.; Steslow, K.; Marambaud, P.; d’Abramo, C. Anti-tau conformational scFv MC1 antibody efficiently reduces pathological tau species in adult JNPL3 mice. Acta Neuropathol. Commun.,  2018, 6(1), 82.
 [http://dx.doi.org/10.1186/s40478-018-0585-2] [PMID: 30134961]

[56]
Vitale, F.; Ortolan, J.; Volpe, B.T.; Marambaud, P.; Giliberto, L.; d’Abramo, C. Intramuscular injection of vectorized-scFvMC1 reduces pathological tau in two different tau transgenic models. Acta Neuropathol. Commun.,  2020, 8(1), 126.
 [http://dx.doi.org/10.1186/s40478-020-01003-7] [PMID: 32762731]

[57]
Zhang, Y.; Qian, L.; Kuang, Y.; Liu, J.; Wang, D.; Xie, W.; Zhang, L.; Fu, L. An adeno-associated virus-mediated immunotherapy for Alzheimer’s disease. Mol. Immunol.,  2022, 144, 26-34.
 [http://dx.doi.org/10.1016/j.molimm.2022.02.006 ] [PMID: 35172225]

[58]
Danis, C.; Dupré, E.; Zejneli, O.; Caillierez, R.; Arrial, A.; Bégard, S.; Mortelecque, J.; Eddarkaoui, S.; Loyens, A.; Cantrelle, F.X.; Hanoulle, X.; Rain, J.C.; Colin, M.; Buée, L.; Landrieu, I. Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment. Mol. Ther.,  2022, 30(4), 1484-1499.
 [http://dx.doi.org/10.1016/j.ymthe.2022.01.009] [PMID: 35007758]

[59]
Guo, T.; Noble, W.; Hanger, D.P. Roles of tau protein in health and disease. Acta Neuropathol.,  2017, 133(5), 665-704.
 [http://dx.doi.org/10.1007/s00401-017-1707-9] [PMID: 28386764]

[60]
Spencer, B.; Brüschweiler, S.; Sealey-Cardona, M.; Rockenstein, E.; Adame, A.; Florio, J.; Mante, M.; Trinh, I.; Rissman, R.A.; Konrat, R.; Masliah, E. Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders. Acta Neuropathol.,  2018, 136(1), 69-87.
 [http://dx.doi.org/10.1007/s00401-018-1869-0] [PMID: 29934874]

[61]
Panza, F.; Lozupone, M.; Solfrizzi, V.; Sardone, R.; Piccininni, C.; Dibello, V.; Stallone, R.; Giannelli, G.; Bellomo, A.; Greco, A.; Daniele, A.; Seripa, D.; Logroscino, G.; Imbimbo, B.P. BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Rev. Neurother.,  2018, 18(11), 847-857.
 [http://dx.doi.org/10.1080/14737175.2018.1531706] [PMID: 30277096]

[62]
Marino, M.; Zhou, L.; Rincon, M.Y.; Callaerts-Vegh, Z.; Verhaert, J.; Wahis, J.; Creemers, E.; Yshii, L.; Wierda, K.; Saito, T.; Marneffe, C.; Voytyuk, I.; Wouters, Y.; Dewilde, M.; Duqué, S.I.; Vincke, C.; Levites, Y.; Golde, T.E.; Saido, T.C.; Muyldermans, S.; Liston, A.; De Strooper, B.; Holt, M.G. AAV‐mediated delivery of an anti‐BACE1 VHH alleviates pathology in an Alzheimer’s disease model. EMBO Mol. Med.,  2022, 14(4), e09824.
 [http://dx.doi.org/10.15252/emmm.201809824] [PMID: 35352880]

[63]
Fahrenholz, F. Alpha-secretase as a therapeutic target. Curr. Alzheimer Res.,  2007, 4(4), 412-417.
 [http://dx.doi.org/10.2174/156720507781788837] [PMID: 17908044]

[64]
Lichtenthaler, S.F.; Tschirner, S.K.; Steiner, H. Secretases in Alzheimer’s disease: Novel insights into proteolysis of APP and TREM2. Curr. Opin. Neurobiol.,  2022, 72, 101-110.
 [http://dx.doi.org/10.1016/j.conb.2021.09.003] [PMID: 34689040]

[65]
He, P.; Xin, W.; Schulz, P.; Sierks, M.R. Bispecific antibody fragment targeting app and inducing α-site cleavage restores neuronal health in an alzheimer’s mouse model. Mol. Neurobiol.,  2019, 56(11), 7420-7432.
 [http://dx.doi.org/10.1007/s12035-019-1597-z] [PMID: 31041656]

[66]
Zhao, L.; Meng, F.; Li, Y.; Liu, S.; Xu, M.; Chu, F.; Li, C.; Yang, X.; Luo, L. Multivalent nanobody conjugate with rigid, reactive oxygen species scavenging scaffold for multi‐target therapy of Alzheimer’s Disease. Adv. Mater.,  2023, 35(17), 2210879.
 [http://dx.doi.org/10.1002/adma.202210879] [PMID: 36786375]

[67]
Saleh, M.; Markovic, M.; Olson, K.E.; Gendelman, H.E.; Mosley, R.L. Therapeutic strategies for immune transformation in parkinson’s disease. J. Parkinsons Dis.,  2022, 12(s1), S201-S222.
 [http://dx.doi.org/10.3233/JPD-223278] [PMID: 35871362]

[68]
Massey, A.; Boag, M.; Magnier, A.; Bispo, D.; Khoo, T.; Pountney, D. Glymphatic system dysfunction and sleep disturbance may contribute to the pathogenesis and progression of Parkinson’s Disease. Int. J. Mol. Sci.,  2022, 23(21), 12928.
 [http://dx.doi.org/10.3390/ijms232112928] [PMID: 36361716]

[69]
Dong-Chen, X.; Yong, C.; Yang, X.; Chen-Yu, S.; Li-Hua, P. Signaling pathways in Parkinson’s disease: Molecular mechanisms and therapeutic interventions. Signal Transduct. Target. Ther.,  2023, 8(1), 73.
 [http://dx.doi.org/10.1038/s41392-023-01353-3] [PMID: 36810524]

[70]
Forloni, G. Alpha synuclein: Neurodegeneration and inflammation. Int. J. Mol. Sci.,  2023, 24(6), 5914.
 [http://dx.doi.org/10.3390/ijms24065914] [PMID: 36982988]

[71]
Castonguay, A-M.; Gravel, C.; Lévesque, M. Treating Parkinson’s Disease with antibodies: Previous studies and future directions. J. Parkinsons Dis.,  2021, 11(1), 71-92.
 [http://dx.doi.org/10.3233/JPD-202221]

[72]
Knecht, L.; Folke, J.; Dodel, R.; Ross, J.A.; Albus, A. Alpha-synuclein immunization strategies for synucleinopathies in clinical studies: A biological perspective. Neurotherapeutics,  2022, 19(5), 1489-1502.
 [http://dx.doi.org/10.1007/s13311-022-01288-7] [PMID: 36083395]

[73]
Gupta, V.; Salim, S.; Hmila, I.; Vaikath, N.N.; Sudhakaran, I.P.; Ghanem, S.S.; Majbour, N.K.; Abdulla, S.A.; Emara, M.M.; Abdesselem, H.B.; Lukacsovich, T.; Erskine, D.; El-Agnaf, O.M.A. Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity. Sci. Rep.,  2020, 10(1), 8137.
 [http://dx.doi.org/10.1038/s41598-020-65035-8] [PMID: 32424162]

[74]
Gupta, V.; Sudhakaran, I.P.; Islam, Z.; Vaikath, N.N.; Hmila, I.; Lukacsovich, T.; Kolatkar, P.R.; El-Agnaf, O.M.A. Expression, purification and characterization of α-synuclein fibrillar specific scFv from inclusion bodies. PLoS One,  2020, 15(11), e0241773.
 [http://dx.doi.org/10.1371/journal.pone.0241773] [PMID: 33156828]

[75]
Fassler, M.; Benaim, C.; George, J. A single chain fragment variant binding misfolded alpha-synuclein exhibits neuroprotective and antigen-specific anti-inflammatory properties. Cells,  2022, 11(23), 3822.
 [http://dx.doi.org/10.3390/cells11233822] [PMID: 36497081]

[76]
Hmila, I.; Vaikath, N.N.; Majbour, N.K.; Erskine, D.; Sudhakaran, I.P.; Gupta, V.; Ghanem, S.S.; Islam, Z.; Emara, M.M.; Abdesselem, H.B.; Kolatkar, P.R.; Achappa, D.K.; Vinardell, T.; El-Agnaf, O.M.A. Novel engineered nanobodies specific for N-terminal region of alpha-synuclein recognize Lewy‐body pathology and inhibit in-vitro seeded aggregation and toxicity. FEBS J.,  2022, 289(15), 4657-4673.
 [http://dx.doi.org/10.1111/febs.16376] [PMID: 35090199]

[77]
Cookson, M.R. LRRK2 pathways leading to neurodegeneration. Curr. Neurol. Neurosci. Rep.,  2015, 15(7), 42.
 [http://dx.doi.org/10.1007/s11910-015-0564-y] [PMID: 26008812]

[78]
Gilligan, P. Inhibitors of leucine-rich repeat kinase 2 (LRRK2): Progress and promise for the treatment of Parkinson’s disease. Curr. Top. Med. Chem.,  2015, 15(10), 927-938.
 [http://dx.doi.org/10.2174/156802661510150328223655] [PMID: 25832719]

[79]
Mata, I.; Salles, P.; Cornejo-Olivas, M.; Saffie, P.; Ross, O.A.; Reed, X.; Bandres-Ciga, S. LRRK2: Genetic mechanisms vs genetic subtypes. Handb. Clin. Neurol.,  2023, 193, 133-154.
 [http://dx.doi.org/10.1016/B978-0-323-85555-6.00018-7] [PMID: 36803807]

[80]
Taymans, J.M.; Greggio, E. LRRK2 kinase inhibition as a therapeutic strategy for Parkinson’s disease, where do we stand? Curr. Neuropharmacol.,  2016, 14(3), 214-225.
 [http://dx.doi.org/10.2174/1570159X13666151030102847] [PMID: 26517051]

[81]
Singh, R.K.; Soliman, A.; Guaitoli, G.; Störmer, E.; von Zweydorf, F.; Dal Maso, T.; Oun, A.; Van Rillaer, L.; Schmidt, S.H.; Chatterjee, D.; David, J.A.; Pardon, E.; Schwartz, T.U.; Knapp, S.; Kennedy, E.J.; Steyaert, J.; Herberg, F.W.; Kortholt, A.; Gloeckner, C.J.; Versées, W. Nanobodies as allosteric modulators of Parkinson’s disease–associated LRRK2. Proc. Natl. Acad. Sci.,  2022, 119(9), e2112712119.
 [http://dx.doi.org/10.1073/pnas.2112712119] [PMID: 35217606]

[82]
Rüb, U.; Vonsattel, J.P.G.; Heinsen, H.; Korf, H.W. The neuropathology of Huntington’s disease: Classical findings, recent developments and correlation to functional neuroanatomy. Adv. Anat. Embryol. Cell Biol.,  2015, 217, 1-146.
 [http://dx.doi.org/10.1007/978-3-319-19285-7] [PMID: 26767207]

[83]
Palaiogeorgou, A.; Papakonstantinou, E.; Golfinopoulou, R.; Sigala, M.; Mitsis, T.; Papageorgiou, L.; Diakou, I.; Pierouli, K.; Dragoumani, K.; Spandidos, D.; Bacopoulou, F.; Chrousos, G.; Eliopoulos, E.; Vlachakis, D. Recent approaches on Huntington’s disease (Review). Biomed. Rep.,  2022, 18(1), 5.
 [http://dx.doi.org/10.3892/br.2022.1587] [PMID: 36544856]

[84]
Khoshnan, A.; Ou, S.; Ko, J.; Patterson, P.H. Antibodies and intrabodies against huntingtin: production and screening of monoclonals and single-chain recombinant forms. Methods Mol. Biol.,  2013, 1010, 231-251.
 [http://dx.doi.org/10.1007/978-1-62703-411-1_15] [PMID: 23754229]

[85]
Denis, H.L.; David, L.S.; Cicchetti, F. Antibody-based therapies for Huntington’s disease: Current status and future directions. Neurobiol. Dis.,  2019, 132, 104569.
 [http://dx.doi.org/10.1016/j.nbd.2019.104569] [PMID: 31398458]

[86]
Amaro, I.A.; Henderson, L.A. An intrabody drug (rAAV6-INT41) reduces the binding of N-terminal huntingtin fragment(s) to DNA to basal levels in PC12 cells and delays cognitive loss in the R6/2 animal model. J. Neurodegener. Dis.,  2016, 2016, 1-10.
 [http://dx.doi.org/10.1155/2016/7120753] [PMID: 27595037]

[87]
Perche, F.; Uchida, S.; Akiba, H.; Lin, C.Y.; Ikegami, M.; Dirisala, A.; Nakashima, T.; Itaka, K.; Tsumoto, K.; Kataoka, K. Improved brain expression of anti-amyloid β scFv by complexation of mRNA including a secretion sequence with PEG-based block catiomer. Curr. Alzheimer Res.,  2017, 14(3), 295-302.
 [http://dx.doi.org/10.2174/1567205013666161108110031] [PMID: 27829339]

[88]
Xie, J.; Gonzalez-Carter, D.; Tockary, T.A.; Nakamura, N.; Xue, Y.; Nakakido, M.; Akiba, H.; Dirisala, A.; Liu, X.; Toh, K.; Yang, T.; Wang, Z.; Fukushima, S.; Li, J.; Quader, S.; Tsumoto, K.; Yokota, T.; Anraku, Y.; Kataoka, K. Dual-sensitive nanomicelles enhancing systemic delivery of therapeutically active antibodies specifically into the brain. ACS Nano,  2020, 14(6), 6729-6742.
 [http://dx.doi.org/10.1021/acsnano.9b09991] [PMID: 32431145]

[89]
Tsitokana, M.E.; Lafon, P.A.; Prézeau, L.; Pin, J.P.; Rondard, P. Targeting the brain with single-domain antibodies: Greater potential than stated so far? Int. J. Mol. Sci.,  2023, 24(3), 2632.
 [http://dx.doi.org/10.3390/ijms24032632] [PMID: 36768953]

[90]
Hultqvist, G.; Syvänen, S.; Fang, X.T.; Lannfelt, L.; Sehlin, D. Bivalent brain shuttle increases antibody uptake by monovalent binding to the transferrin receptor. Theranostics,  2017, 7(2), 308-318.
 [http://dx.doi.org/10.7150/thno.17155] [PMID: 28042336]

[91]
Meier, S.R.; Syvänen, S.; Hultqvist, G.; Fang, X.T.; Roshanbin, S.; Lannfelt, L.; Neumann, U.; Sehlin, D. Antibody-based in vivo PET imaging detects amyloid-β reduction in alzheimer transgenic mice after BACE-1 inhibition. J. Nucl. Med.,  2018, 59(12), 1885-1891.
 [http://dx.doi.org/10.2967/jnumed.118.213140] [PMID: 29853653]

[92]
Fang, X.T.; Hultqvist, G.; Meier, S.R.; Antoni, G.; Sehlin, D.; Syvänen, S. High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain. Neuroimage,  2019, 184, 881-888.
 [http://dx.doi.org/10.1016/j.neuroimage.2018.10.011] [PMID: 30300753]

[93]
Stocki, P.; Szary, J.; Rasmussen, C.L.M.; Demydchuk, M.; Northall, L.; Logan, D.B.; Gauhar, A.; Thei, L.; Moos, T.; Walsh, F.S.; Rutkowski, J.L. Blood‐brain barrier transport using a high affinity, brain‐selective VNAR antibody targeting transferrin receptor 1. FASEB J.,  2021, 35(2), e21172.
 [http://dx.doi.org/10.1096/fj.202001787R] [PMID: 33241587]

[94]
Syvänen, S.; Fang, X.T.; Hultqvist, G.; Meier, S.R.; Lannfelt, L.; Sehlin, D. A bispecific Tribody PET radioligand for visualization of amyloid-beta protofibrils – a new concept for neuroimaging. Neuroimage,  2017, 148, 55-63.
 [http://dx.doi.org/10.1016/j.neuroimage.2017.01.004] [PMID: 28069541]

[95]
Rofo, F.; Meier, S.R.; Metzendorf, N.G.; Morrison, J.I.; Petrovic, A.; Syvänen, S.; Sehlin, D.; Hultqvist, G. A brain-targeting bispecific-multivalent antibody clears soluble amyloid-beta aggregates in alzheimer’s disease mice. Neurotherapeutics,  2022, 19(5), 1588-1602.
 [http://dx.doi.org/10.1007/s13311-022-01283-y] [PMID: 35939261]

[96]
Sehlin, D.; Stocki, P.; Gustavsson, T.; Hultqvist, G.; Walsh, F.S.; Rutkowski, J.L.; Syvänen, S. Brain delivery of biologics using a cross-species reactive transferrin receptor 1 VNAR shuttle. FASEB J.,  2020, 34(10), 13272-13283.
 [http://dx.doi.org/10.1096/fj.202000610RR] [PMID: 32779267]

[97]
Clarke, E.; Stocki, P.; Sinclair, E.H.; Gauhar, A.; Fletcher, E.J.R.; Krawczun-Rygmaczewska, A.; Duty, S.; Walsh, F.S.; Doherty, P.; Rutkowski, J.L. A single domain shark antibody targeting the transferrin receptor 1 delivers a TrkB agonist antibody to the brain and provides full neuroprotection in a mouse model of Parkinson’s Disease. Pharmaceutics,  2022, 14(7), 1335.
 [http://dx.doi.org/10.3390/pharmaceutics14071335] [PMID: 35890231]

[98]
Wouters, Y.; Jaspers, T.; Rué, L.; Serneels, L.; De Strooper, B.; Dewilde, M. VHHs as tools for therapeutic protein delivery to the central nervous system. Fluids Barriers CNS,  2022, 19(1), 79.
 [http://dx.doi.org/10.1186/s12987-022-00374-4] [PMID: 36192747]

[99]
Alata, W.; Yogi, A.; Brunette, E.; Delaney, C.E.; Faassen, H.; Hussack, G.; Iqbal, U.; Kemmerich, K.; Haqqani, A.S.; Moreno, M.J.; Stanimirovic, D.B. Targeting insulin‐like growth factor‐1 receptor (IGF1R) for brain delivery of biologics. FASEB J.,  2022, 36(3), e22208.
 [http://dx.doi.org/10.1096/fj.202101644R] [PMID: 35192204]

[100]
Yogi, A.; Hussack, G.; van Faassen, H.; Haqqani, A.S.; Delaney, C.E.; Brunette, E.; Sandhu, J.K.; Hewitt, M.; Sulea, T.; Kemmerich, K.; Stanimirovic, D.B. Brain delivery of IGF1R5, a single-domain antibody targeting insulin-like growth factor-1 receptor. Pharmaceutics,  2022, 14(7), 1452.
 [http://dx.doi.org/10.3390/pharmaceutics14071452] [PMID: 35890347]

[101]
Aguiar, S.I.; Días, J.N.R.; André, A.S.; Silva, M.L.; Martins, D.; Carrapiço, B.; Castanho, M.; Carriço, J.; Cavaco, M.; Gaspar, M.M.; Nobre, R.J.; Pereira de Almeida, L.; Oliveira, S.; Gano, L.; Correia, J.D.G.; Barbas, C., III; Gonçalves, J.; Neves, V.; Aires-da-Silva, F. Highly specific blood-brain barrier transmigrating single-domain antibodies selected by an in vivo phage display screening. Pharmaceutics,  2021, 13(10), 1598.
 [http://dx.doi.org/10.3390/pharmaceutics13101598] [PMID: 34683891]

[102]
Vangijzegem, T.; Lecomte, V.; Ternad, I.; Van Leuven, L.; Muller, R.N.; Stanicki, D.; Laurent, S. Superparamagnetic iron oxide nanoparticles (SPION): From fundamentals to state-of-the-art innovative applications for cancer therapy. Pharmaceutics,  2023, 15(1), 236.
 [http://dx.doi.org/10.3390/pharmaceutics15010236] [PMID: 36678868]

[103]
Liu, X.; Lu, S.; Liu, D.; Zhang, L.; Zhang, L.; Yu, X.; Liu, R. ScFv-conjugated superparamagnetic iron oxide nanoparticles for MRI-based diagnosis in transgenic mouse models of Parkinson’s and Huntington’s diseases. Brain Res.,  2019, 1707, 141-153.
 [http://dx.doi.org/10.1016/j.brainres.2018.11.034 ] [PMID: 30481502]

[104]
Liu, X.G.; Zhang, L.; Lu, S.; Liu, D.Q.; Zhang, L.X.; Yu, X.L.; Liu, R.T. Multifunctional superparamagnetic iron oxide nanoparticles conjugated with Aβ oligomer-specific scFv antibody and class a scavenger receptor activator show early diagnostic potentials for Alzheimer’s Disease. Int. J. Nanomedicine,  2020, 15, 4919-4932.
 [http://dx.doi.org/10.2147/IJN.S240953] [PMID: 32764925]

[105]
Liu, X.; Zhang, L.; Lu, S.; Liu, D.; Huang, Y.; Zhu, J.; Zhou, W.; Yu, X.; Liu, R. Superparamagnetic iron oxide nanoparticles conjugated with Aβ oligomer-specific scFv antibody and class A scavenger receptor activator show therapeutic potentials for Alzheimer’s disease. J. Nanobiotechnology,  2020, 18(1), 160.
 [http://dx.doi.org/10.1186/s12951-020-00723-1] [PMID: 33160377]
Cite As
Current Neuropharmacology

Recombinant Antibody Fragments for Neurological Disorders: An Update

Abstract

Graphical Abstract
