UB-311, a novel UBITh® amyloid β peptide vaccine for mild Alzheimer's disease
Chang Yi Wang, Pei-Ning Wang, Ming-Jang Chiu, Connie L Finstad, Feng Lin, Shugene Lynn, Yuan-Hung Tai, Xin De Fang, Kesheng Zhao, Chung-Ho Hung, Yiting Tseng, Wen-Jiun Peng, Jason Wang, Chih-Chieh Yu, Be-Sheng Kuo, Paul A Frohna, Chang Yi Wang, Pei-Ning Wang, Ming-Jang Chiu, Connie L Finstad, Feng Lin, Shugene Lynn, Yuan-Hung Tai, Xin De Fang, Kesheng Zhao, Chung-Ho Hung, Yiting Tseng, Wen-Jiun Peng, Jason Wang, Chih-Chieh Yu, Be-Sheng Kuo, Paul A Frohna
Abstract
Introduction: A novel amyloid β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial.
Methods: UB-311 is constructed with two synthetic Aβ1-14-targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh®) and formulated in a Th2-biased delivery system. The hAPP751 transgenic mouse model was used to perform the proof-of-concept study. Baboons and macaques were used for preclinical safety, tolerability, and immunogenicity evaluation. Patients with mild-to-moderate Alzheimer's disease (AD) were immunized by intramuscular route with 3 doses of UB-311 at weeks 0, 4, and 12, and monitored until week 48. Safety and immunogenicity were assessed per protocol, and preliminary efficacy was analyzed by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Mini-Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC).
Results: UB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of Aβ1-42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (Aβ1-10) antibodies across all animal species examined. In AD patients, UB-311 induced a 100% responder rate; injection site swelling and agitation were the most common adverse events (4/19 each). A slower rate of increase in ADAS-Cog from baseline to week 48 was observed in the subgroup of mild AD patients (MMSE ≥ 20) compared with the moderate AD subgroup, suggesting that UB-311 may have a potential of cognition improvement in patients with early stage of Alzheimer's dementia.
Discussion: The UBITh® platform can generate a high-precision molecular vaccine with high responder rate, strong on-target immunogenicity, and a potential of cognition improvement, which support UB-311 for active immunotherapy in early-to-mild AD patients currently enrolled in a phase-II trial (NCT02551809).
Keywords: Alzheimer's disease; Amyloid β vaccine; FIH clinical trial; UB-311; UBITh® platform.
Figures
References
- Hardy J., Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356.
- Kayed R., Lasagna-Reeves C.A. Molecular mechanisms of amyloid oligomers toxicity. J Alzheimers Dis. 2013;33:S67–S78.
- Kumar D.K., Choi S.H., Washicosky K.J., Eimer W.A., Ghofrani J., Leftkowitz A. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med. 2016;8:340ra72.
- Soscia S.J., Kirby J.E., Washicosky K.J., Tucker S.M., Ingelsson M., Hyman B. The Alzheimer's disease-associated amyloid-beta-protein is an antimicrobial peptide. PLoS One. 2010;5:e9505.
- Qian X.X., Hamad B., Dias-Lalcaca G. The Alzheimer disease market. Nat Rev Drug Discov. 2015;14:675–676.
- Schenk D., Barbour R., Dunn W., Gordon G., Grajeda H., Guido T. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–177.
- Orgogozo J.M., Gilman S., Dartigues J.F., Laurent B., Puel M., Kirby L.C. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46–54.
- Gilman S., Koller M., Black R.S., Jenkins L., Griffith S.G., Fox N.C. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–1562.
- Pasquier F., Sadowsky C., Holstein A., Leterme G.L., Peng Y., Jackson N. Two phase 2 multiple ascending-dose studies of vautide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer's disease. J Alzheimers Dis. 2016;51:1131–1143.
- Winblad B., Andreasen N., Minthon L., Floesser A., Imbert G., Dumortier T. Safety, tolerability and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 2012;11:597–604.
- Savage M.J., Wu G., McCampbell A., Wessner K.R., Citron M., Ling X. A novel multivalent Abeta peptide vaccine with preclinical evidence of a central immune response that generates antisera recognizing a wide range of Abeta peptide species. Alzheimers Dement. 2010;6:S142. Abstract No. O3-07-03.
- Hendrix S., Ellison N., Stanworth S., Tierney L., Mattner F., Schmidt W. Methodological aspects of the phase II study AFF006 evaluating amyloid-beta-targeting vaccine AFFITOPE AD02 in early Alzheimer's disease—prospective use of novel composite scales. J Prev Alzheimers Dis. 2015;2:91–102.
- Marciani D.J., Ellison N., Stanworth S., Tierney L., Mattner F., Schmidt W. A retrospective analysis of the Alzheimer's disease vaccine progress—the critical need for new development strategies. J Neurochem. 2016;137:687–700.
- Agadjanyan M.G., Petrovsky N., Ghochikyan A. A fresh perspective from immunologists and vaccine researchers: active vaccination strategies to prevent and reverse Alzheimer's disease. Alzheimers Dement. 2015;11:1246–1259.
- Farlow M.R., Andreasen N., Riviere M.E., Vostiar I., Vitaliti A., Sovago J. Long-term treatment with Aβ immunotherapy with CAD106 in mild Alzheimer's disease. Alzheimers Res Ther. 2015;7:23.
- Vandenberghe R., Riviere M.E., Caputo A., Sovago J., Maguire R.P., Farlow M. Active Aβ immunotherapy CAD106 in Alzheimer's disease: A phase 2b study. Alzheimers Dement (N Y) 2017;3:10–22.
- Cummings J., Morstort T., Lee G. Alzheimer's drug development pipeline: 2016. Alzheimers Dement (N Y) 2016;2:222–232.
- Wang C.Y., Finstad C.L., Walfield A.M., Sia C., Sokoll K.K., Chang T.Y. Site-specific UBITh® amyloid-β vaccine for immunotherapy of Alzheimer's disease. Vaccine. 2007;25:3041–3052.
- Monsonego A., Zota V., Karni A., Krieger J.I., Bar-Or A., Bitan G. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest. 2003;112:415–422.
- Greenberg S.M., Bacskai B.J., Hyman B.T. Alzheimer disease's double edged vaccine. Nat Med. 2003;9:389–390.
- Ghochikyan A., Mkrtichyan M., Petrushina I., Movsesyan N., Karapetyan A., Cribbs D.H. Prototype Alzheimer's disease epitope vaccine induced strong Th2-type anti-Abeta antibody response with Alum to Quil A adjuvant switch. Vaccine. 2006;24:2275–2282.
- Pellicano M., Bulati M., Buffa S., Barbagallo M., Di Prima A., Misiano G. Systemic immune responses in Alzheimer's disease: in vitro mononuclear cell activation and cytokine production. J Alzheimers Dis. 2010;21:181–192.
- Marciani D.J. Alzheimer's disease vaccine development: a new strategy focusing on immune modulation. J Neuroimmunol. 2015;287:54–63.
- Giunta B., Fernandez F., Nikolic W.V., Obregon D., Rrapo E., Town T. Inflammaging as a prodrome to Alzheimer's disease. J Neuroinflammation. 2008;5:51.
- Reale M., Iarlori C., Feliciani C., Gambi D. Peripheral chemokine receptors, their ligands, cytokines and Alzheimer's disease. J Alzheimers Dis. 2008;14:147–159.
- Montagne A., Barnes S.R., Sweeney M.D., Halliday M.R., Sagare A.P., Zhao Z. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85:296–302.
- Wang C.Y., Chang T.Y., Walfield A.M., Ye J., Shen M., Chen S.P. Effective synthetic peptide vaccine for foot-and-mouth disease in swine. Vaccine. 2002;20:2603–2610.
- Wang C.Y., Shen M., Tam G., Fang X.D., Ye J., Shen F. Synthetic AIDS vaccine by targeting HIV receptor. Vaccine. 2002;21:89–97.
- Wang C.Y., Walfield A.M., Fang X.D., Hammerberg B., Ye J., Li M.L. Synthetic IgE peptide vaccine for immunotherapy of allergy. Vaccine. 2003;21:1580–1590.
- Wang C.Y., Walfield A.M. Site-specific peptide vaccines for immunotherapy and immunization against chronic diseases, cancer, infectious diseases, and for veterinary applications. Vaccine. 2005;23:2049–2056.
- Bayer A.J., Bullock R., Jones R.W., Wilkinson D., Paterson K.R., Jenkins L. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology. 2005;64:94–101.
- Ghiso J., Frangione B. Amyloidosis and Alzheimer's disease. Adv Drug Deliv Rev. 2002;54:1539–1551.
- Zlokovic B.V. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011;12:723–738.
- Masters C.L., Simms G., Weinman N.A., Multhaup G., McDonald B.L., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985;82:4245–4249.
- DeMattos R.B., Bales K.R., Cummins D.J., Dodart J.C., Paul S.M., Holtzman D.M. Peripheral anti-Abeta antibody alters CNS and plasma Abeta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001;98:8850–8855.
- Zhao L.N., Long H., Mu Y., Chew L.Y. The toxicity of amyloid oligomers. Int J Mol Sci. 2012;13:7303–7327.
- Kayed R., Head E., Thompson J.L., McIntire T.M., Milton S.C., Cotman C.W. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003;300:486–489.
- Shankar G.M., Li S., Mehta T.H., Garcia-Munoz A., Shepardson N.E., Smith I. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–842.
- Stancu I.C., Vasconcelos B., Terwel D., Dewachter I. Models of β-amyloid induced Tau-pathology: the long and “folded” road to understand the mechanism. Mol Neurodegener. 2014;9:51.
- Parajuli B., Sonobe Y., Horiuchi H., Takeuchi H., Mizuno T., Suzumara A. Oligomeric amyloid beta induces IL-1β processing via production of ROS: implication in Alzheimer's disease. Cell Death Dis. 2013;4:e975.
- Wisniewski T., Goni F. Immunotherapeutic approaches for Alzheimer's disease. Neuron. 2015;85:1162–1176.
- Wisniewski T., Drummond E. Developing therapeutic vaccines against Alzheimer's disease. Expert Rev Vaccines. 2016;15:401–415.
- Salloway S., Sperling R., Fox N.C., Blennow K., Klunk W., Raskind M. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med. 2014;370:322–333.
- Siemers E.R., Sundell K.L., Carlson C., Case M., Sethuraman G., Liu-Seifert H. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2016;12:110–120.
- Sperling R., Salloway S., Brooks D.J., Tampieri D., Barakos J., Fox N.C. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012;11:241–249.
- Sevigny J., Chiao P., Bussiere T., Weinreb P.H., Williams L., Maier M. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016;537:50–56.
- Bouter Y., Lopez Noguerola J.S., Tucholla P., Crespi G.A., Parker M.W., Wiltfang J. Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models. Acta Neuropathol. 2015;130:713–729.
- Reiman E.M. Attack on amyloid-β protein. Nature. 2016;537:36–37.
- Zempel H., Luedtke J., Kumar Y., Biermat J., Dawson H., Mandelkow E. Amyloid-β oligomers induce synaptic damage via tau-dependent microtubule severing by TTLL6 and spastin. EMBO J. 2013;32:2920–2937.
- Seward M.E., Swanson E., Norambuena A., Reimann A., Cochran J.N., Li R. Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease. J Cell Sci. 2013;126:1278–1286.
- Wang Y., Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17:5–21.
Source: PubMed