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WO 2016/120843 Al 4 August 2016 (04.08.2016) P O P C T

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WO 2016/120843 Al 4 August 2016 (04.08.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/120843 Al 4 August 2016 (04.08.2016) P O P C T (51) International Patent Classification: (74) Agent: VIEIRA PEREIRA FERREIRA, Maria Silvina; C07K 16/18 (2006.01) C07K 14/18 (2006.01) CLARKE, MODET & CO., Rua Castilho, 50-9°, 1269-163 A61K 51/10 (2006.01) G01N 33/50 (2006.01) Lisboa (PT). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/IB20 16/050467 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) Date: International Filing BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 29 January 2016 (29.01 .2016) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 1081 8 1 29 January 2015 (29.01.2015) PT SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 1081 82 29 January 2015 (29.01.2015) PT TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: TECHNOPHAGE, INVESTIGACAO E (84) Designated States (unless otherwise indicated, for every DESENVOLVIMENTO EM BIOTECNOLOGIA, SA kind of regional protection available): ARIPO (BW, GH, [PT/PT]; Avenida Professor Egas Moniz Edificio Egas GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Moniz, Piso 2, sala A8, 1649-028 Lisboa (PT). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: VOLKER CORTE-REAL, Sofia; Rua dos DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Bombeiros Voluntarios do Dafundo N2 2J, 1495-714 Cruz LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Quebrada-Dafundo (PT). SANTOS NEVES, Vera Luisa; SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Rua Amelia Rey Colaco, N° 5, 7° D, 1500-037 Lisboa GW, KM, ML, MR, NE, SN, TD, TG). (PT). CORREIA CANHAO, Pedro Manuel; Rua da Liberdade N° 38, 7160-234 Vila Vicosa (PT). FLEMING Published: OUTEIRO, Tiago; Av. Krus Abecassis N° 30, 1A, 1750- — with international search report (Art. 21(3)) 456 Lisboa (PT). RICO BOTAS CASTANHO, Miguel — before the expiration of the time limit for amending the Augusto; Rua Vasco da Gama N° 16E, 5° Dt °, 2000-232 claims and to be republished in the event of receipt of Santarem (PT). CASTANHEIRA AIRES DA SILVA, amendments (Rule 48.2(h)) Frederico Nuno; Rua Actor Isidore N° 26, 3° Esq ", 1900- 019 Lisboa (PT). SANTIAGO DE OLIVEIRA, Soraia Rafaela; Rua Fernando Cabral n°4 1°B, 1750-329 Lisboa (PT). (54) Title: ANTIBODY MOLECULES AND PEPTIDE DELIVERY SYSTEMS FOR USE IN ALZHEIMER'S DISEASE AND RELATED DISORDERS o (57) Abstract: The present invention relates to antibody molecules and peptide delivery systems for use in the treatment and man agement of Alzheimer's disease and related disorders. In particular, the antibody molecules preferentially bind oligomeric forms of beta- amyloid peptide, in single domain format, and the peptide delivery systems facilitate specific transport of such antibody mo - lecules, as well as other cargo molecules, across the blood-brain barrier. The invention also relates to constructs of the antibody mo - o lecules and the delivery peptides, as well as pharmaceutical compositions comprising effective amounts of the antibody molecules, delivery peptides, and/or their constructs, including humanized versions of the antibody molecules and constructs. The invention fur ther relates to methods of making these products and pharmaceutical compositions thereof; and methods of using the pharmaceutical compositions in treating or preventing Alzheimer's and related disorders, such as those involving accumulation of beta-amyloid pep tide or other peptides that aggregate in the brain; as well as to methods and kits for diagnosing these disorders. Bo o ecu es e systems FOR use Disease ISO e S ie O tx e em io [0001] The present invention relates to antibody molecules and peptide delivery systems for use in the treatment and management of Alzheimer's disease and related disorders. In particular, the antibody molecules preferentially bind oligomeric forms of beta-amyloid peptide, in single domain format, and the peptide delivery systems facilitate specific transport of such antibody molecules, as well as other cargo molecules, across the blood-brain barrier. The invention also relates to constructs of the antibody molecules and the delivery peptides, as well as pharmaceutical compositions comprising effective amounts of the antibody molecules, delivery peptides, and/or their constructs, including humanized versions of the antibody molecules and constructs. The invention further relates to methods of making these products and pharmaceutical compositions thereof; and methods of using the pharmaceutical compositions in treating or preventing Alzheimer's and related disorders, such as those involving accumulation of beta-amyloid peptide or other peptides that aggregate in the brain; as well as to methods and kits for diagnosing these disorders. CROSS RereRence o Re eD o s [0002] This application claims foreign priority to Portuguese Patent Application No. 108182D, filed Jan. 29, 2015 and Portuguese Patent Application No. 108181C, filed Jan. 29, 2015, the entire disclosure of each of which are hereby incorporated by reference herein. seo enc isi nG [0003] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on January 28, 2016, is named 14116-105015PC_SL.txt and is 168,632 bytes in size. ncx Ro ms [0004] Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease are increasingly common due to aging of the human population. These diseases are known as "proteinopathies", as they are characterized by the dysfunction of specific proteins, leading to extracellular and intracellular accumulation of protein aggregates. [0005] Alzheimer's disease (AD) is the most common form of dementia worldwide. Recent data show an exponential increase in the number of cases of Alzheimer's patients, emphasizing the need to develop effective treatments. Today about 35.6 million people worldwide live with this disease; by 2050 it is expected that the numbers reach close to 115 million. Indeed, the sector with highest growth potential in the pharmaceutical industry concerns developing drugs for neurological disease. [0006] AD is characterized neuropathologically by accumulation of beta-amyloid peptide (BAP), which results from the processing of amyloid precursor protein (APP). BAP forms the main component of senile plaques, which are the starting point of AD pathogenesis. [0007] Although, in recent years, there have been advances in understanding and treating brain pathologies, many disorders of the central nervous system (CNS), including AD, continue to be devastating and poorly treatable. One problem in treating these disorders is that many drug are unable to cross the blood-brain barrier (BBB) to reach the CNS, a problem especially seen with large molecule drugs. The BBB is formed by specialized endothelial cells (brain endothelial cells) that line capillaries supplying the brain and which prevent, or hinder, the passage of substances from the blood into the CNS. [0008] Various approaches have been attempted to overcome this difficulty. For example, controlled release systems have been used, but these systems sometimes interfere with the operation of the BBB. Another approach involves developing lipophilic drugs, but these have the disadvantage of being rapidly excreted into the bloodstream. Surgical procedures to temporarily open the barrier also have been tested, for example using mannitol injections to decrease cell size and leave voids between the cells, but such procedures may be unsafe, potentially causing swelling, convulsion, and increased susceptibility to infection. Still another approach to deliver drugs across the BBB involves linking the drug to an antibody specific for receptors on the BBB, such as the insulin, leptin, or transferrin receptor, and taking advantage of existing "portals" across the BBB using receptor mediated cytosis. Nonetheless, delivery using this approach is limited by receptor saturation and poor penetration into the extravascular tissue. Moreover, these receptors are expressed in other tissues and are implicated in metabolically critical cellular functions, creating safety risks. [0009] An alternative approach involves using cell-penetrating peptides (CPPs), having translocation capacity. Following the discovery that the third helix of Antennapedia homeodomain crosses biological membranes, investigators have studied different CPPs capable of carrying various cargo loads to the interior of cells, including low molecular weight drugs, liposomes, plasmids, antibodies, and nanoparticles. Nonetheless, use of CPPs as delivery systems is limited by a lack of cell specificity in CPP-mediated cargo delivery. [0010] Further, having crossed the BBB, it is advantageous for a therapeutic to exert its therapeutic effect, and then be efficiently cleared from the brain and CNS and returned to the general circulation for elimination from a patient's body. [0011] Accordingly, there remains a need in the art for therapeutics for treating and managing AD, and related disorders, in particular, a need for therapeutics capable of crossing the BBB specifically and then being cleared therefrom efficiently, as well as delivery systems that safely deliver therapeutics across the barrier to the CNS. There also remains a need for effective diagnosis of initial and late stages of AD.
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