Dosing regimes for treatment of synucleinopathies

Abstract

The invention provides dosage regimes for treatment of synucleinopathies. In one regime, a subject receives 3000-5000 mg of an antibody intravenously every 3-5 weeks. In another regime, a subject receives 1300-1700 mg of an antibody intravenously every 3-5 weeks.

1 . A method of treating or effecting prophylaxis of a subject having or at risk of a synucleinopathy comprising intravenously administering to the subject a dose of 3000-5000 mg of an antibody against alpha-synuclein at intervals of 3-5 weeks, or administering another regime that delivers the antibody to the subject with substantially the same area under the curve. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein a subject with a weight less than 65 kg receives a dose of 3500 mg antibody and a subject with a weight greater or equal to 65 kg receives a dose of 4500 mg. 
     
     
         5 . The method of  claim 1 , wherein the dose is 45-75 mg/kg. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the subject receives between at least six to at least 18 doses of the antibody at the intervals of 3-5 weeks. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the subject receives the antibody every 4 weeks for at least 52 weeks. 
     
     
         13 . The method of  claim 1 , further comprising monitoring the subject for a change in movement, cognitive deficit, autonomic dysfunction, gastrointestinal dysfunction, visual hallucination or a psychological symptom. 
     
     
         14 . The method of  claim 13 , wherein the monitoring comprises
 (a) providing a subject with a mobile device programmed to receive and transmit data acquired from sensors internal and/or external to the device relating to movement deficits of a subject having or suspected of having a synucleinopathy, whereafter the subject undergoes a series of movements to reveal movement deficits, if present, and the internal or external sensors of the device acquire data relating to the movements;   (b) collecting data transmitted from the mobile device; and   (c) comparing the data acquired from the subjects with control data to assess presence or extent of movement deficits in the subject.   
     
     
         15 . The method of  claim 14 , wherein the mobile device is programmed to receive and transmit data from at least two external sensors attached to upper and lower limbs of the subject. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 14 , wherein the mobile device is carried by the subject and acquires data from an internal sensor. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the antibody binds within residues 115-130 of alpha synuclein. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein the antibody comprises three heavy CDRs designated SEQ ID NOs: 139-141 respectively and three light chain CDRs designated SEQ ID NOs: 143-145 respectively. 
     
     
         25 . The method of  claim 1 , wherein the antibody comprises a heavy chain variable region designated SEQ ID NO: 138 and a light chain variable region designated SEQ ID NO:142. 
     
     
         26 . The method of  claim 1 , wherein the antibody comprises the three light chain Kabat CDRs of SEQ ID NO:5 and the three heavy chain Kabat CDRs of SEQ ID NO:10. 
     
     
         27 . The method of  claim 1 , wherein the antibody comprises a heavy chain variable region of any of SEQ ID NOs: 8-11 and a light chain variable region of any of SEQ ID NO:3-5, preferably wherein the heavy chain variable region is of SEQ ID NO: 10 and a light chain variable region of SEQ ID NO:5. 
     
     
         28 . The method of  claim 1 , wherein the antibody is of human IgG 1 isotype. 
     
     
         29 . The method of  claim 28 , wherein the antibody comprises a heavy chain constant region of SEQ ID NO:35 provided the C-terminal lysine of SEQ ID NO:35 may be absent and a light chain constant region of SEQ ID NO:30. 
     
     
         30 . The method of  claim 28 , wherein the antibody comprises a heavy chain constant region of SEQ ID NO:35 provided the C-terminal lysine of SEQ ID NO:35 may be absent and a light chain constant region of SEQ ID NO: 13. 
     
     
         31 . The method of  claim 1 , wherein the antibody is 9E4, NI-202.12F4, or NI-202.21D11. 
     
     
         32 . The method of  claim 1 , wherein the antibody comprises three heavy CDRs designated SEQ ID NOs: 146-148 respectively and three light chain CDRs designated SEQ ID NOs: 149-151 respectively. 
     
     
         33 . The method of  claim 1 , wherein the antibody comprises a heavy chain designated SEQ ID NO:37 and a light chain designated SEQ ID NO:32, wherein the C-terminal lysine of SEQ ID NO:37 may be absent. 
     
     
         34 . The method of  claim 1 , wherein the antibody binds within residues 1-20 of alpha-synuclein. 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . The method of  claim 1 , wherein the antibody comprises three heavy CDRs designated SEQ ID NOs: 131-133 respectively and three light chain CDRs designated SEQ ID NOs: 135-137 respectively. 
     
     
         38 . The method of  claim 1 , wherein the antibody comprises a heavy chain variable region designated SEQ ID NO: 130 and a light chain variable region designated SEQ ID NO: 134. 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 1 , wherein administering the antibody within the range of 3000-5000 mg is preceded by administering a loading dose of 2000 mg of the antibody and optionally uptitration at one or more subsequent dose at greater or equal to 2000 mg but less than 3500 mg until a dose of 3500 mg is reached, all doses being separated by intervals of 3-5 weeks. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 1 , wherein the antibody is administered at 4500 mg preceded by administration of a loading dose of 2000 mg of the antibody and optionally uptitration with one or more subsequent doses of greater than or equal to 2000 mg but less than 4500 mg until a dose of 4500 mg is reached with all doses being separated by intervals of 3-5 weeks. 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 44 , further comprising monitoring the subject for a change in movement, cognitive deficit autonomic dysfunction, gastrointestinal dysfunction, visual hallucination or a psychological symptom. 
     
     
         48 . The method of  claim 47 , wherein the monitoring comprises
 (a) providing a subject with a mobile device programmed to receive and transmit data acquired from sensors internal and/or external to the device relating to movement deficits of a subject having or suspected of having a synucleinopathy, whereafter the subject undergoes a series of movements to reveal movement deficits, if present, and the internal or external sensors of the device acquire data relating to the movements;   (b) collecting data transmitted from the mobile device; and   (c) comparing the data acquired from the subjects with control data to assess presence or extent of movement deficits in the subject.   
     
     
         49 . The method of  claim 48 , wherein the mobile device is programmed to receive and transmit data from at least two external sensors attached to upper and lower limbs of the subject. 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 48 , wherein the mobile device is carried by the subject and acquires data from an internal sensor. 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . The method of  claim 1 , wherein the synucleinopathy is Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supra nuclear palsy, REM sleep behavior disorder, or Alzheimer's disease with amygdala Lewy bodies. 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . The method of  claim 1 , wherein the subject is not receiving symptomatic treatment for Parkinson's disease concomitant with the antibody. 
     
     
         62 . The method of  claim 1 , wherein the antibody is administered concomitantly with levodopa. 
     
     
         63 . A method of treating or effecting prophylaxis of a subject having a Lewy body disease comprising intravenously administering to the subject a dose of 1300-1700 mg of an antibody against alpha-synuclein at intervals of 3-5 weeks, or administering another regime that delivers the antibody to the subject with substantially the same area under the curve. 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . The method of  claim 63 , wherein the subject receives a dose of 18-25 mg/kg. 
     
     
         67 . (canceled) 
     
     
         68 . (canceled) 
     
     
         69 . The method of  claim 63 , wherein the subject receives between at least six doses to at least 18 doses of the antibody at the intervals of 3-5 weeks. 
     
     
         70 . (canceled) 
     
     
         71 . (canceled) 
     
     
         72 . The method of  claim 63 , wherein the interval is 4 weeks. 
     
     
         73 . The method of  claim 63 , wherein the subject receives the antibody every 4 weeks for at least 52 weeks. 
     
     
         74 . The method of  claim 63 , further comprising monitoring the subject for a change in movement, cognitive deficit autonomic dysfunction, gastrointestinal dysfunction, visual hallucination or a psychological symptom. 
     
     
         75 . The method of  claim 74 , wherein the monitoring comprises
 (a) providing a subject with a mobile device programmed to receive and transmit data acquired from sensors internal and/or external to the device relating to movement deficits of a subject having or suspected of having a Lewy body disease, whereafter the subject undergoes a series of movements to reveal movement deficits, if present, and the internal or external sensors of the device acquire data relating to the movements;   (b) collecting data transmitted from the mobile device; and   (c) comparing the data acquired from the subjects with control data to assess presence or extent of movement deficits in the subject.   
     
     
         76 . The method of  claim 75 , wherein the mobile device is programmed to receive and transmit data from at least two external sensors attached to upper and lower limbs of the subject. 
     
     
         77 . (canceled) 
     
     
         78 . The method of  claim 75 , wherein the mobile device is carried by the subject and acquires data from an internal sensor. 
     
     
         79 . (canceled) 
     
     
         80 . (canceled) 
     
     
         81 . The method of  claim 63 , wherein the antibody binds within residues 115-130 of alpha synuclein. 
     
     
         82 . (canceled) 
     
     
         83 . (canceled) 
     
     
         84 . (canceled) 
     
     
         85 . The method of  claim 63 , wherein the antibody comprises three heavy CDRs designated SEQ ID NOs: 139-141 respectively and three light chain CDRs designated SEQ ID NOs: 143-145 respectively. 
     
     
         86 . The method of  claim 63 , wherein the antibody comprises a heavy chain variable region designated SEQ ID NO: 138 and a light chain variable region designated SEQ ID NO:142. 
     
     
         87 . The method of  claim 63 , wherein the antibody comprises the three light chain Kabat CDRs of SEQ ID NO:5 and the three heavy chain Kabat CDRs of SEQ ID NO:10. 
     
     
         88 . The method of  claim 63 , wherein the antibody comprises a heavy chain variable region of any of SEQ ID NOs: 8-11 and a light chain variable region of any of SEQ ID NO:3-5, preferably wherein the heavy chain variable region is of SEQ ID NO: 10 and a light chain variable region of SEQ ID NO:5. 
     
     
         89 . The method of  claim 63 , wherein the antibody is of human IgG 1 isotype. 
     
     
         90 . The method of  claim 89 , wherein the antibody comprises a heavy chain constant region of SEQ ID NO:35 provided the C-terminal lysine may be absent and a light chain constant region of SEQ ID NO:30. 
     
     
         91 . The method of  claim 89 , wherein the antibody comprises a heavy chain constant region of SEQ ID NO:35 provided the C-terminal lysine may be absent and a light chain constant region of SEQ ID NO: 13. 
     
     
         92 . The method of  claim 63  wherein the antibody comprises three heavy CDRs designated SEQ ID NOs: 146-148 respectively and three light chain CDRs designated SEQ ID NOs: 149-151 respectively. 
     
     
         93 . The method of  claim 63 , wherein the antibody comprises a heavy chain designated SEQ ID NO:37 and a light chain designated SEQ ID NO:32, wherein the C-terminal lysine of SEQ ID NO:37 may be absent. 
     
     
         94 . The method of  claim 63 , wherein the antibody binds within residues 1-20 of alpha-synuclein. 
     
     
         95 . (canceled) 
     
     
         96 . The method of  claim 63 , wherein the antibody is NI-202.12F4 or NI-202.21D11. 
     
     
         97 . The method of  claim 63 , wherein the antibody comprises three heavy CDRs designated SEQ ID NOs: 131-133 respectively and three light chain CDRs designated SEQ ID NOs: 135-137 respectively. 
     
     
         98 . The method of  claim 63 , wherein the antibody comprises a heavy chain variable region designated SEQ ID NO: 130 and a light chain variable region designated SEQ ID NO: 134. 
     
     
         99 . The method of  claim 63 , wherein the Lewy body disease is Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supra nuclear palsy, REM sleep behavior disorder, or Alzheimer's disease with amygdala Lewy bodies. 
     
     
         100 . (canceled) 
     
     
         101 . (canceled) 
     
     
         102 . (canceled) 
     
     
         103 . (canceled) 
     
     
         104 . (canceled) 
     
     
         105 . (canceled) 
     
     
         106 . The method of  claim 1 , wherein the subject is not receiving symptomatic treatment for Parkinson's disease concomitant with the antibody. 
     
     
         107 . The method of  claim 1 , wherein the antibody is administered concomitantly with levodopa.