Immunotherapy Regimes Dependent On APOE Status

• US 20090155256A1
• Filed: 10/17/2008
• Published: 06/18/2009
• Est. Priority Date: 10/17/2007
• Status: Abandoned Application

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth LLC (Pfizer Inc.)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC), Wyeth (Pfizer Inc.)
• Inventors: Tchistiakova, Lioudmila, Widom, Angela, Gill, Davinder, Callaway, James, Grundman, Michael, Lieberburg, Ivan, Jacobsen, Jack Steven, Black, Ronald, Gregg, Keith M., Ekman, Lars
• Application Number:
  US12/253,929
• Publication Number:
  US 20090155256A1
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: G06Q 99/00 Subject matter not provided for in other groups of this subclass

Abstract

The invention provides methods of immunotherapy of Alzheimer'"'"'s and similar diseases in which the regime administered to a patient depends on the ApoE genotype of the patient.

Claims

1. A method of treating Alzheimer'"'"'s disease, comprising administering to a patient having zero ApoE4 alleles (“

ApoE4 non-carrier patient”

) and Alzheimer'"'"'s disease, an effective regime of an antibody that specifically binds to a N-terminal epitope of Aβ

, wherein a dosage of the antibody within a range of about 0.15 mg/kg to about 2 mg/kg is administered by intravenous infusion.

2. The method of claim 1, wherein antibody specifically binds to an epitope within:

residues 1-7 of Aβ

;

residues 1-5 of Aβ

;

or

residues 3-7 of Aβ

.

4. The method of claim 2, wherein the dosage is administered every:

4 to 16 weeks;

10 to 14 weeks;

or

13 weeks.

5. The method of claim 4, wherein the dosage is about 0.5 mg/kg to about 1 mg/kg.

6. The method of claim 2, wherein the antibody is a humanized form of a mouse 3D6 antibody (ATCC accession number PTA-5130), and positions 234, 235 and 237 in the heavy chain constant region are occupied by Ala, Ala and Ala respectively, wherein positions are numbered by the EU numbering system.

7. The method of claim 5, wherein the antibody is bapineuzumab.

8. The method of claim 7, further comprising monitoring for vasogenic edema.

9. The method of claim 8, comprising administering a corticosteroid to the patient to treat vasogenic edema detected by the monitoring.

3. (canceled)

10. A method of treating Alzheimer'"'"'s disease, comprising administering to an ApoE4 non-carrier patient an antibody that specifically recognizes the N-terminal region of Aβ

in a regime effective to maintain a mean serum concentration of the antibody in the range of about 0.1 μ

g/ml to about 60 μ

g/ml.

12. The method of claim 10, wherein the maximum serum concentration is within a range of about 4-28 μ

g antibody/ml serum.

11. (canceled)

13-14. -14. (canceled)

15. A method of treating Alzheimer'"'"'s disease, comprising administering to an ApoE4 non-carrier patient bapienuzumab in a regime effective to achieve a mean plasma Aβ

concentration of at least 450 pg/ml.

16. The method of claim 15, wherein the mean plasma Aβ

concentration is in the range of about 600 pg/ml to about 3000 pg/ml.

17-18. -18. (canceled)

19. A method of reducing cognitive decline in a patient having zero ApoE4 alleles (“

ApoE4 non-carrier patient”

),

comprising administering to the patient bapineuzumab in a regime effective to reduce the cognitive decline of the patient relative to a control patient to whom the bapineuzumab is not administered, wherein a dosage of the bapineuzumab within a range of about 0.15 mg/kg to about 2 mg/kg is administered by intravenous infusion

wherein;

the ApoE4 non-carrier patient and control patient have been diagnosed with mild to moderate Alzheimer'"'"'s disease;

and the cognitive decline is measured by ADAS-COG, NTB, MMSE or CDR-SB.

20-22. -22. (canceled)

23. A method of reducing brain volume decline in a patient having zero ApoE4 alleles (“

ApoE4 non-carrier patient”

),

comprising administering to the ApoE4 non-carrier patient bapineuzumab in a regime effective to reduce the brain volume decline of the ApoE4 non-carrier patient relative to a control patient to whom the bapineuzumab is not administered;

wherein the ApoE4 non-carrier patient and control patient have been diagnosed with mild to moderate Alzheimer'"'"'s disease; and

,

wherein a dosage of the antibody within a range of about 0.15 mg/kg to about 2 mg/kg is administered by intravenous infusion.

27. The method of claim 23, wherein the brain volume decline is measured by MRI.

24-26. -26. (canceled)

28. A method of treating Alzheimer'"'"'s disease, comprising subcutaneously administering to a patient having the disease and one or two copies of an ApoE4 allele an effective regime of bapineuzumab at a dose of 0.01-0.6 mg/kg and a frequency of between weekly and monthly.

29. The method of claim 28 further comprising monitoring for vasogenic edema.

30-33. -33. (canceled)

34. A method of treating Alzheimer'"'"'s disease, comprising

administering to a patient having the disease and one or two ApoE4 alleles an effective regime of bapineuzumab;

and

administering a corticosteroid to the patient to treat vasogenic edema arising from the administration of the bapineuzumab.

36. The method of claim 34, wherein the dose or frequency of administration of the antibody is reduced or eliminated during the vasogenic edema relative to the dose or frequency before the vasogenic edema.

37. The method of claim 36, wherein the dose or frequency of administration of the antibody is increased after resolution of the vasogenic edema relative to the dose or frequency either before or during the vasogenic edema.

35. (canceled)

38. A method of treating or effecting prophylaxis in a population of patients of an amyloidogenic disease characterized by amyloid deposits of Aβ

in the brain, comprising;

administering different regimes to different patients in the population depending on which allelic forms of ApoE are present in the patients;

wherein at least one of the regimes comprises administering an antibody to Aβ

to a patient.

39. The method of claim 38, wherein a first regime comprises administering an antibody to Aβ

to a patient and a second regime lacks an antibody to Aβ

or an agent that induces an antibody to Aβ and

the first regime is administered to patients having zero copies of an ApoE4 allele and the second regime is administered to patients having one or two copies of an ApoE4 allele.

40. The method of claim 38, wherein the different regimes comprise first and second regimes each comprises administering an antibody to Aβ

; and

the second regime differs from the first regime in at least one of (i)-(vi) below;

(i) the dose of the antibody is reduced;

(ii) the frequency of administration of the antibody is reduced;

(iii) the capacity of the antibody to induce a clearing response to amyloid deposits is reduced;

(iv) the mean serum concentration of the antibody is reduced;

(v) the maximum serum concentration of the antibody is reduced;

(vi) the time of initiation of treatment relative to disease progression is earlier;

whereby the first and second regimes are administered such that at least one of (a), (b) and (c) occurs;

(a) the second regime is administered in patients having two copies of an ApoE4 allele and the first regime in patients having zero copies of an ApoE4 allele;

(b) the second regime is administered in patients having one copy of an ApoE4 allele and the first regime in patients having zero copies of an ApoE4 allele; and

/or

(c) the second regime is administered in patients having two copies of an ApoE4 allele and the first regime is administered to patients having one copy of an ApoE4 allele.

41. The method of claim 40, wherein a first regime comprises administering a first antibody to Aβ

and the second regime comprises administering a second antibody to Aβ and

the second antibody has reduced binding to an Fcγ

receptor and/or C1q relative to the first antibody, and the first antibody is administered to patients having zero copies of an ApoE4 allele and the second antibody is administered to patients having one or two copies of an ApoE4 allele.

42. The method of claim 41, wherein the second antibody has one or more mutations in the constant region that reduce binding to the Fcγ

receptor and/or C1 q, the mutations not being present in the first antibody.

43. The method of claim 42, wherein the one or more mutations is/are at position(s) in a heavy chain constant region selected from the group consisting of positions 234, 235, 236 and 237 (EU numbering).

44. The method of claim 43, wherein the one or more mutations are mutations at positions 234, 235 and 237.

45. The method of claim 44, wherein the one or more mutations are L234A, L235A and G237A.

47. The method of any of claims 42-45, wherein the isotype of the constant region is human IgG4.

48. The method of claim 41, wherein the first antibody is bapineuzumab and the second antibody is an L234A, L235A, G237A variant of bapineuzumab.

51. The method of claim 38 or, further comprising determining which alleles of ApoE are present in the patient.

55. The method of claim 38, wherein the dose of the antibody and/or the frequency of administration of the antibody and/or the capacity of the antibody to induce a clearing response to amyloid deposits is reduced in (a) patients having two ApoE4 alleles relative to patients having one ApoE4 allele;

and/or (b) patients having one copy of an ApoE4 allele relative to patients having zero copies of an ApoE4 allele, and/or (c) patients having two copies of an ApoE4 allele relative to patients having one copy of an ApoE4 allele.

57. The method of claim 38, wherein patients in the population having one or two ApoE4 alleles are administered a dose of 0.15-1 mg/kg, and patients in the population having zero ApoE4 alleles are administered a dose of 0.5-2 mg/kg of an antibody specifically binding within residues 1-11 of Aβ

.

60. The method of claim 38, wherein the patients in the population having one or two ApoE4 alleles are administered an antibody with reduced capacity to induce a clearing response to amyloid deposits relative to bapineuzumab.

61. The method of claim 38, further comprising monitoring at least some of the patients in the population for vasogenic edema.

64. The method of claim 38, wherein the antibody binds to an epitope within residues 1-11 of Aβ

.

69. The method of claim 38, wherein patients with one or two ApoE4 alleles are administered 1-3 doses of humanized 266 antibody following by subsequent doses of bapineuzumab and patients with zero ApoE4 alleles are administered the same total number of doses but all with bapineuzumab.

70. The method of claim 38, wherein patients with one or two ApoE4 alleles are administered humanized 266 antibody and patients with zero ApoE4 alleles are administered bapineuzumab.

46. (canceled)

49-50. -50. (canceled)

52-54. -54. (canceled)

56. (canceled)

58-59. -59. (canceled)

62-63. -63. (canceled)

65-68. -68. (canceled)

71-74. -74. (canceled)

75. A method of monitoring a population of patients undergoing treatment or prophylaxis for Alzheimer'"'"'s disease with an antibody to Aβ

, the method comprising;

performing different monitoring regimes in different patients in the population for vasogenic edema, wherein the frequency of monitoring is greater for;

(a) patients having two copies of ApoE4 relative to patients having zero copies of ApoE4;

(b) patients having one copy of an ApoE4 allele relative to patients having zero copies of an ApoE4 allele; and

/or

(c) patients having two copies of an ApoE4 allele relative to patients having one copy of an ApoE4 allele.

76-84. -84. (canceled)

85. A method of treating or effecting prophylaxis of a patient for Alzheimer'"'"'s disease, comprising

administering to a patient with at least one ApoE4 allele a humanized form of a mouse 3D6 antibody (ATCC accession number PTA-5130), and positions 234, 235 and 237 in the heavy chain constant region are occupied by Ala, Ala and Ala respectively, wherein positions are numbered by the EU numbering system, and

monitoring the patient for vasogenic edema by MRI.

88. The method of claim 85, wherein the antibody is an L234A, L235A, G237A variant of bapineuzumab comprising a humanized light chain having an amino acid sequence comprising SEQ ID NO:

48 and a humanized heavy chain having an amino acid sequence comprising SEQ ID NO;

66 or 67.

86-87. -87. (canceled)

89-96. -96. (canceled)

97. A method of treating or effecting prophylaxis of Alzheimer'"'"'s disease in a patient, comprising

administering an antibody to the patient in a regime in which 0.15-2 mg/kg of antibody is administered quarterly by intravenous administration, or at a dose frequency and route of administration that generates an equivalent average serum concentration or area under the curve, wherein the antibody is an L234A, L235A, G237A variant of bapineuzumab comprising a humanized light chain having an amino acid sequence comprising SEQ ID NO:

48 and a humanized heavy chain having an amino acid sequence comprising SEQ ID NO;

66 or 67.

98-105. -105. (canceled)

106. A method of treating or effecting prophylaxis of Alzheimer'"'"'s disease in a population of patients, comprising

administering an antibody that specifically binds to an epitope within residues 1-11 of Aβ

to the patients, wherein the antibody is administered at a dose of 0.15-1 mg/kg in patients of the population having one or two ApoE4 alleles and a dose of 0.5-2.5 mg/kg in patients of the population having zero ApoE4 alleles, and the mean dose is higher in the patients having zero ApoE4 alleles.

107. The method of claim 106, wherein the antibody is a humanized form of a mouse 3D6 antibody (ATCC accession number PTA-5130), and positions 234, 235 and 237 in the heavy chain constant region are occupied by Ala, Ala and Ala respectively, wherein positions are numbered by the EU numbering system.

108. The method of claim 106, wherein the antibody is bapineuzumab.

109. The method of claim 106, wherein the antibody is an L234A, L235A, G237A variant of bapineuzumab comprising a humanized light chain having an amino acid sequence comprising SEQ ID NO:

48 and a humanized heavy chain having an amino acid sequence comprising SEQ ID NO;

66 or 67.

110. The method of claim 106, wherein the dose is 0.5 mg/kg in patients of the population having one or two ApoE4 alleles and 2 mg/kg in patients of the population having zero ApoE4 alleles.

111. A method of effecting prophylaxis of Alzheimer'"'"'s disease in a patient comprising

administering an effective regime of an agent that is an antibody to Aβ

or an agent that induces an antibody to Aβ

on administration to a patient, wherein the patient has at least one ApoE4 allele, wherein the patient has a mini-mental test score of 27 or higher.

112-117. -117. (canceled)

118. A method of treating or effecting prophylaxis of a disease characterized by amyloid deposits of Aβ

in the brain in a patient comprising

administering a first regime and a second regime each comprises administering an antibody to Aβ

to the patient;

monitoring the patient for vasogenic edema;

maintaining the first regime if vasogenic edema does not appear; and

administering a second regime to the patient if vasogenic edema does appear,

wherein the second regime differs relative to the first regime in at least one of (i)-(v) below;

(i) the dose of the antibody is reduced;

(ii) the frequency of administration of the antibody is reduced;

(iii) a different antibody with reduced capacity to bind an Fcγ

receptor;

(iv) a different antibody with reduced capacity to bind C1q;

(v) the antibody to Aβ

is not administered;

wherein the second regime is maintained at least for the duration of the vasogenic edema.

120. The method of claim 118, wherein the first antibody is bapineuzumab and the second antibody is an L234A, L235A, G237A variant of bapineuzumab comprising a humanized light chain having an amino acid sequence comprising SEQ ID NO:

48 and a humanized heavy chain having an amino acid sequence comprising SEQ ID NO;

66 or 67.

119. (canceled)

121. A method of treating or effecting prophylaxis of Alzheimer'"'"'s disease in a patient population, comprising

administering an antibody that specifically binds to an epitope within residues 1-11 of Aβ

and has mutations in the constant region that reduce binding to an Fcγ

receptor and/or C1q to the patient, wherein the antibody is administered at the same dose and/or frequency to each patient regardless of the number of ApoE4 alleles in the patient.

122. The method of claim 121, wherein the antibody is an L234A, L235A, and G237A variant of bapineuzumab comprising a humanized light chain having an amino acid sequence comprising SEQ ID NO:

48 and a humanized heavy chain having an amino acid sequence comprising SEQ ID NO;

66 or 67.

123. (canceled)

124. A method of treating or effecting prophylaxis of Alzheimer'"'"'s disease in a patient population, comprising

administering an antibody to Aβ

to some of the patients in the population, wherein patients in the population having zero ApoE4 alleles receive the antibody and patients in the population having one or two ApoE4 alleles do not receive the antibody.

125-127. -127. (canceled)

128. A method of treating or effecting prophylaxis of a disease characterized by Aβ

deposits in the brain of patient comprising administering an effective regime of a humanized antibody to the patient;

wherein the humanized antibody comprises a mature light chain variable region sequence of SEQ ID NO;

2 and a mature heavy chain variable region sequence of SEQ ID NO;

3, and a human heavy chain constant of IgG1 isotype with L234A, L235A, and G237A mutations, wherein position are numbered by the EU numbering system.

129. The method of claim 128, wherein the patient has at least one ApoE4 allele.

131. The method of claim 128, wherein the dose is 0.15-2 mg/kg.

132. The method of claim 128, further comprising monitoring the patient by MRI for vasogenic edema.

130. (canceled)

133. (canceled)

134. A humanized form of a 10D5 antibody (ATCC accession number PTA-5129) comprising a human heavy chain constant region with L234A, L235A and G237A mutations, wherein positions are numbered by the EU numbering system.

135. The humanized antibody of claim 134, comprising a light chain variable region of SEQ ID NO:

8 or SEQ ID NO;

73 and a heavy chain variable region of SEQ ID NO;

9 or SEQ ID NO;

74.

136. (canceled)

137. A humanized form of a 12A11 antibody (ATCC accession number PTA-7271) comprising a human heavy chain constant region with L234A, L235A and G237A mutations, wherein positions are numbered by the EU numbering system.

138. The humanized antibody of claim 137, comprising a light chain variable region of SEQ ID NO:

10 and a heavy chain variable region of SEQ ID NO;

11.

139. (canceled)

140. A humanized form of a 3D6 antibody (ATCC accession number PTA-5130) comprising a human heavy chain constant region with L234A, L235A and G237A mutations, wherein positions are numbered by the EU numbering system.

142. The humanized antibody of claim 140, comprising a humanized light chain having an amino acid sequence comprising SEQ ID NO:

48 and a humanized heavy chain having an amino acid sequence comprising SEQ ID NO;

66 or 67.

141. (canceled)

143. (canceled)

144. An isolated nucleic acid having a sequence comprising SEQ ID NO:

68 provided that residues 1-57 encoding a signal sequence may or may not be present.

145. An isolated humanized antibody comprising a mature light chain variable region sequence of SEQ ID NO:

2 and a mature heavy chain variable region sequence of SEQ ID NO;

3, and a human heavy chain constant region of IgG isotype with L234A, L235A, and G237A mutations, wherein positions are numbered by the EU numbering system.

146. (canceled)

147. An isolated humanized form of a 12B4 antibody, wherein the 12B4 antibody is characterized by a light chain variable region sequence of SEQ ID NO:

31, and heavy chain variable region sequence of SEQ ID NO;

32, and a human heavy chain constant region of IgG isotype with L234A, L235A, and G237A mutations, wherein positions are numbered by the EU numbering system.

148. (canceled)

149. A humanized form of a 266 antibody (ATCC accession number PTA-6123) comprising a human heavy chain constant region with L234A, L235A and G237A mutations, wherein positions are numbered by the EU numbering system.

150. The humanized antibody of claim 149, comprising a light chain variable region of SEQ ID NO:

33 and a heavy chain variable region of SEQ ID NO;

34.

151. (canceled)

152. An isolated antibody comprising a human heavy chain constant region of isotype IgG1, wherein amino acids at positions 234, 235, and 237 (EU numbering) are each alanine.

153. The antibody of claim 152, wherein no other amino acid from positions 230-240 or 315-325 in the human heavy chain constant region is occupied by an amino acid not naturally found at that position in a human IgG1 constant region.

154. The antibody of claim 153, wherein no amino acid in the human heavy chain constant region other than positions 234, 235 and 237 is occupied by an amino acid not naturally found at that position in a human IgG1 constant region.

155. The antibody of claim 152, wherein the human heavy chain constant region comprise CH1, hinge, CH2 and CH3 regions.

156. The antibody of claim 152, wherein the human heavy chain constant region has an amino acid sequence comprising SEQ ID NO:

66 or SEQ ID NO;

67 or an allotype of either of these sequences.

158. The isolated antibody of claim 152 that is a fully human antibody.

159. The isolated antibody of claim 152 that is a humanized antibody.

157. (canceled)

160. (canceled)

161. A method of determining a regime for bapineuzumab administration comprising providing instructions to a healthcare professional that assists the healthcare professional determine a regime of bapineuzumab to administer to a patient having zero copies of an ApoE4 allele, wherein the regime is characterized by administering 0.5-2 mg/kg of bapineuzumab quarterly by intravenous administration, further comprising monitoring the patient for vasogenic edema.

171. The method of claim 161 or claim 166, further comprises providing bapineuzumab to a healthcare professional in combination with the instructions.

162-165. -165. (canceled)

166. A method of determining a regime for bapineuzumab administration comprising providing instructions to a healthcare professional that assists the healthcare professional determine a regime of bapineuzumab to administer to a patient having one or two copies of an ApoE4 allele, wherein the instructions specify a regime is characterized by administering bapineuzumab at a dose of 0.15-1 mg/kg quarterly by intravenous administration, or at a dose frequency and route of administration and further comprising monitoring the patient for vasogenic edema.

167-170. -170. (canceled)

172-177. -177. (canceled)

178. A kit for bapineuzumab administration comprising instructions to a healthcare professional that assist the healthcare professional determine which regime of bapineuzumab to administer to a patient having zero, one or two copies of an ApoE4 allele.

182. The kit of claim 178, wherein the instructions specify that the regime is different for a patient having one or two copies of an ApoE4 allele.

179-181. -181. (canceled)

183-193. -193. (canceled)

194. A method for improving the safety of bapineuzumab in patients having one or two ApoE4 alleles, comprising advising the physician to administer a lower dose of bapineuzumab to a patient having one or two ApoE alleles relative to that of a patient having zero ApoE alleles.

195. A method for improving the safety of bapineuzumab in patients having one or two ApoE4 alleles, comprising advising the physician to monitor the patient by MRI more frequently than a patient having one or two ApoE alleles relative to that of a patient having zero ApoE alleles.