Immunotherapy Regimes Dependent On APOE Status

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.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]Provisional U.S. Application Nos. 60 / 999,423 and 61 / 083,827, filed Oct. 17, 2007 and Jul. 25, 2008, respectively, are incorporated by reference in their entirety for all purposes.REFERENCE TO A SEQUENCE LISTING[0002]The Substitute Sequence Listing written in file Sequence_Listing_for—15270C-000420US.txt is 164,721 bytes and was created on Oct. 14, 2008 for the instant application. The information contained in this file is hereby incorporated by reference.BACKGROUND OF THE INVENTIONI. General[0003]Alzheimer's disease (AD) is a progressive disease resulting in senile dementia. See generally Selkoe, TINS 16:403 (1993); Hardy et al., WO 92 / 13069; Selkoe, J. Neuropathol. Exp. Neurol. 53:438 (1994); Duff et al., Nature 373:476 (1995); Games et al., Nature 373:523 (1995). Broadly speaking, the disease falls into two categories: late onset, which occurs in old age (65+ years) and early onset, which develops well before the senile period, i.e., bet...

AI Technical Summary

Benefits of technology

[0009]The invention also provides 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 an antibody that specifically binds to an N-terminal epitope of Aβ in a regime effective to reduce the brain volume decline of the ApoE4 non-carrier patient relative to a control patient to whom the antibody is not administered; wherein the ApoE4 non-carrier patient and control patient have been diagnosed with mild to moderate Alzheimer's disease. Optionally, the antibody is administered by intravenous infusion at a dosage within a range of about 0.15 mg / kg to about 2 mg / kg. Optionally, the antibody is bapineuzumab. Optionally, the dosage is about 0.5 mg / kg. Optionally, the dosage is about 2 mg / kg. Optionally, the brain volume decline is measured by MRI.

[0018]Optionally, the dose of the agent and / or the frequency of administration of the agent and / or the capacity of the agent 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. Optionally, the dose of the agent and / or the frequency of administration of the agent and / or the capacity of the agent to induce a clearing response to amyloid deposits is reduced in patients having one or two ApoE4 alleles relative to patients having zero ApoE4 alleles of an ApoE4 allele. Optionally, 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. Optionally, the patients in the population having one or two ApoE4 alleles are administered a lower dosage of agent than patients having zero ApoE4 alleles until vasogenic edema has appeared and resolved, and the same dosage of agent thereafter.

[0029]The invention further provides a method of selecting a regime for treatment or prophylaxis of a disease characterized by amyloid deposits in the brain of a patient, the method comprising determining the number of ApoE4 alleles present in a patient; selecting from different regimes based on the number of ApoE4 alleles present, wherein the different regimes each comprise administering an agent that is an antibody to Aβ or an agent that induces an antibody to Aβ on administration to a patient, and the dose of the agent and / or the frequency of administration of the agent and / or the capacity of the agent to induce a clearing response to amyloid deposits and / or the mean serum concentration of the agent or antibodies induced by the agent and / or the maximum serum concentration of the agent or antibodies induced by the agent is reduced and / or the time of initiation of treatment relative to disease progression is earlier in (a) patients having two copies of an ApoE4 allele relative to patients having zero copies of an 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.

[0031]The invention further provides a use of at least one agent that is an antibody to Aβ or an agent that induces an antibody to Aβ on administration to a patient in the manufacture of a medicament for the treatment or prophylaxis of a disease characterized by amyloid deposits in the brain of a patient by different regimes depending on the number of ApoE4 alleles in the patient, wherein the different regimes comprise administering an agent to a patient and the dose of the agent and / or the frequency of administration of the agent and / or the capacity of the agent to induce a clearing response to amyloid deposits and / or the mean serum concentration of the agent or antibodies induced by the agent and / or the maximum serum concentration of the agent or antibodies induced by the agent is reduced and / or the time of initiation of treatment relative to disease progression is earlier in (a) patients having two copies of an ApoE4 allele relative to patients having zero copies of an 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.

[0048]The invention further provides 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.

Problems solved by technology

Accumulation of amyloid plaques in the brain eventually leads to neuronal cell death.

Nonetheless, even persons with two E4 alleles do not always get Alzheimer's disease.

Genetic screening for E4 has not been routinely performed, because it has not been known how to use this information for a therapeutic regime.

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