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US 2007/0166311 A1Published application
Monoclonal antibody
AssigneeAC Immune SA
InventorsRuth Greferath, David Hickman, Andreas Muhs, Andrea Pfeifer, Claude Nicolau
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AssigneeAC Immune SA
InventorsRuth Greferath, David Hickman, Andreas Muhs, Andrea Pfeifer, Claude Nicolau
Estimating the term…
The present invention is related to methods and compositions for the therapeutic and diagnostic use in the treatment of diseases and disorders which are caused by or associated with amyloid or amyloid-like proteins including amyloidosis, a group of disorders and abnormalities associated with amyloid protein such as Alzheimer's disease. The present invention provides novel methods and compositions comprising highly specific and highly effective antibodies having the ability to specifically recognize and bind to specific epitopes from a range of β-amyloid proteins. The antibodies enabled by the teaching of the present invention are particularly useful for the treatment of diseases and disorders which are caused by or associated with amyloid or amyloid-like proteins including amyloidosis, a group of diseases and disorders associated with amyloid plaque formation including secondary amyloidosis and age-related amyloidosis including, but not limited to, neurological disorders such as Alzheimer's Disease (AD).
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody, upon co-incubation with amyloid monomeric peptides, particularly β-amyloid monomeric peptides such as, for example, Aβ monomeric peptides 1-39;
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody, upon co-incubation with preformed high molecular polymeric amyloid fibrils or filaments formed by the aggregation of amyloid monomeric peptides, particularly β-amyloid monomeric peptides such as, for example, Aβ monomeric peptides 1-39;
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody, upon co-incubation with amyloid monomeric peptides, particularly β-amyloid monomeric peptides such as, for example, Aβ monomeric peptides 1-39;
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody directly and specifically binds to Aβ fibers by targeting an epitopic region of the Aβ polypeptide confined by amino acid residues aan-aam with n being an integer between 13 and 15, but especially 14 and m being an integer between 22 and 24, but especially 23, wherein n and m cannot be identical numbers and n must always be a smaller number than m, with the difference between n and m≧2.
A monoclonal antibody, including any functionally equivalent antibody or functional parts thereof according to any of the preceding claims, which recognized the native conformation of amyloid in that it specifically binds to amyloid oligomers and fibers, but not to not linearized amyloid species.
A monoclonal antibody, including any functionally equivalent antibody or functional parts thereof according to any of the preceding claims, which antibody or fragment binds to an Aβ monomer with a binding affinity of at least about 1×10−6 to at least about 1×10−8, particularly of at least about 1×10−6 to at least about 1×10−7, more particularly of at least about 1×10−7 to at least about 1×10−8, even more particularly of at least about 1×10−7 to at least about 4×10−7, but, preferably, does not show any significant cross-reactivity with amyloid precursor protein (APP).
A monoclonal antibody, including any functionally equivalent antibody or functional parts thereof according to any of the preceding claims, which antibody or fragment binds to an Aβ fiber, fibril or filament with a binding affinity of at least about 1×10−7 to at least about 1×10−9, particularly of at least about 1×10−7 to at least about 1×10−8, more particularly of at least about 1×10−8 to at least about 1×10−9, even more particularly of at least about 1×10−8 to at least about 5×10−8, but, preferably does not show any significant cross-reactivity with amyloid precursor protein (APP).
A monoclonal antibody, including any functionally equivalent antibody or functional parts thereof according to of the preceding claims, which antibody or fragment exhibits an binding affinity to an Aβ fiber, fibril or filament which is at least 5 times, particularly at least 10 times, more particularly at least 15 times, higher than the binding affinity to an Aβ monomer.
A monoclonal antibody according to any of the preceding claims including any functionally equivalent antibody or functional parts thereof, which antibody exhibits high specificity to Aβ1-42 monomeric peptides but shows essentially no cross-reactivity to Aβ1-38, Aβ1-39, Aβ1-40, and/or Aβ1-41 monomeric peptides.
A monoclonal antibody according to any of the preceding claims including any functionally equivalent antibody or functional parts thereof which antibody is capable of decreasing the total amount of soluble Aβ in the brain of an animal, particularly a mammal, but especially a human suffering from a disease or condition leading to increased concentrations of soluble Aβ in the brain.
A monoclonal antibody according to any of the preceding claims including any functionally equivalent antibody or functional parts thereof which antibody is capable of disrupting plaques thus decreasing the plaque load in the brain of an animal, particularly a mammal, but especially a human suffering from a disease or condition leading to an increased plaque load in the brain.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody incorporates at least one of the properties selected from the group consisting of aggregation inhibition, disaggregation, induction of conformational transition, recognition of and direct binding to an epitope, particularly a conformational discontinuous epitope in the 14-23, particularly in the 14-20 region, preventing or slowing down the formation of amyloid plaques, decreasing the total amount of soluble Aβ in the brain, decreasing the plaque load in the brain, reducing the amount of plaques in the brain, retaining or increasing cognitive memory capacity, but especially a combination of two or more of said properties.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody recognizes and binds to at least one distinct binding site, particularly to a least two distinct binding sites on the β-amyloid protein wherein the said at least one or said at least two distinct binding sites comprise at least one amino acid residue and at least two consecutive amino acid residues, respectively, predominantly involved in the binding of the antibody, wherein, in a specific embodiment of the invention, the at least one residue constituting the first distinct binding site is Leu and the at least two consecutive amino acid residues, constituting the second distinct binding site, are -Phe-Phe- embedded within the following core sequence:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody recognizes and binds to at least one distinct binding site, particularly to a least two distinct binding sites, more particularly to at least three distinct binding sites on the β-amyloid protein wherein said distinct binding sites comprise at least one and at least two consecutive amino acid residues, respectively, predominantly involved in the binding of the antibody, wherein the at least one and the at least two consecutive amino acids, which are separated by at least one amino acid residue not involved in antibody binding or to a significantly smaller extent as compared to the amino acid residues predominantly involved in the binding of the antibody, are -His- and -Lys-Leu-, respectively, embedded within the following core sequence:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody recognizes and binds to at least one distinct binding site, particularly to a least two distinct binding sites, more particularly to at least three distinct binding sites on the β-amyloid protein wherein said distinct binding sites comprise at least one and at least two consecutive amino acid residues, respectively, predominantly involved in the binding of the antibody, wherein the at least two consecutive amino acid residues representing a first binding site are -Phe-Phe- and the at least one amino acid residue is -His- embedded within the following core sequence:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody recognizes and binds to at least one distinct binding site, particularly to a least two distinct binding sites, more particularly to at least three distinct binding sites on the β-amyloid protein wherein said distinct binding sites comprise at least one and at least two consecutive amino acid residues, respectively, predominantly involved in the binding of the antibody, wherein the first of the at least two consecutive amino acid residues predominantly involved in the binding of the antibody are -Lys- and -Leu-, and the second of the at least two consecutive amino acid residues are -Phe-Phe- embedded within the following core sequence:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody recognizes and binds to at least one distinct binding site, particularly to a least two distinct binding sites, more particularly to at least three distinct binding sites on the β-amyloid protein wherein said distinct binding sites comprise at least one and at least two consecutive amino acid residues, respectively, predominantly involved in the binding of the antibody, wherein the first of the at least two consecutive amino acid residues predominantly involved in the binding of the antibody are -Lys-Leu-, and the second of the at least two consecutive amino acid residues are-Phe-Phe-, and the third at least one amino residue is -His- embedded within the following core sequence:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody recognizes and binds to at least one distinct binding site, particularly to a least two distinct binding sites, more particularly to at least three distinct binding sites on the β-amyloid protein wherein said distinct binding sites comprise at least one and at least two consecutive amino acid residues, respectively, predominantly involved in the binding of the antibody, wherein the first of the at least two consecutive amino acid residues predominantly involved in the binding of the antibody are -Lys-Leu-, and the second of the at least two consecutive amino acid residues are -Phe-Phe-, and the third at least one amino residue is -Asp- embedded within the following core sequence:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody binds to 4 distinct binding sites on the β-amyloid protein wherein said 4 distinct binding sites comprise one amino acid residue and two consecutive amino acid residues, respectively, which residues are predominantly involved in the binding of the antibody, wherein said 4 distinct binding sites are located in close proximity to each other on the antigen, separated by at least one amino acid residue not involved in antibody binding or to a significantly smaller extent as compared to said one amino acid residue and said two consecutive amino acid residues of the 4 distinct binding sites thus forming a conformational discontinuous epitope.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which comprises the Light Chain Variable Region (LCVR) of SEQ ID NO:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which comprises the Heavy Chain Variable Region (HCVR) of SEQ ID NO:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which comprises both the Heavy Chain Variable Region (HCVR) of SEQ ID NO:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof comprising a Light Chain Variable Region (LCVR) or Heavy Chain Variable Region (HCVR) or both, a Light Chain Variable Region (LCVR) and a Heavy Chain Variable Region (HCVR) that is homolgous to any of the peptides provided in SEQ ID NO:
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced by hybridoma cell line FP 12H3, deposited on Dec. 1, 2005 and Dec. 9, 2005, respectively as DSM ACC2752.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced by hybridoma cell line FP 12H3-C2, deposited on Dec. 1, 2005 and Dec. 9, 2005, respectively as DSM ACC2750.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced by hybridoma cell line FP 12H3-G2, deposited on Dec. 1, 2005 and Dec. 9, 2005, respectively as DSM ACC2751.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced by hybridoma cell line ET 7E3, deposited on Dec. 8, 2005 as DSM ACC2755.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced by hybridoma cell line EJ 7H3, deposited on Dec. 8, 2005 as DSM ACC2756.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof produced by hybridoma cell line FP 12H3, deposited on Dec. 1, 2005 and Dec. 9, 2005, respectively as DSM ACC2752 including functional equivalents thereof.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof produced by hybridoma cell line FP 12H3-C2, deposited on Dec. 1, 2005 and Dec. 9, 2005, respectively as DSM ACC2750 including functional equivalents thereof.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof produced by hybridoma cell line FP 12H3-G2, deposited on Dec. 1, 2005 and Dec. 9, 2005, respectively as DSM ACC2751 including functional equivalents thereof.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof produced by hybridoma cell line ET 7E3, deposited on Dec. 8, 2005 as DSM ACC2755 including functional equivalents thereof.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof produced by hybridoma cell line EJ 7H3, deposited on Dec. 8, 2005 as DSM ACC2756 including functional equivalents thereof.
A monoclonal antibody including any functionally equivalent antibody or functional parts thereof, which antibody has been raised against a supramolecular antigenic construct comprising an antigenic peptide corresponding to the amino acid sequence of the β-amyloid peptide, particularly of β-amyloid peptide Aβ1-15, Aβ1-16 and Aβ1-16(Δ14), modified with hydrophobic moieties such as, for example, palmitic acid or a hydrophilic moiety such as, for example, polyethylene glycol (PEG) or a combination of both, wherein said hydrophobic and hydrophilic moiety, respectively, is covalently bound to each terminus through an amino acid such as, for example, lysine or any other suitable amino acid or amino acid analogue capable of serving as a linker molecule.
A polynucleotide comprising a nucleotide sequence encoding a monoclonal antibody including any functionally equivalent antibody or functional parts thereof, comprising
A polynucleotide comprising a nucleotide sequence encoding a monoclonal antibody including any functionally equivalent antibody or functional parts thereof, comprising
A polynucleotide comprising a nucleotide sequence encoding a monoclonal antibody including any functionally equivalent antibody or functional parts thereof, comprising
A polynucleotide comprising a nucleotide sequence encoding a monoclonal antibody including any functionally equivalent antibody or functional parts thereof, comprising
The Light Chain Variable Region (LCVR) of SEQ ID NO:
The Heavy Chain Variable Region (HCVR) of SEQ ID NO:
A polynucleotide encoding the Light Chain Variable Region (LCVR) of SEQ ID NO:
A polynucleotide encoding the Heavy Chain Variable Region (HCVR) of SEQ ID NO:
A hybridoma cell line characterized in that it produces a monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced by hybridoma cell line FP 12H3, deposited on Dec. 1, 2005 as DSM ACC2752.
A hybridoma cell line characterized in that it produces a monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced hybridoma cell line FP 12H3-C2, deposited on Dec. 1, 2005 as DSM ACC2750.
A hybridoma cell line characterized in that it produces a monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced hybridoma cell line FP 12H3-C2, deposited on Dec. 1, 2005 as DSM ACC2751.
A hybridoma cell line characterized in that it produces a monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced hybridoma cell line ET 7E3, deposited on Dec. 8, 2005 as DSM ACC2755.
A hybridoma cell line characterized in that it produces a monoclonal antibody including any functionally equivalent antibody or functional parts thereof which antibody has the characteristic properties of an antibody produced hybridoma cell line EJ 7H3, deposited on Dec. 8, 2005 as DSM ACC2756.
Hybridoma cell line hybridoma cell line FP 12H3, deposited on Dec. 1, 2005 as DSM ACC2752.
Hybridoma cell line hybridoma cell line FP 12H3-C2, deposited on Dec. 1, 2005 as DSM ACC2750.
Hybridoma cell line hybridoma cell line FP 12H3-G2, deposited on Dec. 1, 2005 as DSM ACC2751.
Hybridoma cell line hybridoma cell line ET 7E3, deposited on Dec. 8, 2005 as DSM ACC2755.
Hybridoma cell line hybridoma cell line EJ 7H3, deposited on Dec. 8, 2005 as DSM ACC2756.
Method of diagnosis of an amyloid-associated disease or condition in a patient comprising detecting the immunospecific binding of a monoclonal antibody or an active fragment thereof to an epitope of the amyloid protein in a sample or in situ which includes the steps of
A method for diagnosing a predisposition to an amyloid-associated disease or condition in a patient comprising detecting the immunospecific binding of a monoclonal antibody or an active fragment thereof to an epitope of the amyloid protein in a sample or in situ which includes the steps of
A method for monitoring minimal residual disease in a patient following treatment with an antibody or a vaccine composition according to any one of the preceding claims, wherein said method comprises:
A method for predicting responsiveness of a patient being treated with an antibody or a vaccine composition according to any one of the preceding claims comprising:
Dependencies are inferred from the claim text.