US 2014/0369940 A1 · Anti-Alpha Synuclein Binding Molecules

Abstract

Provided are anti-human α-synuclein-specific binding molecules, e.g., antibodies or antigen-binding fragments, variants or derivatives thereof, as methods related thereto. Further provided are anti-human α-synuclein binding molecules which bind to specific N-terminal and C-terminal epitopes on human α-synuclein. The binding molecules described herein can be used in pharmaceutical and diagnostic compositions for α-synuclein targeted immunotherapy and diagnosis, respectively.

Claims42

Dependent claims

1-81. (canceled)

An isolated binding molecule

(A) which specifically binds to an epitope within amino acids 4 to 15 of human α-synuclein (SEQ ID NO:1);
or
(B) which competitively inhibits the binding of reference monoclonal antibody NI-202.12F4 to α-synuclein;
or
(C) which is not human monoclonal antibody NI-202.12F4, or an antigen-binding fragment, variant, or derivative thereof;
or
(D) which is (A), (B), or (C), and which is an antibody or antigen-binding fragment thereof;
or
(E) which specifically binds to an epitope within amino acids 113 to 123 of α-synuclein (SEQ ID NO:1);
or
(F) which is (E) and which specifically binds to an epitope within amino acids 117 to 123 of SEQ ID NO:1;
or
(G) which specifically binds to the same human α-synuclein epitope as the reference monoclonal antibody NI-202.22D11;
or
(H) which specifically binds to α-synuclein, which competitively inhibits the binding reference monoclonal antibody NI-202.22D11 to human α-synuclein;
or
(I) which is (E), (F), (G), or (H) and which is an antibody, or antigen-binding fragment thereof;
or
(J) which is (I) and which is the human monoclonal antibody NI-202.22D11, or an antigen-binding fragment, variant, or derivative thereof;
or
(K) which is an isolated antibody or antigen binding fragment thereof comprising an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL), wherein the VH comprises a polypeptide sequence at least 90% identical to SEQ ID NO:15 or SEQ ID NO:20, and wherein an antibody or antigen-binding fragment thereof comprising the VH region specifically binds to human α-synuclein (SEQ ID NO:1);
or
(L) which is the antibody or fragment thereof of (K), wherein the VH comprises SEQ ID NO:15 or SEQ ID NO:20;
or
(M) which is an isolated antibody or antigen binding fragment thereof comprising a VH and a VL, wherein the VL comprises a polypeptide sequence at least 90% identical to SEQ ID NO:22 or SEQ ID NO:26, and wherein an antibody or antigen-binding fragment thereof comprising the VH region specifically binds to human α-synuclein (SEQ ID NO:1);
or
(N) which is the antibody or fragment thereof of (M), wherein the VL comprises SEQ ID NO:22 or SEQ ID NO:26;
or
(O) which is an isolated antibody or antigen binding fragment thereof comprising a VH and a VL wherein the VH and VL comprise, respectively, polypeptide sequences at least 90% identical to the reference polypeptides SEQ ID NO:15 and SEQ ID NO:22, SEQ ID NO:15 and SEQ ID NO:26, SEQ ID NO:20 and SEQ ID NO:22, or SEQ ID NO:20 and SEQ ID NO:26, and wherein an antibody or antigen-binding fragment thereof comprising the VH and VL specifically binds to human α-synuclein (SEQ ID NO:1);
or
(P) which is the isolated antibody or antigen binding fragment thereof of (O), wherein the VH and VL comprise, respectively, SEQ ID NO:15 and SEQ ID NO:22, SEQ ID NO:15 and SEQ ID NO:26, SEQ ID NO:20 and SEQ ID NO:22, or SEQ ID NO:20 and SEQ ID NO:26;
or
(Q) an isolated antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof specifically binds to human α-synuclein (SEQ ID NO:1);
or
(R) the antibody or fragment thereof of any one of (D) or (I)-(Q), which specifically binds to human α-synuclein (SEQ ID NO:1), with an affinity characterized by a dissociation constant (KD) no greater than 5×10−2 M, 10−2 M, 5×10−3 M, 10−3 M, 5×10−4 M, 10−4 M, 5×10−5 M, 10−5 M, 5×10−6 M, 10−6 M, 5×10−7 M, 10−7 M, 5×10−8 M, 10−8 M, 5×10−9 M, 10−9 M, 5×10−10 M, 10−10 M, 5×10−11 M, 10−11 M, 5×10−12 M, 10−12 M, 5×10−13 M, 10−13 M, 5×10−14 M, M, 5×10−15 M, or 10−15 M;
or
(S) the antibody or fragment thereof of any one of (D) or (I)-(Q), which preferentially binds to a linear epitope;
or
(T) the antibody or fragment thereof of any one of (D) or (I)-(Q), which preferentially binds to a non-linear conformational epitope;
or
(U) the antibody or fragment thereof of any one of (D) or (I)-(Q), which preferentially binds human α-synuclein in the oligomeric or aggregated form;
or
(V) the antibody or fragment thereof of any one of (D) or (I)-(Q), which does not specifically bind to human β-synuclein (SEQ ID NO:3) or human γ-synuclein (SEQ ID NO:4);
or
(W) the antibody or fragment thereof of any one of (D) or (I)-(Q), which does not specifically bind to murine α-synuclein (SEQ ID NO:2);
or
(X) the antibody or fragment thereof of any one of (D) or (I)-(Q), which specifically binds to an epitope within amino acids 113 to 123 of human α-synuclein (SEQ ID NO:1);
or
(Y) the antibody or fragment thereof of (X), which specifically binds to an epitope within amino acids 117 to 123 of SEQ ID NO:1;
or
(Z) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a signal peptide fused to the VH;
or
(AA) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a signal peptide fused to the VL;
or
(BB) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CHI domain fused to the VH;
or
(CC) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CH2 domain fused to the VH;
or
(DD) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CH3 domain fused to the VH;
or
(EE) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising hinge region fused to the VH;
or
(FF) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CK domain fused to the VL;
or
(GG) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CL domain fused to the VL;
or
(HH) the antibody or antigen-binding fragment thereof of any one of (D) or (I)-(Q), which is humanized;
or
(II) the antibody or antigen-binding fragment thereof of any one of (D) or (I)-(Q), which is chimeric;
or
(JJ) the antibody or antigen-binding fragment thereof of any one of (D) or (I)-(Q), which is fully human;
or
(KK) the antigen-binding fragment of any one of (D) or (I)-(Q), which is an Fab′ fragment;
or
(LL) the antigen-binding fragment of any one of (D) or (I)-(Q), which is an Fab′ fragment;
or
(MM) the antigen-binding fragment of any one of (D) or (I)-(Q), which is an F(ab)2 fragment;
or
(NN) the antigen-binding fragment of any one of (D) or (I)-(Q), which is a single-chain Fv fragment;
or
(OO) the antigen-binding fragment of any one of (D) or (I)-(Q), which is a single chain antibody;
or
(PP) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a heterologous polypeptide fused thereto;
or
(QQ) the antibody or fragment thereof of any one of (D) or (I)-(Q), wherein the antibody is conjugated to an agent selected from the group consisting of a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a virus, a lipid, a biological response modifier, a pharmaceutical agent, and PEG.

82 more elements

An isolated polypeptide comprising

(A) a VH, wherein the CDR1 region of the VH is identical, or identical except for less than 3 conservative amino acid substitutions, to reference heavy chain CDR1 sequence SEQ ID NO:16, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1);
or
(B) a VH, wherein the CDR2 region of the VH is identical, or identical except for less than 5 conservative amino acid substitutions, to reference heavy chain CDR2 sequence SEQ ID NO:17, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1);
or
(C) a VH, wherein the CDR3 region of the VH is identical, or identical except for less than 5 conservative amino acid substitutions, to reference heavy chain CDR3 sequence SEQ ID NO:18, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1);
or
(D) a VL, wherein the CDR1 region of the VL is identical, or identical except for less than 5 conservative amino acid substitutions, to reference light chain CDR1 sequence SEQ ID NO:23, and wherein an antibody or antigen-binding fragment thereof comprising the VL specifically binds to human α-synuclein (SEQ ID NO:1);
or
(E) a VL, wherein the CDR2 region of the VL is identical, or identical except for less than 3 conservative amino acid substitutions, to reference heavy chain CDR2 sequence SEQ ID NO:24, and wherein an antibody or antigen-binding fragment thereof comprising the VL specifically binds to human α-synuclein (SEQ ID NO:1);
or
(F) a VL, wherein the CDR3 region of the VL is identical, or identical except for less than 3 conservative amino acid substitutions, to reference heavy chain CDR3 sequence SEQ ID NO:25, and wherein an antibody or antigen-binding fragment thereof comprising the VL specifically binds to human α-synuclein (SEQ ID NO:1);
or
(G) a VH, wherein the CDR1, CDR2, and CDR3 regions of the VH are identical, respectively, or identical except for less than 20 total conservative amino acid substitutions, to reference heavy chain CDR1, CDR2, and CDR3 sequences SEQ ID NO:15, SEQ ID NO:17, and SEQ ID NO:18, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1);
or
(H) a polypeptide of any one of (A) to (G), further comprising a heterologous polypeptide fused thereto;
or
(I) a polypeptide of any one of (A) to (G), wherein said polypeptide is conjugated to an agent selected from the group consisting of a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a virus, a lipid, a biological response modifier, a pharmaceutical agent, or PEG;
or
(J) a VL, wherein the CDR1, CDR2, and CDR3 regions of the VL are identical respectively, or identical except for less than 20 total conservative amino acid substitutions, to reference light chain CDR1, CDR2, and CDR3 sequences SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1).

16 more elements

Dependencies are inferred from the claim text.

Facts

Application

14/128,497Filed 22 Jun 2012

Priority

23 Jun 2011

Published

18 Dec 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07K 16/18
Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies: against material from animals or humans
A61K 47/6849
The modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site: the antibody targeting a receptor, a cell…
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/16
For treating abnormal movements, e.g. chorea, dyskinesia: anti-Parkinson drugs

Abstract

Claims42

Dependent claims

1-81. (canceled)

An isolated binding molecule

(A) which specifically binds to an epitope within amino acids 4 to 15 of human α-synuclein (SEQ ID NO:1);
or
(B) which competitively inhibits the binding of reference monoclonal antibody NI-202.12F4 to α-synuclein;
or
(C) which is not human monoclonal antibody NI-202.12F4, or an antigen-binding fragment, variant, or derivative thereof;
or
(D) which is (A), (B), or (C), and which is an antibody or antigen-binding fragment thereof;
or
(E) which specifically binds to an epitope within amino acids 113 to 123 of α-synuclein (SEQ ID NO:1);
or
(F) which is (E) and which specifically binds to an epitope within amino acids 117 to 123 of SEQ ID NO:1;
or
(G) which specifically binds to the same human α-synuclein epitope as the reference monoclonal antibody NI-202.22D11;
or
(H) which specifically binds to α-synuclein, which competitively inhibits the binding reference monoclonal antibody NI-202.22D11 to human α-synuclein;
or
(I) which is (E), (F), (G), or (H) and which is an antibody, or antigen-binding fragment thereof;
or
(J) which is (I) and which is the human monoclonal antibody NI-202.22D11, or an antigen-binding fragment, variant, or derivative thereof;
or
(K) which is an isolated antibody or antigen binding fragment thereof comprising an immunoglobulin heavy chain variable region (VH) and an immunoglobulin light chain variable region (VL), wherein the VH comprises a polypeptide sequence at least 90% identical to SEQ ID NO:15 or SEQ ID NO:20, and wherein an antibody or antigen-binding fragment thereof comprising the VH region specifically binds to human α-synuclein (SEQ ID NO:1);
or
(L) which is the antibody or fragment thereof of (K), wherein the VH comprises SEQ ID NO:15 or SEQ ID NO:20;
or
(M) which is an isolated antibody or antigen binding fragment thereof comprising a VH and a VL, wherein the VL comprises a polypeptide sequence at least 90% identical to SEQ ID NO:22 or SEQ ID NO:26, and wherein an antibody or antigen-binding fragment thereof comprising the VH region specifically binds to human α-synuclein (SEQ ID NO:1);
or
(N) which is the antibody or fragment thereof of (M), wherein the VL comprises SEQ ID NO:22 or SEQ ID NO:26;
or
(O) which is an isolated antibody or antigen binding fragment thereof comprising a VH and a VL wherein the VH and VL comprise, respectively, polypeptide sequences at least 90% identical to the reference polypeptides SEQ ID NO:15 and SEQ ID NO:22, SEQ ID NO:15 and SEQ ID NO:26, SEQ ID NO:20 and SEQ ID NO:22, or SEQ ID NO:20 and SEQ ID NO:26, and wherein an antibody or antigen-binding fragment thereof comprising the VH and VL specifically binds to human α-synuclein (SEQ ID NO:1);
or
(P) which is the isolated antibody or antigen binding fragment thereof of (O), wherein the VH and VL comprise, respectively, SEQ ID NO:15 and SEQ ID NO:22, SEQ ID NO:15 and SEQ ID NO:26, SEQ ID NO:20 and SEQ ID NO:22, or SEQ ID NO:20 and SEQ ID NO:26;
or
(Q) an isolated antibody or antigen-binding fragment thereof, wherein the antibody or fragment thereof specifically binds to human α-synuclein (SEQ ID NO:1);
or
(R) the antibody or fragment thereof of any one of (D) or (I)-(Q), which specifically binds to human α-synuclein (SEQ ID NO:1), with an affinity characterized by a dissociation constant (KD) no greater than 5×10−2 M, 10−2 M, 5×10−3 M, 10−3 M, 5×10−4 M, 10−4 M, 5×10−5 M, 10−5 M, 5×10−6 M, 10−6 M, 5×10−7 M, 10−7 M, 5×10−8 M, 10−8 M, 5×10−9 M, 10−9 M, 5×10−10 M, 10−10 M, 5×10−11 M, 10−11 M, 5×10−12 M, 10−12 M, 5×10−13 M, 10−13 M, 5×10−14 M, M, 5×10−15 M, or 10−15 M;
or
(S) the antibody or fragment thereof of any one of (D) or (I)-(Q), which preferentially binds to a linear epitope;
or
(T) the antibody or fragment thereof of any one of (D) or (I)-(Q), which preferentially binds to a non-linear conformational epitope;
or
(U) the antibody or fragment thereof of any one of (D) or (I)-(Q), which preferentially binds human α-synuclein in the oligomeric or aggregated form;
or
(V) the antibody or fragment thereof of any one of (D) or (I)-(Q), which does not specifically bind to human β-synuclein (SEQ ID NO:3) or human γ-synuclein (SEQ ID NO:4);
or
(W) the antibody or fragment thereof of any one of (D) or (I)-(Q), which does not specifically bind to murine α-synuclein (SEQ ID NO:2);
or
(X) the antibody or fragment thereof of any one of (D) or (I)-(Q), which specifically binds to an epitope within amino acids 113 to 123 of human α-synuclein (SEQ ID NO:1);
or
(Y) the antibody or fragment thereof of (X), which specifically binds to an epitope within amino acids 117 to 123 of SEQ ID NO:1;
or
(Z) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a signal peptide fused to the VH;
or
(AA) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a signal peptide fused to the VL;
or
(BB) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CHI domain fused to the VH;
or
(CC) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CH2 domain fused to the VH;
or
(DD) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CH3 domain fused to the VH;
or
(EE) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising hinge region fused to the VH;
or
(FF) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CK domain fused to the VL;
or
(GG) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a CL domain fused to the VL;
or
(HH) the antibody or antigen-binding fragment thereof of any one of (D) or (I)-(Q), which is humanized;
or
(II) the antibody or antigen-binding fragment thereof of any one of (D) or (I)-(Q), which is chimeric;
or
(JJ) the antibody or antigen-binding fragment thereof of any one of (D) or (I)-(Q), which is fully human;
or
(KK) the antigen-binding fragment of any one of (D) or (I)-(Q), which is an Fab′ fragment;
or
(LL) the antigen-binding fragment of any one of (D) or (I)-(Q), which is an Fab′ fragment;
or
(MM) the antigen-binding fragment of any one of (D) or (I)-(Q), which is an F(ab)2 fragment;
or
(NN) the antigen-binding fragment of any one of (D) or (I)-(Q), which is a single-chain Fv fragment;
or
(OO) the antigen-binding fragment of any one of (D) or (I)-(Q), which is a single chain antibody;
or
(PP) the antibody or fragment thereof of any one of (D) or (I)-(Q), further comprising a heterologous polypeptide fused thereto;
or
(QQ) the antibody or fragment thereof of any one of (D) or (I)-(Q), wherein the antibody is conjugated to an agent selected from the group consisting of a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a virus, a lipid, a biological response modifier, a pharmaceutical agent, and PEG.

82 more elements

An isolated polypeptide comprising

(A) a VH, wherein the CDR1 region of the VH is identical, or identical except for less than 3 conservative amino acid substitutions, to reference heavy chain CDR1 sequence SEQ ID NO:16, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1);
or
(B) a VH, wherein the CDR2 region of the VH is identical, or identical except for less than 5 conservative amino acid substitutions, to reference heavy chain CDR2 sequence SEQ ID NO:17, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1);
or
(C) a VH, wherein the CDR3 region of the VH is identical, or identical except for less than 5 conservative amino acid substitutions, to reference heavy chain CDR3 sequence SEQ ID NO:18, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1);
or
(D) a VL, wherein the CDR1 region of the VL is identical, or identical except for less than 5 conservative amino acid substitutions, to reference light chain CDR1 sequence SEQ ID NO:23, and wherein an antibody or antigen-binding fragment thereof comprising the VL specifically binds to human α-synuclein (SEQ ID NO:1);
or
(E) a VL, wherein the CDR2 region of the VL is identical, or identical except for less than 3 conservative amino acid substitutions, to reference heavy chain CDR2 sequence SEQ ID NO:24, and wherein an antibody or antigen-binding fragment thereof comprising the VL specifically binds to human α-synuclein (SEQ ID NO:1);
or
(F) a VL, wherein the CDR3 region of the VL is identical, or identical except for less than 3 conservative amino acid substitutions, to reference heavy chain CDR3 sequence SEQ ID NO:25, and wherein an antibody or antigen-binding fragment thereof comprising the VL specifically binds to human α-synuclein (SEQ ID NO:1);
or
(G) a VH, wherein the CDR1, CDR2, and CDR3 regions of the VH are identical, respectively, or identical except for less than 20 total conservative amino acid substitutions, to reference heavy chain CDR1, CDR2, and CDR3 sequences SEQ ID NO:15, SEQ ID NO:17, and SEQ ID NO:18, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1);
or
(H) a polypeptide of any one of (A) to (G), further comprising a heterologous polypeptide fused thereto;
or
(I) a polypeptide of any one of (A) to (G), wherein said polypeptide is conjugated to an agent selected from the group consisting of a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a virus, a lipid, a biological response modifier, a pharmaceutical agent, or PEG;
or
(J) a VL, wherein the CDR1, CDR2, and CDR3 regions of the VL are identical respectively, or identical except for less than 20 total conservative amino acid substitutions, to reference light chain CDR1, CDR2, and CDR3 sequences SEQ ID NO:23, SEQ ID NO:24, and SEQ ID NO:25, and wherein an antibody or antigen-binding fragment thereof comprising the VH specifically binds to human α-synuclein (SEQ ID NO:1).

16 more elements

Dependencies are inferred from the claim text.

Anti-Alpha Synuclein Binding Molecules

Life of this patent

Abstract

Claims42

Anti-Alpha Synuclein Binding Molecules

Life of this patent

Abstract

Claims42