US 9,310,383 B2Granted

Antibodies, kit and method for detecting amyloid beta oligomers

AssigneesAcumen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp.

InventorsWilliam F. Goure, Renee C. Gaspar, Alexander McCampbell, Mary J. Savage, Paul J. Shughrue, Fubao Wang, Weirong Wang, Abigail L. Wolfe, Ningyan Zhang, Wei-Qin Zhao, Min Xu

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Abstract

This invention is a selective Aβ oligomer kit and immunoassay method capable of reliably and sensitively detecting Aβ oligomers in a biological sample of a patient. In one embodiment the inventive assay uses a pair of anti-Aβ oligomer antibodies, as capture and detection antibodies, to detect and quantify Aβ oligomers. The method can be used to differentiate Alzheimer's disease (AD) patients from non-AD patients and/or to stratify AD patients according to the severity of their disease.

Claims8

Dependent claims

A kit comprising:

(a) an isolated antibody, or antigen binding fragment thereof, having:
a light chain variable region comprising,
(i) a CDR1 having the sequence Arg-Ser-Ser-Gln-Ser-Ile-Val-His-Ser-Xaa1-Gly-Xaa2-Thr-Tyr-Leu-Glu (SEQ ID NO:1), wherein Xaa1 is Asn, Ser, Thr, Ala, Asp or Glu and Xaa2 is Asn, His, Gln, Ser, Thr, Ala, or Asp,
(ii) a CDR2 having the sequence Lys-Ala-Ser-Xaa1-Arg-Phe-Ser (SEQ ID NO:2), wherein Xaa1 is Asn, Gln, Ser, Thr, or Ala, and
(iii) a CDR3 having the sequence Phe-Gln-Gly-Ser-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5 (SEQ ID NO:3), wherein Xaa1 is Arg, Lys or Tyr, Xaa2 is Val or Ala, Xaa3 is Pro or His, Xaa4 is Ala, Pro, or Val, and Xaa5 is Ser, Gly, Arg or Phe;
and
a heavy chain variable region comprising,
(i) a CDR1 of SEQ ID NO:4,
(ii) a CDR2 of SEQ ID NO:5, and
(iii) a CDR3 of SEQ ID NO:6;
or
a light chain variable region comprising,
(i) a CDR1 having the sequence Arg-Ser-Ser-Gln-Ser-Ile-Val-His-Ser-Xaa1-Gly-Xaa2-Thr-Tyr-Leu-Glu (SEQ ID NO:1), wherein Xaa1 is Ser, Thr, Ala, Asp or Glu and Xaa2 is Asn, His, Gln, Ser, Thr, Ala, or Asp,
(ii) a CDR2 having the sequence Lys-Ala-Ser-Xaa1-Arg-Phe-Ser (SEQ ID NO:2), wherein Xaa1 is Asn, Gln, Ser, Thr, or Ala, and
(iii) a CDR3 of SEQ ID NO:16;
and
a heavy chain variable region comprising,
(i) a CDR1 of SEQ ID NO:4,
(ii) a CDR2 of SEQ ID NO:5, and
(iii) a CDR3 of SEQ ID NO:6;
and
(b) an antibody selected from the group consisting of 6E10, BAM-10, W0-2, 26D6, 2A10, 2B4, 4C2, 4E2, 2H4, 20C2, 2D6, 5F10, 1F4, 1F6, 2E12, 3B3 or 82E1 wherein the selected antibody is detectably labeled.

19 more elements

A method for detecting oligomers of amyloid beta comprising:

(a) obtaining a biological sample having oligomers of amyloid beta from an animal;
(b) contacting said biological sample with an isolated antibody, or antigen binding fragment thereof, comprising:
a light chain variable region comprising,
(i) a CDR1 having the sequence Arg-Ser-Ser-Gln-Ser-Ile-Val-His-Ser-Xaa1-Gly-Xaa2-Thr-Tyr-Leu-Glu (SEQ ID NO:1), wherein Xaa1 is Asn, Ser, Thr, Ala, Asp or Glu and Xaa2 is Asn, His, Gln, Ser, Thr, Ala, or Asp,
(ii) a CDR2 having the sequence Lys-Ala-Ser-Xaa1-Arg-Phe-Ser (SEQ ID NO:2), wherein Xaa1 is Asn, Gln, Ser, Thr, or Ala, and
(iii) a CDR3 having the sequence Phe-Gln-Gly-Ser-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5 (SEQ ID NO:3), wherein Xaa1 is Arg, Lys or Tyr, Xaa2 is Val or Ala, Xaa3 is Pro or His, Xaa4 is Ala, Pro, or Val, and Xaa5 is Ser, Gly, Arg or Phe;
and
a heavy chain variable region comprising,
(i) a CDR1 of SEQ ID NO:4,
(ii) a CDR2 of SEQ ID NO:5, and
(iii) a CDR3 of SEQ ID NO:6;
or
a light chain variable region comprising,
(i) a CDR1 having the sequence Arg-Ser-Ser-Gln-Ser-Ile-Val-His-Ser-Xaa1-Gly-Xaa2-Thr-Tyr-Leu-Glu (SEQ ID NO:1), wherein Xaa1 is Ser, Thr, Ala, Asp or Glu and Xaa2 is Asn, His, Gln, Ser, Thr, Ala, or Asp,
(ii) a CDR2 having the sequence Lys-Ala-Ser-Xaa1-Arg-Phe-Ser (SEQ ID NO:2), wherein Xaa1 is Asn, Gln, Ser, Thr, or Ala, and
(iii) a CDR3 of SEQ ID NO:16;
and
a heavy chain variable region comprising,
(i) a CDR1 of SEQ ID NO:4,
(ii) a CDR2 of SEQ ID NO:5, and
(iii) a CDR3 of SEQ ID NO:6
under conditions sufficient to form a capture antibody/oligomer of amyloid beta complex;
(c) contacting the complex of step (b) with a detection antibody selected from the group consisting of 6E10, BAM-10, W0-2, 26D6, 2A10, 2B4, 4C2, 4E2, 2H4, 20C2, 2D6, 5F10, 1F4, 1F6, 2E12, 3B3 or 82E1, under conditions sufficient to form capture antibody/oligomer of amyloid beta/detection antibody complex, wherein the detection antibody recognizes an N-terminal linear epitope of amyloid beta 1-42 peptide;
and
(d) detecting the complex of step (c).

22 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/729,343Filed 3 Jun 2015 · continuation
Priority: 14 Jul 2010
Published: US 2015/0260731 A117 Sep 2015
Granted: 12 Apr 2016
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

G01N 33/6896
Related to diseases not provided for elsewhere: neurological disorders, e.g. Alzheimer's disease
C07K 16/18
Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies: against material from animals or humans
C07K 2317/24
Characterized by taxonomic origin: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
C07K 2317/55
Characterized by immunoglobulin fragments: fab or Fab'

Family

Application61/364,210Us provisional application · filed 14 Jul 2010
PCT/US2011/043866Parent of this continuation-in-part · filed 13 Jul 2011
Application61/507,332Us provisional application · filed 13 Jul 2011
Application13/544,600Parent of this continuation · filed 9 Jul 2012
US 2015/0260731 A1Pre-grant publication · published 17 Sep 2015
Application13/544,600Parent of this continuation-in-part
US 2013/0130288 A1Published application
US 9,176,151 B2Related patent
US 9,310,383 B2This patent

From the US filing history. Foreign family members aren’t listed.