Transthyretin (ttr) monomer binding antibodies
AssigneeAdrx, Inc.
InventorsDavid James Leibly, Anna Rose Lay, Marcin Izydor Apostol, Margaret Lee Karow, Tracey Elizabeth Mullen, Colby Amsden Souders
Life of this patent
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Abstract
The disclosure provides antibodies that bind to forms of human transthyretin (TTR), monomer TTR specific antibodies, and methods of using the same.
Claims98
An isolated antibody that binds to human transthyretin (TTR) wherein the antibody:
- (a) binds to human TTR with an EC50 of less than about 200 nM as determined in a sandwich ELISA;
- and/or
- (b) binds to human TTR with a KD of less than about 20 nM as determined in a biolayer interferometry assay.
An antibody that binds to human transthyretin (TTR), the antibody comprising
- a heavy chain variable domain (VH) comprising
- (a) a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs:
- 2-8;
- (b) a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:
- 9-15;
- and
- (c) a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:
- 16-22;
- and
- a light chain variable domain (VL) comprising
- (d) a CDR-L1 comprising the amino acid sequence of any one of SEQ ID NOs:
- 23-29;
- (e) a CDR-L2 comprising the amino acid sequence of any one of SEQ ID NOs:
- 30-36;
- and
- (f) a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs:
- 37-43.
A method of diagnosing a disease associated with transthyretin (TTR) amyloidosis, or monitoring the treatment of the disease with an anti-TTR therapy comprising assaying the level of monomeric TTR in a sample of a body fluid from a subject, wherein the presence or an elevated level of monomeric TTR in the sample of the subject compared to a control indicates the presence of a disease associated with TTR amyloidosis.
A method comprising:
- contacting a sample from a subject with a sample of a bodily fluid from a subject having or suspected of having transthyretin (TTR) amyloidosis;
- and
- detecting or measuring monomeric TTR in the sample.
An isolated antibody which recognizes a conformational epitope on monomeric TTR prepared from F87M L110M TTR that is not present on tetrameric TTR and physiological, cellular full-length TTR.
An isolated antibody which recognizes a TTR mutation selected from any of V30M, D38A and V1221, wherein, the antibody specifically binds TTR comprising the amino acid sequence set forth in any of SEQ ID NOs:
- 145-147.
A method of producing a cell that produces an antibody that specifically binds to a monomeric form of human transthyretin (TTR), the method comprising:
- (a) immunizing a non-human animal with a monomeric form of TTR;
- (b) screening blood or tissue from the animal for an antibody which specifically binds to the monomeric form of human TTR but does not bind to wild-type tetrameric TTR or to a dimeric or tetrameric form of TTR;
- and
- (c) identifying and isolating a cell from the animal that produces the antibody that specifically binds to the monomeric form of human TTR but does not bind to wild-type tetrameric TTR or to a dimeric or tetrameric form of TTR.
A method for producing a monoclonal antibody that specifically binds to a monomeric form of human transthyretin (TTR), said method comprising:
- (a) introducing into a non-human animal at least one of any one of
- TTR F87M L110M comprising the amino acid sequence set forth in SEQ ID NO:
- 80;
- TTR F87M comprising the amino acid sequence set forth in SEQ ID NO:
- 143;
- and
- TTR L110M comprising the amino acid sequence set forth in SEQ ID NO:
- 144;
- (b) recovering antibody-producing cells from the animal and rendering these cells into a single cell suspension;
- (c) generating an immortalized cell line from the single cell suspension;
- (d) screening the supernatant of the immortalized cell line for the presence of an antibody having binding specifically for a monomeric form of human TTR;
- and
- (e) selecting, as the monoclonal antibody, an antibody that specifically binds to the monomeric form of human TTR.
A method comprising:
- (a) assaying a library of molecules for a molecule peptide or polypeptide that:
- (i) binds one or more monomeric TTR peptides having amino acid an amino acid sequence selected from SEQ ID NOs:
- 80 and 143-147 and 149-152;
- and
- (ii) exhibits substantially no binding affinity for a tetrameric human TTR protein having the amino acid sequence of SEQ ID NO:
- 153.
- (b) identifying a molecule that exhibits the binding properties of (i) and (ii);
- and
- (c) isolating the molecule identified in (b), or isolating a cell that expresses said molecules.
Dependencies are inferred from the claim text.