Fixaxfx bispecific antibody with common light chain
AssigneeKymab Limited
InventorsWei WANG, E-Chiang LEE, John Kenneth BLACKWOOD, Roberto MAGLIOZZI
Life of this patent
Estimating the term…
Abstract
Bispecific antigen binding molecules (e.g., antibodies) that bind blood clotting factors, factor IXa (FIXa) and factor X (FX), and enhance the FIXa-catalysed activation of FX to FXa. Use of the bispecific antigen binding molecules to control bleeding, by replacing natural cofactor FVIIIa which is deficient in patients with haemophilia A.
Claims65
Bispecific antibody that binds FIXa and FX and catalyses FIXa-mediated activation of FX, wherein the antibody comprises two immunoglobulin heavy-light chain pairs, wherein
- a first heavy-light chain pair comprises a FIXa binding Fv region comprising a first VH domain paired with a first VL domain, and
- a second heavy-light chain pair comprises a FX binding Fv region comprising a second VH domain paired with a second VL domain, wherein
- the first VH domain comprises a set of HCDRs comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences defined wherein HCDR1 is SEQ ID NO:
- 406, HCDR2 is SEQ ID NO:
- 407 and HCDR3 is SEQ ID NO:
- 408, and/or wherein the first VH domain is at least 95% identical to the N1280H VH domain at the amino acid sequence level;
- the second VH domain is at least 95% identical to the T0201H VH domain SEQ ID NO:
- 470 at the amino acid sequence level, and
- the first VL domain and the second VL domain each comprise a set of LCDRs comprising LCDR1, LCDR2 and LCDR3 with amino acid sequences defined wherein LCDR1 is SEQ ID NO:
- 6, LCDR2 is SEQ ID NO:
- 7 and LCDR3 is SEQ ID NO:
- 8, and/or wherein the first VL domain and the second VL domain are at least 95% identical to the 0128L VL domain SEQ ID NO:
- 10 at the amino acid sequence level.
Bispecific antibody that binds FIXa and FX and catalyses FIXa-mediated activation of FX, wherein the antibody comprises two immunoglobulin heavy-light chain pairs, wherein
- a first heavy-light chain pair comprises a FIXa binding Fv region comprising a first VH domain paired with a first VL domain, and
- a second heavy-light chain pair comprises a FX binding Fv region comprising a second VH domain paired with a second VL domain, wherein
- the first VH domain is a product of recombination of human immunoglobulin heavy chain v, d and j gene segments, wherein the v gene segment is IGHV3-7 (e.g., VH3-7*01) and the j gene segment is IGHJ6 (e.g., JH6*02),
- the second VH domain is a product of recombination of human immunoglobulin heavy chain v, d and j gene segments, wherein the v gene segment is IGHV1-46 (e.g., VH1-46*03) and the j gene segment is IGHJ1 (e.g., JH1*01), and optionally wherein the d gene segment is IGHD6-6 (e.g., DH6-6*01), and
- the first VL domain and the second VL domain are both products of recombination of human immunoglobulin light chain v and j gene segments, wherein the v gene segment is IGLV3-21 (e.g., VL3-21*d01) and the j gene segment is IGLJ2 (e.g., JL2*01) or IGLJ3 (e.g., JL3*02).
Bispecific antibody that binds FIXa and FX and catalyses FIXa-mediated activation of FX, wherein the antibody comprises two immunoglobulin heavy-light chain pairs, wherein
- a first heavy-light chain pair comprises a FIXa binding Fv region comprising a first VH domain paired with a first VL domain, and
- a second heavy-light chain pair comprises a FX binding Fv region comprising a second VH domain paired with a second VL domain, wherein
- the first VH domain has at least 95% amino acid sequence identity with the N1280H VH domain SEQ ID NO:
- 443,
- the second VH domain has at least 95% amino acid sequence identity with the 10201H VH domain SEQ ID NO:
- 470, and
- the first VL domain and the second VL domain each have at least 95% amino acid sequence identity with the 0128L VL domain SEQ ID NO:
- 10.
Bispecific antibody according to any preceding claim, wherein the first VH domain comprises a set of HCDRs comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences defined wherein HCDR1 is SEQ ID NO:
- 406, HCDR2 is SEQ ID NO:
- 407 and HCDR3 is SEQ ID NO:
- 408.
Bispecific antibody according to any preceding claim, wherein the first VH domain has at least 96%, at least 97%, at least 98% or at least 99% amino acid sequence identity to N1280H.
Bispecific antibody according to any preceding claim, wherein the first VH domain comprises a set of N1280H HCDRs comprising N1280H HCDR1 SEQ ID NO:
- 441, N1280H HCDR2 SEQ ID NO:
- 436 and N1280H HCDR3 SEQ ID NO:
- 433.
Bispecific antibody according to any preceding claim, wherein the second VH domain comprises an HCDR1 which is the T0201H HCDR1 SEQ ID NO:
- 462, an HCDR2 which is the T0201H HCDR2 SEQ ID NO:
- 467, and/or an HCDR3 which is the T0201H HCDR3 SEQ ID NO:
- 468.
Bispecific antibody according to any preceding claim wherein the second VH domain comprises HCDR1 SEQ ID NO:
- 636 or SEQ ID NO:
- 598;
- wherein the second VH domain comprises HCDR2 SEQ ID NO:
- 467;
- and/or wherein the second VH domain comprises HCDR3 SEQ ID NO:
- 637, SEQ ID NO:
- 638, SEQ ID NO:
- 639 or SEQ ID NO:
- 565.
Bispecific antibody according to any preceding claim, wherein the second VH domain comprises SEQ ID NO:
- 632.
Bispecific antibody according to any preceding claim, wherein the first VL domain and the second VL domain each have at least 96%, at least 97%, at least 98% or at least 99% amino acid sequence identity with 0128L SEQ ID NO:
- 10.
Bispecific antibody according to any preceding claim, wherein the first VL domain and the second VL domain each comprise a set of 0128L CDRs comprising 0128L LCDR1 SEQ ID NO:
- 6, 0128L LCDR2 SEQ ID NO:
- 7 and 0128L LCDR3 SEQ ID NO:
- 8.
Bispecific antibody according to any preceding claim, wherein the first VL domain and the second VL domain are identical in amino acid sequence.
Bispecific antibody according to any preceding claim, wherein each heavy-light chain pair further comprises a CL constant domain paired with a CH1 domain.
Bispecific antibody according to any preceding claim, wherein the heavy-light chain pairs comprise a common light chain.
Bispecific antibody according to any preceding claim, wherein the heavy chain of each heavy-light chain comprises a heavy chain constant region and wherein the first and second heavy-light chain pairs associate to form tetrameric immunoglobulin through dimerisation of the heavy chain constant regions.
Bispecific antibody that binds FIXa and FX and catalyses FIXa-mediated activation of FX, wherein the antibody comprises two immunoglobulin heavy-light chain pairs, wherein
- a first heavy-light chain pair comprises a FIXa binding Fv region comprising a first VH domain paired with a first VL domain, wherein the first VH domain is at least 98% identical in amino acid sequence to the N1280H VH domain SEQ ID NO:
- 443, and
- a second heavy-light chain pair comprises a FX binding Fv region comprising a second VH domain paired with a second VL domain, wherein the second VH domain is at least 98% identical in amino acid sequence to the 10999H VH domain SEQ ID NO:
- 632, and wherein
- the first and second heavy-light chain pairs each comprise a common light chain comprising the 0325L light chain amino acid sequence SEQ ID NO:
- 414.
Bispecific antibody that binds FIXa and FX and catalyses FIXa-mediated activation of FX, wherein the antibody comprises two immunoglobulin heavy-light chain pairs, wherein
- a first heavy-light chain pair comprises a FIXa binding Fv region comprising a first VH domain paired with a first VL domain, wherein the first VH domain is at least 98% identical in amino acid sequence to the N1441H VH domain SEQ ID NO:
- 456, and
- a second heavy-light chain pair comprises a FX binding Fv region comprising a second VH domain paired with a second VL domain, wherein the second VH domain is at least 98% identical in amino acid sequence to the 10999H VH domain SEQ ID NO:
- 632, and wherein
- the first and second heavy-light chain pairs each comprise a common light chain comprising the 0325L light chain amino acid sequence SEQ ID NO:
- 414.
Bispecific antibody according to any preceding claim, which reduces the coagulation time of FVIII-deficient human blood plasma to 22-28 seconds in an aPTT assay.
Bispecific antibody according to any preceding claim, which enhances the FIXa-mediated activation of FX to FXa to at least the same extent as emicizumab.
Bispecific antibody according to any preceding claim, wherein the antibody has an EC50 for Cmax in a fluorometric thrombin generation assay (TGA) that is within 10% of or is lower than the Cmax EC50 of emicizumab in said assay, and/or wherein the antibody generates a maximal response of Cmax between 200 and 450 nM thrombin in a fluorometric TGA.
Bispecific antibody according to any preceding claim, wherein the maximal response of Cmax is between 250 nM and 400 nM.
Anti-FIXa antibody comprising two copies of the first heavy-light chain pair as defined in any preceding claim.
Isolated nucleic acid encoding an antibody according to any preceding claim.
Dependencies are inferred from the claim text.