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AssigneeSanquin IP B.V.
InventorsJohannes Jacobus VOORBERG, Nuno Alexandre GOMES GRAÇA, Bogaç ERÇIG
Estimating the term…
The invention relates to ADAMTS13 protein variants comprising residues 1 to 685 of ADAMTS13 and wherein one or more N-linked glycosylation sites are added as compared to wild-type ADAMTS13 and/or one or more existing N-linked glycosylation sites are shifted as compared to wild-type ADAMTS13. The invention further relates to compositions comprising such ADAMTS13 variants, methods for their preparation and uses thereof, in particular as an antithrombotic agent, and in the treatment of thrombotic disease, thrombotic microangiopathy, thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), ischemic stroke, systemic thrombosis, COVID19, antiphospholipid syndrome, pre-eclampsia/HELLP syndrome, sepsis and sickle cell disease.
An ADAMTS13 protein variant comprising residues 1 to 685 of ADAMTS13 and wherein one or more N-linked glycosylation sites are added as compared to wild-type ADAMTS13 and/or one or more existing N-linked glycosylation sites are shifted as compared to wild-type ADAMTS13 in a spacer domain comprising amino acid residues S556 to A685 of ADAMTS13 as shown in FIG. 1.
The ADAMTS13 protein variant according to p 1 or 2, wherein one or more N-linked glycosylation sites are added as compared to wild-type ADAMTS13 and/or one or more existing N-linked glycosylation sites are shifted in part of the spacer domain comprising residues R568 to R670 of the ADAMTS13 sequence, as shown in FIG. 1.
The ADAMTS13 protein variant according to any one of the preceding claims, comprising an N-linked glycosylation site at an amino acid residue of ADAMTS13 as shown in FIG. 1 selected from the group consisting of residues 568, 591, 608, 609, 636, 637, 665, 668 and combinations thereof.
The ADAMTS13 protein variant according to any one of the preceding claims, comprising an N-linked glycosylation site at an amino acid residue of ADAMTS13 as shown in FIG. 1 selected from the group consisting of residues 608, 609, 665 and combinations thereof.
The ADAMTS13 protein variant according to any one of the preceding claims, comprising an N-linked glycosylation site at amino acid residue 608 of ADAMTS13 as shown in FIG. 1.
The ADAMTS13 protein variant according to any one of the preceding claims, having proteolytic activity against Von Willebrand Factor (VWF) that is at least 10% of the proteolytic activity against VWF of wildtype ADAMTS13 protein.
The ADAMTS13 protein variant according to any one of the preceding claims comprising an N-linked glycosylation site comprising an amino acid residue selected from the group consisting of R568, L591, V604, V605, A606, G607, K608, M609, R636, L637, P638, R639, Y665, L668 and combinations thereof, preferably comprising a mutation selected from the group consisting of R568N, L591N, V604N, V605N, A606N, G607N, K608N, M609N, R636N, L637N, P638N, R639N, Y665N, L668N and combinations thereof.
The ADAMTS13 protein variant according to any one of the preceding claims, comprising a mutation selected from the group consisting of 568REY570 to 568NET570 (NGLY1), 591LFT593 to 591NFT593 (NGLY2), 608KMSI611 to 608NMSI611 (NGLY3), 608KMSI611 to 608KNST611 (NGLY4), 636RLPR639 to 636NLSR639 (NGLY5), 636RLPL639 to 636RNAS639 (NGLY6), 665YGNL668 to 665NVTL668 (NGLY7), 667NLTRP671 to 667LNVTA671 (NGLY8), and combinations thereof.
The ADAMTS13 protein variant according to any one of the preceding claims comprising a mutation selected from the group consisting of 608KMSI611 to 608NMS1611 (NGLY3), 608KMSI611 to 608KNST611 (NGLY4) and 665YGNL668 to 665NVTL668 (NGLY7).
The ADAMTS13 protein variant according to any one of the preceding claims comprising mutation 608KMSI611 to 608NMSI611 (NGLY3).
The ADAMTS13 protein variant according to any one of the preceding claims further comprising a further mutation at one or more amino acid residues.
The ADAMTS13 protein variant according to any one of the preceding claims further comprising a mutation at an amino acid residue selected from the group consisting of R568, L591, F592, R636, L637, L668, L591, F592, R636, L637, R660, Y661, Y665. L668 and combinations thereof.
The ADAMTS13 protein variant according to any one of the preceding claims comprising a mutation selected from the group consisting of R568K, R568A, R568N, L591A, F592Y, F592A, F592N, R636A, L637A, R660K, R660A, R660N, Y661F, Y661A, Y661N, Y665F, Y665A, Y665N, L668A and combinations thereof.
The ADAMTS13 protein variant according to any one of the preceding claims comprising mutations R568A and Y665A or mutations L591A, R636A, L637A, and L668A.
The ADAMTS13 protein variant according to any one of the preceding claims comprising an N-glycan at said one or more N-linked glycosylation sites that are added and/or wherein said one or more existing N-linked glycosylation sites that are shifted comprise an N-linked glycan.
Dependencies are inferred from the claim text.