公开(公告)号：WO2022108452A1

公开(公告)日：2022-05-27

申请号：PCT/NL2021/050714

申请日：2021-11-22

申请人： SYNAFFIX B.V.

发明人： VAN DELFT, Floris Louis ,  BRUINS, Jorick Julian ,  ALBADA, Hendrik Bauke ,  WIJDEVEN, Maria Antonia

IPC分类号： A61K47/68 ,  A61P35/00

摘要： The present invention concerns the finding that that natural N-glycoprotein are not sensitive to oxidative enzymes like tyrosinase or (poly)phenol oxidase, however if the native N-glycan is modified such that the glycoprotein does not contain a glycan longer than two monosaccharide residues within 10 amino acids of a tyrosine residue, that tyrosine residue of the glycoprotein becomes exposed, and susceptible to oxidative enzymes, leading to the formation of ortho-quinone. By performing the enzymatic oxidation in the presence of a strained alkyne or alkene, the resulting ortho-quinone undergoes in situ [4+2] cycloaddition to form conjugates having structure (1a) or (1b): (1a); Pr–[Z1–L–(Q2)x]y or (1b); Pr–[Z1–L–(D)x]y wherein: - Pr is an N-glycoprotein; - Z1 comprises structure (Za) or (Zb): wherein the carbon labelled with * is directly connected to the peptide chain of the antibody at an amino acid located within 10 amino acids of an N-glycosylation site, which has been modified such that the glycoprotein does not contain a glycan longer than two monosaccharide residues within 10 amino acids of the amino acid residue, and both of the carbon atoms labelled with ** are connected to L, and the bond depicted as (I) is a single bond or a double bond; - L is a linker; - x is an integer in the range of 1 – 4; - y is an integer in the range of 1 – 4; - Q2 is a chemical handle that is reactive towards an appropriately functionalized payload; - D is a payload.

公开(公告)号：WO2021144314A1

公开(公告)日：2021-07-22

申请号：PCT/EP2021/050598

申请日：2021-01-13

申请人： SYNAFFIX B.V.

发明人： VAN DELFT, Floris Louis ,  HOOGENBOOM, Jorin ,  POPAL, Sorraya ,  VAN SCHAIK, Arnoldus Jacobus ,  DE BEVER, Laureen ,  VAN GEEL, Remon ,  WIJDEVEN, Maria Antonia ,  VAN BERKEL, Sander Sebastiaan

IPC分类号： A61K47/68 ,  A61K47/64 ,  A61P35/00 ,  A61K47/642 ,  A61K47/6849 ,  A61K47/6855 ,  A61K47/6889 ,  A61K47/6891

摘要： The present invention provides antibody-payload conjugates having a payload-to-antibody ratio of 1. The antibody-payload conjugate is according to structure (1): formula (1), wherein: - a, b, c and d are each independently 0 or 1; - e is an integer in the range of 0 - 10; - L1, L2 and L3 are linkers; - D is a payload; - BM is a branching moiety; - Su is a monosaccharide; - G is a monosaccharide moiety; - GlcNAc is an N-acetylglucosamine moiety; - Fuc is a fucose moiety; - Z are connecting groups. The invention further provides a method for preparing the antibody-payload conjugate according to the invention, an intermediate compound in that preparation method, and medical uses of the antibody-payload conjugate according to the invention.

公开(公告)号：WO2020245229A1

公开(公告)日：2020-12-10

申请号：PCT/EP2020/065395

申请日：2020-06-03

申请人： SYNAFFIX B.V.

IPC分类号： A61K47/68 ,  A61P35/00

摘要： The current invention concerns compounds, such as antibody-conjugates, with an enhanced selectivity of payload release inside a tumour or in the tumour microenvironment versus payload release in circulation or in healthy cells. The enhanced selectivity is achieved by incorporation of a cleavable linker that requires two consecutive mechanisms for release of the payload. The compounds according to the invention have structure (1) or a salt thereof, wherein AB is an antibody or a reactive moiety capable of reacting with a functional group on an antibody, L1 and L2 are linkers, moiety I contains an activating group and an aromatic ring, X is O or N and D is the payload. The invention further concerns application of these compounds in for example a method of targeting a cell and a method for enhancing the bystander effect of an amino-containing payload. The invention also concerns the payloads that may be released from the compounds according to the invention.

公开(公告)号：WO2021260232A1

公开(公告)日：2021-12-30

申请号：PCT/EP2021/067754

申请日：2021-06-28

申请人： SYNAFFIX B.V.

发明人： VERKADE, Jorge Merijn Mathieu ,  VAN BERKEL, Sander Sebastiaan ,  VAN DELFT, Floris Louis

IPC分类号： C07C307/04 ,  C07D207/46 ,  A61K47/50 ,  A61K47/54 ,  A61K47/6889 ,  C07C2602/46 ,  C07D249/18 ,  C07D471/04 ,  C07D519/00 ,  C07K5/06026 ,  C07K5/06034 ,  C07K5/06043 ,  C07K5/06052 ,  C07K5/06078 ,  C07K5/06156 ,  C07K5/0806

摘要： The present invention concerns a method for the preparation of an alkyne-linker-payload construct of structure Q-L-C (O)-NR3-D (1), comprising reacting (i) an alkyne compound of structure Q-L- C(O)-X (2), wherein Q is an alkyne moiety selected from the group consisting of terminal alkyne and (hetero)cycloalkyne; L is a linker, and X is a leaving group selected from halogen, SR1, O-succinimidyl, O-(hetero)aryl(R2)1-5, wherein R1 is selected from C1 - C6 alkyl and (hetero)aryl; and R2 is C1 - C6 alkyl, halogen or NO2; with (ii) a molecule of structure D-NHR3 (3), wherein D is a payload, and R3 is selected from hydrogen, optionally substituted C1 - C24 alkyl, optionally substituted aryl. The activated ester derivatives (2) are highly stable and provide for smooth and high-yielding attachment to a cytotoxic payload. The invention further concerns a method for preparing bioconjugates and alkyne compound of structure Q-L-C (O)-X (2).

公开(公告)号：WO2017137459A1

公开(公告)日：2017-08-17

申请号：PCT/EP2017/052792

申请日：2017-02-08

申请人： SYNAFFIX B.V.

发明人： VAN GEEL, Remon ,  WIJDEVEN, Maria Antonia ,  HURKMANS, Inge Catharina Josephina ,  VAN DELFT, Floris Louis ,  VAN BERKEL, Sander Sebastiaan

IPC分类号： C12N9/24

CPC分类号： C12N9/24 ,  C07K2319/00 ,  C12Y302/01096

摘要： The invention concerns fusion proteins, wherein two endoglycosidases are fused, possibly via a linker. The fusion enzymes according to the invention have structure (1): EndoX-(L) p -EndoY (1), wherein EndoX is an endoglycosidase, EndoY is an endoglycosidase distinct from EndoX, L is a linker and p is 0 or 1. Such fusion enzymes capable of trimming glycoproteins comprising at least two distinct glycoforms in a single step. The invention further concerns the use of the fusion enzyme according to the invention for trimming glycoproteins. In another aspect, the invention relates to the process of production of the fusion enzyme. In a further aspect, the inventions concerns a process for trimming glycoproteins, comprising trimming the glycoprotein with a fusion enzyme according to the invention, to obtain a trimmed glycoprotein.

摘要翻译： 本发明涉及融合蛋白，其中两种内切糖苷酶可能通过接头融合。 根据本发明的融合酶具有结构（1）：EndoX-（L）p -EndoY（1），其中EndoX是内切糖苷酶，EndoY是不同于EndoX的内切糖苷酶，L是接头 并且p是0或1.这种融合酶能够在单一步骤中修剪包含至少两种不同糖型的糖蛋白。 本发明进一步涉及根据本发明的融合酶用于修剪糖蛋白的用途。 另一方面，本发明涉及生产融合酶的方法。 另一方面，本发明涉及修剪糖蛋白的方法，包括用根据本发明的融合酶修剪糖蛋白以获得修剪的糖蛋白。

公开(公告)号：WO2017137457A1

公开(公告)日：2017-08-17

申请号：PCT/EP2017/052790

申请日：2017-02-08

申请人： SYNAFFIX B.V.

发明人： VAN BERKEL, Sander Sebastiaan ,  VERKADE, Jorge Merijn Mathieu ,  WIJDEVEN, Maria Antonia ,  HEESBEEN, Ryan ,  VAN DE SANDE, Petrus Josephus Jacobus Maria ,  VAN GEEL, Remon ,  JANSSEN, Brian Maria Gerardus ,  HURKMANS, Inge Catharina Josephina ,  VAN DELFT, Floris Louis

IPC分类号： A61K47/34 ,  A61K47/42 ,  A61K47/59 ,  A61K47/68 ,  A61P35/00 ,  A61P35/02

CPC分类号： A61K47/6869 ,  A61K47/549 ,  A61K47/6803 ,  A61K47/6817 ,  A61K47/6849 ,  A61K47/6851

摘要： The present invention concerns novel and improved antibody-conjugates for targeting HER2. The inventors found that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index. The mode of conjugation comprises a first step (i) of contacting a glycoprotein comprising 1 - 4 core N-acetylglucosamine moieties with a compound of the formula S(F 1 ) x -P in the presence of a catalyst, wherein S(F 1 ) x is a sugar derivative comprising x functional groups F1 capable of reacting with a functional group Q 1 , x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F 1 ) x moiety to the core-GlcNAc moiety, to obtain a modified antibody; and a second step (ii) of reacting the modified antibody with a linker-conjugate comprising a functional group Q 1 capable of reacting with functional group F 1 and a target molecule D connected to Q 1 via a linker L 2 to obtain the antibody-conjugate wherein linker L comprises S-Z 3 -L 2 and wherein Z 3 is a connecting group resulting from the reaction between Q 1 and F 1 . The invention also relates to a use for improving the therapeutic index of an antibody-conjugate and to a method for targeting HER2-expressing cells.

摘要翻译： 本发明涉及用于靶向HER2的新型和改进的抗体 - 缀合物。 本发明人发现，当使用特定模式的缀合制备抗体 - 缀合物时，它们表现出改善的治疗指数。 缀合方式包括第一步骤（i）：使包含1-4核心N-乙酰葡糖胺部分的糖蛋白与式S（F 1）x化合物接触， -P在催化剂存在下进行反应，其中S（F 1）x-x是包含x个官能团F1的糖衍生物，所述官能团F1能够与官能团Qs- 1，x是1或2，并且P是核苷单磷酸或二磷酸，并且其中催化剂能够将S（F 1/2） 部分连接至核心-GlcNAc部分，以获得修饰的抗体; 和使修饰的抗体与包含能够与官能团F 1反应的官能团Q 1和靶分子D的连接剂 - 缀合物反应的第二步骤（ii） 通过接头L 2与Q 1连接以获得抗体 - 缀合物，其中接头L包含SZ 3 -L 2 - 并且其中Z 3是由Q 1与F 1反应得到的连接基团。 本发明还涉及用于改善抗体 - 缀合物的治疗指数的用途以及用于靶向HER2表达细胞的方法。

公开(公告)号：WO2017137423A1

公开(公告)日：2017-08-17

申请号：PCT/EP2017/052719

申请日：2017-02-08

申请人： SYNAFFIX B.V.

发明人： VAN BERKEL, Sander Sebastiaan ,  HEESBEEN, Ryan ,  VERKADE, Jorge Merijn Mathieu ,  WIJDEVEN, Maria Antonia ,  VAN DELFT, Floris Louis

IPC分类号： A61K47/68 ,  C07K14/435 ,  A61P35/00

CPC分类号： A61K47/6855 ,  A61K47/6803 ,  A61K47/6889 ,  C07K14/00 ,  C07K14/435

摘要： The invention relates to a novel linker for use in bioconjugates such as antibody-drug-conjugates. The linker according to the invention is represented by formula: (I) wherein: - BM is a branching moiety; - E is a capping group; - SG is a sulfamide group; - b, c, d, e, g, i, k, I are independently 0 or 1; - f is an integer in the range of 1 to 10; - Sp 1 , Sp 2 , Sp 3 , Sp 4 , Sp 5 and Sp 6 are a spacer moieties; - Z 1 and Z 2 are connecting groups. The linker according to the invention is useful in the preparation of linker-conjugates and bioconjugates, and can be used for (a) improving conjugation efficiency in the preparation of the bioconjugate, (b) reducing aggregation during the preparation of the bioconjugate and/or of the bioconjugate, (c) increasing stability of the bioconjugate, and/or (d) increasing therapeutic index of the bioconjugate.

摘要翻译： 本发明涉及用于生物缀合物例如抗体 - 药物缀合物中的新型接头。 根据本发明的接头由式（I）表示：其中：-BM是支化部分; - E是封顶组; - SG是磺酰胺基团; - b，c，d，e，g，i，k，I独立地为0或1; - f是1至10范围内的整数; - Sp 1，Sp 2，Sp 3，Sp 4，Sp 5， 和Sp 6是间隔基部分; - Z ^{1 和Z 2 是连接组。 根据本发明的接头可用于制备接头 - 缀合物和生物缀合物，并且可用于（a）改善制备生物缀合物中的缀合效率，（b）减少制备生物缀合物期间的聚集和/或 （c）增加生物缀合物的稳定性，和/或（d）增加生物缀合物的治疗指数。}

公开(公告)号：WO2016053107A1

公开(公告)日：2016-04-07

申请号：PCT/NL2015/050697

申请日：2015-10-05

申请人： SYNAFFIX B.V.

发明人： VERKADE, Jorge Merijn Mathieu ,  WIJDEVEN, Maria Antonia ,  VAN DE SANDE, Petrus Josephus Jacobus Maria ,  VAN BERKEL, Sander Sebastiaan ,  VAN DELFT, Floris Louis

IPC分类号： A61K47/48

CPC分类号： A61K47/6803 ,  A61K47/6811 ,  A61K47/6851 ,  A61K47/6855 ,  A61K47/6889 ,  C07K16/32

摘要： The present invention relates to a compound comprising an alpha-end and an omega-end, the compound comprising on the alpha-end a reactive group Q l capable of reacting with a functional group F 1 present on a biomolecule and on the omega-end a target molecule, the compound further comprising a group according to formula (1) or a salt thereof: Said compound may also be referred to as a linker-conjugate. The invention also relates to a process for the preparation of a bioconjugate, the process comprising the step of reacting a reactive group Q 1 of a linker-conjugate according to the invention with a functional group F 1 of a biomolecule. The invention further relates to a bioconjugate obtainable by the process according to the invention. In a preferred embodiment, the invention concerns a process for the preparation of a bioconjugate via a cycloaddition, such as a (4+2)-cycloaddition (e.g. a Diels-Alder reaction) or a (3+2)-cycloaddition (e.g. a 1,3-dipolar cycloaddition).

摘要翻译： 本发明涉及一种包含α端和ω-末端的化合物，该化合物在α端包含能够与存在于生物分子上的官能团F1反应的反应性基团和ω-末端的靶分子， 所述化合物还包含根据式（1）的基团或其盐：所述化合物也可称为接头 - 缀合物。 本发明还涉及制备生物缀合物的方法，该方法包括使根据本发明的接头 - 偶联物的反应性基团Q1与生物分子的官能团F1反应的步骤。 本发明还涉及可通过本发明的方法获得的生物缀合物。 在优选的实施方案中，本发明涉及通过环加成制备生物缀合物的方法，例如（4 + 2） - 环加成（例如Diels-Alder反应）或（3 + 2） - 环加成（例如 1,3-偶极环加成）。

公开(公告)号：WO2015057063A1

公开(公告)日：2015-04-23

申请号：PCT/NL2014/050714

申请日：2014-10-14

申请人： SYNAFFIX B.V.

发明人： VAN DELFT, Floris Louis ,  VAN GEEL, Remon ,  WIJDEVEN, Maria Antonia ,  VERKADE, Jorge Merijn Mathieu ,  HEESBEEN, Ryan

IPC分类号： C12P21/00 ,  C07K16/00 ,  A61P35/00

CPC分类号： C07K16/40 ,  A61K47/6871 ,  C07K16/32 ,  C07K2317/41 ,  C12P21/00 ,  C12P21/005

摘要： The invention relates to a glycoprotein comprising an optionally fucosylated glycan according to formula (105) or (106), wherein Su(A)x is a modified sugar moiety comprising one or more functional groups A. Functional group A is independently selected from the group consisting of a thiol group, a halogen, a sulfonyloxy group, a halogenated acetamido group, a mercaptoacetamido group and a sulfonated hydroxyacetamido group. The invention also relates to a glycoprotein-conjugate wherein a glycoprotein according to the invention is conjugated to a molecule of interest. Said molecule of interest may for example be an active substance. The invention further relates to a process for the preparation of a modified glycoprotein, and to a method for the preparation of a glycoprotein-conjugate. The invention particularly relates to modified antibodies, antibody-conjugates, antibody-drug conjugates and methods for the preparation thereof.

摘要翻译： 本发明涉及包含根据式（105）或（106）的任选岩藻糖基化聚糖的糖蛋白，其中Su（A）x是包含一个或多个官能团A的修饰的糖部分。官能团A独立地选自 由硫醇基，卤素，磺酰氧基，卤代乙酰氨基，巯基乙酰氨基和磺化羟基乙酰氨基组成。 本发明还涉及一种糖蛋白结合物，其中根据本发明的糖蛋白与感兴趣的分子缀合。 所述感兴趣的分子可以例如是活性物质。 本发明还涉及一种制备修饰的糖蛋白的方法，以及制备糖蛋白 - 缀合物的方法。 本发明特别涉及修饰的抗体，抗体缀合物，抗体 - 药物偶联物及其制备方法。

公开(公告)号：WO2022058395A1

公开(公告)日：2022-03-24

申请号：PCT/EP2021/075401

申请日：2021-09-15

申请人： SYNAFFIX B.V.

发明人： HOOGENBOOM, Jorin ,  VAN SCHAIK, Arnoldus Jacobus ,  POPAL, Sorraya ,  DE BEVER, Laureen ,  WIJDEVEN, Maria Antonia ,  VAN GEEL, Remon ,  HURKMANS, Inge Catharina Josephina ,  VAN DE SANDE, Peter ,  VAN BERKEL, Sander Sebastiaan ,  VAN DELFT, Floris Louis

IPC分类号： A61K47/68 ,  A61P35/00 ,  C07D491/00

摘要： The present invention concerns an antibody-drug conjugate, having structure (1) wherein AB is an antibody; L1 and L2 are linkers; w is 0 or 1; Z is a connecting group obtained by a metal-free click reaction or by thiol ligation; each R17 is individually an amino acid side chain; n is an integer in the range of 1 - 5; A is a 5- or 6-membered aromatic or heteroaromatic ring; x is an integer in the range of 1 - 8; R21 is selected from H, R22, C(0)0H and C(0)R22, wherein R22 is C1 - C24 (hetero)alkyl groups, C3 - C10 (hetero)cycloalkyl groups, C2 - C10 (hetero)aryl groups, C3 - C10 alkyl(hetero)aryl groups and C3 - C10 (hetero)arylalkyl groups, which optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR23 wherein R23 is independently selected from the group consisting of hydrogen and C1 - C4 alkyl groups.