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1. 发明申请

US20190194641A1 SITE-SPECIFIC CONJUGATION TO ANTIBODY LYSINE RESIDUES WITH SOLID-PHASE IMMOBILIZED MICROBIAL TRANSGLUTAMINASE MTG AND MTG IN SOLUTION 审中-公开
公开(公告)号：US20190194641A1
公开(公告)日：2019-06-27
申请号：US16319502
申请日：2017-07-11
申请人： PAUL SCHERRER INSTITUT
发明人： PHILIPP RENE SPYCHER , MARTIN BEHE , ROGER SCHIBLI , DAVID HURWITZ
IPC分类号： C12N11/08 , A61K47/64 , C07K16/18 , A61K47/68 , A61K47/60 , A61K47/69
CPC分类号： C12N11/08 , A61K47/60 , A61K47/64 , A61K47/6811 , A61K47/6887 , A61K47/6937 , C07K16/18 , C12Y203/02013
摘要： Site-specific modification of proteins with microbial transglutaminase (MTG) is a powerful and versatile strategy for a controlled modification of proteins under physiological conditions. Solid-phase microbead-immobilization is used to site-specifically and efficiently attach different functional molecules important for further downstream applications to proteins of therapeutic relevance including scFV, Fab-fragment and antibodies. MTG remained firmly immobilized with no detectable column bleeding and enzyme activity was sustained during continuous operation. Immobilized MTG shows enhanced selectivity towards a certain residue in the presence of several reactive residues which are all targeted when the conjugation was carried out in solution. The generation of dual site-specifically conjugated IgG1 with immobilized and MTG in solution is reported, i.e. site-specific conjugation to glutamine and lysine residues of IgG1 antibody. Site-specific glutamine conjugation with small peptides containing a lysine residue and a functional moiety is also described.

2. 发明申请

US20210361735A1 MINIGASTRIN DERIVATES, IN PARTICULAR FOR USE IN CCK2 RECEPTOR POSITIVE TUMOUR DIAGNOSIS AND/OR TREATMENT 有权
公开(公告)号：US20210361735A1
公开(公告)日：2021-11-25
申请号：US16649637
申请日：2018-08-27
申请人： PAUL SCHERRER INSTITUT
发明人： MARTIN BEHE , NATHALIE GROB , THOMAS L. MINDT , ROGER SCHIBLI
IPC分类号： A61K38/10 , A61K51/08 , A61K51/12 , A61K51/04
摘要： It is therefore the objective of the present invention to provide minigastrin derivates which further improve the accumulation in CCK-2 receptor positive tumours by simultaneously very low accumulation in other organs, e.g. the kidneys. This objective is achieved according to the present invention by a minigastrin derivate having the formula: X-Z-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (Y), wherein at least one of the connecting or terminal amide bonds between, before or after the amino acids of the sequence Z, Ala, Tyr, Gly, Trp, Met, Asp, Phe and NH2 or Y (C-terminal) is replaced by a 1,4-disubstituted or a 1,5-disubstituted 1,2,3-triazole, while X stands for a chemical group attached to the peptide for the purpose of diagnostic and/or therapeutic intervention at CCK-2 receptor relevant diseases, Y stands for C-terminal modifications of the peptide, such as amide, primary and secondary amides, free carboxylic acids and carboxylic ester derivatives including but not limited to amides and esters derived from linear or branched alkyl-,alkenyl-, alkynyl- aromatic-, and heterocyclic alcohols, and Z stands for a linker or DGlu* wherein DGlu* stands for a chain of DGlu having 1 to 6 repetitions (-DGlu-to-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-). These minigastrin derivates have a high specific internalization, excellent IC50 values and sufficient plasma stability.

3. 发明申请

US20160256580A1 MINI-GASTRIN ANALOGUE, IN PARTICULAR FOR USE IN CCK2 RECEPTOR POSITIVE TUMOUR DIAGNOSIS AND/OR TREATMENT 审中-公开
标题翻译： MINI-GASTRIN ANALOGUE，特别用于CCK2受体阳性肿瘤诊断和/或治疗
公开(公告)号：US20160256580A1
公开(公告)日：2016-09-08
申请号：US15034943
申请日：2014-10-23
申请人： PAUL SCHERRER INSTITUT
发明人： MARTIN BEHE , ROGER SCHIBLI
IPC分类号： A61K51/08 , C07B59/00 , C07K14/595 , C07K1/13 , A61K38/22 , C07K7/08
CPC分类号： A61K51/088 , A61K38/2207 , C07B59/008 , C07K1/13 , C07K7/08 , C07K14/57572 , C07K14/595 , G01N33/57484 , G01N2333/726
摘要： A gastrin analogue shows high uptake in CCK-2 receptor positive tumors and simultaneously a very low accumulation in the kidneys. This is achieved by a mini-gastrin analogue PP-F11 having the formula: PP-F11-X-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Y-Asp-Phe-NH2, wherein Y is an amino acid replacing methionine and X is a chemical group attached to the peptide for diagnostic and/or therapeutic intervention at CCK-2 receptor relevant diseases. Very suitable compounds with respect to a high tumor to kidney ratio are mini-gastrin analogues with six D-glutamic acids or six glutamines. These compounds still possess a methionine which can be oxidized easily which is a disadvantage for clinical application under GMP due to the forms which may occur. The elimination of the methionine leads to a lower affinity to oxidation which in general favors the tumor-kidney-ratio. Ideally, the methionine is replaced by norleucine. This PP-F11N mini gastrin exhibits currently the best tumor-kidney-ratio and is the most promising candidate.
摘要翻译：胃泌素类似物在CCK-2受体阳性肿瘤中显示高摄取量，并且在肾脏中同时具有非常低的积累。这是通过具有下式的微型胃泌素类似物PP-F11实现的：PP-F11-X-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Y-Asp-Phe-NH2，其中Y是取代甲硫氨酸的氨基酸，X是与该肽连接的用于CCK-2受体相关疾病的诊断和/或治疗干预的化学基团。非常合适的化合物相对于高肿瘤与肾脏的比例是与六个D-谷氨酸或六个谷氨酰胺的微型胃泌素类似物。这些化合物仍然具有可以容易地氧化的甲硫氨酸，这是由于可能发生的形式而在GMP下临床应用的缺点。消除甲硫氨酸导致对氧化的较低亲和力，其通常有利于肿瘤 - 肾脏比例。理想情况下，甲硫氨酸被正亮氨酸取代。这种PP-F11N微型胃泌素显示出目前最好的肿瘤 - 肾脏比例，是最有希望的候选者。

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