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EP-4151278-B1 - BIOTIN-MODIFIED DIMER AND USE THEREOF

EP4151278B1EP 4151278 B1EP4151278 B1EP 4151278B1EP-4151278-B1

Inventors

  • KANAI MOTOMU
  • ZHAO Songji
  • UKON Naoyuki
  • SUZUKI MIHO
  • YAMATSUGU KENZO
  • TATSUMI Toshifumi
  • KODAMA TATSUHIKO
  • SUGIYAMA AKIRA
  • TSUKAGOSHI Masanobu
  • TODA YUZO
  • WASHIYAMA Kohshin
  • TAKAHASHI KAZUHIRO

Dates

Publication Date
20260513
Application Date
20210413

Claims (8)

  1. A compound represented by the following formula (1) or a salt thereof: wherein L 1 represents a trivalent linking group, L 2 represents a divalent linking group, Hal represents a halogen, p represents an integer of 1 to 5, and q, r, s, and t each independently represent an integer of 1 to 8.
  2. The compound according to claim 1 or a salt thereof, wherein L 1 represents the following:
  3. The compound according to claim 1 or 2, or a salt thereof, wherein L 2 represents a divalent linking group consisting of a combination of groups selected from -CONH-, -NHCO-, -COO-, -OCO-, -CO-, -O-, and an alkylene group containing 1 to 10 carbon atoms.
  4. The compound according to any one of claims 1 to 3, or a salt thereof, which is a compound represented by the following formula (2) or a salt thereof: wherein individual symbols are as defined in claim 1.
  5. The compound according to any one of claims 1 to 4, or a salt thereof, wherein Hal is I, 125 I, or 211 At.
  6. The compound according to any one of claims 1 to 5, or a salt thereof, wherein p is 1.
  7. The compound according to claim 1, or a salt thereof, represented by the following formulae:
  8. A kit for use in the treatment or diagnosis, comprising: (1) the compound according to any one of claims 1 to 7; and (b) a mutant streptavidin-molecular probe conjugate obtained by binding a molecular probe to a mutant streptavidin comprising the amino acid sequence as outlined in SEQ ID NO: 1 (provided that the amino acid sequence consisting of six histidine residues at the C-terminus may be partially or entirely deleted).

Description

Technical Field The present invention relates to a biotin-modified dimer and the use thereof. Background Art Avidin and biotin, or streptavidin and biotin, have an extremely high affinity between them (Kd = 10-15 to 10-14 M). This is one of the extremely strong interactions between two biomolecules. Presently, the interaction between avidin/streptavidin and biotin has been widely applied in biochemistry, molecular biology, and medicine. A drug delivery method in which high binding ability between avidin/streptavidin and biotin is combined with an antibody molecule, namely, a pre-targeting method, has been devised. Since chicken-derived avidin or microorganism-derived streptavidin exhibits high immunogenicity to a human body, such avidin or streptavidin is problematic in that an anti-avidin/streptavidin antibody is generated in an early stage after the administration thereof to a human body. This causes prevention of the practical use of the pre-targeting method. Low immunogenic streptavidin that solves the problem above has been reported (International Publication WO2010/095455). Low immunogenic streptavidin is characterized by reduced immunogenicity to a human body. Since the low immunogenic streptavidin has an affinity for biotin existing in a human body, the low immunogenic streptavidin has been problematic in that it causes high background when used for diagnoses or in that it is not likely to exhibit medicinal effects specifically on a disease when used for treatments. Under such circumstances, a mutant streptavidin with a reduced affinity for natural biotin and modified biotin having a high affinity for the mutant streptavidin with a reduced affinity for natural biotin have been reported (International Publication WO2014/129446). Moreover, a mutant streptavidin with a reduced affinity for natural biotin and a biotin-modified dimer having a high affinity for the mutant streptavidin with a low affinity for natural biotin have been reported (International Publication WO2015/125820). WO 2015/125820, WO 2020/032165, WO 2019/189867, WO 2018/151301 disclose biotin-modified dimers. Prior Art Documents Patent Documents Patent Document 1: International Publication WO2010/095455Patent Document 2: International Publication WO2014/129446Patent Document 3: International Publication WO2015/125820 Summary of Invention Object to be Solved by the Invention It is an object of the present invention to provide a novel halogenated biotin-modified dimer capable of performing imaging diagnosis or treatment. Furthermore, it is another object of the present invention to provide a diagnostic kit and/or a therapeutic kit, in which a combination of the above-described biotin-modified dimer and a mutant streptavidin is used. Means for Solving the Object Colorectal cancer has a high incidence rate and is on the increase. Even if colorectal cancer is stage 4, resection of distant metastasis is considered, and combination chemotherapy and molecular target drugs are used for this cancer. However, adjunctive therapy effective for vital prognosis has not yet been established. A majority of such colorectal cancers express carcinoembryonic antigen (CEA); thus, radio immunotherapy involving a specific anti-CEA antibody labeled with RI can be applied. In the present invention, it is an object of the invention to combine a drug delivery system (Cupid-Psyche system) with alpha-radionuclide astatine-211 (211At) so as to provide a novel radiopharmaceutical agent and a companion diagnostic agent for the treatment of refractory cancer. Cupid-Psyche system is pre-targeting radio immunotherapy of utilizing a monoclonal antibody, to which a modified biotin (Psyche) and a tetrameric streptavidin (Cupid) bind, and this Cupid-Psyche system have been developed based on molecular dynamics simulation performed by a supercomputer. In the Examples of the present invention, a treatment method of efficiently delivering 211At to colorectal cancer using the Cupid-Psyche system was developed. By using a Cupid-binding single chain variable fragment (scFv)-type antibody and 211At-labeled Psyche, the targeting of the Cupid-binding scFv-type antibody to the colorectal cancer cells was confirmed. At the same time, the stability of the 211At-labeled Psyche and the binding ability of the 211At-labeled Psyche to the Cupid-binding scFv-type antibody was confirmed. Moreover, the pharmacokinetics of Cupid-211At-labeled Psyche were analyzed, and the efficacy thereof in colorectal cancer animal models was evaluated. The present invention has been completed based on the above-described findings. According to the present invention, the following inventions are provided. <1> A compound represented by the following formula (1) or a salt thereof: wherein L1 represents a trivalent linking group,L2 represents a divalent linking group,Hal represents a halogen,p represents an integer of 1 to 5, andq, r, s, and t each independently represent an integer of 1 to 8.<2> The compound acc