JPWO2021019243A5 - - Google Patents

Description

を有する第一のペプチドリガンド;がN-(酸-PEG ₃ )-N-ビス(PEG ₃ -アジド)リンカーを介して、
(b)CD137に結合し、その両方が配列
（化２）

を有する2つの第二のペプチドリガンド;
にコンジュゲートしたもの
:を含み、ここで、該ペプチドリガンドの各々が、2つのループ配列によって隔てられた3つの反応性システイン基(C _i 、C _ii 、及びC _iii )を含むポリペプチド、並びに、1,1',1''-(1,3,5-トリアジナン-1,3,5-トリイル)トリプロパ-2-エン-1-オン(TATA)であり、かつ該ポリペプチドの反応性システイン基と共有結合を形成する分子スキャフォールドを含み、その結果、2つのポリペプチドループが該分子スキャフォールド上に形成され;
ここで、Acがアセチルを表し、HArgがホモアルギニンを表し、HyPがtrans-4-ヒドロキシ-L-プロリンを表し、1Nalが1-ナフチルアラニンを表し、tBuAlaがt-ブチル-アラニンを表し、PYAが4-ペンチン酸を表し、かつNleがノルロイシンを表す、ヘテロタンデム二環式ペプチド複合体。
（態様２）
BCY13272:
（化３）

である、態様1記載のヘテロタンデム二環式ペプチド複合体。
（態様３）
前記医薬として許容し得る塩が、遊離酸又はナトリウム、カリウム、カルシウム、アンモニウム塩から選択される、態様1又は態様2記載のヘテロタンデム二環式ペプチド複合体。
（態様４）
態様1～3のいずれか一項記載のヘテロタンデム二環式ペプチド複合体を1以上の医薬として許容し得る賦形剤との組合せで含む、医薬組成物。
（態様５）
癌の予防、抑制、又は治療において使用するための、態様1～3のいずれか一項記載のヘテロタンデム二環式ペプチド複合体。
（態様６）
癌を治療する方法であって、態様1～3のいずれか一項記載のヘテロタンデム二環式ペプチド複合体のインビトロEC ₅₀ を上回る該複合体の血漿濃度を維持しない投薬頻度での該複合体の投与を含む、前記方法。
FIG. 5A shows a sensorgram demonstrating that BCY13272 binds to EphA2 (human) with an affinity of 2.0 nM. FIG. 5B shows a sensorgram of BCY13272 binding with high affinity to CD137 (human). Due to the presence of two CD137-binding bicycles in BCY13272, the dissociation rate of the immobilized CD137 protein is very slow and the reported _KD may be an overestimate (Fig. 4B).
The present application provides inventions of the following aspects.
(Aspect 1)
(a) binds to EphA2 and sequences
(Chem. 1)

through an N-(acid-PEG3 ₎ -N-bis(PEG3 _- azido) linker,
(b) binds to CD137, both of which are sequences
(Chemical 2)

two second peptide ligands having
conjugated to
wherein each of said peptide ligands comprises three reactive cysteine groups (C _i , C _ii , and C _iii ) separated by two loop sequences; ,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) and covalently bonded to the reactive cysteine group of the polypeptide; forming a molecular scaffold, such that two polypeptide loops are formed on the molecular scaffold;
where Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4-hydroxy-L-proline, 1Nal represents 1-naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid and Nle represents norleucine.
(Aspect 2)
BCY13272:
(Chemical 3)

The heterotandem bicyclic peptide conjugate according to embodiment 1, which is
(Aspect 3)
The heterotandem bicyclic peptide conjugate according to embodiment 1 or embodiment 2, wherein said pharmaceutically acceptable salt is selected from the free acid or sodium, potassium, calcium, ammonium salts.
(Aspect 4)
A pharmaceutical composition comprising a heterotandem bicyclic peptide conjugate according to any one of aspects 1-3 in combination with one or more pharmaceutically acceptable excipients.
(Aspect 5)
A heterotandem bicyclic peptide conjugate according to any one of aspects 1-3 for use in the prevention, suppression or treatment of cancer.
(Aspect 6)
A method of treating cancer, wherein the heterotandem bicyclic peptide conjugate according to any one of aspects 1-3 at a dosing frequency that does not maintain plasma concentrations of the conjugate above the in vitro EC 50 of the _conjugate The above method, comprising the administration of

Claims (6)

(a) binds to EphA2 and sequences

through an N-(acid- _PEG3 )-N-bis( _PEG3 -azido) linker,
(b) binds to CD137, both of which are sequences

two second peptide ligands having
conjugated to
wherein each of said peptide ligands comprises three reactive cysteine groups (C _i , C _ii , and C _iii ) separated by two loop sequences; ,1″-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one (TATA) and covalently bonded to the reactive cysteine group of the polypeptide; forming a molecular scaffold, such that two polypeptide loops are formed on the molecular scaffold;
where Ac represents acetyl, HArg represents homoarginine, HyP represents trans-4-hydroxy-L-proline, 1Nal represents 1-naphthylalanine, tBuAla represents t-butyl-alanine, PYA represents 4-pentynoic acid and Nle represents norleucine, or a pharmaceutically acceptable salt thereof. BCY13272:

2. The heterotandem bicyclic peptide conjugate of claim 1, or a pharmaceutically acceptable salt thereof, which is 3. The heterotandem bicyclic peptide conjugate of claim 1 or claim 2, wherein said pharmaceutically acceptable salt is selected from the free acid or sodium, potassium, calcium, ammonium salts. A pharmaceutical composition comprising the heterotandem bicyclic peptide conjugate of any one of claims 1-3 in combination with one or more pharmaceutically acceptable excipients. A heterotandem bicyclic peptide conjugate according to any one of claims 1 to 3 for use in the prevention, suppression or treatment of cancer. A pharmaceutical composition for treating cancer comprising the heterotandem bicyclic peptide conjugate of any one of claims 1-3, which does not maintain plasma concentrations of the conjugate above the in vitro _EC50 Said pharmaceutical composition, wherein said conjugate is administered at a dosing frequency.