JPWO2020210694A5

JPWO2020210694A5 -

Info

Publication number: JPWO2020210694A5
Application number: JP2021559800A
Authority: JP
Publication date: 2024-07-11

Description

一部の実施形態では、抗体は、アブシキシマブ、アダリムマブ、アレムツズマブ、アリロクマブ、アビバクタム、バシリキシマブ、ベンラリズマブ、ベズロトクスマブ、ブリナツモマブ、ブロダルマブ、ブロスマブ、カナキヌマブ、カプラシズマブ、セルトリズマブペゴル、ダクリズマブ、デノスマブ、デュピルマブ、エクリズマブ、エミシズマブ、エレヌマブ、エボロクマブ、フレマネズマブ、ガルカネズマブ、ゴリムマブ、グセルクマブ、イバリズマブ、イダルシズマブ、インフリキシマブ、イトリズマブ、イキセキズマブ、ラナデルマブ、ロキベトマブ、メポリズマブ、ナタリズマブ、オビルトキサキシマブ、オクレリズマブ、オマリズマブ、パリビズマブ、ラニビズマブ、ラキシバクマブ、レスリズマブ、ラムシルマブ（Ｒｍａｂ）、ロベリズマブ、ルプリズマブ、サリルマブ、セクキヌマブ、チルドラキズマブ、チオマブ、トシリズマブ、ウステキヌマブ、またはベドリズマブである。ある種のより具体的な実施形態では、抗体は、アブリルマブ、アクトクスマブ、アデュカヌマブ、アファセビクマブ、アフェリモマブ、アニフロルマブ、アンルキンズマブ（ＩＭＡ－６３８）、アセリズマブ、アトロリムマブ、バピネウズマブ、ＢＣＤ－１００、ベルチリムマブ、ベシレソマブ、ビシロマブ、ビマグルマブ、ビメキズマブ、ビルタミマブ、ブレセルマブ、ブロソズマブ、ボコシズマブ、ブラジクマブ、ブリアキヌマブ、ブロルシズマブ、カルルマブ、カロツキシマブ、セデリズマブ、クラザキズマブ、クレノリキシマブ、コンシズマブ、コスフロビキシマブ、ＣＲ６２６１、クレネズマブ、クリザンリズマブ、クロテデュマブ、デパツキシズマブ、マフォドチン、デルロツキシマブビオチン、デザミズマブ、ディリダブマブ、ドマグロズマブ、デュシギツマブ、エクロメキシマブ、エドバコマブ、エファリズマブ、エフングマブ、エルデルマブ、エレザヌマブ、エノキズマブ、エプチネズマブ、エリズマブ、エトロリズマブ、エビナクマブ、エクスビビルマブ、ファノレソマブ、ファラリモマブ、ファリシマブ、ファシヌマブ、フェルビズマブ、フェザキヌマブ、フランボツマブ、フレチクマブ、フロテツズマブ、フォントリズマブ、フォラビルマブ、フロボシマブ、フルラヌマブ、ガンテネルマブ、ガビリモマブ、ゲボキズマブ、ギムシルマブ、ゴミリキシマブ、ゴスラネマブ、イアナルマブ、インクラクマブ、イノリモマブ、Ｉｏｍａｂ－Ｂ、ケリキシマブ、ランパリズマブ、ランドグロズマブ、ラルカビキシマブ、レブリキズマブ、レンベルビマブ（Ｌｅｎｖｅｒｖｉｍａｂ）、レルデリムマブ、レトリズマブ、リビビルマブ、リゲリズマブ、ロデルシズマブ、ルリズマブペゴル、マルスタシマブ、マブリリムマブ、メテリムマブ、ミリキズマブ、モタビズマブ、ムロモナブＣＤ３、ネバクマブ、ネモリズマブ、ＮＥＯＤ００１、ニルセビマブ、オデュリモマブ、オレンダリズマブ、オロキズマブ、ＯＭＳ７２１、オピシヌマブ、オルチクマブ、オテリキシズマブ、オチリマブ、オクセルマブ、オザネズマブ、オゾラリズマブ、パギバキシマブ、パノバクマブ、パスコリズマブ、パテクリズマブ、ＰＤＲ００１、ペラキズマブ、ペキセリズマブ、プラクルマブ、プロザリズマブ、ポネズマブ、ポルガビキシマブ、プラシネズマブ、プリリキシマブ、ＰＲＯ１４０、キリズマブ、ラフィビルマブ、ラルパンシズマブ、ラネベトマブ、ラバガリマブ、ラブリズマブ、レファネズマブ、レガビルマブ、レラトリマブ、リヌクマブ、リサンキズマブ、ロレヅマブ、ロモソズマブ、ロンタリズマブ、ＳＡ２３７、サトラリズマブ、セビルマブ、ＳＨＰ６４７、シファリムマブ、シムツズマブ、シプリズマブ、シルクマブ、ソラネズマブ、ソネプシズマブ、スパルタリズマブ、スタムルマブ、スレソマブ、スプタブマブ、スチムリマブ、スビズマブ、スブラトクスマブ、タドシズマブ、タリズマブ、タムツベトマブ、タネズマブ、テフィバズマブ、テリモマブアリトクス（Ｔｅｌｉｍｏｍａｂａｒｉｔｏｘ）、テネリキシマブ、テプリズマブ、テプロツムマブ、テゼペルマブ、チブリズマブ、トラリズマブ、トラロキヌマブ、トレボグルマブ、ツビルマブ、ウロクプルマブ（Ｕｌｏｃｕｐｌｕｍａｂ）、ウルトキサズマブ、バリサクマブ、ベパリモマブ（Ｖｅｐａｌｉｍｏｍａｂ）、ベセンクマブ（Ｖｅｓｅｎｃｕｍａｂ）、ビシリズマブ、ボバリリズマブ、またはゾリモマブアリトクス（Ｚｏｌｉｍｏｍａｂａｒｉｔｏｘ）である。一部のより具体的な実施形態では、モノクローナル抗体は、トラスツズマブ、ゲムツズマブ、ブレンツキシマブ、ボルセツズマブ、ロルボツズマブ、カンツズマブ、ビバツズマブ、イノツズマブ、またはバダスツキシマブである。 In some embodiments, the antibody is selected from the group consisting of abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, benralizumab, bezlotoxumab, blinatumomab, brodalumab, burosumab, canakinumab, caplacizumab, certolizumab pegol, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, erenumab, evolocumab, fremanezumab, galcanezumab, golimumab, guselkumab, iba idarucizumab, idarucizumab, infliximab, itolizumab, ixekizumab, lanadelumab, lokivetmab, mepolizumab, natalizumab, obiltoxaximab, ocrelizumab, omalizumab, palivizumab, ranibizumab, raxibacumab, reslizumab, ramucirumab (Rmab), rovelizumab, ruplizumab, sarilumab, secukinumab, tildrakizumab, thiomab, tocilizumab, ustekinumab, or vedolizumab. In certain more specific embodiments, the antibody is selected from the group consisting of abrilumab, actoxumab, aducanumab, afasevicumab, afelimomab, anifrolumab, anrukinzumab (IMA-638), acelizumab, atorlimumab, bapineuzumab, BCD-100, bertilimumab, besilesomab, biciromab, bimagrumab, bimekizumab, bilirum ... Tamimab, bleselumab, brosozumab, bococizumab, brazikumab, briakinumab, brolucizumab, carlumab, carotuximab, cedelizumab, clazakizumab, clenoliximab, concizumab, cosfrobiximab, CR6261, crenezumab, crizanlizumab, clotedumab, depatuxizumab, mafodotin, delroy Simab-biotin, desamizumab, dilidabumab, domagrozumab, dusigitumab, ecromeximab, edovacomab, efalizumab, efungumab, eldelumab, elezanumab, enokizumab, eptinezumab, elizumab, etrolizumab, evinacumab, exbivirumab, fanolesomab, faralimomab, faricimab, facine Mab, Felvizumab, Fezakinumab, Franvotumab, Fletikumab, Flotetuzumab, Fontolizumab, Foravirumab, Flobocimab, Furlanumab , Gantenerumab, Gavilimomab, Gevokizumab, Gimsilumab, Gomiliximab, Goslanemab, Ianalumab, Inclacumab, Inolimomab, Iomab-B, Keliximab, Ran Palizumab, landgrozumab, ralcaviximab, lebrikizumab, lenvervimab, lerdelimumab, letolizumab, ribivirumab, ligelizumab, roderucizumab, lurizumab pegol, marstacimab, mavrilimumab, metelimu- mab, mirikizumab, motavizumab, muromonab CD3, nebacumab, nemoris Mab, NEOD001, nirsevimab, odulimomab, orendalizumab, olokizumab, OMS721, opicinumab, olticumab, otelixizumab, otilimab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, panobacumab, pascolizumab, pateclizumab, PDR001, perakizumab, pexelizumab, plaque Lumab, prosalizumab, ponezumab, polgabiximab, prasinezumab, priliximab, PRO140, kiruzumab, rafivirumab, ralpancizumab, ranevetomab, ravagalimab, ravulizumab, refanezumab, regavirumab, relatorimab, rinukumab, risankizumab, loredumab, romosozumab, rontalizumab, SA237 , satralizumab, sevirumab, SHP647, sifalimumab, simtuzumab, siplizumab, sirukumab, solanezumab, sonepcizumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, sublatoxumab, tadocizumab, talizumab, tamtubetomab, tanezumab, tefibazumab, terimomab Telimomab aritox, Teneliximab, Teplizumab, Teprotumumab, Tezepelumab, Tiburizumab, Toralizumab, Tralokinumab, Trevoglumab, Tubilumab, Ulocuplumab, Urtoxazumab, Balisacumab, Vepalimomab, Vesencumab, Visilizumab, Bovalilizumab, or Zolimomab aritox. In some more specific embodiments, the monoclonal antibody is trastuzumab, gemtuzumab, brentuximab, borsetuzumab, lorvotuzumab, cantuzumab, bivatuzumab, inotuzumab, or vadastuximab.

Claims

A compound having the following structure (I):

(I)
or a stereoisomer, pharma- ceutically acceptable salt, or tautomer thereof, wherein
M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye;
L ^a , independently at each occurrence, is an optional physiologically cleavable linker and L ^b , independently at each occurrence, is an optional non-physiologically cleavable linker, provided that at least one occurrence of L ^a and L ^b together contain more than four carbons;
L and ^L are ^, independently at each occurrence, an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, or heteroatom linker;
^L3 is independently at each occurrence a heteroalkylene, heteroalkenylene, or heteroalkynylene linker greater than 3 atoms in length, the heteroatoms of the heteroalkylene, heteroalkenylene, and heteroalkynylene linkers being selected from O, N, and S;
R ¹ is, independently at each occurrence, H, alkyl, or alkoxy;
R ² and R ³ are each independently H, OH, SH, alkyl, alkoxy, alkyl ether, heteroalkyl, -OP(=R _a )(R _b )R _c , Q or a protected form thereof, or L';
^R4 is, independently at each occurrence, ^O- , ^S- , OZ, SZ, or N( ^R6 ) ₂ , where Z is a cation and each ^R6 is independently H or alkyl;
^R5 is independently at each occurrence oxo, thioxo, or absent;
R _a is O or S;
R _b is OH, SH, O ⁻ , S ⁻ , OR _d or SR _d ;
_Rc is OH, SH, ^O- , ^S- , _ORd , OL', _SRd , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkyl ether, alkoxyalkyl ether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkyl ether, or thiophosphoalkyl ether;
R _d is a counter ion;
Q is, independently at each occurrence, a moiety that contains a reactive group, or a protected form thereof, capable of forming a covalent bond with the complementary reactive group Q′ of the targeting moiety;
L' is, independently at each occurrence, a linker that includes a covalent bond to Q, a targeting moiety, a linker that includes a covalent bond to a targeting moiety, a linker that includes a covalent bond to a solid support, a linker that includes a covalent bond to a solid support moiety, a linker that includes a covalent bond to a nucleoside, or a linker that includes a covalent bond to an additional compound of structure (I);
m is, independently at each occurrence, an integer equal to or greater than zero;
and n is an integer of 1 or more.

^L3 is polyethylene oxide and the compound has the following structure (IB):

(IB)
(Wherein,
z is an integer from 2 to 30;
^x1 and ^x2 each independently represent an integer of 0 to 6;
^x3 and ^x4 each independently represent an integer from 0 to 6.
2. The compound of claim 1 having the formula:

A) z is an integer from 3 to 6 and m is 3 for at least one occurrence of n;
B) z is an integer from 22 to 27 for at least one occurrence of m;
C) z is an integer from 44 to 54 for at least one occurrence of m;
D) z is 3 for at least one occurrence of m and m is 3 for at least one occurrence of n; or E) z is 6 for at least one occurrence of m and m is 3 for at least one occurrence of n.

The compound of any one of claims 1 to 3, wherein at least one occurrence of L ^a comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence, a ketone, a diol, a cyano, a nitro, or a combination thereof.

5. The compound of claim 4, wherein ^L comprises an amino acid sequence recognized by a sortase enzyme, wherein the amino acid sequence is Leu-Pro-X-Thr-Gly, where X is any amino acid residue.

A) at least one occurrence of ^L has the following structure:

including one of
B) At least one occurrence of L has the structure:

including,
C) at least one occurrence of L comprises one or more amino acid residues, and wherein at least one occurrence of ^L comprises valine; or D) at least one occurrence of ^L has the structure:

or

The compound according to any one of claims 1 to 5, comprising one of:

A) at least one occurrence of L ^b contains a thioether bond;
B) At least one occurrence of ^L has the following structure:

or C) at least one occurrence of L ^b has the following structure:

The compound according to any one of claims 1 to 6, comprising one of:

L' has the following structure:

(Wherein,
m″ and n″ are independently integers from 1 to 10;
R ^e is H, an electron pair or a counter ion, and L″ is a targeting moiety or a linking group to a targeting moiety.
The compound according to any one of claims 1 to 7, having the formula:

A) the targeting moiety is an antibody, a cell surface receptor antagonist, or a cell surface receptor agonist, wherein the antibody, cell surface receptor antagonist, or cell surface receptor agonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate, or a MET inhibitor; or B) The targeting moiety is a monoclonal antibody, wherein the monoclonal antibody is selected from the group consisting of abciximab, adalimumab, alemtuzumab, alirocumab, avibactam, basiliximab, benralizumab, bezlotoxumab, blinatumomab, brodalumab, burosumab, canakinumab, caplacizumab, certolizumab pegol, daclizumab, denosumab, dupilumab, eculizumab, emicizumab, erenumab, evolocumab, fremanezumab, gaclopramide ... Lucanezumab, golimumab, guselkumab, ibalizumab, idarucizumab, infliximab, itolizumab, ixekizumab, lanadelumab, lokivetmab, mepolizumab, natalizumab, obiltoxaximab, ocrelizumab, omalizumab, palivizumab, ranibizumab, raxibacumab, reslizumab, ramucirumab (Rmab), rovelizumab, ruplizumab, sarilumab, secukinumab, tildrakizumab, thiomab, tocilizumab, uste Kinumab, vedolizumab, abrilumab, actoxumab, aducanumab, afasevicumab, afelimomab, anifrolumab, anrukinzumab (IMA-638), acelizumab, atollimumab, bapineuzumab, BCD-100, bertilimumab, besilesomab, biciromab, bimagrumab, bimekizumab, vilutamimab, bleselumab, brosozumab, bococizumab, brazikumab, briakinumab, brolucizumab, carlumab, carlotoxicam ... Mab, cedelizumab, clazakizumab, crenoliximab, concizumab, cosfrobiximab, CR6261, crenezumab, crizanlizumab, cloteduumab, depatuxizumab, mafodotin, dellotuximab biotin, dezamizumab, dilidabumab, domaglozumab, dusigitumab, ecromeximab, edovacomab, efalizumab, efungumab, eldelumab, elezanumab, enokizumab, eptinezumab, elizumab, etrol ... Mab, evinacumab, exbivirumab, fanolesomab, faralimomab, faricimab, fasinumab, felvizumab, fezakinumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foravirumab, flobocimab, fullanumab , gantenerumab, gavilimomab, gevokizumab, gimsilumab, gomilikimab, goslanemab, ianalumab, inlacumab, inolimomab, Iomab-B, keliximab, lampalizumab , landgrozumab, ralcaviximab, lebrikizumab, lenvervimab, lerdelimumab, letolizumab, ribivirumab, ligelizumab, roderucizumab, lurizumab pegol, marstacimab, mavrilimumab, metelimumab, mirikizumab, motavizumab, muromonab CD3, nebacumab, nemolizumab, NEOD001, nirsevimab, odulimomab, orendalizumab, olokizumab, OMS721, opicinumab , olticumab, otelixizumab, otilimab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, panobacumab, pascolizumab, pateclizumab, PDR001, perakizumab, pexelizumab, placulumab, prozalizumab, ponezumab, polgabiximab, prasinezumab, priliximab, PRO140, kirusumab, rafivirumab, ralpancizumab, ranevtomab, ravagalimab, ravolizumab, refanezumab, regavi lumab, relatorimab, linukumab, risankizumab, loredumab, romosozumab, rontalizumab, SA237, satralizumab, sevirumab, SHP647, sifalimumab, simtuzumab, siplizumab, sirukumab, solanezumab, sonepcizumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, sublatoxumab, tadocizumab, talizumab, tamtubetomab, tanezumab, tefibazumab, terimomab Telimomab aritox, Teneliximab, Teplizumab, Teprotumumab, Tezepelumab, Tiburizumab, Toralizumab, Tralokinumab, Trevoglumab, Tubilumab, Ulocuplumab, Urtoxazumab, Valisacumab, Vepalimomab, Vesencumab, Visilizumab, Bovalilizumab, Zolimomab 9. The compound of claim 1, which is selected from the group consisting of ribozyme, ribozyme aritox, trastuzumab, gemtuzumab, brentuximab, borsetuzumab, lorvotuzumab, cantuzumab, bivatuzumab, inotuzumab, and vadastuximab.

A) ^R2 or ^R3 has the following structure:

or B) R ³ has the following structure:

The compound according to any one of claims 1 to 9, having the formula:

A) at least one occurrence of m is an integer from 1 to 15;
B) at least one occurrence of m is an integer from 1 to 10;
C) at least one occurrence of m is an integer from 1 to 5;
D) m, for each occurrence, is an integer from 1 to 15;
E) m, for each occurrence, is an integer from 1 to 10;
F) m, for each occurrence, is an integer from 1 to 5;
A compound according to any one of claims 1 to 10, wherein G) n is an integer from 1 to 100; or H) n is an integer from 1 to 10.

A) at least one occurrence of M is an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and an EGFR inhibitor or an alkylating agent;
B) at least one occurrence of M is an antitumor agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, or an alkylating agent;
C) at least one occurrence of M is selected from the group consisting of auristatin F, monomethylauristatin F, monomethylauristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, aveimicin, ticamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, polothramycin, prothracarcin, sivanomycin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, siratecan, cositecan, exatecan, rutotecan, gimatecan, belotecan, and rubitecan; or D) at least one occurrence of M is selected from the group consisting of:

The compound according to any one of claims 1 to 11, having one of the following:

One of the following structures:

or

wherein M is, independently at each occurrence, a biologically active moiety or fragment thereof, a prodrug of a biologically active moiety or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding moiety, provided that at least one occurrence of M is not a fluorescent dye;
R2 ^is

and
dT has the following structure:

wherein R is hydrogen or a direct bond;
Compound.