Formulation of a conjugate of a tubulysin analog to a cell-binding molecule

Patent metadata

Field	Value
Publication number	US-12576124-B2
Application number	US-202017596956-A
Country	US
Kind code	B2
Filing date	Feb 18, 2020
Priority date	Jun 24, 2019
Publication date	Mar 17, 2026
Grant date	Mar 17, 2026

Abstract

A formulation of conjugates of tubulysin analogs with a cell-binding molecule having a structure represented by Formula (I), wherein T, L, m, n, ----, R 1 , R 2 , R 3 , R 4 , R 1 , R 6 , R 7 , R 1 , R 9 , R 10 , R 11 , R 12 , and R 13 are as defined herein, can be used for targeted treatment of cancer, autoimmune disease, and infectious disease.

First claim

What is claimed is:

1 . A formulation which is a liquid composition prior to lyophilization, or in a formulated lyophilized solid, or a reconstituted formulation from a lyophilized solid, comprising: a conjugate of a tubulysin compound to a cell-binding agent of Formula (I) or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof; or a polymorphic crystalline structure thereof; or an isotope, optical isomer, racemate, diastereomer or enantiomer thereof in an amount of 0.01%-99% by weight as a major ingredient; 0.0%-20.0% of one or more polyols; 0.0%-2.0% of one or more surfactants; 0.0%-5.0% of one or more preservatives; 0.0%-30% of one or more amino acids; 0.0%-5.0% of one or more antioxidants; 0.0%-0.3% of one or more metal chelating agents; 0.0%-30.0% of one or more buffer salts for adjusting pH of the formulation to pH 4.5 to 8.5; and 0.0%-30.0% of one or more of isotonic agents for adjusting osmotic pressure between about 250 to 350 mOsm after reconstituted for administration to a patient,

wherein T is a cell-binding agent; L is a releasable linker; is a linkage bond that L connects to an atom inside the bracket independently; n is 1; and m is 1-10;
wherein T is an antibody; a single chain antibody; an antibody fragment that binds to the target cell; a monoclonal antibody; a single chain monoclonal antibody; or a monoclonal antibody fragment that binds the target cell; a chimeric antibody; a chimeric antibody fragment that binds to the target cell; a domain antibody; a domain antibody fragment that binds to the target cell;
wherein the linker L has a formula: —Ww-(Aa)r--Vv-; wherein: —W— is a Stretcher unit; w is 0 or 1; each --Aa-- is independently an amino acid unit; r is independently an integer ranging from 0 to 12; —V— is a Spacer unit; and v is 0, 1 or 2; the Stretcher unit W may independently contain a self-immolative spacer, a peptide unit, a hydrazone bond, a disulfide or thioether bond; the Stretcher unit (—W—), when present, links a targeted binding molecular unit (T) to the amino acid unit (--Aa--), or links V when an Aa is not present; W linked to T has a structure of:

wherein R 20 is selected from —C 1 -C 9 alkylene-, —C 1 -C 7 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, —C 1 -C 9 alkylene-arylene-, -arylene, —C 1 -C 9 alkylene-, —C 1 -C 9 alkylene-(C 1 -C 8 carbocyclo)-, —(C 3 -C 7 carbocyclo)-C 1 -C 9 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 9 alkylene-, —(CH 2 CH 2 O) k —, —(CH(CH 3 )CH 2 O) k —, and —(CH 2 CH 2 O) k —CH 2 —; k is an integer ranging from 1-20;
the Spacer unit (—V—), when present, links an amino acid unit to an antimitotic agent when the amino acid unit is present; or, the Spacer unit links the Stretcher unit to an antimitotic agent when the amino acid unit is absent; or the Spacer unit links an antimitotic agent to the binding molecule (T) when both the amino acid unit and Stretcher unit are absent; the Spacer unit may contain one or more function groups that substantially increase water solubility, biological transport, preferential renal clearance, uptake, absorption, biodistribution, and/or bioavailability of the conjugate; the Spacer unit is self-immolative or non-self-immolative; a non-self-immolative Spacer unit is one in which part or all of the Spacer unit remains bound to the antimitotic agent after cleavage of the amino acid unit from the antimitotic agent-Linker-binding molecule conjugate or the antimitotic agent-Linker Compound; the self-immolative unit includes an aromatic compound that is electronically similar to a para-aminobenzyl-carbamoyl (PAB) group, 2-aminoimidazol-5-methanol compound, heterocyclic PAB compound, beta-glucuronide, and ortho or para-aminobenzylacetal; or one of following structures:

wherein an (*) atom is a point of attachment of additional spacer or releasable linker unit(s), the antimitotic agent, and/or the cell binding agent (T); X, Y and Z 3 are independently NH, O, or S; Z 2 is H, NH, O or S; v is 0 or 1; Q is independently H, OH, C 1 -C 6 alkyl, (OCH 2 CH 2 ) n F, Cl, Br, I, OR 17 , SR 17 , NR 17 R 18 , N═NR 17 , N═R 17 , NR 17 R 18 , NO 2 , SOR 17 R 18 , SO 2 R 17 , SO 3 R 17 , OSO 3 R 17 , PR 17 R 18 , POR 17 R 18 , PO 2 R 17 R 18 , OPO(OR 17 )(OR 18 ), or OCH 2 PO(OR 17 (OR 18 ), wherein R 17 and R 18 are independently H, C 1 -C 8 alkyl; C 2 -C 8 alkenyl, alkynyl, or heteroalkyl; C 3 -C 8 aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, or alkylcarbonyl; or a pharmaceutical cation salt thereof;
the non-self-immolative spacer linker has a structure:

or L- or D-natural or unnatural peptide containing 1-20 same or different amino acids;
wherein “*” and “ ” atoms are a point of attachment of additional spacer or releasable linker, the antimitotic agent, and/or the cell-binding molecule; m is 1-10; n is 1-20; X 2 , X 3 , X 4 , X 5 , or X 6 , are independently selected from NH; NHNH; N(R 12 ); N(R 12 )N(R 12′ ); O; S; C 1 -C 6 alkyl; C 2 -C 6 heteroalkyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; CH 2 OR 12 , CH 2 SR 12 , CH 2 NHR 12 , or 1-8 amino acids; wherein R 12 and R 12′ are independently H; C 1 -C 8 alkyl; C 2 -C 8 hetero-alkyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; or C 1 -C 8 ester, ether, or amide; or a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p or (OCH 2 CH(CH 3 )) p , wherein p is an integer from 0 to about 1000, or a combination thereof;
a releasable component of the linker L that at least one bond in L can be broken under physiological conditions: a pH-labile, acid-labile, base-labile, oxidatively labile, metabolically labile, biochemically labile or enzyme-labile bond, which has one of following structures: —(CR 15 R 16 ) m (Aa)r(CR 17 R 18 )n(OCH 2 CH 2 ) t —, —(CR 15 R 16 ) m (CR 17 R 18 ) n (Aa) r (OCH 2 CH 2 ) t —, -(Aa) r -(CR 15 R 16 ) m (CR 17 R 18 ) n (OCH 2 CH 2 ) t —, —(CR 15 R 16 ) m (CR 17 R 18 ) n (OCH 2 CH 2 )(Aa) t -, —(CR 15 R 16 ) m (CR 17 ═CR 18 )(CR 19 R 20 ) n (Aa) t (OCH 2 CH 2 ) r —, —(CR 15 R 16 ) m (NR 11 CO)(Aa) t (CR 19 R 20 ) n —(OCH 2 CH 2 ) r —, —(CR 15 R 16 ) m (Aa) t (NR 21 CO)(CR 19 R 20 ) n (OCH 2 CH 2 ) r —, —(CR 15 R 16 ) m (OCO)(Aa) t -(CR 19 R 20 ) n (OCH 2 CH 2 ) r —, —(CR 15 R 16 ) m (OCNR 17 )(Aa) t (CR 19 R 20 ) n (OCH 2 CH 2 ) r —, —(CR 15 R 16 ) m —(CO)(Aa) t -(CR 19 R 20 ) n (OCH 2 CH 2 ) r —, —(CR 15 R 16 ) m (NR 21 CO)(Aa) t (CR 19 R 20 ) n (OCH 2 CH 2 ) r -, —(C

Assignees

• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao Robert
• Yang Qingliang
• Huang Yuanyuan
• Gai Shun
• Ye Hangbo
• Zhao Linyao
• Guo Huihui
• Bai Lu
• Li Wenjun
• Jia Junxiang
• Guo Zhixiang
• Zheng Jun
• Chen Xiaoxiao
• Kong Xiangfei
• Lin Chen
• Du Yong
• Zhang Yu
• Zhou Lei
• Zhang Xiuzhen
• Zheng Xiuhong
• Chen Binbin
• Yang Yanlei
• Dai Meng
• Xu Yifang
• Fan Zhongliang
• Zhou Xiaomai
• Jiang Xingyan
• Chen Miaomiao
• Zhang Lingli
• Li Yanhua

Classifications

• A61K51/088

  conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10) · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K47/64

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title