WO2018200812A1 - Conjugués d'anticorps comprenant un agoniste de sting - Google Patents

Conjugués d'anticorps comprenant un agoniste de sting Download PDF

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Publication number
WO2018200812A1
WO2018200812A1 PCT/US2018/029570 US2018029570W WO2018200812A1 WO 2018200812 A1 WO2018200812 A1 WO 2018200812A1 US 2018029570 W US2018029570 W US 2018029570W WO 2018200812 A1 WO2018200812 A1 WO 2018200812A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
alkynyl
alkenyl
crc
independently selected
Prior art date
Application number
PCT/US2018/029570
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English (en)
Inventor
Thomas W. Dubensky Jr.
Jacob Robert BRUML
Stephen CANHAM
Charles Y. CHO
Kelsey GAUTHIER
Laura Hix GLICKMAN
Xueshi Hao
David Kanne
Shailaja Kasibhatla
George Edwin KATIBAH
Thanh Ngoc Lan LE
Justin Leong
Jeffrey Mckenna
Sarah McWHIRTER
Chudi Obioma Ndubaku
Weijia Ou
Leonard Sung
George Scott Tria
Tetsuo Uno
Tom Yao-Hsiang Wu
Yongqin Wan
Original Assignee
Novartis Ag
Aduro Biotech, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag, Aduro Biotech, Inc. filed Critical Novartis Ag
Priority to JP2019558397A priority Critical patent/JP2020517700A/ja
Priority to EP18724677.2A priority patent/EP3615080A1/fr
Priority to CN201880043438.4A priority patent/CN110799218A/zh
Publication of WO2018200812A1 publication Critical patent/WO2018200812A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
    • C07K9/003—Peptides being substituted by heterocyclic radicals, e.g. bleomycin, phleomycin

Definitions

  • n is an integer from 1 to 20;
  • n is an integer from 1 to 8.
  • n is an integer from 1 to 8.
  • the luciferase reporter gene is the 5xlSRE-mlFNb-GL4 reporter gene and the STING-expressing cell is a cell expressing wild-type human STING protein, and optionally the STING agonist activity is determined by the hSTING wt assay described in Table 7.
  • the immunoconjugate stimulates IP-10 secretion from a STING-expressing cell targeted by the Ab at an EC50 of 5 nanomolar (nM) or less in an IP-10 secretion assay.
  • R 2 and R 3 are connected to form CrCgalkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - O-CrCsalkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 2 and R 3 are connected, the 0 is bound at the R 3 position;
  • R 4 and R 3 are connected to form CrCsalkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, - O-CrCsalkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 4 and R 3 are connected, the 0 is bound at the R 3 position;
  • R and R are connected to form C ⁇ Csalkylene, C 2 -C 3 alkenylene, C 2 -C 6 alkynylene, -O-CrCealkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 4a and R 3a are connected, the 0 is bound at the R 3a position;
  • X D is C, and each Z 4 is N;
  • Y 10 is -CH 2 -, -NH-, -0- or -S;
  • X 4 is -0(CH 2 ) n SSC(R 12 ) 2 (CH 2 ) n - or -(CH 2 ) n C(R 12 ) 2 SS(CH 2 ) n O-;
  • X 5 is where the ** indicates orientation toward the Drug moiety;
  • each R 111 is independently selected from H, C r C 6 alkyl, F, CI, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -
  • FIG. 7 is a line graph showing the anti-HER2 mAb1 -C1 conjugate inhibits HCC1954 breast tumor growth in mice.
  • FIG. 1 1 illustrates certain compounds which can be used as a Drug moiety.
  • C 2 -C 6 alkynyl refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to six carbon atoms.
  • C r C 6 hydroxyalkyl refers to a C 1-6 alkyl radical as defined above, wherein one of the hydrogen atoms of the C 1-6 alkyl radical is replaced by OH.
  • hydroxyC ⁇ alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy- propyl, 3-hydroxy-propyl and 5-hydroxy-pentyl
  • C 3 -C 8 cycloalkyl refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system.
  • Non-limiting examples of fused bicyclic or bridged polycyclic ring systems include bicyclo[1 .1 .1 ]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1 ]octane, bicyclo[2.2.2]octane and adamantanyl.
  • Non-limiting examples monocyclic C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • the C 2 - C 6 haloalkynyl groups can be diC 2 -C 6 haloalkynyl wherein such C 2 -C 6 haloalkynyl groups can have two halo atoms independently selected from iodo, bromo, chloro or fluoro.
  • the C 2 -C 6 haloalkynyl groups can be polyC 2 -C 6 haloalkynyl wherein such C 2 -C 6 haloalkenyl groups can have two or more of the same halo atoms or a combination of two or more different halo atoms.
  • heterocyclyl includes partially saturated or aromatic monocyclic or fused bicyclic heterocyclyl containing from 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S. In a preferred embodiment, the heteroatoms are nitrogen.
  • substituents include oxo, halo, C 1-6 alkyl, C ⁇ alkoxy, amino, C ⁇ alkylamino, di-C ⁇ alkylamino.
  • the heterocyclic group can be attached at a heteroatom or a carbon atom.
  • Heterocyclyl also includes 6-membered monocyclic partially saturated ring having 1-3 heteroatoms (preferably nitrogen).
  • Examples of partially saturated monocyclic heterocyclyl are pyrimidine-one and pyrimidine-dione, specifically pyrimidin-2(1 H)-one and pyrimidin-1 -yl-2,4(1 H, 3H)-dione.
  • tautomer is used to designate 2 molecules with the same molecular formula but different connectivity, which can interconvert in a rapid equilibrium.
  • phosporothioic acid and phosphoric acid moieties can exist in the respective equilibrium as shown below.
  • VH heavy chain variable domain
  • HCDR1 e.g., insertion(s) after position 35
  • homologous refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules.
  • two nucleic acid molecules such as, two DNA molecules or two RNA molecules
  • polypeptide molecules between two polypeptide molecules.
  • a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are homologous or identical at that position.
  • the homology between two sequences is a direct function of the number of matching or homologous positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 of 10), are matched or homologous, the two sequences are 90% homologous.
  • Percentage of "sequence identity" can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the amino acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences.
  • the percentage can be calculated by determining the number of positions at which the identical amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity.
  • the output is the percent identity of the subject sequence with respect to the query sequence.
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • an optical isomer or "a stereoisomer”, as used herein, refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
  • the term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • P-cadherin also refers to proteins and amino acid sequences that over their full length have at least about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence of the above GenBank accession Nos.
  • pharmaceutically acceptable salt refers to a salt which does not abrogate the biological activity and properties of the compounds of the invention, and does not cause significant irritation to a subject to which it is administered.
  • STING agonist refers to a compound or antibody conjugate capable of binding to STING and activating STING.
  • Activation of STING activity may include, for example, stimulation of inflammatory cytokines, including interferons, such as type 1 interferons, including IFN-a, IFN- ⁇ , type 3 interferons, e.g., IFN , IP10, TNF, IL-6, CXCL9, CCL4, CXCL11 , CCL5, CCL3, or CCL8.
  • interferons such as type 1 interferons, including IFN-a, IFN- ⁇ , type 3 interferons, e.g., IFN , IP10, TNF, IL-6, CXCL9, CCL4, CXCL11 , CCL5, CCL3, or CCL8.
  • terapéuticaally effective amount or “therapeutically effective dose” interchangeably refers to an amount sufficient to effect the desired result (i.e., reduction or inhibition of an enzyme or a protein activity, amelioration of symptoms, alleviation of symptoms or conditions, delay of disease progression, a reduction in tumor size, inhibition of tumor growth, prevention of metastasis, inhibition or prevention of viral, bacterial, fungal or parasitic infection).
  • a therapeutically effective amount does not induce or cause undesirable side effects.
  • a therapeutically effective amount induces or causes side effects but only those that are acceptable by the healthcare providers in view of a patient's condition.
  • a therapeutically effective amount can be determined by first administering a low dose, and then incrementally increasing that dose until the desired effect is achieved.
  • Y 7 is 0 or S
  • CrCshaloalkyl C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r C 6 alkyl), -0(C 2 -C 3 alkenyl), - 0(C 2 -C 6 alkynyl), -OC(0)OCrC 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, - OC(0)C r C 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3 are substituted by 0,1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;
  • R 3a and R 6a are connected to form Crdalkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, -0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 3a and R 6a are connected, the O is bound at the R 3a position;
  • R 2 and R 3 are connected to form d-Calkylene, C 2 -C 6 alkenylene, C 2 -
  • R 5 and R 6 are connected to form C ⁇ Cealkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, -0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5 and R 6 are connected, the 0 is bound at the R 5 position;
  • R 5a and R 7a are connected to form CrCsalkylene, C 2 -C 6 alkenylene, C 2 - C 6 alkynylene, -0-C r C 6 alkylene, -0-C 2 -C 6 alkenylene, -0-C 2 -C 6 alkynylene, such that when R 5a and R 7a are connected, the O is bound at the R 5a position;
  • R 6 and R 6a are H
  • R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
  • Embodiment 1 , 2 or 3 wherein:
  • R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
  • Y 9 and Y 10 are 0 or S;
  • Embodiment 12 A compound of Formula (E), Formula (E-1) or Formula (E-2) of
  • Embodiment 1 , 2 or 3 wherein:
  • R 3a and R 4a is H and the other is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrCehaloalkyl, C 2 -
  • C 6 alkyl, -OC(0)OC 2 -C 6 alkenyl, -OC(0)OC 2 -C 6 alkynyl, -OC ⁇ CrCealkyl, -OC(0)C 2 - C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3 or R 4 are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 , and one of R 5 and R 7 is H and the other is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r C 6 haloalkyl, C 2 - C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r Csal
  • Embodiment 1 1, 2, 3 or 12 wherein:
  • Y 5 is O or S
  • Y 7 is O or S
  • R 3a , R a is H and the other is H, OH, OCH 3 or F;
  • R 3 , R 4 is H and the other is H, OH, OCH 3 or F;
  • R 5 and R 7 are H and the other is H, OH, OCH 3 or F, and
  • Embodiment 14 A compound of Formula (F), Formula (F-1) or Formula (F-2) of
  • R 2 and R 2a are H; each R e and R ea are H;
  • each R 7a and R 7 are H;
  • R 8 , R 9 , R 8a and R 9a are independently H or C r C 6 alkyl
  • R 3a and R a is H and the other is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C r C 6 haloalkyl, C 2 -
  • C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R 3 or R 4 are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 , and
  • R 5 is selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r
  • Embodiment 15 A compound of Formula (F), Formula (F-1) or Formula (F-2) of
  • Embodiment 1 1, 2, 3 or 12 wherein:
  • Y 1 and Y 2 are 0, CH 2 or S;
  • each Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
  • R 2 , R 2a , R 6 , R 6a , R 6 , R 7 and R 7a are H;
  • R 3 , R 4 is H and the other is H, OH, OCH 3 or F;
  • R is substituted with 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, OH, SH, NH 2 , D, CD 3 , C r C s alkyl, C r
  • Y 3 is OH, 0 " , OR 10 , N(R 10 ) 2 , SH or S " ;
  • each R 6 is independently selected from the group consisting of H, -OH, F, CI, Br, I, D, CD 3 , CN, N 3 , C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, CrCehaloalkyl, C 2 -C 3 haloalkenyl, C 2 -
  • CrCshaloalkyl C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, -0(C r C 6 alkyl), -0(C 2 -C 3 alkenyl), - 0(C 2 -C 6 alkynyl), -OC(0)OCrC 6 alkyl, -0C(0)0C 2 -C 6 alkenyl, -0C(0)0C 2 -C 6 alkynyl, - OC(0)C r C 6 alkyl, -OC(0)C 2 -C 6 alkenyl and -OC(0)C 2 -C 6 alkynyl of R s are substituted by 0, 1 , 2 or 3 substituents independently selected from F, CI, Br, I, OH, CN, and N 3 ;

Abstract

L'invention concerne des immunoconjugués comprenant des agonistes de STING. L'invention concerne également des méthodes de fabrication des immunoconjugués et des méthodes de traitement du cancer à l'aide des immunoconjugués.
PCT/US2018/029570 2017-04-28 2018-04-26 Conjugués d'anticorps comprenant un agoniste de sting WO2018200812A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2019558397A JP2020517700A (ja) 2017-04-28 2018-04-26 Ｓｔｉｎｇアゴニストを含む抗体コンジュゲート
EP18724677.2A EP3615080A1 (fr) 2017-04-28 2018-04-26 Conjugués d'anticorps comprenant un agoniste de sting
CN201880043438.4A CN110799218A (zh) 2017-04-28 2018-04-26 包含sting激动剂的抗体缀合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762491879P 2017-04-28 2017-04-28
US62/491,879 2017-04-28

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WO2018200812A1 true WO2018200812A1 (fr) 2018-11-01

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JP (1) JP2020517700A (fr)
CN (1) CN110799218A (fr)
AR (1) AR113224A1 (fr)
WO (1) WO2018200812A1 (fr)

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WO2020092617A1 (fr) * 2018-10-31 2020-05-07 Novartis Ag Conjugués d'anticorps dc-sign comprenant des agonistes de sting
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WO2020236817A2 (fr) 2019-05-20 2020-11-26 Novartis Ag Conjugués anticorps-médicament inhibiteurs de mcl-1 et méthodes d'utilisation
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WO2024020164A2 (fr) 2022-07-21 2024-01-25 Firefly Bio, Inc. Agonistes du récepteur des glucocorticoïdes et leurs conjugués
JP7440504B2 (ja) 2018-07-10 2024-02-28 エフ－スター・セラピューティクス・インコーポレイテッド 疾患を治療するための化合物、組成物及び方法

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