WO2023161877A1 - Chimères ciblant la cytotoxicité pour des cellules exprimant l'intégrine avb6 - Google Patents

Chimères ciblant la cytotoxicité pour des cellules exprimant l'intégrine avb6 Download PDF

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WO2023161877A1
WO2023161877A1 PCT/IB2023/051746 IB2023051746W WO2023161877A1 WO 2023161877 A1 WO2023161877 A1 WO 2023161877A1 IB 2023051746 W IB2023051746 W IB 2023051746W WO 2023161877 A1 WO2023161877 A1 WO 2023161877A1
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formula
compound
antibody
seq
cancer
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PCT/IB2023/051746
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English (en)
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Christina Ng Di Marco
Matthew Robert SENDER
Brandon TURUNEN
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Glaxosmithkline Intellectual Property Development Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39583—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials not provided for elsewhere, e.g. haptens, coenzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids

Definitions

  • the present disclosure relates to heterobifunctional molecules, referred to as cytotoxicity targeting chimeras (CyTaCs) or antibody recruiting molecules (ARMs) that are able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein.
  • CyTaCs cytotoxicity targeting chimeras
  • ARMs antibody recruiting molecules
  • the present disclosure also relates to agents capable of binding to a receptor on a surface of a pathogenic cell and inducing the depletion of the pathogenic cell in a subject for use in the treatment of cancer.
  • Antibody-based therapeutics have promising properties as drug candidates for these indications due to their selectivity for pathogenic cell-surface targets and their ability to direct immune surveillance to target-expressing tissues or cells to induce depletion of the pathogenic cells. Examples of such depletion mechanisms include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependant cytotoxicity (CDC).
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • CDC complement-dependant cytotoxicity
  • antibody-based therapeutics often suffer from a lack of bioavailability, high cost, thermal instability, and difficult manufacturing due to their size, complexity and peptide based structures.
  • small molecule therapeutics often provide affordability, stability, and the convenience of oral dosing, but may suffer from poor selectivity and off-target effects, while also lacking the immune control of therapeutic antibodies.
  • compositions and related methods are provided in the present disclosure.
  • the present disclosure provides a heterobifunctional molecule referred to as a cytoxicity targeting chimera (CyTaC) or an antibody recruiting molecule (ARM), wherein the ARM comprises a moiety that binds a target cell-surface protein on a cell and a moiety that binds an exogenous antibody.
  • the ARM comprises a divalent linker that links the target-binding moiety to the antibody-binding moiety.
  • the target-binding moiety is an integrin aV ⁇ 6-binding moiety.
  • the exogenous antibody is an anti-cotinine antibody, or antigen-binding fragment thereof.
  • the ARM is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is C 1-4 alkyl or C 3-6 cycloalkyl
  • Y is a bond or a divalent spacer moiety of one to twelve atoms in length; and L is a divalent linker as described herein.
  • the ARM is a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is C 1-4 alkyl or C 3-6 cycloalkyl.
  • the present disclosure provides a method of treating and/or preventing a disease or disorder in a patient in need thereof, comprising: administering to the patient a compound of Formula (I) as disclosed herein and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • the present disclosure provides a method of increasing antibodydependent cell cytotoxicity (ADCC) of integrin ⁇ V ⁇ 6-expressing cells comprising: contacting the cells with a compound of Formula (I) as disclosed herein and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • ADCC antibodydependent cell cytotoxicity
  • the present disclosure provides a method of depleting integrin ⁇ V ⁇ 6- expressing cells comprising: contacting the cells with a compound of Formula (I) as disclosed herein and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • the present disclosure provides a compound of Formula (I) as disclosed herein for use in therapy.
  • the present disclosure provides a combination comprising a compound of Formula (I) as disclosed herein and an anti-cotinine antibody, or antigen-binding fragment thereof, for use in therapy.
  • the present disclosure provides a combination comprising a compound of Formula (I) as disclosed herein and an anti-cotinine antibody, or antigen-binding fragment thereof, for use in the treatment of a disease or disorder.
  • the present disclosure provides use of a compound of Formula (I) as disclosed herein in the manufacture of a medicament for the treatment of a disease or disorder.
  • the present disclosure provides use of a combination comprising a compound of Formula (I) as disclosed herein and an anti-cotinine antibody, or antigenbinding fragment thereof, in the manufacture of a medicament for the treatment of a disease or disorder.
  • the present disclosure provides a combination comprising a compound of Formula (I) as disclosed herein and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • FIG. 1 Schematic representation of cytotoxicity targeting chimeras (CyTaCs) technology compared to current antibody technology.
  • FIG. 2A and FIG. 2B PK analysis of compounds of Formula (I) in mice as described in Example 6;
  • FIG. 2A shows PK analysis of the compound of Example 2 dosed in the presence of anti-cotinine antibody;
  • FIG. 2B shows PK analysis of the compound of Example 1 dosed in the presence of anti-cotinine antibody.
  • the present disclosure provides a compound of Formula (I):
  • R 1 is C 1-4 alkyl or C 3-6 cycloalkyl
  • Y is a bond or a divalent spacer moiety of one to twelve atoms in length
  • L is a divalent linker of Formula (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g), (L-h), (L-i), (L-j), (L- k), (L-m), (L-n-i), (L-n-ii), (L-n-iii), or (L-n-iv).
  • L is a divalent linker of Formula (L-a): (L-a), or a stereoisomer thereof, wherein:
  • Ring A and Ring B are each independently C 4-6 cycloalkylene
  • L 1a is C 3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NR a -; each R a is independently hydrogen or C 1-3 alkyl; and L 2a is -O-, -NHC(O)-, or -CH 2 -O-; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • Ring A and Ring B of Formula (L-a) are each independently
  • L is a divalent linker of Formula (L-a-i):
  • Ring A is C4-6 cycloalkylene
  • L 1a is C 3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NR a -; each R a is independently hydrogen or C 1-3 alkyl; and
  • L 2a is -O-, -NHC(O)-, or -CH 2 -O-; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • Ring A of Formula (L-a-i) is
  • L is a divalent linker of Formula (L-a-ii): or a stereoisomer thereof, wherein:
  • L 1a is C 3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with -O- or -NR a -; each R a is independently hydrogen or C 1-3 alkyl;
  • L 2a is -O-, -NHC(O)-, or -CH 2 -O-; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from wherein: j is 1 , 2, 3, or 4; k is 0, 1 , 2, or 3; the sum of j and k is 2, 3, or 4; q is 1 or 2; r is 1 or 2; s is 0 or 1 ; the sum of q, r, and s is 2 or 3;
  • X 1 and X 2 are independently -O- or NR a ; and each R a is independently hydrogen or C 1-3 alkyl; wherein represents a covalent bond to the C(O) group of Formula (L-a), (L-a-i), or (L-a- ii), and represents a covalent bond to Ring B of Formula (L-a) or to the cyclohexylene group of Formula (L-a-i) or (L-a-ii).
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from - (CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 4 O-, -(CH 2 ) 2 OCH 2 -, -(CH 2 ) 3 OCH 2 -, -(CH 2 ) 2 O(CH 2 ) 2 -, -CH 2 OCH 2 -, - CH 2 O(CH 2 ) 2 -, -CH 2 O(CH 2 ) 3 -, -CH 2 OCH 2 O-, or -CH 2 OCH 2 OCH 2 -.
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH 2 ) 2 O-, -(CH 2 ) 3 O-, -(CH 2 ) 2 OCH 2 -, or - (CH 2 ) 3 OCH 2 -.
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH 2 ) 2 NR a -, -(CH 2 ) 3 NR a -, -(CH 2 ) 4 NR a -, -(CH 2 ) 2 NR a CH 2 -, -(CH 2 ) 3 NR a CH 2 -, -(CH 2 ) 2 NR a (CH 2 ) 2 - -CH 2 NR a CH 2 -, -CH 2 NR a (CH 2 ) 2 -, -CH 2 NR a (CH 2 ) 3 -, -CH 2 NR a CH 2 NR a -, or -
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH 2 ) 2 NR a -, -(CH 2 ) 3 NR a - , -(CH 2 ) 2 NR a CH 2 -, or -(CH 2 ) 3 NR a CH 2 -, wherein R a is hydrogen or C 1-3 alkyl.
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH 2 ) 2 NH-, -(CH 2 ) 3 NH-, -(CH 2 ) 4 NH-, -(CH 2 ) 2 NHCH 2 -, -(CH 2 ) 3 NHCH 2 -, -(CH 2 ) 2 NH(CH 2 ) 2 -, -CH 2 NHCH 2 -, -CH 2 NH(CH 2 ) 2 - , -CH 2 NH(CH 2 ) 3 -, -CH 2 NHCH 2 NH-, or -CH 2 NHCH 2 NHCH 2 -.
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -(CH 2 ) 2 NH-, -(CH 2 ) 3 NH-, -(CH 2 ) 2 NHCH 2 -, or - (CH 2 ) 3 NHCH 2 -.
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -CH 2 OCH 2 NR a -, -CH 2 NR a CH 2 O-, -CH 2 OCH 2 NR a CH 2 -, -CH 2 NR a CH 2 OCH 2 -, wherein R a is independently hydrogen or C 1-3 alkyl.
  • L 1a of Formula (L-a), (L-a-i), or (L-a-ii) is selected from -CH 2 OCH 2 NH-, -CH 2 NHCH 2 O-, -CH 2 OCH 2 NHCH 2 -, - CH 2 NHCH 2 OCH 2 -.
  • L is a divalent linker of Formula (L-a-iii): (L-a-iii), or a stereoisomer thereof wherein: p is 1 or 2; m is 1 or 2; and n is 1 , 2, or 3; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-a) selected from the group consisting of:
  • L is a divalent linker of Formula (L-b):
  • Ring A is C4-6 cycloalkylene or C7-9 bridged bicyclic cycloalkylene;
  • L 1b is -CH 2 -NH-C(O)-, -NHC(O)-, or -C(O)NH-;
  • L 2b is C6-12 linear alkylene, wherein 1 , 2, 3, or 4 methylene units are replaced with -O-, -NR 1b - , -C(O)NR 1b -, or -NR 1b C(O)-; or wherein n is 1 , 2, 3, or 4, and represents a covalent bond to L 1b ; and each R 1b is independently hydrogen or C 1-3 alkyl; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • Ring A of Formula (L-b) is
  • L is a divalent linker of Formula (L-b-i): (L-b-i), or a stereoisomer thereof, wherein:
  • L 1b is -CH 2 -NH-C(O)-, -NHC(O)-, or -C(O)NH-;
  • L 2b is C 6-12 linear alkylene, wherein 1 , 2, 3, or 4 methylene units are replaced with -O-, -NR 1b - , -C(O)NR 1b -, or -NR 1b C(O)-; or
  • L 2b is , wherein n is 1 , 2, 3, or 4, and represents a covalent bond to L 1b ; each R 1b is independently hydrogen or C 1-3 alkyl; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L 2b of Formula (L-b) or (L-b-i) is selected from wherein: j is 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10; k is 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10; the sum of j and k is 5, 6, 7, 8, 9, 10, or 11 ; q is 1 , 2, 3, 4, 5, 6, 7, 8, or 9; r is 1 , 2, 3, 4, 5, 6, 7, 8, or 9; s is O, 1 , 2, 3, 4, 5, 6, 7, or 8; the sum of q, r, and s is 4, 5, 6, 7, 8, 9, or 10; t is 1 , 2, 3, 4, 5, 6, or 7; u is 1 , 2, 3, 4, 5, 6, or 7; v is 1 , 2, 3, 4, 5, 6, or 7; w is 0, 1 , 2, 3, 4, 5, or 6; the sum of t, u, v, and w is 3, 4, 5, 6, 7, 8, or 9; a is 1 , 2, 3, 4, or 5; b is 1 , 2, 3, 4, or 5;
  • X 1 , X 2 , X 3 , and X 4 are independently -O-, -NR 1b -, -C(O)NR 1b -, or -NR 1b C(O)-; and each R 1b is independently hydrogen or C 1-3 alkyl; wherein represents a covalent bond to L 1b of Formula (L-b) or (L-b-i), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-b) selected from the group consisting of:
  • L is a divalent linker of Formula (L-c): (L-c), or a stereoisomer thereof, wherein:
  • L 1c is C 2-10 linear alkylene, wherein 1 , 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-;
  • Ring A is C 4-6 cycloalkylene or C 7-9 bridged bicyclic cycloalkylene
  • L 2c is -O- or a saturated C 2-10 linear alkylene, wherein 1 , 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • Ring A of Formula (L-c) is N-(2-aminoethyl)
  • L is a divalent linker of Formula (L-c-i) : (L-c-i), or a stereoisomer thereof, wherein:
  • L 1c is C 2-10 linear alkylene, wherein 1 , 2, or 3 methylene units are replaced with -O-, -NH-, - NHC(O)-, or -C(O)NH-;
  • L 2c is -O- or a saturated C 2-10 linear alkylene, wherein 1 , 2, or 3 methylene units are replaced with -O-, -NH-, -NHC(O)-, or -C(O)NH-; p is 1 or 2; and m is 1 or 2; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L 1c of Formula (L-c) or (L-c-i) is selected from wherein: j is 1 , 2, 3, 4, 5, 6, 7, 8, or 9; k is O, 1 , 2, 3, 4, 5, 6, 7, or 8; the sum of j and k is 1 , 2, 3, 4, 5, 6, 7, 8, or 9; q is 1 , 2, 3, 4, 5, 6, or 7; r is 1 , 2, 3, 4, 5, 6, or 7; s is 0, 1 , 2, 3, 4, 5, or 6; the sum of q, r, and s is 2, 3, 4, 5, 6, 7, or 8; t is 1 , 2, 3, 4, or 5; u is 1 , 2, 3, 4, or 5; v is 1 , 2, 3, 4, or 5; w is 0, 1 , 2, 3, or 4; the sum of t, u, v, and w is 3, 4, 5, 6, or 7; and
  • X 1 , X 2 and X 3 are independently -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to the C(O) group of Formula (L-c) or (L-c-i), and represents a covalent bond to the ring of Formula (L-c) or (L-c-i).
  • L 2c of Formula (L-c) or (L-c-i) is selected from wherein: j is 0, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; k is O, 1 , 2, 3, 4, 5, 6, 7, 8, or 9; the sum of j and k is 1 , 2, 3, 4, 5, 6, 7, 8, or 9; q is 0, 2, 3, 4, 5, 6, or 7; r is 1 , 2, 3, 4, 5, 6, 7, or 8; s is 0, 1 , 2, 3, 4, 5, 6, or 7; the sum of q, r, and s is 1 , 2, 3, 4, 5, 6, 7, or 8; t is 0, 1 , 2, 3, 4, or 5; u is 1 , 2, 3, 4, 5, or 6; v is 1 , 2, 3, 4, 5, or 6; w is 0, 1 , 2, 3, 4, or 5; the sum of t, u, v, and w is 2, 3, 4, 5, 6, or 7; and
  • X 1 , X 2 and X 3 are independently -O-, -NH-, -NHC(O)-, or -C(O)NH-; wherein represents a covalent bond to the ring of Formula (L-c) or (L-c-i), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-c) selected from the group consisting of:
  • L is a divalent linker of Formula (L-d): wherein:
  • L 1d is C 12-31 linear alkylene, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L 1d is a C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , or C 31 linear alkylene, wherein 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)- , or -NHC(O)-NH-.
  • L 1d is C 12-22 linear alkylene, for example, C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , or C 22 , wherein 1,2,3, 4, or 5 methylene units are replaced with -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-.
  • L 1d of Formula (L-d) is selected from wherein: j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; kis 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; the sum of j and kis 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; r is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; the sum of q, r, and s is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; t is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; u is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17; v is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17
  • X 1 , X 2 , X 3 , X 4 , and X 5 are independently -NH-, -O-, -C(O)NH-, -NHC(O)-, or -NHC(O)-NH-; wherein represents a covalent bond to the C(O) group of Formula (L-d), and represents a covalent bond to the methylene group of Formula (I).
  • L 1d of Formula (L-d) is wherein n is 4, 5, 6, 7, 8, 9, or 10; wherein represents a covalent bond to the C(O) group of Formula (L-d), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-d) selected from the group consisting of:
  • L is a divalent linker of Formula (L-e): wherein: n is an integer of 3 to 50; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • n of Formula (L-e) is 3 to 25, 3 to 10, 3 to 8, 3 to 7, 3 to 5, or 3 to 4. In another embodiment, n of Formula (L-e) is 5 to 22, 7 to 15, or 9 to 13. In another embodiment, n of Formula (L-e) is 3, 4, 5, 7, 8, 11 , 22, or 50.
  • L is a divalent linker of Formula (L-f): (L-f), or a stereoisomer thereof, wherein:
  • L 1f is a bond; C 1-6 linear alkylene, wherein 0, 1 , or 2 methylene units are replaced with -O-, - NH-, or -C(O)-; or -(C 3-6 cycloalkylene)-NHC(O)-;
  • L 2f is a bond, -NHC(O)-, -C(O)NH-, or a C 1-6 linear alkylene, wherein 0, 1 , or 2 methylene units are replaced with -O-; and each of Z 1 and Z 2 is independently N or CH; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L 1f of Formula (L-f) is selected from wherein: j is 1 , 2, 3, 4, or 5; k is 0, 1 , 2, 3, or 4; the sum of j and k is 1 , 2, 3, 4, or 5; q is 1 , 2, or 3; r is 1 , 2, or 3; s is 0, 1 , 2; the sum of q, r, and s is 2, 3, or 4; and
  • X 1 and X 2 are independently -O-, -NH-, or -C(O)-; or -(C 3-6 cycloalkylene)-NHC(O)-; wherein represents a covalent bond to the C(O) group of Formula (L-f), and represents a covalent bond to the ring of Formula (L-f).
  • L 2f of Formula (L-f) is selected from wherein: j is 1 , 2, 3, 4, or 5; k is 0, 1 , 2, 3, or 4; the sum of j and k is 1 , 2, 3, 4, or 5; q is 1 , 2, or 3; r is 1 , 2, or 3; s is 0, 1 , 2; and the sum of q, r, and s is 2, 3, or 4; wherein represents a covalent bond to the ring of Formula (L-f), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-f) selected from the group consisting of:
  • L is a divalent linker of Formula (L-g): wherein:
  • Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms
  • L 1g is a bond, -CH 2 -, -NH-, or -O-;
  • L 2g is wherein n is 1 , 2, 3, 4, or 5, and represents a covalent bond to L 1g ; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-g-i) : wherein:
  • L 1g is a bond, -CH 2 -, -NH-, or -O-;
  • L 2g is wherein n is 1 , 2, 3, 4, or 5, and represents a covalent bond to
  • L 1g ; Z 1 , Z 2 , and Z 3 are each independently selected from N or CH, provided that one or two of Z 1 , Z 2 , and Z 3 is N; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-g) selected from the group consisting of:
  • L is a divalent linker of Formula (L-h): stereoisomer thereof, wherein: each Z 1 is independently N or CH; L 1h is a bond, -C(O)-, -C(O)-NH-, or -NHC(O)-;
  • L 2h is C 2-10 linear alkylene o r , wherein n is 1 , 2, 3, or 4, and represents a covalent bond to L 1h and represents a covalent bond to L 3h ;
  • L 3h is a bond, -C(O)CH 2 -, -O-(C 3.6 cycioaikylene)-0-, or -C(O)NH(CH 2 ) 3 OCH 2 -;
  • L 4h is a bond, -C(O)-, -CH 2 C(O)-, or -C(O)CH 2 -; and m is 1 , 2, or 3; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-h) selected from the group consisting of:
  • L is a divalent linker of Formula (L-i):
  • L 1 ' is a bond, C1-12 linear alkylene, or , wherein n is 1 , 2, 3, 4, or 5, and represents a covalent bond to L 3 ' and represents a covalent bond to NH;
  • L 2 ' is a bond, C1-12 linear alkylene, or , wherein n is 1 , 2, 3, 4, or 5, and represents a covalent bond to HN; and L 3 ' is a bond or -C(O)-; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-i) selected from the group consisting of:
  • L is a divalent linker of Formula (L-j): (L-j), or a stereoisomer thereof, wherein:
  • Z 1 is C, CH, or N; each of Z 2 , Z 3 , Z 4 and Z 5 is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N;
  • L 1i is -NH-, -C(O)NH-, -NHC(O)-, or -O-;
  • L 2j is C 1-6 linear alkylene or , wherein n is 1 or 2, and represents a covalent bond to L 1j ; and represents a single bond or a double bond; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-j) selected from the group consisting of:
  • L is a divalent linker of Formula (L-k):
  • Ring A is phenyl or a 5 or 6 membered heteroarylene having 1 or 2 nitrogen ring atoms; each of Z 1 and Z 2 is independently CH or N;
  • L 1k is a bond, -C(O)-, -C(O)NH- or -NHC(O)-;
  • L 2k is a C 3-8 straight chain alkylene or , wherein n is 1 , 2, or 3, and represents a covalent bond to L 1 k ; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-k) selected from the group consisting of:
  • L is a divalent linker of Formula (L-m): (L-m), or a stereoisomer thereof, wherein:
  • Z 1 is CH or N; m is 1 or 2; p is 1 or 2;
  • L 1m is a bond, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O) 2 NH- or -NHS(O) 2 -;
  • L 2m is C 3-6 linear alkylene, C 3-6 cycloalkylene, or wherein n is 1 or 2, and represents a covalent bond to L 1 m ; wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-m) selected from the group consisting of:
  • L is a divalent linker of Formula (L-n-i): wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-n-ii): wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-n-iii): wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • L is a divalent linker of Formula (L-n-iv): wherein represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the N atom of Formula (I), and represents a covalent bond to the methylene group of Formula (I).
  • Y is selected from a bond; -NH-; -(C 1-12 alkylene)- , wherein 1 , 2, or 3 methylene units are replaced with -O-, -NH-, -C(O)-, -NHC(O)-, -C(O)NH- , -(C 3-6 cycloalkylene)-, -(C 3-6 cycloalkenylene)-, 3- to 6-membered heterocycloalkylene, arylene, or heteroarylene; or -(C 2-12 alkenylene)-, wherein 1 , 2, or 3 methylene units are replaced with -O-, -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, -(C 3.6 cycloalkylene)-, -(C 3-6 cycloalkenylene)-, 3- to 6-membered heterocycloalkylene, arylene, or heteroarylene;
  • Y is selected from a bond; -NH-; -(C 1-6 alkylene)-O-; -(C 1-6 alkenylene)-O-; -(C 1-6 alkylene)-C(O)-; -(C 1-6 alkenylene)-C(O)-; phenylene; piperidinylene; - (C 1-6 alkylene)-O-phenylene-; -(C 1-6 alkenylene)-O-piperidinylene; -(C1-5 alkylene)-NH-, wherein 0, 1 , or 2 methylene units are replaced with -O-; -NH-(C 1-5 alkylene)-NH-; -(C 3-6 cycloalkylene)-NH-; -(C 3-6 cycloalkenylene)-NH-; or , wherein Y 1a is a bond, -O-, -NH-, -NHC(O)-, -C(O)-,
  • Y is selected from the group consisting of:
  • R 1 is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, or t- butyl. In another embodiment, R 1 is methyl. In another embodiment, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the compound of Formula (I) is selected from a compound as listed in Table 1 :
  • the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is C 1-4 alkyl or C 3-6 cycloalkyl.
  • R 1 is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, or t- butyl. In another embodiment, R 1 is methyl. In another embodiment, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, the compound of Formula (II) is:
  • composition “comprising” encompasses “including” or “consisting” e.g. a composition “comprising” X may consist exclusively of X or may include something additional, e.g., X + Y.
  • pathogenic cells includes a cell subset that causes or is capable of causing disease. Examples of pathogenic cells include, but are not limited to, cancer or tumor cells.
  • composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • an amount of a compound, or antibody, or antigen-binding portion thereof, according to the invention refers to an amount of a compound, or antibody, or antigen-binding portion thereof, according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.
  • the amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
  • alkyl represents a saturated, linear or branched hydrocarbon moiety having the specified number of carbon atoms.
  • C 1-3 alkyl refers to an unsubstituted alkyl moiety containing 1 , 2 or 3 carbon atoms; exemplary alkyls include methyl, ethyl and propyl.
  • alkylene represents a saturated, linear or branched hydrocarbon moiety having the specified number of carbon atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms.
  • C 1-3 alkylene refers to an unsubstituted alkyl moiety containing 1 , 2 or 3 carbon atoms with two points of attachment; exemplary C 1-3 alkylene groups include methylene, ethylene and propylene.
  • alkenyl represents an unsaturated, linear or branched hydrocarbon moiety having the specified number of carbon atoms.
  • C 2 -6 alkenyl refers to an unsubstituted alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms; exemplary alkenyls include propenyl, butenyl, pentenyl and hexenyl.
  • alkenylene represents an unsaturated, linear or branched hydrocarbon moiety having the specified number of carbon atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms.
  • C2-6 alkenylene refers to an unsubstituted alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms with two points of attachment; exemplary C2-6 alkenylene groups include propenylene, butenylene, pentenylene and hexenylene.
  • cycloalkyl represents a saturated cyclic hydrocarbon moiety having the specified number of carbon atoms.
  • C 3-6 cycloalkyl refers to an unsubstituted cycloalkyl moiety containing 3, 4, 5 or 6 carbon atoms; exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkylene represents a saturated cyclic hydrocarbon moiety having the specified number of carbon atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms.
  • C4-6 cycloalkylene refers to an unsubstituted cycloalkylene moiety containing 4, 5, or 6 carbon atoms with two points of attachment.
  • Exemplary cycloalkylene groups include cyclobutane-1 ,3-diyl, cyclopentane-1 ,3- diyl, cyclohexane-1 ,3-diyl, or cyclohexane-1 ,4-diyl.
  • cycloalkenylene represents an unsaturated cyclic hydrocarbon moiety having the specified number of carbon atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms.
  • C 3-6 cycloalkenylene refers to an unsubstituted cycloalkenylene moiety containing 3, 4, 5, or 6 carbon atoms with two points of attachment.
  • heterocycloalkylene refers to a saturated cyclic hydrocarbon moiety containing 1 or 2 heteroatoms independently selected from oxygen, sulphur or nitrogen atoms, with two points of attachment. The two points of attachment can be from the same or different carbon atoms.
  • 3- to 6-membered heterocycloalkylene refers to a 3- to 6-membered saturated cyclic moiety containing 2, 3, 4 or 5 carbon atoms in addition to 1 or 2 oxygen, sulphur or nitrogen atoms, with two points of attachment.
  • the 3- to 6-membered heterocycloalkylene group contains 1 oxygen or nitrogen atom.
  • such group contains 3 carbon atoms and 1 oxygen or nitrogen atom, such as azetidindiyl or oxetandiyl.
  • such group contains 4 or 5 carbon atoms and 1 oxygen or nitrogen atom, such as tetrahydrofurandiyl, tetrahydropyrandiyl, pyrrolidindiyl or piperidindiyl.
  • bridged bicyclic cycloalkylene refers to a saturated bicyclic hydrocarbon moiety having at least one bridge, with two points of attachment.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). The two points of attachment can be from the same or different carbon atoms.
  • C 7-9 bridged bicyclic cycloalkylene refers to an unsubstituted bridged bicyclic cycloalkylene moiety containing 7, 8, or 9 carbon atoms with two points of attachment.
  • arylene refers to a monocyclic or bicyclic ring system wherein at least one ring in the system is aromatic, with two points of attachment.
  • exemplary arylene groups include phenylene, biphenylene, naphthylene, and anthracylene.
  • heteroarylene refers to a monocyclic or bicyclic ring system wherein at least one ring in the system is aromatic, and having, in addition to carbon atoms, from one to five heteroatoms independently selected from oxygen, sulphur or nitrogen atoms, with two points of attachment.
  • the term “5- to 6-membered heteroarylene” refers to a 5- to 6-membered cyclic aromatic moiety containing 2, 3, 4 or 5 carbon atoms in addition to 1 , 2, or 3 heteroatoms independently selected from oxygen, sulphur or nitrogen atoms, with two points of attachment.
  • salts, including pharmaceutically acceptable salts, of the compounds according to Formulae (I) and (II) may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formulae (I) and (II) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to salts, including pharmaceutically-acceptable salts, of the compounds according to Formulae (I) and (II). The invention is further directed to free or unsalted compounds of Formulae (I) and (II).
  • salts including pharmaceutically acceptable salts, of the compounds of the invention are readily prepared by those of skill in the art.
  • Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1 ,2-disulfonate (edisy
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N'- dibenzylethylenediamine), b/s-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolidine-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium
  • the compounds according to Formulae (I) and (II) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in a compound of Formulae (I) or (II) or in any chemical structure illustrated herein, if not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formulae (I) and (II) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • a mixture of stereoisomers in which the relative configuration of all of the stereocenters is known may be depicted using the symbol “&” together with an index number (e.g., “&1 ”).
  • a group of two stereogenic centers labeled with the symbol “&1 ” represents a mixture of two possible stereoisomers in which the two stereogenic centers have a relative configuration as depicted.
  • Divalent groups are groups having two points of attachment. For all divalent groups, unless otherwise specified, the orientation of the group is implied by the direction in which the formula or structure of the group is written.
  • Ranges provided herein include all values within a particular range described and values about an endpoint for a particular range.
  • Concentrations described herein are determined at ambient temperature and pressure. This may be, for example, the temperature and pressure at room temperature or in a particular portion of a process stream. Preferably, concentrations are determined at a standard state of 25 S C and 1 bar of pressure.
  • the compounds of Formulae (I) and (II) as disclosed herein are heterobifunctional synthetic agents designed such that one terminus interacts with a cell surface integrin ⁇ V ⁇ 6 target, while the other terminus binds a specific antibody. More specifically, the ARM simultaneously binds the cell surface integrin ⁇ V ⁇ 6 target as well as the specific antibody.
  • This ternary complex directs immune surveillance to integrin ⁇ V ⁇ 6-expressing tissue/cells and unites the mechanisms of antibody function with the dose-control of small molecules. This mechanism may include antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), or complement dependant cytotoxicity (CDC), and preferably includes ADCC.
  • ADCC antibody dependent cellular cytotoxicity
  • ADCP antibody dependent cellular phagocytosis
  • CDC complement dependant cytotoxicity
  • the same Fc receptor expressing immune cells that initiate destruction of the ARM/antibody tagged cells also participate in presentation of endogenous antigens for the potential for long term
  • the compounds of Formulae (I) and (II) as disclosed herein include an integrin ⁇ V ⁇ 6- binding moiety that is capable of binding integrin ⁇ V ⁇ 6 present on the surface of a cell.
  • the integrin ⁇ V ⁇ 6 is expressed on a pathogenic cell.
  • the pathogenic cell is a tumor cell or cancer cell.
  • the tumor cells or cancer cells are solid tumor cells.
  • the tumor cells or cancer cells are lung cancer cells (e.g., non-small cell lung cancer (NSCLC) cells), hepatocellular carcinoma (HCC) cells, colorectal cancer (CRC) cells, cervical cancer cells (e.g., cervical squamous cell carcinoma (CESC) cells), head and neck cancer cells (e.g., head and neck squamous cell carcinoma (HNSC) cells), pancreatic cancer cells, prostate cancer cells (e.g., metastatic castration-resistant prostate cancer (mCRPC) cells), ovarian cancer cells, endometrial cancer cells, bladder cancer cells, or breast cancer cells, preferably breast cancer cells, lung cancer cells, head and neck cancer cells, or cervical cancer cells.
  • lung cancer cells e.g., non-small cell lung cancer (NSCLC) cells
  • HCC hepatocellular carcinoma
  • CRC colorectal cancer
  • cervical cancer cells e.g., cervical squamous cell carcinoma (CESC) cells
  • head and neck cancer cells e.g.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formulae (I) or (II) as disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the present disclosure provides an antibody, or antigen-binding fragment thereof, that binds to a cotinine moiety.
  • anti-cotinine antibody or antigen-binding fragment thereof refers to an antibody, or antigen binding fragment thereof that binds to a cotinine moiety.
  • Cotinine has the following structure:
  • the term “cotinine moiety” refers to cotinine or an analog of cotinine.
  • Compounds of Formulae (I) and (II) described herein comprise a cotinine moiety linked via a linker to an integrin ⁇ V ⁇ 6-binding moiety.
  • the cotinine moiety has the following structure: wherein R 1 is C 1-4 alkyl or C 3-6 cycloalkyl.
  • R 1 is methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, or t-butyl.
  • R 1 is methyl.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • antibody is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulph ide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holl iger and Hudson, Nature Biotechnology, 2005, 23(9): 1126-1136).
  • DAB domain antibody
  • the term, full, whole or intact antibody refers to a heterotetrameric glycoprotein with an approximate molecular weight of 150,000 daltons.
  • An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds. This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment.
  • the Fab fragment is composed of the variable domain at the aminoterminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CH1 (heavy) and CL (light).
  • the Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions.
  • the Fc may elicit effector functions by binding to receptors on immune cells or by binding C1q, the first component of the classical complement pathway.
  • the five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called p, a, y, s and 6 respectively, each heavy chain can pair with either a K or A light chain.
  • the majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG (lgG1 , lgG2, lgG3 and lgG4), the sequences of which differ mainly in their hinge region.
  • CDRs are defined as the complementarity determining region amino acid sequences of an antibody or antigen binding fragment thereof. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.
  • variable domain sequences and variable domain regions within full-length antigen binding sequences are numbered according to the Kabat numbering convention.
  • the terms “CDR”, “CDRL1 ”, “CDRL2”, “CDRL3”, “CDRH1 ”, “CDRH2”, “CDRH3” used in the Examples follow the Kabat numbering convention.
  • Kabat et al. Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987).
  • Table 2 below represents one definition using each numbering convention for each CDR or binding unit. It should be noted that some of the CDR definitions may vary depending on the individual publication used.
  • the anti-cotinine antibody is humanized.
  • the Fc region of the anti-cotinine antibody is modified to increase ADCC activity, ADCP activity, and/or CDC activity, suitable modifications of which are provided below.
  • the Fc region of the anti-cotinine antibody is modified to increase ADCC activity.
  • Fc engineering methods can be applied to modify the functional or pharmacokinetics properties of an antibody. Effector function may be altered by making mutations in the Fc region that increase or decrease binding to C1 q or Fey receptors and modify CDC or ADCC activity respectively. Modifications to the glycosylation pattern of an antibody can also be made to change the effector function. The in vivo half-life of an antibody can be altered by making mutations that affect binding of the Fc to the FcRn (neonatal Fc receptor).
  • effector function refers to one or more of antibody-mediated effects including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-mediated complement activation including complement-dependent cytotoxicity (CDC), complementdependent cell-mediated phagocytosis (CDCP), antibody dependent complement-mediated cell lysis (ADCML), and Fc-mediated phagocytosis or antibody-dependent cellular phagocytosis (ADCP).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • DCP complementdependent cell-mediated phagocytosis
  • ADCML antibody dependent complement-mediated cell lysis
  • FcR Fc receptors
  • FcR Fc receptors
  • FcR Fc receptors
  • FcR FcyRI
  • FcyRII CD32
  • FcyRIII CD16
  • FcRn C1 q
  • type II Fc receptors FcRs
  • Significant biological effects can be a consequence of effector functionality.
  • the ability to mediate effector function requires binding of the antigen binding protein or antibody to an antigen and not all antigen binding proteins or antibodies will mediate every effector function.
  • Effector function can be assessed in a number of ways including, for example, evaluating ADCC effector function of antibody coated to target cells mediated by Natural Killer (NK) cells via FcyRIII, or monocytes/macrophages via FcyRI, or evaluating CDC effector function of antibody coated to target cells mediated by complement cascade via C1q.
  • NK Natural Killer
  • an antibody, or antigen binding fragment thereof, of the present invention can be assessed for ADCC effector function in a Natural Killer cell assay.
  • Examples of assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38.
  • Antibodies, or antigen binding fragments thereof, of the present invention may include any of the following mutations.
  • Enhanced CDC Fc engineering can be used to enhance complement-based effector function.
  • Fc engineering can be used to enhance complement-based effector function.
  • K326W/E333S; S267E/H268F/S324T; and lgG1/lgG3 cross subclass can increase C1q binding;
  • E345R Diebolder et al., Science, 2014, 343: 1260-1293
  • E345R/E430G/S440Y results in preformed IgG hexamers (Wang et al., Protein Cell, 2018, 9(1 ): 63-73).
  • Fc engineering can be used to enhance ADCC. For example (with reference to lgG1 ), F243L/R292P/Y300LA/305I/P396L; S239D/I332E; and
  • S298A/E333A/K334A increase FcyRllla binding
  • S239D/I332E/A330L increases FcyRllla binding and decreases FcyRllb binding
  • G236A/S239D/I332E improves binding to FcyRlla, improves the FcyRlla/FcyRllb binding ratio (activating/inhibitory ratio), and enhances phagocytosis of antibody-coated target cells by macrophages.
  • Fc engineering can be used to enhance ADCP.
  • G236A/S239D/I332E increases FcyRlla binding and increases FcyRllla binding (Richards, J. et al., Mol. Cancer Ther., 2008, 7: 2517-2527).
  • Fc engineering can be used to increase co-engagement with FcRs. For example (with reference to lgG1 ), S267E/L328F increases FcyRllb binding; N325S/L328F increases FcyRlla binding and decreases FcyRllla binding Wang et al., Protein Cell, 2018, 9(1 ): 63-73).
  • an antibody, or antigen binding fragment thereof, of the present invention may comprise a heavy chain constant region with an altered glycosylation profile, such that the antibody, or antigen binding fragment thereof, has an enhanced effector function, e.g., enhanced ADCC, enhanced CDC, or both enhanced ADCC and CDC.
  • an enhanced effector function e.g., enhanced ADCC, enhanced CDC, or both enhanced ADCC and CDC.
  • suitable methodologies to produce an antibody, or antigen binding fragment thereof, with an altered glycosylation profile are described in WO 2003/011878, WO 2006/014679 and EP1229125.
  • an antibody, or antigen binding fragment thereof comprising a chimeric heavy chain constant region.
  • the antibody, or antigen binding fragment thereof comprises an lgG1/lgG3 chimeric heavy chain constant region, such that the antibody, or antigen binding fragment thereof, has an enhanced effector function, for example enhanced ADCC or enhanced CDC, or enhanced ADCC and CDC functions.
  • a chimeric antibody, or antigen binding fragment thereof, of the invention may comprise at least one CH2 domain from lgG3.
  • the antibody, or antigen binding fragment thereof comprises one CH2 domain from lgG3 or both CH2 domains may be from lgG3.
  • the chimeric antibody, or antigen binding fragment thereof comprises an IgG 1 CH1 domain, an lgG3 CH2 domain, and an lgG3 CH3 domain. In a further embodiment, the chimeric antibody, or antigen binding fragment thereof, comprises an lgG1 CH1 domain, an lgG3 CH2 domain, and an lgG3 CH3 domain except for position 435 that is histidine.
  • the chimeric antibody, or antigen binding fragment thereof comprises an lgG1 CH1 domain and at least one CH2 domain from lgG3.
  • the chimeric antibody, or antigen binding fragment thereof comprises an lgG1 CH1 domain and the following residues, which correspond to lgG3 residues, in a CH2 domain: 274Q, 276K, 296F, 300F and 339T.
  • the chimeric antibody, or antigen binding fragment thereof also comprises 356E, which corresponds to an lgG3 residue, within a CH3 domain.
  • the antibody, or antigen binding fragment thereof also comprises one or more of the following residues, which correspond to lgG3 residues within a CH3 domain: 358M, 384S, 392N, 397M, 422I, 435R, and 436F.
  • Also provided is a method of producing an antibody, or antigen binding fragment thereof, according to the invention comprising the steps of: a) culturing a recombinant host cell comprising an expression vector comprising a nucleic acid sequence encoding a chimeric Fc region having both lgG1 and lgG3 Fc region amino acid residues (e.g. as described above); and b) recovering the antibody, or antigen binding fragment thereof.
  • Such methods for the production of antibody, or antigen binding fragment thereof, with chimeric heavy chain constant regions can be performed, for example, using the COMPLEGENT technology system available from BioWa, Inc. (Princeton, NJ) and Kyowa Hakko Kirin Co., Ltd.
  • the COMPLEGENT system comprises a recombinant host cell comprising an expression vector in which a nucleic acid sequence encoding a chimeric Fc region having both lgG1 and lgG3 Fc region amino acid residues is expressed to produce an antibody, or antigen binding fragment thereof, having enhanced CDC activity, i.e.
  • CDC activity is increased relative to an otherwise identical antibody, or antigen binding fragment thereof, lacking such a chimeric Fc region, as described in WO 2007/011041 and US 2007/0148165, each of which are incorporated herein by reference.
  • CDC activity may be increased by introducing sequence specific mutations into the Fc region of an IgG chain.
  • the present invention also provides a method of producing an antibody, or antigen binding fragment thereof, according to the invention comprising the steps of: a) culturing a recombinant host cell comprising an expression vector comprising a nucleic acid encoding the antibody, or antigen binding fragment thereof, optionally wherein the FUT8 gene encoding alpha-1 ,6-fucosyltransferase has been inactivated in the recombinant host cell; and b) recovering the antibody, or antigen binding fragment thereof.
  • Such methods for the production of an antibody, or antigen binding fragment thereof can be performed, for example, using the POTELLIGENT technology system available from BioWa, Inc. (Princeton, NJ) in which CHOK1 SV cells lacking a functional copy of the FUT8 gene produce monoclonal antibodies having enhanced ADCC activity that is increased relative to an identical monoclonal antibody produced in a cell with a functional FUT8 gene as described in US Patent No. 7,214,775, US Patent No. 6,946,292, WO 00/61739 and WO 02/31240, all of which are incorporated herein by reference. Those of ordinary skill in the art will also recognize other appropriate systems.
  • the antibody, or antigen binding fragment thereof is produced in a host cell in which the FUT8 gene has been inactivated. In a further embodiment, the antibody, or antigen binding fragment thereof, is produced in a -I- FUT8 host cell. In a further embodiment, the antibody, or antigen binding fragment thereof, is afucosylated at Asn297 (lgG1 ).
  • an antibody, or antigen binding fragment thereof comprising a heavy chain constant region that comprises a both a mutated and chimeric heavy chain constant region, individually described above.
  • an antibody, or antigen binding fragment thereof comprising at least one CH2 domain from lgG3 and one CH2 domain from lgG1 , and wherein the lgG1 CH2 domain has one or more mutations at positions selected from 239, 332 and 330 (for example the mutations may be selected from S239D, I332E and A330L), such that the antibody, or antigen binding fragment thereof, has enhanced effector function, e.g.
  • the lgG1 CH2 domain has the mutations S239D and I332E. In another embodiment, the lgG1 CH2 domain has the mutations S239D, A330L, and I332E.
  • an antibody, or antigen binding fragment thereof comprising both a chimeric heavy chain constant region and an altered glycosylation profile, as individually described above.
  • the antibody, or antigen binding fragment thereof comprises an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less.
  • the heavy chain constant region comprises at least one CH2 domain from lgG3 and one CH2 domain from lgG1 and has an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less, for example wherein the antibody, or antigen binding fragment thereof, is defucosylated.
  • Said antibody, or antigen binding fragment thereof has an enhanced effector function, e.g. enhanced ADCC or enhanced CDC, or enhanced ADCC and enhanced CDC, in comparison to an equivalent antibody, or antigen binding fragment thereof, with an lgG1 heavy chain constant region lacking said glycosylation profile.
  • the antibody, or antigen binding fragment thereof has at least one lgG3 heavy chain CH2 domain and at least one heavy chain constant domain from lgG1 wherein both IgG CH2 domains are mutated in accordance with the limitations described herein.
  • a method of producing an antibody, or antigen binding fragment thereof comprising the steps of: a) culturing a recombinant host cell containing an expression vector comprising a nucleic acid sequence encoding a chimeric Fc domain having both lgG1 and lgG3 Fc domain amino acid residues (e.g. as described above); and wherein the FUT8 gene encoding alpha- 1 ,6-fucosyltransferase has been inactivated in the recombinant host cell; and b) recovering the antibody, or antigen binding fragment thereof.
  • Such methods for the production of an antibody, or antigen binding fragment thereof can be performed, for example, using the ACCRETAMAB technology system available from BioWa, Inc. (Princeton, NJ) that combines the POTELLIGENT and COMPLEGENT technology systems to produce an antibody, or antigen binding fragment thereof, having both enhanced ADCC and CDC activity relative to an otherwise identical monoclonal antibody that lacks a chimeric Fc domain and that is fucosylated.
  • the ACCRETAMAB technology system available from BioWa, Inc. (Princeton, NJ) that combines the POTELLIGENT and COMPLEGENT technology systems to produce an antibody, or antigen binding fragment thereof, having both enhanced ADCC and CDC activity relative to an otherwise identical monoclonal antibody that lacks a chimeric Fc domain and that is fucosylated.
  • an antibody, or antigen binding fragment thereof comprising a mutated and chimeric heavy chain constant region wherein said antibody, or antigen binding fragment thereof, has an altered glycosylation profile such that the antibody, or antigen binding fragment thereof, has enhanced effector function, e.g. enhanced ADCC or enhanced CDC, or both enhanced ADCC and CDC.
  • the mutations are selected from positions 239, 332 and 330, e.g. S239D, I332E and A330L.
  • the heavy chain constant region comprises at least one CH2 domain from lgG3 and one CH1 domain from lgG1.
  • the heavy chain constant region has an altered glycosylation profile such that the ratio of fucose to mannose is 0.8:3 or less, e.g. the antibody, or antigen binding fragment thereof, is defucosylated, such that said antibody, or antigen binding fragment thereof, has an enhanced effector function in comparison with an equivalent non-chimeric antibody, or antigen binding fragment thereof, lacking said mutations and lacking said altered glycosylation profile.
  • the anti-cotinine antibody, or antigen binding fragment thereof comprises a heavy chain CDR1 having SEQ ID NO: 1 , a heavy chain CDR2 having SEQ ID NO: 2, a heavy chain CDR3 having SEQ ID NO: 3, a light chain CDR1 having SEQ ID NO: 4, a light chain CDR2 having SEQ ID NO: 5, and a light chain CDR3 having SEQ ID NO: 6.
  • the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1 , a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.
  • the anti-cotinine antibody is of lgG1 isotype.
  • the anti- cotinine antibody is of lgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity.
  • the anti-cotinine antibody is of lgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D/I332E or S239D/I332E/A330L, wherein residue numbering is according to the EU Index.
  • the anti-cotinine antibody is of lgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D/I332E, wherein residue numbering is according to the EU Index.
  • the anti-cotinine antibody, or antigen binding fragment thereof comprises a heavy chain variable region (VH) having SEQ ID NO: 7, a light chain variable region (VL) having SEQ ID NO: 8.
  • the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.
  • the anti-cotinine antibody is of lgG1 isotype.
  • the anti-cotinine antibody is of lgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity.
  • the anti- cotinine antibody is of lgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D/I332E or S239D/I332E/A330L, wherein residue numbering is according to the EU Index.
  • the anti- cotinine antibody is of lgG1 isotype comprising a substitution in an Fc region to increase or enhance ADCC activity, wherein the substitution is S239D/I332E, wherein residue numbering is according to the EU Index.
  • the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an anti-cotinine antibody, or antigen binding fragment thereof as disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the present disclosure also provides a combination comprising the compound of Formulae (I) or (II) as disclosed herein, preferably a compound of Formula (I) as disclosed herein, and an anti-cotinine antibody, or antigen-binding fragment thereof as disclosed herein.
  • the compound of Formulae (I) or (II) and anti-cotinine antibody, or antigen binding fragment thereof can be present in the same composition or in separate compositions.
  • a combination comprises a pharmaceutical composition comprising the compound of Formulae (I) or (II) as disclosed herein, preferably a compound of Formula (I) as disclosed herein, and an anti-cotinine antibody, or antigen binding fragment thereof as disclosed herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a combination comprises a first pharmaceutical composition comprising a compound of Formulae (I) or (II) as disclosed herein, preferably a compound of Formula (I) as disclosed herein, and a pharmaceutically acceptable carrier, diluent, or excipient; and a second pharmaceutical composition comprising an anti-cotinine antibody or antigen binding fragment thereof as disclosed herein, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof are capable of simultaneously binding a cell surface-expressed integrin ⁇ V ⁇ 6 and an anti-cotinine antibody, or antigen binding fragment thereof to form a ternary complex for the treatment and/or prevention of diseases or disorders associated with integrin ⁇ V ⁇ 6-expressing cells.
  • the present disclosure provides a method of treating and/or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the disease or disorder is selected from a cancer.
  • the compound and the antibody, or antigen-binding fragment thereof are administered simultaneously.
  • the compound and the antibody, or antigen-binding fragment thereof are administered simultaneously from a single composition, including as a fixed-dose composition or by pre-mixing the compound and the antibody, or antigen-binding fragment thereof, prior to administration.
  • the compound and the antibody, or antigen-binding fragment thereof can be pre-mixed about 2 seconds to about 30 seconds, about 30 seconds to about 2 minutes, about 2 minutes to about 10 minutes, about 10 minutes to about 30 minutes, or about 30 minutes to about 2 hours prior to administration.
  • the compound and the antibody, or antigen-binding fragment thereof are administered simultaneously from two separate compositions.
  • the compound and the antibody, or antigen-binding fragment thereof are administered sequentially.
  • the compound and the antibody, or antigen-binding fragment thereof may be administered by the same route or may be administered by different routes.
  • the compound and the antibody, or antigen-binding fragment thereof are both administered intraveneously or subcutaneously, in the same composition or in separate compositions.
  • the compound is administered orally and the antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously.
  • the compound and the antibody, or antigen-binding fragment thereof are administered in a molar ratio of compound to antibody, or antigen-binding fragment thereof, of about 2:1 , about 1 .8:1 , about 1 .6:1 , about 1 .5:1 , about 1 .4:1 , about 1 .3:1 , about 1 .2:1 , about 1 :1 , about 1 :1 .2, about 1 :1 .3, about 1 :1 .4, about 1 :1 .5, about 1 :1 .6, about 1 :1 .8, about 1 :2, about 2:1 to about 1 .5:1 , about 1 .5:1 to about 1 .2:1 , about 1 .2:1 to about 1 :1 , about 1 :1 to about 1 :1 .2, about 1 :1 .2 to about 1 :1 .5, or about 1 :1 .5 to about 1 :2.
  • the compound and the antibody, or antigen-binding fragment thereof are present as a combination in a molar ratio of compound to antibody, or antigenbinding fragment thereof, of about 2:1 , about 1.8:1 , about 1 .6:1 , about 1.5:1 , about 1 .4:1 , about 1 .3:1 , about 1 .2:1 , about 1 :1 , about 1 :1 .2, about 1 :1 .3, about 1 :1 .4, about 1 :1 .5, about 1 :1 .6, about 1 :1 .8, about 1 :2, about 2:1 to about 1 .5:1 , about 1.5:1 to about 1.2:1 , about 1.2:1 to about 1 :1 , about 1 :1 to about 1 :1 .2, about 1 :1 .2 to about 1 :1 .5, or about 1 :1 .5 to about 1 :2.
  • the compound and the antibody, or antigen-binding fragment thereof are administered at a dosage of compound of 0.0001 mg/kg to 1 mg/kg and antibody of 0.01 mg/kg to 100 mg/kg.
  • the compound is administered at a dosage of about 0.0001 mg/kg to about 0.0002 mg/kg, about 0.0002 mg/kg to about 0.0003 mg/kg, about 0.0003 mg/kg to about 0.0004 mg/kg, about 0.0004 mg/kg to about 0.0005 mg/kg, about 0.0005 mg/kg to about 0.001 mg/kg, about 0.001 mg/kg to about 0.002 mg/kg, about 0.002 mg/kg to about 0.003 mg/kg, about 0.003 mg/kg to about 0.004 mg/kg, about 0.004 mg/kg to about 0.005 mg/kg, about 0.005 mg/kg to about 0.01 mg/kg, about 0.01 mg/kg to about 0.02 mg/kg, about 0.02 mg/kg to about 0.
  • the compound and the antibody, or antigen-binding fragment thereof are administered at a dosage of compound of 0.007 mg to 70 mg and antibody of 0.7 mg to 7000 mg.
  • the compound is administered at a dosage of about 0.007 mg to about 0.01 mg, about 0.01 mg to about 0.02 mg, about 0.02 mg to about 0.03 mg, about 0.03 mg to about 0.04 mg, about 0.04 mg to about 0.05 mg, about 0.05 mg to about 0.1 mg, about 0.1 mg to about 0.2 mg, about 0.2 mg to about 0.3 mg, about 0.3 mg to about 0.4 mg, about 0.4 mg to about 0.5 mg, about 0.5 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, about 4 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg.
  • the compound and the antibody, or antigen-binding fragment thereof are administered in a molar ratio and/or dosage as described herein once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks for a period of one week to one year, such as a period of one week, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or twelve months.
  • the present disclosure provides a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof for use in therapy.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and anti-cotinine antibody, or antigen-binding fragment thereof can be used in treating or preventing a disease or disorder selected from a cancer.
  • the present disclosure provides a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof for the manufacture of a medicament.
  • the medicament can be used in treating or preventing a disease or disorder selected from a cancer.
  • the disease or disorder is mediated by integrin ⁇ V ⁇ 6 and/or is associated with integrin ⁇ V ⁇ 6-positive pathogenic cells.
  • integrin ⁇ V ⁇ 6-positive cell types are identified by testing for expression of integrin aV06 by immunohistochemistry or flow cytometry.
  • the disease or disorder is a cancer selected from lung cancer (e.g., non-small cell lung cancer (NSCLC)), hepatocellular carcinoma (HCC), colorectal cancer (CRC), cervical cancer (e.g., cervical squamous cell carcinoma (CESC)), head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSC)), pancreatic cancer, prostate cancer (e.g., metastatic castration-resistant prostate cancer (mCRPC)), ovarian cancer, endometrial cancer, bladder cancer, or breast cancer, preferably a cancer selected from breast cancer, lung cancer, head and neck cancer, or cervical cancer.
  • lung cancer e.g., non-small cell lung cancer (NSCLC)
  • HCC hepatocellular carcinoma
  • CRC colorectal cancer
  • cervical cancer e.g., cervical squamous cell carcinoma (CESC)
  • head and neck cancer e.g., head and neck squamous cell carcinoma (HNSC)
  • the disease or disorder is a solid tumor.
  • the disease or disorder is a solid tumor selected from lung cancer (e.g., NSCLC), HCC, CRC, cervical cancer (e.g., CESC), head and neck cancer (e.g., HNSC), pancreatic cancer, prostate cancer (e.g., mCRPC), ovarian cancer, endometrial cancer, bladder cancer, or breast cancer, preferably a solid tumor selected from breast cancer, lung cancer, head and neck cancer, or cervical cancer.
  • the disease or disorder is a PD-1 relapsed or refractory cancer, such as a PD-1 relapsed or refractory lung cancer (e.g., NSCLC), HCC, CRC, cervical cancer (e.g., CESC), head and neck cancer (e.g., HNSC), pancreatic cancer, prostate cancer (e.g., mCRPC), ovarian cancer, endometrial cancer, bladder cancer, or breast cancer, preferably a PD-1 relapsed or refractory breast cancer, lung cancer, head and neck cancer, or cervical cancer.
  • a PD-1 relapsed or refractory lung cancer e.g., NSCLC
  • HCC e.g., CRC
  • cervical cancer e.g., CESC
  • head and neck cancer e.g., HNSC
  • pancreatic cancer e.g., prostate cancer (e.g., mCRPC), ovarian cancer, endometrial cancer, bladder cancer, or breast
  • the disease or disorder is a non-solid cancer. In a further embodiment, the disease or disorder is a leukemia, a lymphoma, or a myeloma.
  • the present disclosure provides a method of increasing antibodydependent cell cytotoxicity (ADCC) of integrin ⁇ V ⁇ 6-expressing cells comprising contacting the cells with an effective amount of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the integrin ⁇ V ⁇ 6-binding moiety of the compound binds the integrin ⁇ V ⁇ 6 expressed on the cells.
  • ADCC antibodydependent cell cytotoxicity
  • the present disclosure provides a method of increasing antibody dependent cellular phagocytosis (ADCP) of integrin ⁇ V ⁇ 6-expressing cells comprising contacting the cells with an effective amount of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the integrin ⁇ V ⁇ 6-binding moiety of the compound binds the integrin ⁇ V ⁇ 6 expressed on the cells.
  • ADCP antibody dependent cellular phagocytosis
  • the present disclosure provides a method of increasing complement dependant cytotoxicity (CDC) of integrin ⁇ V ⁇ 6-expressing cells comprising contacting the cells with an effective amount of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the integrin ⁇ V ⁇ 6-binding moiety of the compound binds the integrin ⁇ V ⁇ 6 expressed on the cells.
  • CDC complement dependant cytotoxicity
  • the present disclosure provides a method of conditioning a patient for therapy with a chimeric antigen receptor (CAR) T cell therapy, comprising administering to a patient an effective amount of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof.
  • the compound of Formula (I), or pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof are administered in combination with the CAR-T cell therapy.
  • a compound of Formula (I), or pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof may be administered as a conditioning therapy or combination therapy to improve efficacy in treatment of solid tumor cancers.
  • a compound of Formula (I), or pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof may be administered as a neoadjuvant treatment for other therapies, including but not limited to immunotherapy, surgical resection, radiation, and/or chemotherapy.
  • the present disclosure provides a method of depleting integrin ⁇ V ⁇ 6-expressing cells comprising contacting the cells with the compound of Formula (I), or pharmaceutically acceptable salt thereof, and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the integrin ⁇ V ⁇ 6-binding moiety of the compound binds the integrin ⁇ V ⁇ 6 expressed on the cells.
  • the integrin ⁇ V ⁇ 6-expressing cells are pathogenic cells.
  • the pathogenic cell is a tumor cell or cancer cell.
  • the tumor cells or cancer cells are lung cancer cells (e.g., non-small cell lung cancer (NSCLC) cells), hepatocellular carcinoma (HCC) cells, colorectal cancer (CRC) cells, cervical cancer cells (e.g., cervical squamous cell carcinoma (CESC) cells), head and neck cancer cells (e.g., head and neck squamous cell carcinoma (HNSC) cells), pancreatic cancer cells, prostate cancer cells (e.g., metastatic castration-resistant prostate cancer (mCRPC) cells), ovarian cancer cells, endometrial cancer cells, bladder cancer cells, or breast cancer cells, preferably breast cancer cells, lung cancer cells, head and neck cancer cells, or cervical cancer cells.
  • lung cancer cells e.g., non-small cell lung cancer (NSCLC) cells
  • HCC hepatocellular carcinoma
  • CRC colorectal cancer
  • cervical cancer cells e.g., cervical squamous cell carcinoma (CESC) cells
  • head and neck cancer cells e.g.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the use of at least one other pharmaceutically active agent.
  • the compounds of the invention and the other pharmaceutically active agents may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compounds of the invention and the other pharmaceutically active agents and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compound of the present invention when administered in combination with one or more other therapeutically active agents normally administered by the inhaled, intravenous, oral, intranasal, ocular topical or other route, that the resultant pharmaceutical composition may be administered by the same route. Alternatively, the individual components of the composition may be administered by different routes.
  • the compounds and pharmaceutical composition disclosed herein are used in combination with, or include, one or more additional therapeutic agents.
  • the additional therapeutic agent is a checkpoint inhibitor or an immune modulator.
  • the checkpoint inhibitor is selected from a PD-1 inhibitor (e.g., an anti-PD-1 antibody including, but not limited to, pembrolizumab, nivolumab, cemiplimab, or dostarlimab), a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody including, but not limited to, atezolizumab, avelumab, or durvalumab), or a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody including, but not limited to, ipilimumab or tremilumumab).
  • a PD-1 inhibitor e.g., an anti-PD-1 antibody including, but not limited to, pembrolizumab, nivolumab, cemiplimab, or dostarlimab
  • a PD-L1 inhibitor e.g., an anti-PD-L1 antibody including, but not limited to, atezolizumab, ave
  • the checkpoint inhibitor is selected from a CD226 axis inhibitor, including but not limited to a TIGIT inhibitor (e.g., an anti-TIGIT antibody), a CD96 inhibitor (e.g., an anti-CD96 antibody), and/or a PVRIG inhibitor (e.g., an anti-PVRIG antibody).
  • a TIGIT inhibitor e.g., an anti-TIGIT antibody
  • a CD96 inhibitor e.g., an anti-CD96 antibody
  • PVRIG inhibitor e.g., an anti-PVRIG antibody
  • the immune modulator is an ICOS agonist (e.g., an anti-ICOS antibody including, but not limited to feladilimab), a PARP inhibitor (e.g., niraparib, olaparib), or a STING agonist.
  • ICOS agonist e.g., an anti-ICOS antibody including, but not limited to feladilimab
  • PARP inhibitor e.g., niraparib, olaparib
  • STING agonist e.g., a STING agonist
  • the ARMs described herein are administered as a raw chemical or are formulated as pharmaceutical compositions.
  • Pharmaceutical compositions disclosed herein include an ARM and one or more of: a pharmaceutically acceptable carrier, diluent or excipient.
  • An ARM is present in the composition in an amount which is effective to treat a particular disease, disorder or condition of interest.
  • the activity of the ARM can be determined by one skilled in the art, for example, as described in the biological assays described below. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • the ARM is present in the pharmaceutical composition in an amount from about 25 mg to about 500 mg.
  • the ARM is present in the pharmaceutical composition in an amount of about 0.01 mg to about 300 mg. In certain embodiments, ARM is present in the pharmaceutical composition in an amount of about 0.01 mg, 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or about 500 mg.
  • compositions of the invention are prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and in specific embodiments are formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • Exemplary routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral (e.g., intramuscular, subcutaneous, intravenous, or intradermal), sublingual, buccal, rectal, vaginal, and intranasal.
  • parenteral e.g., intramuscular, subcutaneous, intravenous, or intradermal
  • sublingual e.g., sublingual
  • buccal e.g., subcutaneous, intravenous, or intradermal
  • vaginal e.g., intranasal
  • Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia. College of Pharmacy and Science, 2000).
  • the composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings described herein.
  • compositions disclosed herein are prepared by methodologies well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection is prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a surfactant is added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
  • the ARMs approach provides the following advantages: uniting the pharmacology of antibodies with the dose-control of small molecules, dose controlled PK/PD allowing temporal cell depletion, simpler multimerization, and rapid reversal of cell depletion through dosing of the antibody-binding component (e.g., cotinine hapten) which can uncouple therapeutic effects from potential adverse events.
  • the antibody-binding component e.g., cotinine hapten
  • the compounds according to Formulae (I) and (II) are prepared using conventional organic synthetic methods.
  • a suitable synthetic route is depicted below in the following general reaction schemes. All the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • racemic trans-4-cotininecarboxylic acid (304 g, 1 .38 mol) was purified by chiral prep HPLC (61 injections) on Chiralpak 1 A 20u 101 x 210 mm at 500 mL/min eluting with 50 % acetonitrile in methanol containing 0.1 % formic acid. The desired fractions were collected and were concentrated at 45 °C. The solid residue was stirred in acetonitrile, was filtered, and was dried under reduced pressure for 18 h to provide the title compound as a white solid (143.6 g, 652 mmol, 94.5 % yield). Analytical chiral HPLC: 95 % ee at ret.
  • Step 1 methyl (E)-4-(((1r,4r)-4-(2-(Dibenzylamino)ethoxy)cyclohexyl)oxy)but-2- enoate.
  • (1 r,4r)-4-(2-(dibenzylamino)ethoxy)cyclohexan-1 -ol (250 g, 736 mmol) in toluene (2500 mL) were added methyl but-2-ynoate (140 g, 1423 mmol), triphenylphosphine (19.32 g, 73.6 mmol), and acetic acid (16.86 mL, 295 mmol) at RT and the resulting solution was stirred at 1 15 °C for 16 h.
  • the reaction mixture was cooled to room temperature and concentrated under reduced pressure to the crude compound.
  • the crude compound was adsorbed on silicagel (500 g, 60-120mesh), and purified by manual column chromatography(1 .5 kg , 100-200 mesh) eluted with 15 % EtOAc in pet-ether to afford methyl (E&Z)-4-(((1 r,4r)-4-(2-(dibenzylamino)ethoxy)cyclohexyl)oxy)but-2-enoate (350 g) as a mixture of E/Z isomers (52.48 % and 21 .15 %).
  • Step 2 (E)-4-(((1,4-trans)-4-(2-(Dibenzylamino)ethoxy)cyclohexyl)oxy)but-2-enoic acid
  • tert-butyl (1 ,4-trans)-4- aminocyclohexane-1 -carboxylate (4.11 g, 20.60 mmol) was added as a solution in DMF (10 ml) followed by addition of a solution of DIEA (10.80 mL, 61.8 mmol) in DMF (10 ml). An additional 10 ml of DMF was added and the heterogeneous mixture was stirred for 15 hours at room temperature. Additional HATU (1.724 g, 4.53 mmol) was added and the almost homogeneous reaction was stirred for 60 minutes. The cloudy reaction was stirred for an additional 60 minutes.
  • the reaction was diluted with 200 ml of EtOAc and 200 ml of water and stirred for 10 minutes.
  • the resulting homogeneous biphasic mixture was transferred to a separatory funnel and the layers were separated.
  • the aqueous layer was extracted twice more with 150 ml EtOAc and the combined EtOAc layers were washed 4 x with water and 2 x with saturated NaCI in order to remove DMF.
  • Step 5 tert-butyl (1R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-Methyl-5-oxo-2-(pyridin-3- yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1- carboxylate.
  • Step 6 (1 R,4r)-4-(4-(((1S,4R)-4-(2-((2S,3S)-1-Methyl-5-oxo-2-(pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1 -carboxylic acid, Hydrochloride salt.
  • Step 1 1-((2S,3S)-1-Methyl-5-oxo-2-(pyridin-3-yl)pyrrolidin-3-yl)-1-oxo- 5,8,11 ,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oic acid,
  • the crude material was purified by reverse phase chromatography (loading as a solution in ⁇ 6 mL of 10mM aqueous ammonium bicarbonate in H20 adjusted to pH 10 with ammonia, C18 100g Gold column, 60mL/min, gradient 5-50% 10mM aqueous ammonium bicarbonate in H20 adjusted to pH 10 with ammonia to MeCN over 23 min) to afford the title compound (1 .3 g, 1 .351 mmol, 83 % yield) as a colorless oil (87% purity by NMR, the material contains CH 2 CI 2 ).
  • Step 1 methyl (E)-4-(((1r,4r)-4-(2-(Dibenzylamino)ethoxy)cyclohexyl)oxy)but-2- enoate.
  • the crude compound was adsorbed on silicagel (500 g, 60-120mesh), and purified by manual column chromatography(1 .5 kg , 100-200 mesh) eluted with 15 % EtOAc in pet-ether to afford methyl (E&Z)-4-(((1 r,4r)-4-(2-(dibenzylamino)ethoxy)cyclohexyl)oxy)but-2-enoate (350 g) as a mixture of E/Z isomers (52.48 % and 21 .15 %).
  • Step 3 Methyl 4-(((1S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin-3- yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanoate
  • Step 4 Methyl (S)-3-(3-(piperazin-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoate hydrochloride
  • Example 1 (S)-3-(3-(4-((1 R,4S)-4-(4-(((1 S,4R)-4-(2-((2S,3S)-1 -Methyl-5-oxo-2- (pyridin-3-yl)pyrrolidine-3- carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1-carbonyl)piperazin-1- yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1- yl)butanoic acid
  • Step 1 Methyl (S)-3-(3-(4-((1R,4S)-4-(4-(((1 S,4R)-4-(2-((2S,3S)-1-methyl-5-oxo-2-(pyridin- 3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1- carbonyl)piperazin-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoate
  • Step 2 (S)-3-(3-(4-((1 R,4S)-4-(4-(((1 S,4R)-4-(2-((2S,3S)-1-Methyl-5-oxo-2-(pyridin- 3-yl)pyrrolidine-3-carboxamido)ethoxy)cyclohexyl)oxy)butanamido)cyclohexane-1- carbonyl)piperazin-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)ethyl)pyrrolidin-1-yl)butanoic acid
  • Example Compounds 1-4 which are compounds of Formulae (I) and (II) having an integrin ⁇ V ⁇ 6 binding moiety were tested in various biological assays as described in more detail below.
  • ADCC antibody dependent cellular cytotoxicity reporter assay was conducted using the following four assay components: (i) ARM compound of Formula (I) targeting integrin ⁇ V ⁇ 6 (concentrations ranging from 1 pM to 10 pM); (ii) anti-cotinine antibody having a heavy chain sequence of SEQ ID NO: 11 and a light chain sequence of SEQ ID NO: 12 (rabbit variable region with human lgG1 Fc domain containing DE mutation (S239D/I332E)) (concentrations ranging from 0.01 pg / mL - 200 pg / mL); (iii) Target cells: BT-20 cells (typically 1000-20,000 cells per well); and (iv) Reporter cells — Jurkat cells engineered to express FcyRllla with a reporter gene luciferase under the control of the NFAT promoter (typically 3000-75,000 cells per well).
  • Reagents were combined in final volume of 20 pL in 384 - well tissue culture treated plate. All four assay components were incubated together for about 12- 18 hours. Thereafter, BioGio Detection reagent (Promega) was added to the wells to lyse the cells and provide a substrate for the luciferase reporter protein.
  • Luminescence signal was measured on a microplate reader capable of measuring luminescence and signal:background was calculated by dividing the signal of a test well by the signal obtained when no compound of formula (I) was included in the assay.
  • ARMs compounds of Formula (I) were tested for ADCC activity in the above assay in one or more experimental runs and the results are shown in Table 3 below. Potency of the compounds of Formula (I) is reported as a pEC50 values.
  • the pEC50 value is the negative log of the EC50 value, wherein the EC50 value is half maximal effective concentration measured in molar (M). For compounds tested in more than one experimental run, the pEC50 value is reported as an average.
  • mice (C57BL6) were dosed intravenously with a PBS solution containing a compound of Formula (I). Peripheral blood from IV dosed mice was analyzed to determine PK properties of the ARM compounds of Formula (I).
  • Formulations preparation On the day of experiment, stock solution of the compound of formula (I) was removed from storage at -20°C and thawed at room temperature.
  • Antibody vials were immediately transferred into wet ice after thawing.
  • Compounds of formula (I) were further diluted in DMSO as per experimental requirements.
  • Formulation composition The formulation composition was Saline: DMSO: PBS. Saline was added based on the quantity required and then stock solution of the compound of formula (I) prepared in DMSO, followed by addition of antibody in PBS. Formulations were incubated at room temperature for 30 minutes before administration to the mouse. DMSO was used at 1 to 2 % (v/v) in the final formulation.
  • Terminal bleeding at end of experiment 72hr: Approximately 250 pL of blood in K 2 EDTA tube and approximately 250 pL of blood in SST (serum separation tube) was collected from each mouse through retro-orbital bleeding under deep isoflurane anesthesia. After bleeding, each mouse was sacrificed by cervical dislocation. The blood distribution at termination was determined as follows: 50 pL of K2EDTA blood was transferred to another tube for PK
  • Drug concentration in blood samples was determined by an LC-MS/MS-based bioanalytical method developed at Syngene. Samples were analyzed on Q-Trap, API-5500 LC-MS/MS system coupled with Exion UHPLC system from SCIEX, USA operated in multiple reaction monitoring mode employing electrospray ionization technique in positive polarity. Analyte and internal standard peaks were resolved on Synergi Polar, 75 X 2.0 mm, 4 p column using mobile phase 10 mM Ammonium acetate in Milli-Q water as phase A and 0.1 % Formic acid in acetonitrile as Phase B.
  • Working dilutions for calibration curve and quality control standards were prepared by serially diluting 20 mg/mL stock solution with DMSO. Spiked concentrations for calibration curve in the whole blood ranged from 1 ng/mL to 1000 ng/mL.
  • the working solution of internal standard (Verapamil, 25 ng/mL) was prepared in acetonitrile. 10 pL of the study sample and calibration curve, quality control, and blank whole blood samples were aliquoted in 96 deep well plates for processing. 10 pL of Milli-Q water was added to all the samples and briefly vortexed to initiate complete hemolysis. 10 pL of 20 mM dithiothreitol (DTT) was added to all the samples and incubated for 30 minutes at 37°C.
  • DTT dithiothreitol
  • DTT enhanced the recovery of ARM compounds of formula (I) from the biological matrix.
  • 300 pL of working internal standard solution was added to all samples except total blank and wash samples, where 300 pL of acetonitrile was added. All the samples were vortex mixed for 5 minutes, followed by centrifugation at 4000 rpm for 10 minutes at 4 °C. Supernatants were transferred to the loading plate and injected 3 pL to LC-MS/MS system for analysis.

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Abstract

La présente divulgation concerne des molécules hétérobifonctionnelles, appelées chimères ciblant la cytotoxicité (CyTaC) ou des molécules de recrutement d'anticorps (ARM, « antibody recruiting molecule ») pouvant se lier simultanément à une protéine de surface cellulaire cible ainsi qu'une protéine d'anticorps exogène. La présente divulgation concerne également des agents aptes à se lier à un récepteur sur une surface d'une cellule pathogène et à induire la déplétion de la cellule pathogène chez un patient pour une utilisation dans le traitement du cancer.
PCT/IB2023/051746 2022-02-25 2023-02-24 Chimères ciblant la cytotoxicité pour des cellules exprimant l'intégrine avb6 WO2023161877A1 (fr)

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EP2700653A2 (fr) * 2011-04-15 2014-02-26 SNU R&DB Foundation Complexe dans lequel un anticorps anti-cotinine est fixé à un matériau lieur de cotinine et une substance de liaison, et utilisation de celui-ci

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