WO2022254377A1 - Neodegrader-anti-cd33 antibody conjugates - Google Patents

Neodegrader-anti-cd33 antibody conjugates Download PDF

Info

Publication number
WO2022254377A1
WO2022254377A1 PCT/IB2022/055168 IB2022055168W WO2022254377A1 WO 2022254377 A1 WO2022254377 A1 WO 2022254377A1 IB 2022055168 W IB2022055168 W IB 2022055168W WO 2022254377 A1 WO2022254377 A1 WO 2022254377A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
seq
set forth
antibody
conjugate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2022/055168
Other languages
English (en)
French (fr)
Inventor
Nathan FISHKIN
Peter U. Park
Chen BAI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Orum Therapeutics Inc
Original Assignee
Orum Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PE2023003198A priority Critical patent/PE20250159A1/es
Priority to US18/566,805 priority patent/US20240252671A1/en
Priority to KR1020247000100A priority patent/KR20240042598A/ko
Priority to CN202280039908.6A priority patent/CN118201641A/zh
Priority to CA3222185A priority patent/CA3222185A1/en
Priority to JP2023574587A priority patent/JP2024521919A/ja
Priority to EP22815474.6A priority patent/EP4346910A4/en
Priority to AU2022284372A priority patent/AU2022284372A1/en
Application filed by Orum Therapeutics Inc filed Critical Orum Therapeutics Inc
Priority to MX2023014282A priority patent/MX2023014282A/es
Priority to IL308812A priority patent/IL308812A/en
Publication of WO2022254377A1 publication Critical patent/WO2022254377A1/en
Priority to CONC2023/0016712A priority patent/CO2023016712A2/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL

Definitions

  • ASCII text file Name: 4547_017PC02_Seqlisting_ST25; Size: 42, 724 bytes; and Date of Creation: May 31, 2022 filed with the application is incorporated herein by reference in its entirety.
  • FIELD [0002] The present disclosure provides neoDegrader conjugates, wherein the neoDegrader is conjugated to an anti-CD33 antibody or antigen-binding portin thereof. Also provided are compositions comprising the conjugates.
  • the conjugates and compositions are useful for treating cancer in a subject in need thereof.
  • BACKGROUND [0003] Protein degradation has been validated as a therapeutic strategy by the effectiveness of immunomodulatory imide drugs. These compounds have the ability to bind to cereblon (CRBN) and promote recruitment and ubiquitination of substrate proteins mediated by CRL4 CRBN E3 ubiquitin ligase. It is thought that immunomodulatory imides act as “molecular glues,” filling the binding interface as a hydrophobic patch that reprograms protein interactions between the ligase and neosubstrates.
  • the present invention is based on the discovery that combining a GSPT1 degrading payload molecule with a CD33 targeting antibody can improve both the clinical efficacy and the tolerability of a GSPT1 degrader.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) complementarity determining region (CDR) 1 (VH- CDR1) compising the amino acid sequence as set forth in SEQ ID NO: 1, a VH-CDR2 comprising the amino acid as sequence set forth in SEQ ID NO: 2, a VH-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 3, a light chain variable region (VL) CDR1 (VL-CDR1) comprising the amino acid sequence as set forth in SEQ ID NO: 5, a VL-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 6, and a VL-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7.
  • VH heavy chain variable region
  • CDR1 VH- CDR1
  • the anti-CD33 antibody or antigen- binding portion thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:4 and a VL comprising the amino acid sequence as set forth in SEQ ID NO:8.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises a constant region, wherein the constant region comprises at least one amino acid different from Gemtuzumab.
  • the anti-CD33 antibody or antigen-binding portion thereof is an IgG1 antibody or antigen- binding portion thereof.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises alanine at amino acid 297 corresponding to the constant region.
  • the anti-CD33 antibody comprises a heavy chain as set forth in SEQ ID NO: 9 and a light chain as set forth in SEQ ID NO: 10.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises a VH-CDR1 compising the amino acid sequence as set forth in SEQ ID NO: 19, a VH- CDR2 comprising the amino acid as sequence set forth in SEQ ID NO: 20, a VH-CDR3 comprising the amino acid sequenceas set forth in SEQ ID NO: 21, a VL-CDR1 comprising the amino acid sequence as set forth in SEQ ID NO: 22, a VL-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 23, and a VL-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 24.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL comprising the amino acid sequence as set forth in SEQ ID NO:28.
  • the anti-CD33 antibody or antigen-binding portion thereof is an IgG1 antibody or antigen-binding portion thereof.
  • the anti-CD33 antibody comprises a heavy chain as set forth in SEQ ID NO: 25 and a light chain as set forth in SEQ ID NO: 26.
  • a is an integer from 2 to 8.
  • L is a non-cleavable linker.
  • L is selected from the group consisting of and wherein: [0024] p is an integer from 1 to 10; [0025] is the point of attachment to X; and [0026] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof. [0027] In some aspects, L is [0028] In some aspects, p is 5. [0029] In some asepcts, L is a cleavable linker. In some aspects, the cleavable linker is cleavable by a protease. In some aspects, L is selected from the group consisting of
  • Z 1 , Z 2 , Z 3 , and Z 4 are independently absent or selected from the group consisting of L-valine, D-valine, L-citrulline, D-citrulline, L-alanine, D-alanine, L- glutamine, D-glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L- asparagine, D-asparagine, L-phenylalanine, D-phenylalanine, L-lysine, D-lysine, and glycine; provided that at least two of Z 1 , Z 2 , Z 3 , and Z 4 are amino acid residues.
  • Z 1 is absent or glycine
  • Z 2 is absent or selected from the group consisting of L-glutamine, D-glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D- aspartic acid, L-alanine, D-alanine, and glycine
  • Z 3 is selected from the group consisting of L- valine, D-valine, L-alanine, D-alanine, L-phenylalanine, D-phenylalanine, and glycine
  • Z 4 is selected from the group consisting of L-alanine, D-alanine, L-citrulline, D-citrulline, L-asparagine, D-asparagine, L-lysine, D-lysine, L-phenylalamine, D-phenylalanine, and glycine.
  • L is
  • L is a bioreducible linker.
  • L is selected from the group consisting of wherein: [0040] q is an integer from 2 to 10; [0041] R, R’, R’’, and R’’ are each independently selected from hydrogen, C1- C 6 alkoxyC 1 -C 6 alkyl, (C 1 -C 6 ) 2 NC 1 -C 6 alkyl, and C 1 -C 6 alkyl, or, two geminal R groups, together with the carbon atom to which they are attached, can form a cyclobutyl or cyclopropyl ring; [0042] is the point of attachment to X; and [0043] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof.
  • L is an acid cleavable linker. In some asepcts, L is selected from the group consisting of [0045] wherein: [0046] q is an integer from 2 to 10; [0047] is the point of attachment to X; and [0048] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof. [0049] In some aspects, L is a click-to-release linker. In some aspects, L is selected from wherein: [0050] q is an integer from 2 to 10; [0051] is the point of attachment to X; and [0052] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof.
  • L is a pyrophosphatase cleavable linker. In some aspects, L is wherein: [0054] q is an integer from 2 to 10; [0055] is the point of attachment to X; and [0056] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof. [0057] In some aspects, L is a beta-glucuronidase cleavable linker.
  • L is selected from wherein: [0058] q is an integer from 2 to 10; [0059] ---- is absent or a bond; [0060] is the point of attachment to X; and [0061] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof.
  • the present disclosure provides a conjugate of formula (I), wherein: [0063] A is phenyl; [0064] U is NH; [0065] R 1 is halo; and [0066] X is -N(R 2 ) v (CH 2 ) m O(CH 2 ) n -; wherein: [0067] v is 1; [0068] m and n are 2; and [0069] R 2 is methyl.
  • the present disclosure provides a conjugate of formula (I), wherein: [0071] A is phenyl; [0072] U is NH; [0073] R 1 is halo; and [0074] X is -N(R 2 )v(CH2)mO(CH2)n-; wherein: [0075] v is 2; [0076] m and n are 2; and [0077] each R 2 is methyl.
  • the present disclosure provides a conjugate of formula (I), wherein: [0079] A is phenyl; [0080] U is NH; [0081] R 1 is halo; and [0082] X is -O(CH 2 ) n -; wherein: [0083] n is 2. [0084] In certain aspects, the present disclosure provides a conjugate of formula (I), wherein: [0085] A is phenyl; [0086] U is NH; [0087] R 1 is halo; and [0088] X is -S(CH 2 ) n -; wherein: [0089] n is 2.
  • the present disclosure provides a conjugate of formula (I), wherein: [0091] A is phenyl; [0092] U is NH; [0093] R 1 is hydrogen; and [0094] X is -–NR 2 -; wherein: [0095] R 2 is methyl. [0096] In certain aspects, the present disclosure provides a conjugate of formula (I), wherein: [0097] A is phenyl; [0098] U is NH; [0099] R 1 is halo; and [0100] X is -–NR 2 -; wherein: [0101] R 2 is hydrogen.
  • the present disclosure provides a conjugate of formula (I), wherein: [0108] A is a C 4 -C 10 cycloalkyl ring; [0109] U is NH; [0110] R 1 is hydrogen; and [0111] X is -N(R 2 )(CH2)mO(CH2)n-; wherein: [0112] n is 1; [0113] m is 2; and [0114] R 2 is methyl. [0115] In certain aspects, the present disclosure provides a conjugate of formula (V): (V); or a pharmaceutically acceptable salt thereof, wherein Bm is an anti-CD33 antibody or antigen- binding portion thereof.
  • the anti-CD33 antibody or antigen-binding portion thereof can comprise e.g., (i) aVH-CDR1 compising the amino acid sequence as set forth in SEQ ID NO: 1, a VH-CDR2 comprising the amino acids sequence as set forth in SEQ ID NO: 2, a VH-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 3, a VL-CDR1 comprising the amino acid sequence as set forth in SEQ ID NO: 5, a VL-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 6, and a VL-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7, (ii) a VH comprising the amino acid sequence as set forth in SEQ ID NO:4 and a VL comprising the amino acid sequence as set forth in SEQ ID NO:8, (iii) a heavy chain as set forth in SEQ ID NO: 9, and a light chain as set forth in SEQ ID NO: 10, (iv)
  • the present disclosure provides a conjugate of formula (VI): (VI); or a pharmaceutically acceptable salt thereof, wherein Bm is an anti-CD33 or antigen-binding portion thereof.
  • the anti-CD33 antibody or antigen-binding portion thereof can comprise e.g., (i) aVH-CDR1 compising the amino acid sequence as set forth in SEQ ID NO: 1, a VH-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 2, a VH-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 3, a VL-CDR1 comprising the amino acid sequence as set forth in SEQ ID NO: 5, a VL-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 6, and a VL-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7, (ii) a VH comprising the amino acid sequence as set forth in SEQ ID NO: 4 and a VL comprising the
  • the present disclosure provides a conjugate of formula (VI): (VII); or a pharmaceutically acceptable salt thereof, wherein Bm is an anti-CD33 antibody or antigen- binding portion thereof.
  • the anti-CD33 antibody or antigen-binding portion thereof can comprise e.g., (i) aVH-CDR1 compising the amino acid sequence as set forth in SEQ ID NO: 1, a VH-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 2, a VH-CDR3 comprising the amino acid sequencea as set forth in SEQ ID NO: 3, a VL-CDR1 comprising the amino acid sequence as set forth in SEQ ID NO: 5, a VL-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 6, and a VL-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7, (ii) a VH comprising the amino acid sequence as set forth in SEQ ID NO:4 and a VL comprising the amino acid sequence
  • the present disclosure provides a pharmaceutical composition comprising a conjugate or compound provided here, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the present disclosure provides a method of treating cancer or myelodysplastic syndrome in a subject in need thereof, the method comprising administering to the subject a pharmaceutically acceptable amount of a conjugate or composition described above, or a pharmaceutically acceptable salt thereof.
  • the cancer is a hematological/blood cancer.
  • the cancer is a multiple myeloma, leukemia, malignant lymphoma, Hodgkin’s disease, or chronic myeloproliferative disease.
  • the cancer is acute myeloid leukemia or lymphoma. In some aspects, the cancer is acute myeloid leukemia. In some aspects, the cancer is resistant or refractory to Mylotarg. [0120] In some aspects, the method further comprises administering to the subject a pharmaceutically acceptable amount of an additional agent prior to, after, or simultaneously with the conjugate, or a pharmaceutically acceptable salt thereof. In some aspects, the additional agent is a cytotoxic agent or an immune response modifier. In some aspects, the immune response modifier is a checkpoint inhibitor. In some apects, the checkpoint inhibitor comprises a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIM3 inhibitor, and/or a LAG-3 inhibitor.
  • the present disclosure provides a method of preparing a conjugate of formula (I), or a pharmaceutically acceptable salt thereof, the process comprising reacting an anti-CD33 antibody or antigen-binding portion thereof with a compound of formula (I-1): (I-1), [0122] or a pharmaceutically acceptable salt thereof, wherein: [0123] a is an integer from 1 to 10; [0124] A is phenyl or a C 4 -C 10 cycloalkyl ring; [0125] R 1 is independently selected from hydrogen and halo; [0126] U is selected from NH and CF2; [0127] X is selected from –Q(CH 2 ) m Q’(CH 2 ) n -; wherein [0128] v is 1 or 2; [0129] Q and Q’ are each independently O, S, or NR 2 ; [0130] each R 2 is independently hydrogen or C1-C6alkyl; [0131] n is an integer from
  • the anti-CD33 antibody or antigen- binding portion thereof comprises a VH-CDR1 compising the amino acid sequence as set forth in SEQ ID NO: 1, a VH-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 2, a VH-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 3, a VL-CDR1 comprising the amino acid sequence as set forth in SEQ ID NO: 5, a VL-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 6, and a VL-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 7.
  • the anti-CD33 antibody or antigen- binding portion thereof comprises a heavy chain variable region as set forth in SEQ ID NO: 4, and a light chain variable region as set forth in SEQ ID NO: 8.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises a constant region, wherein the constant region comprises at least one amino acid different from Gemtuzumab.
  • the anti-CD33 antibody or antigen-binding portion thereof is an IgG1 antibody or antigen-binding portion thereof.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises alanine at amino acid 297 corresponding to the constant region.
  • the anti-CD33 antibody comprises a heavy chain as set forth in SEQ ID NO: 9 and a light chain as set forth in SEQ ID NO: 10.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises a VH- CDR1 compising the amino acid sequence as set forth in SEQ ID NO: 19, a VH-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 20, a VH-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 21, a VL-CDR1 comprising the amino acid sequence as set forth in SEQ ID NO: 22, a VL-CDR2 comprising the amino acid sequence as set forth in SEQ ID NO: 23, and a VL-CDR3 comprising the amino acid sequence as set forth in SEQ ID NO: 24.
  • the anti-CD33 antibody or antigen-binding portion thereof comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 27 and a VL comprising the amino acid sequence as set forth in SEQ ID NO: 28.
  • the anti-CD33 antibody or antigen- binding portion thereof is an IgG1 antibody or antigen-binding portion thereof.
  • the anti-CD33 antibody comprises a heavy chain as set forth in SEQ ID NO: 25 and a light chain as set forth in SEQ ID NO: 26.
  • the method further comprises reducing the anti-CD33 antibody or antigen-binding portion thereof prior to reacting with the compound of formula (I-1).
  • a is an integer from 2 to 8.
  • L’ is a non-cleavable linker precursor, a cleavable linker precursor, a bioreducible linker precursor, an acid cleavable linker precursor, a click-to-release linker precursor, a pyrophosphatase cleavable linker precursor, a beta-glucoronidase cleavable linker precursor, or any combination thereof.
  • Figure 1 depicts in vivo activity of representative neoDegrader conjugates against MV411 (CD33+) tumors. The X axis shows the day after dosing.
  • the Y axis shows the tumor volume (mm 3 ) after dosing with vehicle, 3 mg/kg CD33AB – Compound (Ia), 2.83 mg/kg CD33AB-Compound (Ie), 2.99 mg/kg CD33AB-Compound (1h), 0.1 mg/kg Mylotarg, 50 mg/kg Venetoclax, and 5 mg/kg CC-90009.
  • Figure 2 depicts the in vitro activity of huMy9-6 (AB1) -Compound (Ia) in CD-33 positive and CD33-negative malignancies.
  • Figure 3 depicts in vivo activity of AB1 based conjugates against MV4-11 (CD33+) tumors.
  • the X axis shows the day after dosing.
  • the Y axis shows the tumor volume (mm 3 ) after dosing with vehicle, AB1 – Compound (Ia), AB1-Compound (Ii), AB1-Compound (Id), AB1- Compound (Ij), AB1-Compound (Ie), AB1-Compound (Ik), Mylotarg, Gemtuzumab-Compound I(a), and CC-90009.
  • Figure 4 depicts the stability of Gemtuzumab and CD33AB conjugates.
  • Figure 5 depicts in vivo activity of Gemtuzumab based conjugates against MV4-11 (CD33+) tumors.
  • the X axis shows the day after dosing.
  • the Y axis shows the tumor volume (mm 3 ) after dosing with vehicle, 3 mg/kg Gemtuzumab – Compound (Ia), 5 mg/kg Gemtuzumab - Compound (Ia), 3 mg/kg CD33AB-Compound (Ia) 5 mg/kg CD33AB-Compound (Ia), 3 mg/kg Gemtuzumab IgG1 LALA-Compound (Ia), 5 mg/kg Gemtuzumab IgG1 LALA-Compound (Ia), 5 mg/kg Gemtuzumab-Compound (Ie), 25 mg/kg Venetoclax, and 50 mg/kg Ventoclax.
  • Figures 6A and 6B depict the in vitro activity of the AB1-Compound (Ia) conjugate against Mylotarg-insensitive AML cells (AML-193 ( Figure 6A) and Kasumi-6 ( Figure 6B)).
  • the X axis shows concentration
  • the Y axis shows the percent viability of the cell line after treatment.
  • the present disclosure also provides the compound above that is fused to the anti- CD33 antibody or antigen-binding portion thereof, the composition comprising the compound or the conjugate, or the method of using or making the compound or the conjugate.
  • the term “a” or “an” entity refers to one or more of that entity; for example, “a nucleotide sequence,” is understood to represent one or more nucleotide sequences.
  • the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.
  • ranges recited are understood to be shorthand for all of the values within the range, inclusive of the recited endpoints.
  • a range of 1 to 10 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • DAR refers to the drug antibody ratio of the conjugate, which is the average number of neoDegrader-linker complexes linked to each antibody. In certain aspects, the DAR of the conjugates described herein is from 1 to 10. In some aspects, the DAR of the conjugates described herein is from 1 to 8.
  • the DAR of the conjugates described herein is 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.
  • antibody also refers to a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease.
  • the immunoglobulin disclosed herein can be of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.
  • the immunoglobulins can be derived from any species. In one aspect, however, the immunoglobulin is of human, murine, or rabbit origin.
  • the term “single domain antibody,” also known as a nanobody is an antibody fragment consisting of a single monomeric variable antibody domain with a molecular weight of from about 12 kDa to about 15kDa.
  • Single body antibodies can be based on heavy chain variable domains or light chains.
  • single domain antibodies include, but are not limited to, VHH fragments and VNAR fragments.
  • Antibody fragments comprise a portion of an intact antibody, generally the antigen binding or variable region thereof.
  • antibody fragments include Fab, Fab’, F(ab’).sub.2, and Fv fragments; diabodies; linear antibodies; fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDR (complementary determining region), and epitope-binding fragments of any of the above which immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • An “intact antibody” is one which comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, CH2 and CH3.
  • the constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variant thereof.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
  • the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method, or may be made by recombinant DNA methods.
  • the “monoclonal antibodies” may also be isolated from phage antibody libraries.
  • the monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • Chimeric antibodies of interest herein include “primatized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g., Old World Monkey, Ape etc.) and human constant region sequences.
  • MAbs monoclonal antibodies
  • Hybridoma technology which refers to a cloned cell line that produces a single type of antibody, uses the cells of various species, including mice (murine), hamsters, rats, and humans.
  • Another method to prepare MAbs uses genetic engineering including recombinant DNA techniques.
  • Monoclonal antibodies made from these techniques include, among others, chimeric antibodies and humanized antibodies.
  • a chimeric antibody combines DNA encoding regions from more than one type of species. For example, a chimeric antibody may derive the variable region from a mouse and the constant region from a human.
  • a humanized antibody comes predominantly from a human, even though it contains nonhuman portions.
  • a humanized antibody may contain a completely human constant region. But unlike a chimeric antibody, the variable region may be partially derived from a human. The nonhuman, synthetic portions of a humanized antibody often come from CDRs in murine antibodies. In any event, these regions are crucial to allow the antibody to recognize and bind to a specific antigen. While useful for diagnostics and short-term therapies, murine antibodies cannot be administered to people long-term without increasing the risk of a deleterious immunogenic response. This response, called Human Anti-Mouse Antibody (HAMA), occurs when a human immune system recognizes the murine antibody as foreign and attacks it. A HAMA response can cause toxic shock or even death.
  • HAMA Human Anti-Mouse Antibody
  • Chimeric and humanized antibodies reduce the likelihood of a HAMA response by minimizing the nonhuman portions of administered antibodies. Furthermore, chimeric and humanized antibodies can have the additional benefit of activating secondary human immune responses, such as antibody dependent cellular cytotoxicity.
  • the intact antibody may have one or more “effector functions” which refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell- mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor; BCR), etc.
  • effector functions include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell- mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor; BCR), etc.
  • intact antibodies can be assigned to different “classes”. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses” (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.
  • the heavy-chain constant domains that correspond to the different classes of antibodies are called alpha, delta, epsilon, gamma, and mu, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • the term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” can modify a numerical value above and below the stated value by a variance of, e.g., 10 percent, up or down (higher or lower).
  • the terms “administration,” “administering,” and grammatical variants thereof refer to introducing a composition, such as an EV (e.g., exosome) of the present disclosure, into a subject via a pharmaceutically acceptable route.
  • a composition such as an EV (e.g., exosome) of the present disclosure
  • introduction of a composition is by any suitable route, including intratumorally, orally, pulmonarily, intranasally, parenterally (intravenously, intra-arterially, intramuscularly, intraperitoneally, or subcutaneously), rectally, intralymphatically, intrathecally, periocularly or topically.
  • Administration includes self-administration and the administration by another.
  • a suitable route of administration allows the composition or the agent to perform its intended function. For example, if a suitable route is intravenous, the composition is administered by introducing the composition or agent into a vein of the subject.
  • antibody encompasses an immunoglobulin whether natural or partly or wholly synthetically produced, and fragments thereof. The term also covers any protein having a binding domain that is homologous to an immunoglobulin binding domain. “Antibody” further includes a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen.
  • antibody is meant to include whole antibodies, polyclonal, monoclonal and recombinant antibodies, fragments thereof, and further includes single-chain antibodies, humanized antibodies, murine antibodies, chimeric, mouse-human, mouse-primate, primate-human monoclonal antibodies, anti-idiotype antibodies, antibody fragments, such as, e.g., scFv, (scFv)2, Fab, Fab’, and F(ab’)2, F(ab1)2, Fv, dAb, and Fd fragments, diabodies, and antibody-related polypeptides.
  • Antibody includes bispecific antibodies and multispecific antibodies so long as they exhibit the desired biological activity or function.
  • the biologically active molecule is an antibody or a molecule comprising an antigen binding fragment thereof.
  • antibody-drug conjugate and “ADC” are used interchangeably and refer to an antibody linked, e.g., covalently, to a therapeutic agent (sometimes referred to herein as agent, drug, or active pharmaceutical ingredient) or agents.
  • the biologically active molecule is an antibody-drug conjugate.
  • the term “approximately,” as applied to one or more values of interest refers to a value that is similar to a stated reference value.
  • the term “approximately” refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic acid
  • a string of amino acids can be conservatively replaced with a structurally similar string that differs in order and/or composition of side chain family members.
  • conserved refers to nucleotides or amino acid residues of a polynucleotide sequence or polypeptide sequence, respectively, that are those that occur unaltered in the same position of two or more sequences being compared. Nucleotides or amino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences.
  • two or more sequences are said to be “completely conserved” or “identical” if they are 100% identical to one another.
  • two or more sequences are said to be “highly conserved” if they are at least about 70% identical, at least about 80% identical, at least about 90% identical, or at least about 95% identical to one another.
  • two or more sequences are said to be “conserved” if they are at least about 30% identical, at least about 40% identical, at least about 50% identical, at least about 60% identical, at least about 70% identical, at least about 80% identical, at least about 90% identical, or at least about 95% identical to one another.
  • linking and “conjugating” are used interchangeably and each refer to the covalent or non-covalent attachment of two or more moieties comprising a neoDegrader and an anti-CD33 antibody or antigen-binding portion thereof. In some aspects the linking or conjugating can comprise a linker.
  • amino acid sequence variant refers to polypeptides having amino acid sequences that differ to some extent from a native sequence polypeptide.
  • amino acid sequence variants will possess at least about 70% sequence identity with at least one receptor binding domain of a native antibody or with at least one ligand binding domain of a native receptor, and typically, they will be at least about 80%, more typically, at least about 90% homologous by sequence with such receptor or ligand binding domains.
  • the amino acid sequence variants possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence of the native amino acid sequence.
  • Amino acids are designated by the conventional names, one-letter and three-letter codes.
  • Sequence identity is defined as the percentage of residues in the amino acid sequence variant that are identical after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity.
  • CDC complement dependent cytotoxicity
  • variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called hypervariable regions both in the light chain and the heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FRs).
  • the variable domains of native heavy and light chains each comprise four FRs, largely adopting a .beta.-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the beta-sheet structure.
  • hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies.
  • the constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC).
  • ADCC antibody dependent cellular cytotoxicity
  • the hypervariable region generally comprises amino acid residues from a “complementarity determining region” or “CDR” (e.g., residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31-35 (H1), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; Kabat et al supra) and/or those residues from a “hypervariable loop” (e.g., residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) in the light chain variable domain and 26-32 (H1), 53-55 (H2) and 96-101 (H3) in the heavy chain variable domain).
  • CDR complementarity determining region
  • “Framework Region” or “FR” residues are those variable domain residues other than the hypervariable region residues as herein defined.
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab’)2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.
  • “Fv” is the minimum antibody fragment which contains a complete antigen- recognition and antigen-binding site. This region consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association.
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab’ fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region.
  • Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear at least one free thiol group.
  • F(ab’)2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • the “light chains” of antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ( ⁇ ) and lambda ( ⁇ ), based on the amino acid sequences of their constant domains.
  • “Single-chain Fv” or “scFv” antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide may further comprise a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding.
  • the term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a variable heavy domain (VH) connected to a variable light domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • An “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment.
  • Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes.
  • the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, or more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a gas phase protein sequencer, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or silver stain.
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody’s natural environment will not be present.
  • a “cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. “Cancer” as used herein refers to primary, metastatic and recurrent cancers. [0186] As used herein, the term “immune response” refers to a biological response within a vertebrate against foreign agents, which response protects the organism against these agents and diseases caused by them.
  • An immune response is mediated by the action of a cell of the immune system (e.g., a T lymphocyte, B lymphocyte, natural killer (NK) cell, macrophage, eosinophil, mast cell, dendritic cell or neutrophil) and soluble macromolecules produced by any of these cells or the liver (including antibodies, cytokines, and complement) that results in selective targeting, binding to, damage to, destruction of, and/or elimination from the vertebrate’s body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • a cell of the immune system e.g., a T lymphocyte, B lymphocyte, natural killer (NK) cell, macrophage, eosinophil, mast cell, dendritic cell or neutrophil
  • soluble macromolecules produced by any of these cells or the liver (including antibodies, cytokines, and complement) that results in selective targeting, binding
  • An immune reaction includes, e.g., activation or inhibition of a T cell, e.g., an effector T cell or a Th cell, such as a CD4 + or CD8 + T cell, or the inhibition of a Treg cell.
  • a T cell e.g., an effector T cell or a Th cell, such as a CD4 + or CD8 + T cell, or the inhibition of a Treg cell.
  • T cell and “T lymphocytes” are interchangeable and refer to any lymphocytes produced or processed by the thymus gland.
  • a T cell is a CD4+ T cell.
  • a T cell is a CD8+ T cell.
  • a T cell is a NKT cell.
  • a “subject” includes any human or nonhuman animal.
  • nonhuman animal includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In some aspects, the subject is a human.
  • subject and “patient” are used interchangeably herein.
  • therapeutically effective amount” or “therapeutically effective dosage” refers to an amount of an agent (e.g., neoDegrader or neoDegrader conjugate disclosed herein) that provides the desired biological, therapeutic, and/or prophylactic result.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation.
  • an effective amount is an amount sufficient to delay tumor development.
  • an effective amount is an amount sufficient to prevent or delay tumor recurrence.
  • An effective amount can be administered in one or more administrations.
  • the effective amount of the composition can, for example, (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and can stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and can stop tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • a “therapeutically effective amount” is the amount of the neoDegrader or neoDegrader conjugate clinically proven to affect a significant decrease in cancer or slowing of progression (regression) of cancer, such as an advanced solid tumor.
  • the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • the term “standard of care” refers to a treatment that is accepted by medical experts as a proper treatment for a certain type of disease and that is widely used by healthcare professionals.
  • an “anti-cancer agent” promotes cancer regression in a subject or prevents further tumor growth.
  • a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer.
  • the terms “effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient.
  • Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
  • immune checkpoint inhibitor refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins.
  • Checkpoint proteins regulate T-cell activation or function. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-L1 and PD-L2. Pardoll, D.M., Nat Rev Cancer 12(4):252-64 (2012). These proteins are responsible for co- stimulatory or inhibitory interactions of T-cell responses.
  • Immune checkpoint proteins regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • neoDegraders [0195] The present disclosure provides neoDegraders of formula (II): (II); or pharmaceutically acceptable salts thereof, wherein: [0196] A is phenyl or a C 4 -C 10 cycloalkyl ring; [0197] U is selected from NH and CF 2 ; [0198] R 1 is independently selected from hydrogen and halo; [0199] R 2 is selected from –C(O)R 3 , -N(R 4 )2, –(CH2)nOH, –(CH2)nSH, –(CH2)nN(R 4 )2, – (CH 2 ) n Q’(CH 2 ) m OH, –(CH 2 ) n Q’(CH 2 ) m SH, and –(CH 2 ) n Q
  • the present disclosure provides compounds of formula (II), or pharmaceutically acceptable salts thereof, wherein: [0207] A is a phenyl ring or a C4-C10cycloalkyl ring; [0208] U is NH; [0209] R 1 is selected from hydrogen and halo; [0210] R 2 is selected from –(CH2)nQ’(CH2)mN(R 4 )2, –(CH2)nOH, –(CH2)nSH, -N(R 4 )2, and –C(O)R 3 ; wherein: [0211] m is 2; [0212] n is 2; [0213] Q’ is –O-; [0214] R 3 is methyl; and [0215] each R 4 is independently selected from hydrogen and methyl; provided that when R 2 is NH2 or–(CH2)nOH, then R 1 is halo.
  • C 1 -C 6 alkoxy refers to a C 1 -C 6 alkyl group attached to the parent molecular moiety through an oxygen atom.
  • C 1 -C 6 alkoxyC 1 -C 6 alkyl refers to a C 1 -C 6 alkoxy group attached to the parent molecular moiety through a C1-C6alkyl group.
  • C1-C6alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six carbon atoms.
  • C4-C10cycloalkyl refers to a a saturated monocyclic, hydrocarbon ring system having four to ten carbon atoms and zero heteroatoms.
  • Representative examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the cycloalkyl groups containing between seven and ten atoms may be monocyclic or fused, spirocyclic, or bridged bicyclic structures.
  • halo refers to F, Cl, Br, or I.
  • the neoDegrader of formula (II) is a compound selected from the group consisting of: ; and . [0222] In some aspects, the neoDegrader of formula (II) is [0223] In some aspects, the neoDegrader of formula (II) is [0224] In some aspects, the neoDegrader of formula (II) is [0225] In some aspects, the neoDegrader of formula (II) is [0226] In some aspects, the neoDegrader of formula (II) is [0227] In some aspects, the neoDegrader of formula (II) is [0228] In some aspects, the neoDegrader of formula (II) is [0229] In some aspects, the neoDegrader of formula (II) is [0230] In some aspects, the present disclosure provides neoDegraders of formula (II), or pharmaceutically acceptable salts thereof
  • the present disclosure provides neoDegraders of formula (II), wherein A is phenyl; U is NH; R 1 is halo; and R 2 is –(CH2)nQ’(CH2)mN(R 4 )2, wherein m and n are 2, Q’ is O, and each R 4 is methyl.
  • the present disclosure provides neoDegraders of formula (II), wherein A is phenyl; U is NH: R 1 is halo; and R 2 is - (CH2)nOH, wherein n is 2.
  • the present disclosure provides neoDegraders of formula (II), wherein A is phenyl; U is NH: R 1 is halo; and R 2 is - (CH 2 ) n SH, wherein n is 2. [0234] In some aspects, the present disclosure provides neoDegraders of formula (II), wherein A is phenyl; U is NH; R 1 is hydrogen; and R 2 is –N(R 4 )2, wherein one R 4 is hydrogen and the other is methyl.
  • the present disclosure provides neoDegraders of formula (II), wherein A is phenyl; U is NH; R 1 is halo; and R 2 is –N(R 4 )2, wherein each R 4 is hydrogen.
  • the present disclosure provides neoDegraders of formula (II), wherein A is phenyl; R 1 is hydrogen; and R 2 –C(O)R 3 , wherein R 3 is methyl.
  • a neoDegrader is a molecule that forms a ternary complex with an E3 ubiquitin ligase which is capable of targeting a protein for degradation. III.
  • NeoDegrader Conjugates [0238] The present disclosure provides conjugates of one or more neoDegraders disclosed herein and an anti-CD33 antibody or antigen-binding portion thereof disclosed herein. These conjugates can degrade proteins by binding to cereblon (CRBN), promoting recruitment and ubiquitination of substrate proteins mediated by CRL4 CRBN E3 ubiquitin ligase. These agents act as “molecular glues,” filling the binding interface as a hydrophobic patch that reprograms protein interactions between the ligase and neosubstrates.
  • CRBN cereblon
  • CRL4 CRBN E3 ubiquitin ligase act as “molecular glues,” filling the binding interface as a hydrophobic patch that reprograms protein interactions between the ligase and neosubstrates.
  • the neoDegrader conjugate described herein has in vitro anti- proliferative activity against a tumor cell line.
  • the neoDegrader conjugate comprising a neoDegrader and an anti-CD33 antibody or antigen-binding portion thereof disclosed herein has in vitro anti-proliferative activity at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100% higher than the neoDegrader alone or the anti-CD33 antibody or antigen-binding portion thereof disclosed herein alone.
  • the neoDegrader conjugate comprising a neoDegrader and an anti- CD33 antibody or antigen-binding portion thereof disclosed herein has in vitro anti-proliferative activity at least about 2 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 6 fold, at least about 7 fold, at least about 8 fold, at least about 9 fold, at least about 10 fold higher than the neoDegrader alone or the anti-CD33 antibody or antigen-binding portion thereof disclosed herein alone.
  • the neoDegrader conjugates described herein have in vitro anti- proliferative activity against a Daudi lymphoma cell line, e.g., higher anti-proliferative activity against a Daudi lymphoma cell line, compared to the neoDegrader alone or the anti-CD33 antibody or antigen-binding portion thereof alone.
  • the neoDegrader conjugates described herein have in vitro anti-proliferative activity against the HL-60 acute myeloid leukemia cell line, e.g., higher anti-proliferative activity against a HL-60 acute myeloid leukemia cell line, compared to the neoDegrader alone or the anti-CD33 antibody or antigen-binding portion thereof alone.
  • the neoDegrader conjugates described herein have in vitro anti-proliferative activity against a Ramos non-Hodgkins lymphoma cell line, e.g., higher anti-proliferative activity against a Ramos non-Hodgkins lymphoma cell line, compared to the neoDegrader alone or the anti-CD33 antibody or antigen-binding portion thereof alone.
  • the neoDegrader conjugates described herein is capable of maintaining their anti-proliferative activity in the presence of human serum.
  • the neoDegrader conjugates described herein can be used in the treatment of cancers.
  • an antibody neoDegrader conjugate is a conjugate of one or more neoDegraders disclosed herein and an anti-CD33 antibody or antigen-binding portion thereof disclosed herein.
  • III.A. Linker [0257] The neoDegrader of the present disclosure can be linked to the anti-CD33 antibody or antigen-binding portion thereof via a linker.
  • linker refers to any chemical moiety capable of connecting the anti-CD33 antibody or antigen-binding portion thereof (Bm) to group X within the compounds of formula (I).
  • the linker can contain a heterobifunctional group.
  • heterobifunctional group refers to a chemical moiety that connects the linker of which it is a part to the anti-CD33 antibody or antigen-binding portion thereof. Heterobifunctional groups are characterized as having different reactive groups at either end of the chemical moiety. Attachment to “Bm,” can be accomplished through chemical or enzymatic conjugation, or a combination of both. Chemical conjugation involves the controlled reaction of accessible amino acid residues on the surface of the anti-CD33 antibody or antigen-binding portion thereof with a reaction handle on the heterobifunctional group.
  • Examples of chemical conjugation include, but are not limited to, lysine amide coupling, cysteine coupling, and coupling via a non- natural amino acid incorporated by genetic engineering, wherein non-natural amino acid residues with a desired reaction handle are installed onto “Bm.”
  • an enzyme mediates the coupling of the linker with an accessible amino residue on the anti-CD33 antibody or antigen-binding portion thereof.
  • Examples of enzymatic conjugation include, but are not limited to, transpeptidation using sortase, transpeptidation using microbial transglutaminase, and N-glycan engineering. Chemical conjugation and enzymatic conjugation may also be used sequentially.
  • enzymatic conjugation can also be used for installing unique reaction handles on “Bm” to be utilized in subsequent chemical conjugation.
  • the heterobifunctional group is selected from: wherein is the point of attachment to the remaining portion of the linker; and the point of attachment to Bm.
  • linker “L” is non-cleavable.
  • non- cleavable linker is any chemical moiety that is capable of linking the anti-CD33 antibody or antigen-binding portion thereof to the neoDegrader in a stable, covalent manner and does not fall under the categories defined herein as “cleavable linkers”.
  • non-cleavable linkers are substantially resistant to acid-induced cleavage, light-induced cleavage, bioreductive cleavge, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.
  • “Substantially resistant to cleavage” means that the chemical bond in the linker or adjoining the linker in at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% of the antibody neoDegrader conjugate population remains non-cleavable by an acid, a photolabile-cleaving agent, a bioreductive agent, a peptidase, an esterase, or a chemical or a physiological compound that cleaves the chemical bond (for example, a disulfide bond) in a cleavable linker, for within a few hours to several days of treatment with any of the agents described above.
  • the linker is not susceptible to acid- induced cleavage, photo-induced cleavage, bioreductive cleavage, enzymatic cleavage, or the like, at conditions under which the neoDegrader and/or anti-CD33 antibody or antigen-binding portion thereof can remain active.
  • ADC catabolites generated from non-cleavable linkers contain a residual amino acid from the antibody. These catabolites can exert unique and unexpected properties in the target cells to which they are delivered. [0261] A person of ordinary skill in the art would readily distinguish non-cleavable from cleavable linkers.
  • non-cleavable linkers include, but are not limited to, SMCC (succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate) linkers, succinimide thioether linkers, and linkers such as: [0263] p is an integer from 1 to 10; [0264] is the point of attachment to X; and [0265] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof. [0266] In some aspects, the linker is: . In some aspects, p is 5. [0267] In certain aspects the linker can be cleavable.
  • the linker can be susceptible to acid-induced cleavage, photo-induced cleavage, bioreductive cleavage, enzymatic cleavage, or the like, at conditions under which the neoDegrader and/or anti-CD33 antibody or antigen-binding portion thereof can remain active.
  • the cleavable linker can be cleaved enzymatically.
  • the cleavable linker can be cleaved by a protease, peptidase, esterase, beta-gluroronidase, glycosidase, phosphodiesterase, phosphatase, pyrophosphatase, or lipase.
  • the cleavable linker can be cleaved by a protease.
  • proteases include, but are not limited to, cathepsin B, VAGP tetrapeptide, and the like.
  • the cleavable linker contains a peptide.
  • the peptide is the site of cleavage of the linker, thereby facilitating release of the drug upon exposure to intracellular proteases, such as lysosomal enzymes.
  • Peptides can be designed and optimized for enzymatic cleavage by a particular enzyme, for example, a tumor-associated protease, cathepsin B, C and D, or a plasmin protease.
  • a tumor-associated protease for example, a tumor-associated protease, cathepsin B, C and D, or a plasmin protease.
  • peptides having two amino acids include, but are not limited to, alanine-alanine (ala-ala), valine-alanine (val-ala), valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe); phenylalanine-lysine (fk or phe-lys); phenylalanine- homolysine (phe-homolys); and N-methyl-valine-citrulline (Me-val-cit).
  • Examples of peptides having three amino acids include, but are not limited to, glycine-valine-citrulline (gly-val-cit), aspartic acid-valine-citrulline (asp-val-cit), alanine-alanine-asparagine (ala-ala-asn), alanine- phenylalanine-lysine (ala-phe-lys), glycine-glycine-phenylalanine (gly-gly-phe), and glycine- glycine-glycine-glycine (gly-gly-gly).
  • peptides having four amino acids include, but are not limited to, glycine-glycine-valine-citrulline (gly-gly-val-cit) and glycine-glycine-phenylalanine- glycine (gly-gly-phe-gly).
  • the amino acid combinations above can also be present in the reverse order (i.e., cit-val).
  • the peptides of the present disclosure can comprise L- or D- isomers of amino acid residues.
  • linker is a protease cleavable linker selected from
  • [0273] q is an integer from 2 to 10; [0274] Z 1 , Z 2 , Z 3 , and Z 4 are each independently absent or a naturally-occurring amino acid residue in the L- or D-configuration, provided that at least two of Z 1 , Z 2 , Z 3 , and Z 4 are amino acid residues; [0275] is the point of attachment to X; and [0276] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof.
  • Z 1 , Z 2 , Z 3 , and Z 4 are independently absent or selected from the group consisting of L-valine, D-valine, L-citrulline, D-citrulline, L-alanine, D-alanine, L- glutamine, D-glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L- asparagine, D-asparagine, L-phenylalanine, D-phenylalanine, L-lysine, D-lysine, and glycine; provided that at least two of Z 1 , Z 2 , Z 3 , and Z 4 are amino acid residues.
  • Z 1 is absent or glycine
  • Z 2 is absent or selected from L-glutamine, D-glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L-alanine, D- alanine, and glycine
  • Z 3 is selected from L-valine, D-valine, L-alanine, D-alanine, L-phenylalanine, D-phenylalanine, and glycine
  • Z 4 is selected from L-alanine, D-alanine, L-citrulline, D- citrulline, L-asparagine, D-asparagine, L-lysine, D-lysine, L-phenylalamine, D-phenylalanine, and glycine.
  • L is . [0280] In some aspects, q is 5. [0281] In certain aspects, L is a pyrophosphatase cleavable linker. [0282] In some aspects, L is a pyrophosphatase cleavable linker which is: wherein: [0283] q is an integer from 2 to 10; [0284] the point of attachment to X; and [0285] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof. [0286] In certain aspects, L is a beta-glucoronidase cleavable linker.
  • L is a beta-glucoronidase cleavable linker selected from: wherein: [0288] q is an integer from 2 to 10; [0289] ---- is absent or a bond; [0290] is the point of attachment to X; and [0291] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof.
  • the linker is bioreducible. Bioreducible linkers take advantage of the difference in reduction potential in the intracellular compartment versus plasma. Reduced glutathione presented in tumor cells’ cytoplasma is up to 1000-fold higher than that present in normal cells’ cytoplasma, and the tumor cells also contain enzymes which can contribute to reduction in cellular compartments.
  • L is a bioreducible linker selected from:
  • R, R’, R’’, and R’’ are each independently selected from hydrogen, C 1 - C6alkoxyC1-C6alkyl, (C1-C6)2NC1-C6alkyl, and C1-C6alkyl, or, two geminal R groups, together with the carbon atom to which they are attached, can form a cyclobutyl or cyclopropyl ring; [0296] the point of attachment to X; and [0297] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof. [0298] In certain aspects, the linker is acid cleavable.
  • Acid-cleavable linkers are specifically designed to remain stable at the neutral pH of blood circulation, but undergo hydrolysis and release the cytotoxic drug in the acidic environment of the cellular compartments.
  • L is an acid cleavable linker selected from wherein: [0300] q is an integer from 2 to 10; [0301] is the point of attachment to X; and [0302] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof. [0303] In certain aspects, L is wherein L is a click-to-release linker, where release of the neoDegrader is chemically triggered by a tetrazine or related compound.
  • L is a click-to-release linker selected from wherein: [0305] q is an integer from 2 to 10; [0306] is the point of attachment to X; and [0307] is the point of attachment to the anti-CD33 antibody or antigen-binding portion thereof.
  • III.B. Anti-CD33 Antibody [0308] The present disclosure provides neoDegraders conjugated to an anti-CD33 antibody or antigen-binding portion thereof.
  • CD33 is a transmembrane receptor expressed on both myeloid and lymphoid cells. It binds sialic acid, and therefore, is a member of the sialic acid-binding immunoglobulin-type lectin (SIGLEC) family.
  • CD33 plays a role in mediating cell-cell interactions and in maintaining immune cells in a resting state.
  • the immunoreceptor tyrosine-based inhibition motif (ITIM) of CD33 present on the cytosolic portion of the protein, is phosphorylated and acts as a docking site for Src homology 2 (SH2) domain-containing proteins like SHP phosphatases. This can result in a cascade that inhibits phagocytosis in the cell.
  • the extracellular portion of CD33 contains two immunoglobulin domains, and the intracellular portion contains the ITIM.
  • CD33 includes, but are not limited to, sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, and p67.
  • Table 1 The canonical amino acid sequence for human CD33 and known isoforms are shown in Table 1 (UniProtKB – P20138; SEQ ID NOs: 13-18). Table 1. Human CD33 Amino Acid Sequences [0311] CD33 is expressed in approximately 90% of acute myeloid leukemia (AML) cases and has demonstrated utility as a target of therapeutic antibodies. High CD33 expression on AML blasts has been reported approximately three decades ago.
  • AML acute myeloid leukemia
  • CD33 was detected on blasts of 85-90% of patients presenting with AML as well as on normal myeloid progenitors and myelocytes. CD33 is restricted to hematopoietic cells, but absent on normal hematopeoietic stem cells, making it an ideal target for AML therapy. [0312] Anti-CD33 antibodies for the conjugates of the present disclosure are capable of specifically binding to CD33.
  • anti-CD33 antibodies described herein bind to human CD33 with high affinity, for example, with a KD of 10 -6 M or less, 10 -7 M or less, 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, 10 -12 M or less, 10 -12 M to 10 -7 M, 10 -11 M to 10- 7 M, 10 -10 M to 10 -7 M, or 10 -9 M to 10 -7 M.
  • the anti-CD33 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) and the light chain comprises a light chain variable region (VL); wherein the VH comprises a VH complementarity determining region (CDR) 1 (VH-CDR1), a VH-CDR2, and a VH-CDR3 and the VL comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3; wherein the VH-CDR3 comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 3.
  • the anti-CD33 antibody comprises a VH-CDR2 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 2.
  • the anti-CD33 antibody comprises a VH-CDR1 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 1.
  • the anti-CD33 antibody comprises a VL-CDR1 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 5.
  • the anti-CD33 antibody comprises a VL-CDR2 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 6.
  • the anti-CD33 antibody comprises a VL-CDR3 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 7.
  • the CDRs comprises the sequences shown in Table 2 below. Table 2.
  • the anti-CD33 antibody heavy chain variable region comprises an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 4.
  • the anti-CD33 antibody light chain variable region comprises an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 8.
  • the anti-CD33 antibody comprises a heavy chain variable region comprising a sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 4, and a light chain variable region comprising a sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 8.
  • the anti-CD33 antibody heavy chain comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 9 or SEQ ID NO: 11.
  • the anti-CD33 antibody comprises a light chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 10 or SEQ ID NO: 12.
  • the anti-CD33 antibody comprises a heavy chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 9 and a light chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 10.
  • the anti-CD33 antibody comprises a heavy chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 11 and a light chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 12.
  • the anti-CD33 antibody is disclosed in US Patent Nos.5,585,089, US 5,693,762, each of which are expressly incorporated herein by reference.
  • the anti-CD33 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) and the light chain comprises a light chain variable region (VL); wherein the VH comprises a VH complementarity determining region (CDR) 1 (VH-CDR1), a VH-CDR2, and a VH-CDR3 and the VL comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3; wherein the VH-CDR3 comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 21.
  • the anti-CD33 antibody comprises a VH-CDR2 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 20.
  • the anti-CD33 antibody comprises a VH-CDR1 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 19.
  • the anti-CD33 antibody comprises a VL-CDR1 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 22.
  • the anti-CD33 antibody comprises a VL-CDR2 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 23.
  • the anti-CD33 antibody comprises a VL-CDR3 comprising an amino acid sequence with at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 24.
  • the CDRs comprises the sequences shown in Table 4 below. Table 4. huMy9-6 and AB1 CDR Sequences and Variable Region Sequences
  • the anti-CD33 antibody heavy chain variable region comprises an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 27.
  • the anti-CD33 antibody light chain variable region comprises an amino acid sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 28.
  • the anti-CD33 antibody comprises a heavy chain variable region comprising a sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 27, and a light chain variable region comprising a sequence with at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to an amino acid sequence of SEQ ID NO: 28.
  • the anti-CD33 antibody heavy chain comprises an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 25.
  • the anti-CD33 antibody comprises a light chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to 26.
  • Table 5 huMy9-6-IgG4-S228P (“AB1”) Anti-CD33 Antibody Amino Acid Sequences.
  • the anti-CD33 antibody comprises a heavy chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 25 and a light chain comprising an amino acid sequence having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 26.
  • the term “CD33AB” comprises a heavy chain as set forth in SEQ ID NO: 25 and a light chain as set forth in SEQ ID NO: 26.
  • Anti-CD33 antibodies include analogs and derivatives that are either modified, i.e., by the covalent attachment of any type of molecule as long as such covalent attachment permits the antibody to retain its antigen binding immunospecificity.
  • the derivatives and analogs of the antibodies include those that have been further modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular antibody unit or other protein, etc.
  • the anti-CD33 antibodies in neoDegrader conjugates can include antibodies having modifications (e.g., substitutions, deletions or additions) in amino acid residues that interact with Fc receptors.
  • antibodies include antibodies having modifications in amino acid residues identified as involved in the interaction between the anti-Fc domain and the FcRn receptor.
  • Antibodies immunospecific for a cancer cell antigen can be obtained commercially, for example, from Genentech (San Francisco, Calif.) or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques.
  • the nucleotide sequence encoding antibodies immunospecific for a cancer cell antigen can be obtained, e.g., from the GenBank database or a database like it, the literature publications, or by routine cloning and sequencing.
  • the antibody of the neoDegrader conjugates can be a monoclonal antibody, e.g. a murine monoclonal antibody, a chimeric antibody, or a humanized antibody.
  • the antibody can be an antibody fragment, e.g. a Fab fragment.
  • the conjugates and/or compounds described herein can be in the form of pharmaceutically or pharmaceutically acceptable salts. In some aspects, such salts are derived from inorganic or organic acids or bases.
  • Suitable acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate,
  • suitable base addition salts include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, and the like.
  • compositions comprising the neoDegrader conjugates described herein may also comprise suitable carriers, excipients, and auxiliaries that may differ depending on the mode of administration.
  • the pharmaceutical compositions can be formulated as a suitable parenteral dosage form. Said formulations can be prepared by various methods known in the art.
  • the pharmaceutical compositions can be administered directly into the bloodstream, into muscle, or directly into an organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous.
  • Suitable devices for parenteral administration include needle injectors, needle-free injectors, and infusion techniques.
  • Parenteral compositions are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents. However, the composition may also be formulated a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile pyrogen-free water.
  • a suitable vehicle such as sterile pyrogen-free water.
  • the preparation of parenteral compositions under sterile conditions, for example, by lyophilization, can be readily accomplished using standard techniques known well to those of skill in the art.
  • Compositions for parenteral administration can be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
  • compositions can be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active agent.
  • parenteral formulations can be admixed with other suitable pharmaceutically acceptable excipients used in parenteral dosage forms such as, but not limited to, preservatives.
  • the pharmaceutical compositions can be formulated as suitable oral dosage forms such as tablets, capsules, powders, pellets, suspensions, solutions, emulsions, and the like.
  • Oral dosage formulations may also contain other suitable pharmaceutical excipients such as sweeteners, vehicle/wetting agents, coloring agents, flavoring agents, preservatives, viscosity enhancing/thickening agents, and the like.
  • suitable pharmaceutical excipients such as sweeteners, vehicle/wetting agents, coloring agents, flavoring agents, preservatives, viscosity enhancing/thickening agents, and the like.
  • the neoDegrader or neoDegrader conjugates described herein can be used to treat various cancers.
  • Certain conjugates of the present disclosure can be superior in terms of efficacy expression, pharmacokinetics (e.g., absorption, distribution, metabolism, excretion), solubility (e.g., water solubility), interaction with other medicaments (e.g., drug-metabolizing enzyme inhibitory action), safety (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity) and/or stability (e.g., chemical stability, stability to an enzyme), and can be useful as a medicament.
  • pharmacokinetics e.g., absorption, distribution, metabolism, excretion
  • solubility e.g., water solubility
  • interaction with other medicaments e.g., drug-metabolizing enzyme inhibitory action
  • safety e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity
  • stability e.g., chemical stability, stability to an enzyme
  • neoDegrader or neoDegrader conjugates of the present disclosure can be used as medicaments such as an agents for the prophylaxis or treatment of diseases, for example, cancers —e.g., colorectal cancers (e.g., colorectal cancer, rectal cancer, anus cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancers (e.g., non-small-cell lung cancer, small-cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancers (e.g., pancreatic ductal carcinoma, pancreatic endocrine tumor), pharynx cancer, larynx cancer, esophageal cancer, stomach/gastric cancers (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), du
  • neoDegraders or neoDegrader conjugates of the present disclosure can be used as a medicament for breast cancer, gastric cancer, ovarian cancer, uterine cancer, lung cancer, pancreatic cancer, liver cancer, lymphoma, or hematological cancers.
  • neoDegrader or neoDegrader conjugates of the present disclosure can be used concurrently with a non-drug therapy.
  • the conjugates can be combined with a non-drug therapy such as (1) surgery, (2) hypertensive chemotherapy using angiotensin II etc., (3) gene therapy, (4) thermotherapy, (5) cryotherapy, (6) laser cauterization and (7) radiotherapy.
  • neoDegrader or neoDegrader conjugate of the present disclosure before or after the above-mentioned surgery and the like, effects such as prevention of emergence of resistance, prolongation of Progression-Free Survival, prolongation of Disease-Free Survival, suppression of cancer metastasis or recurrence, prolongation of life and the like may be afforded.
  • a treatment with a neoDegrader or neoDegrader conjugates of the present disclosure with a supportive therapy: (i) administration of antibiotic (e.g., ⁇ -lactam type such as pansporin and the like, macrolide type such as clarithromycin and the like) for the complication with various infectious diseases, (ii) administration of high- calorie transfusion, amino acid preparation or general vitamin preparation for the improvement of malnutrition, (iii) administration of morphine for pain mitigation, (iv) administration of a pharmaceutical agent for ameliorating side effects such as nausea, vomiting, anorexia, diarrhea, leucopenia, thrombocytopenia, decreased hemoglobin concentration, hair loss, hepatopathy, renopathy, DIC, fever and the like and (v) administration of a pharmaceutical agent for suppressing multiple drug resistance of cancer and the like.
  • antibiotic e.g., ⁇ -lactam type such as pansporin and the like, macrolide type such as clarithromycin and the like
  • the neoDegrader or neoDegrader conjugate of the disclosure can be used in combination with a standard of care therapy, e.g., one or more therapeutic agents (e.g., anti-cancer agents and/or immunomodulating agents).
  • a method of treating a tumor disclosed herein comprises administering the neoDegrader or neoDegrader conjugate of the disclosure in combination with one or more additional therapeutic agents.
  • the neoDegrader or neoDegrader conjugate of the disclosure can be used in combination with one or more anti-cancer agents, such that multiple elements of the immune pathway can be targeted.
  • an anti-cancer agent comprises an immune checkpoint inhibitor (i.e., blocks signaling through the particular immune checkpoint pathway).
  • immune checkpoint inhibitors that can be used in the present methods comprise a CTLA-4 antagonist (e.g., anti-CTLA-4 antibody), PD-1 antagonist (e.g., anti-PD-1 antibody, anti-PD-L1 antibody), TIM-3 antagonist (e.g., anti-TIM-3 antibody), or combinations thereof.
  • CTLA-4 antagonist e.g., anti-CTLA-4 antibody
  • PD-1 antagonist e.g., anti-PD-1 antibody, anti-PD-L1 antibody
  • TIM-3 antagonist e.g., anti-TIM-3 antibody
  • a comprehensive and non-limiting list of combination treatment is disclosed in detail in the Combination Treatments section of this application.
  • the neoDegrader or neoDegrader conjugate of the disclosure is administered to the subject prior to or after the administration of the additional therapeutic agent.
  • the neoDegrader or neoDegrader conjugate of the disclosure is administered to the subject concurrently with the additional therapeutic agent.
  • the neoDegrader or neoDegrader conjugate of the disclosure and the additional therapeutic agent can be administered concurrently as a single composition in a pharmaceutically acceptable carrier.
  • the neoDegrader or neoDegrader conjugate of the disclosure and the additional therapeutic agent are administered concurrently as separate compositions.
  • a subject that can be treated with the neoDegrader or neoDegrader conjugate of the present disclosure is a nonhuman animal such as a rat or a mouse.
  • the subject that can be treated is a human.
  • the linker precursor contain a heterobifunctional group that connects to the anti-CD33 antibody or antigen-binding portion thereof.
  • L’ is a non-cleavable linker precursor. In some aspects, L’ is selected from the group consisting of wherein: p is an integer from 1 to 10; and the point of attachment to X. [0353] In some aspects, L’ is [0354] In some aspects, p is 5. [0355] In certain aspects, L’ is a cleavable linker precursor. [0356] In some aspects, the linker precursor is cleavable by a protease. In some aspects, the linker precursor is selected from the group consisting of
  • q is an integer from 2 to 10;
  • Z 1 , Z 2 , Z 3 , and Z 4 are each independently absent or a naturally-occurring amino acid residue in the L- or D-configuration, provided that at least two of Z 1 , Z 2 , Z 3 , and Z 4 are amino acid residues; and the point of attachment to X.
  • Z 1 , Z 2 , Z 3 , and Z 4 are independently absent selected from the group consisting of L-valine, D-valine, L-citrulline, D-citrulline, L-alanine, D-alanine, L-glutamine, D- glutaimine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, L-asparagine, D- asparagine, L-phenylalanine, D-phenylalanine, L-lysine, D-lysine, and glycine, provided that at least two of Z 1 , Z 2 , Z 3 , and Z 4 are amino acid residues.
  • Z 1 is absent or glycine
  • Z 2 is absent or selected from the group consisting of L-glutamine, D-glutamine, L-glutamic acid, D-glutamic acid, L-aspartic acid, D- aspartic acid, L-alanine, D-alanine, and glycine
  • Z 3 is selected from the group consisting of L- valine, D-valine, L-alanine, D-alanine, L-phenylalanine, D-phenylalanine, and glycine
  • Z 4 is selected from the group consisting of L-alanine, D-alanine, L-citrulline, D-citrulline, L-asparagine, D-asparagine, L-lysine, D-lysine, L-phenylalamine, D-phenylalanine, and glycine.
  • L’ is
  • L’ is a bioreducible linker precursor.
  • the bioreducible linker precursor is selected from the group consisting of wherein: q is an integer from 2 to 10; R, R’, R’’, and R’’ are each independently selected from hydrogen, C 1 -C 6 alkoxyC 1 - C6alkyl, (C1-C6)2NC1-C6alkyl, and C1-C6alkyl, or, two geminal R groups, together with the carbon atom to which they are attached, can form a cyclobutyl or cyclopropyl ring; and is the point of attachment to X.
  • L’ is an acid cleavable linker precursor. In some aspects, L’ is selected from the group consisting of wherein: q is an integer from 2 to 10; and is the point of attachment to X. [0363] In certain aspects, L’ is a click-to-release linker precursor. In some aspects, L’ is selected from wherein: q is an integer from 2 to 10; and the point of attachment to X. [0364] In certain aspects, L’ is a pyrophosphatase cleavable linker precursor. In some aspects, L’ is wherein: q is an integer from 2 to 10; is the point of attachment to X.
  • L’ is a beta-glucoronidase cleavable linker precursor. In some aspects, L’ is selected from wherein: q is an integer from 2 to 10; ---- is absent or a bond; and the point of attachment to X. [0366] In some aspects, the compound of formula (I-1) is selected from
  • the anti-CD33 antibody or antigen-binding portion thereof is pre- treated before it is reacted with the compound of formula (I-1).
  • the compound of formula (I-1) is reacted with an anti-CD33 antibody or antigen-binding portion thereof.
  • the anti-CD33 antibody or antigen-binding portion thereof can be pretreated to reduce interchain disulfides prior to reaction with the compound of formula (I-1).
  • Step 2 Synthesis of Compound 3 [0371] To a stirred solution of 2-(2-chloro-4-nitrophenyl)ethanol (Compound 2, 5.00 g, 24.800 mmol, 1.00 equiv) and tert-butyl 2-bromoacetate (29.0 mL, 148.28 mmol, 8.00 equiv) in toluene (150.00 mL) was added Bu 4 NHSO 4 (6.74 g, 19.84 mmol, 0.80 equiv). To the above mixture was added NaOH (5M in H 2 O) (500.00 mL) dropwise over 40 min at 0 oC. The resulting mixture was stirred for additional 2 h at 25 oC.
  • 2-(2-chloro-4-nitrophenyl)ethanol Compound 2, 5.00 g, 24.800 mmol, 1.00 equiv
  • tert-butyl 2-bromoacetate 29.0 mL, 148.28 mmol, 8.00 e
  • the mixture was stirred at 25 oC for 1 h.
  • the resulting mixture was concentrated under vacuum.
  • the crude product was purified by Prep-HPLC with the following conditions: Column, SunFire C18 OBD Prep Column, 100 ⁇ m, 19x250 mm; mobile phase, water (0.05% TFA) and ACN (5% Phase B up to 60% in 30 min); Detector, UV 220nm.
  • Step 10 Synthesis of Compound (Ia) [0379] To a stirred mixture of 1-(3-chloro-4-[2-[2-(methylamino)ethoxy]ethyl]phenyl)-3- [[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl]urea (neoDegrader P1, 200 mg, 0.38 mmol, 1.00 equiv) and lutidine (81 mg, 0.76 mmol, 2.00 equiv) in DMF (10 mL) were added HOBT (26 mg, 0.19 mmol, 0.50 equiv) and [4-[(2S)-5-(carbamoylamino)-2-[(2S)-2-[6-(2,5- dioxopyrrol-1-yl)hexanamido]-3-methylbutanamido]pentanamido]phenyl]methyl 4-nitrophen
  • the reaction mixture was stirred for 12 hours at 40 degrees C under nitrogen atmosphere. After the reaction was cooled down to room temperature, the reaction was quenched with water (30 mL). The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with water (2 x 30 mL), brine (30 mL), dried over Na 2 SO 4 . After filtration, the filtrate was concentrated to dryness under vacuum. The residue was purified by reverse phase column (C18, mobile phase A: 0.1% FA in water, B: ACN). The collected fraction was concentrated to dryness under vacuum.
  • the crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30x150mm 5um, n; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:33 B to 50 B in 7 min; 220 nm; RT1:5.27min).
  • the final reaction mixture was irradiated with microwave radiation for 2 h at 120 oC.
  • the mixture was cooled down to room temperature and filtered.
  • the filter cake was washed with MeOH (3x30 mL).
  • the filtrate was concentrated under reduced pressure.
  • Step 6 Synthesis of Compound 16 [0385] To a mixture of tert-butyl[2-(2-chloro-4-nitrophenyl)ethoxy]dimethylsilane (Compound 15, 5.70 g, 18.05 mmol, 1.00 equiv) and Fe (10.08 g, 180.45 mmol, 10.00 equiv) in EtOH (110 mL) /water (55 mL) was added NH4Cl (9.65 g, 180.45 mmol, 10 equiv). The mixture was stirred at 80 oC for 2 h. The mixture was cooled down to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOH (3x50 mL).
  • Step 11 Synthesis of Compound (Ib) [0390] To a solution of 1-[3-chloro-4-(2-hydroxyethyl)phenyl]-3-[[2-(2,6-dioxopiperidin- 3-yl)-1-oxo-3H-isoindol-5-yl]methyl]urea (neoDegrader P3, 200.00 mg, 0.42 mmol, 1.00 equiv) and TEA (129 mg, 1.26 mmol, 3.00 equiv) in DMF (4 mL) was added a solution of CDI (138 mg, 0.84 mmol, 2.00 equiv) in DMF (1 mL). The reaction mixture was stirred at room temperature for 2 hours.
  • the combined organic layer was washed with brine (30 mLx3), dried over anhydrous sodium sulfate and evaporated to dryness in vacuum to give the crude product (150 mg) as a yellow solid.
  • the crude product was purified with Prep-HPLC (Column: Xselect CSH OBD Column 30x150mm 5um; Mobile Phase A:Water (0.1%FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:38 B to 58 B in 7 min; 220 nm; RT1:5.12min).
  • Example 3 Synthesis of Compound (Ic) Step 1: Synthesis of Compound 23 [0391] To a stirred solution of tert-butyl (2-aminophenyl)(methyl)carbamate (Compound 22, 300 mg, 1.35 mmol, 1.00 equiv) in DMF (20 mL) was added CDI (218 mg, 1.35 mmol, 1.00 equiv) and TEA (68 mg, 1.35 mmol, 1.00 equiv) dropwise at 0 oC under nitrogen atmosphere. The mixture was stirred at 0 oC for 2 h.
  • CDI tert-butyl (2-aminophenyl)(methyl)carbamate
  • TEA 68 mg, 1.35 mmol, 1.00 equiv
  • neoDegrader P4 [0392] To a stirred solution tert-butyl N-[2-[([[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H- isoindol-5-yl]methyl]carbamoyl)amino]phenyl]-N-methylcarbamate (Compound 23, 300 mg, 1.00 equiv) in DCM (20 mL) was added TFA (5 mL) at 0 oC. The mixture was stirred at 0 oC for 2 h. The resulting mixture was concentrated under vacuum.
  • the reaction mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN;) to afford crude product (60 mg) as a white solid.
  • the crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30x150mm 5um, n; Mobile Phase A:Water (0.1% FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:24 B to 44 B in 7 min; 220 nm; RT1:6.33; RT2:).
  • the resulting mixture was stirred for 3h at room temperature under nitrogen atmosphere.
  • the resulting mixture was quenched with water (30 mL), and extracted with DCM (3 x 30 mL).
  • the combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2SO4. After filtration, the filtrate was concentrated to dryness under vacuum.
  • Scheme 5B Synthesis of NeoDegrader P1-Tripeptide Linker Complex (continued) [0397] Schemes 6A and 6B show how to prepare a complex of neoDegrader P1 with a ⁇ - glucuronide linker.
  • Scheme 6A Synthesis of NeoDegrader P1- ⁇ -Glucuronide Linker Complex Step 1. Synthesis of Compound 25 [0398] To a stirred mixture of 3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-propanoic acid (Compound 24, 5.00 g, 16.06 mmol, 1.00 equiv) in SOCl 2 (25 mL) at room temperature.
  • reaction mixture was stirred overnight at room temperature under nitrogen atmosphere.
  • LCMS indicated the reaction was completed.
  • the reaction mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 10% to 90% gradient in 40 min; detector, UV 254 nm.
  • Scheme 7 shows how to prepare a complex of neoDegrader P6 with a hydrazine linker.
  • Scheme 7 Synthesis of NeoDegrader P6-Hydrazone Linker Complex Step 1.
  • Synthesis of Compound 38 [0409] To a stirred solution of 4-aminoacetophenone (Compound 37, 100 mg, 0.73 mmol, 1.00 equiv) in THF (2.00 mL) were added diphosgene (0.40 mL) dropwise at room temperature. The resulting mixture was stirred for 30 min at 0 oC. The resulting mixture was concentrated under vacuum. The resulting solid was re-dissolved in DMF (1.50 mL).
  • the precipitated solids were collected by filtration and washed with MeOH (2x5 mL).
  • the crude solid was purified by reverse flash chromatography with the following conditions: C18 column; mobile phase, ACN in water (0.1%FA), 10% to 50% gradient in 30 min; detector, UV 254 nm.
  • the collected fraction was extracted with DCM (3x5 mL) and concentrated under vacuum.
  • the reaction mixture was diluted with methanol and the resulting solution was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1%FA), 0% to 50% gradient in 30 min; detector, UV 254 nm to give 100 mg of the product as a colorless solid.
  • the crude product was purified by Prep-HPLC with the following conditions: column: XBridge Shield RP18 OBD Column, 19x250mm, 10um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 14% to 32 % in 7 min; 220 nm; RT1: 5.25 min.
  • the resulting mixture was stirred at room temperature for 16 hours. LCMS traces showed the reaction was completed.
  • the resulting mixture was purified by reverse phase column chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water(0.05%TFA), 5% to 45% gradient in 40 min; detector, UV 254 nm to give 90 mg of the crude product as a yellow oil.
  • Scheme 9A Synthesis of NeoDegrader P13-Peptide Linker Complex
  • Scheme 9B Synthesis of NeoDegrader P13-Peptide Linker Complex
  • Scheme 10 shows the synthesis of compounds of formula (Ih).
  • reaction mixture was stirred for overnight at room temperature under nitrogen atmosphere.
  • LCMS indicated the reaction was completed.
  • the reaction mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 10% to 90% gradient in 40 min; detector, UV 254 nm.
  • the reaction mixture was stirred for 1h at room temperature under nitrogen atmosphere. LCMS indicated the reaction was completed.
  • the reaction mixture was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO prep C18, 30*150, 5um; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 41% B in 7 min, 41% B; Wave Length: 254 nm; RT1(min): 5.8.
  • reaction mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05%TFA), 0% to 50% gradient in 40 min; detector, UV 254 nm. This resulted in 2-amino-N-[[2-(2-chloro-4-nitrophenyl)ethoxy]methyl]acetamide (Compound 82, 750 mg, 76%) as a yellow oil.
  • reaction mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 0% to 50% gradient in 30 min; detector, UV 220 nm. The collected fraction was concentrated under vacuum.
  • the resulting mixture was stirred for 2 h at room temperature.
  • LCMS indicated the reaction was completed.
  • the reaction mixture was directly purified by the following condition: Column: XSelect CSH Prep C18 OBD Column, 19x250mm,5um; Mobile Phase A:Water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL/min; Gradient:25 B to 50 B in 7 min; 254 nm; RT1:6.35min; The collected fraction was lyophilized to give the crude product.
  • the reaction was stirred at room temperature for 1 h.
  • the reaction mixture was purified by reverse flash chromatography with the following conditions: Column: Kinetex EVO C18 Column, 30xl50,5um; Mobile Phase A:xater (0.05%TFA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:23 B to 43 B in 7 min, 254 nm; RT1:6.58).
  • the reaction mixture was purified by the following condition: Column: XSelect CSH Prep C18 OBD Column, 19*250mm,5um; Mobile Phase A:water(0.05%FA), Mobile Phase B:ACN; Flow rate:25 mL/min; Gradient:30 B to 60 B in 7 min, 254 nm; RTl:6.67min to give 75 mg of the crude product.
  • the crude product was re-purified by reverse flash chromatography with the following conditions: Column: XBridge Shield RP18 OBD Column, 19*250mm,10um; Mobile Phase A:water(0.1%FA), Mobile Phase B:ACN; Flow rate:25 mL/min; Gradient:25 B to 44 B in 10 min; 254 nm; RTl:10.52min.
  • the collected fraction was lyophilized to give Compound (II) (41.6 mg, 10%) as a white solid.
  • reaction mixture was purified by reverse flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, ACN in water (0.1%FA), 0% to 60% gradient in 30 min; detector, UV 220 nm to give (2S)-2-[6-(2,5-dioxopyrrol-l-yl)hexanamido]-3-methylbutanoic acid (Compound 142, 1.2 g, 72%) as a brown solid.
  • the resulting mixture was purified by reverse flash chromatography with the following conditions: Column: YMC-Actus Triart C18, 30 mm X 150 mm, 5um; Mobile Phase A:Water (0.1%FA), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient:28 B to 45 B in 10 min, 254 nm; RTl:9.67min.
  • Example 4 Preparation and Characterization of NeoDegrader Conjugates [0493] A solution of antibody was treated with 30 equivalents of tris-(2- carboxyethyl)phosphine (TCEP) and incubated at 37 °C for 1 hour to reduce the interchain disulfides. The reduced antibody was purified into 50 mM EPPS, 5 mM EDTA pH 7.0 buffer using illustra NAP columns (GE Healthcare).
  • TCEP tris-(2- carboxyethyl)phosphine
  • Conjugation was effected by treatment of a solution of reduced anti-CD33 antibody comprising a heavy chain having SEQ ID NO: 9 and a light chain having SEQ ID NO: 10 (“CD33AB”) at 2-5 mg/mL in 50 mM EPPS, 5 mM EDTA pH 7.0 with 12 equivalents of linker- neoDegrader added as a stock solution in N, N -di methyl acetam i de (DMA) such that the final concentration of DMA was 15% (v/v). The resulting reaction mixture was left overnight at 4 °C.
  • the resulting neoDegrader conjugate was purified into 20 mM succinate, 8% sucrose, 0.01% Tween-20 pH 5.5 using illustra NAP columns (GE Healthcare) and concentrated using Amicon Ultra centrifugal concentrators with 50 kD molecular weight cutoff (Millipore).
  • Drug to antibody ratio was determined by hydrophobic interaction chromatography using a 4.6 x 35 mm TSKgel Butyl-NPR column with 2.5 pm particles.
  • Mobile phase A was 1.5 M ammonium sulfate, 25 mM sodium phosphate pH 7.0.
  • Mobile phase B was 25 mM sodium phosphate pH 7.0, 25% (v/v) isopropanol.
  • Analytes were eluted with a linear gradient of 0-100% B in 12 min. at a flow rate of 0.6 mL/min. Detection was at 214 nm.
  • Free linker-payload was determined by mixed-mode chromatography using a 4.6 x
  • Example 5 Treatment of Acute Myeloid Leukemia (AML) with Anti-CD 33 Antibody- neoDegrader Conjugate
  • Anti-CD33 antibody(CD33AB)-neoDegrader compounds were tested in athymic nude mice (Crl:NU(NCr)-Foxnl nu , Charles River). 1 x 10 7 MV411 human acute monocytic leukemia cells (ATCC ® CRL-5991TM) in 50% Matrigel were injected subcutaneously in the flank of the mice (0.1 mL/mouse). The mice were dosed with anti-CD33 antibody-neoDegrader conjugates, non-targeting neoDegrader conjugates, and vehicle control once tumors reached an average size of 100 - 150 mm 3 .
  • CD33AB-Compound (Ih) were diluted with vehicle to obtain 0.3, 0.283, and 0.299 mg/mL dosing solutions, which provided 3, 2.83, and 2.99 mg/kg in a dosing volume of 10 mL/kg (0.2 mL per 20 g mouse), adjusted to the body weight of each animal. This dosing strategy ensured the delivery of the same amount of payloads to each testing group.
  • Mylotarg was diluted in 0.9% sodium chloride solution to 0.01 mg/mL, which provided 3 mg/kg in a dosing volume of 10 mL/kg (0.2 mL per 20 g mouse).
  • Venetoclax was formulated in solvent composed of 60% PG, 30% PEG400, 10% ethanol via ultrasonication to obtain a dosing suspension of 5 mg/mL, which delivered 50 mg/kg when administered in a volume of 10 mL/kg.
  • CC-90009 was centrifuged to collect the powder at the bottom; then N-methyl-2-pyrrolidinone (NMP), PEG400 and saline were added and mixed well one by one to obtain a 0.5 mg/mL dosing solution in 5% NMP, 45% PEG400 and 50% saline, which delivered 5 mg/kg when administered in a volume of 10 mL/kg.
  • NMP N-methyl-2-pyrrolidinone
  • PEG400 and saline were added and mixed well one by one to obtain a 0.5 mg/mL dosing solution in 5% NMP, 45% PEG400 and 50% saline, which delivered 5 mg/kg when administered in a volume of 10 mL/kg.
  • CD33 AB -Compound (la) (3 mg/kg, iv, qd x 1); 3) CD33AB-Compound (Ie) (2.83 mg/kg, iv, qd x 1); 4) CD33AB-Compound (Ih) (2.99 mg/kg, iv, qd x 1); 5) Mylotarg (0.1 mg/kg, iv, qd x 1); 6) Venetoclax (50 mg/kg, po, qd x 21); 7) CC-90009 (5 mg/kg, ip, bid x 10).
  • Test articles for groups 1-5 were administered intravenously (i.v.) as a single dose (qd x 1) in volumes adjusted for body weight (0.200 mL/20 g mouse). Venetoclax was administered orally (po) while CC-90009 was administered intraperitoneally (ip) in a dosing volume of 10 mL/kg (0.2 mL per 20 g mouse) scaled to the BW of each animal.
  • Tumors were measured using calipers twice per week, and each animal was euthanized when its tumor reached the endpoint volume (2,000 mm 3 ) or on the last day (Day 45) of the study, whichever came first.
  • the MTV(n) was defined as the median tumor volume on the last day of the study in the number of animals remaining (n) whose tumors had not attained the endpoint volume.
  • Example 6 Activity of AB1 Compound (la) Conjugate Against Human Leukemia Models
  • In vitro cytotoxicity was measured using a panel of CD33 positive acute myeloid leukemia cell lines and a panel of non-AML CD33-negative cells. The cells, at a predetermined concentration, were plated into 96 well plates, and, after overnight incubation at 37°C/5C02, serial dilutions of each test article (TA) were added to the cells. Cells were incubated with test articles for 72 hours, and viability was detected with CellTiter-Glo® reagent (Promega). The luminescent values were normalized for each cell line, and the IC50s were calculated using Prizm software.
  • Example 7 Treatment of Acute Myeloid Leukemia (AML) with Antibody-neoDegrader
  • Subcutaneous tumor model MV4-11 human acute myelocytic leukemia cells (lxlO 6 cells in 0.1 mL) were subcutaneously inoculated into the right flank of female athymic nude mice. Mice were treated with test article either by intravenous injection into a lateral tail vein, intraperitoneal injection, oral gavage, or combinations thereof starting when tumors reached 150 mm 3 in size. Tumor size and mouse body weight were measured twice per week.
  • Example 8 Stability of CD33AB-Compound (la) and Gemtuzumab-Compound (la) Conjugates
  • Stability assays of antiCD33 -Compound (la) conjugates were carried out over 40 days using Gemtuzumab, IgGl, CD33AB, and IgGl L234A/L235A “LALA” Ab formats at 2.5 mg/mL in 20 mM succinate, 8% sucrose, 0.01% Tween-20 pH 5.5 and assayed by size exclusion chromatrophaphy (SEC). At 4°C, no significant change in concentration or monomer was observed for any of the conjugates.
  • native Gemtuzumab-Compound (la) shows much higher unconjugated antibody than the CD33AB derived conjugate made with the same molar equivalents of payload- linker.
  • having low levels of unconjugated antibody in an ADC, as in CD33AB- Compound (la) is a desirable quality attribute.
  • more TCEP was needed to reduce Gemtuzumab than CD33AB (4.5 vs 2.5 molar equivalents).
  • Using less reducing agent, as in CD33 AB -Compound (la) to manufacture ADCs is desirable to lower cost of goods and simplify the purification process.
  • Example 9 Activity of antiCD 33 neoDegrader Conjugates Against Human Leukemia Models [0509] Subcutaneous tumor model MV4-11 human acute myelocytic leukemia cells (lxlO 6 cells in 0.1 mL) were subcutaneously inoculated into the right flank of female athymic nude mice. Mice were treated with test article either by intravenous injection into a lateral tail vein, intraperitoneal injection, oral gavage, or combinations thereof starting when tumors reached 150 mm 3 in size. Tumor size and mouse body weight were measured twice per week.
  • Example 10 Activity of antiCD 33 neoDegradader Conjugates Against Mylotarg-Insensitive Cell
  • test articles were measured using a panel of CD33 positive acute myeloid leukemia cell lines known to be Mylotarg insensitive (AML- 193 and Kasumi-6). The cells, at a predetermined concentration, were plated into 96 well plates, and, after overnight incubation at 37°C/5C02, serial dilutions of each test article (TA) were added to the cells. Cells were incubated with test articles for 72 hours, and viability was detected with CellTiter-Glo® reagent (Promega). The luminescent values were normalized for each cell line, and the IC50s were calculated using Prizm software.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Cell Biology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/IB2022/055168 2021-06-03 2022-06-02 Neodegrader-anti-cd33 antibody conjugates Ceased WO2022254377A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
EP22815474.6A EP4346910A4 (en) 2021-06-03 2022-06-02 Neodegrader-anti-cd33 antibody conjugates
KR1020247000100A KR20240042598A (ko) 2021-06-03 2022-06-02 신규분해제-항-cd33 항체 접합체
CN202280039908.6A CN118201641A (zh) 2021-06-03 2022-06-02 新降解剂－抗cd33抗体缀合物
CA3222185A CA3222185A1 (en) 2021-06-03 2022-06-02 Neodegrader-anti-cd33 antibody conjugates
JP2023574587A JP2024521919A (ja) 2021-06-03 2022-06-02 ネオデグラダー－抗ｃｄ３３抗体コンジュゲート
PE2023003198A PE20250159A1 (es) 2021-06-03 2022-06-02 Conjugados de neodegradador-anticuerpo anti-cd33
IL308812A IL308812A (en) 2021-06-03 2022-06-02 NEODEGRADER-ANTI-CD33 ANTIBODY conjugates
AU2022284372A AU2022284372A1 (en) 2021-06-03 2022-06-02 Neodegrader-anti-cd33 antibody conjugates
MX2023014282A MX2023014282A (es) 2021-06-03 2022-06-02 Conjugados de neodegradador-anticuerpo anti-cumulo de diferenciación 33 (cd33).
US18/566,805 US20240252671A1 (en) 2021-06-03 2022-06-02 Neodegrader-anti-cd33 antibody conjugates
CONC2023/0016712A CO2023016712A2 (es) 2021-06-03 2023-12-01 Conjugados de neodegradador-anticuerpo anti-cd33

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202163202272P 2021-06-03 2021-06-03
US63/202,272 2021-06-03
US202163282588P 2021-11-23 2021-11-23
US63/282,588 2021-11-23

Publications (1)

Publication Number Publication Date
WO2022254377A1 true WO2022254377A1 (en) 2022-12-08

Family

ID=84323935

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/055168 Ceased WO2022254377A1 (en) 2021-06-03 2022-06-02 Neodegrader-anti-cd33 antibody conjugates

Country Status (13)

Country Link
US (1) US20240252671A1 (https=)
EP (1) EP4346910A4 (https=)
JP (1) JP2024521919A (https=)
KR (1) KR20240042598A (https=)
AU (1) AU2022284372A1 (https=)
CA (1) CA3222185A1 (https=)
CL (2) CL2023003605A1 (https=)
CO (1) CO2023016712A2 (https=)
IL (1) IL308812A (https=)
MX (1) MX2023014282A (https=)
PE (1) PE20250159A1 (https=)
TW (1) TW202313022A (https=)
WO (1) WO2022254377A1 (https=)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023221975A1 (zh) * 2022-05-18 2023-11-23 苏州宜联生物医药有限公司 包含蛋白降解剂类生物活性化合物的抗体药物偶联物及其制备方法和用途
WO2024169913A1 (zh) * 2023-02-15 2024-08-22 石药集团巨石生物制药有限公司 一种度胺类分子胶衍生物及其用途
WO2024222841A1 (zh) * 2023-04-27 2024-10-31 石药集团巨石生物制药有限公司 一种抗体药物偶联物
WO2024249235A1 (en) * 2023-06-01 2024-12-05 Abbvie Inc. Anti-human cd33 bet degrader antibody-drug conjugates
WO2025085489A1 (en) * 2023-10-17 2025-04-24 Bristol-Myers Squibb Company Gspt1-degrading compounds, anti-cd33 antibodies and antibody-drug conjugates and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010053732A1 (en) * 2008-10-29 2010-05-14 Celgene Corporation Isoindoline compounds for use in the treatment of cancer
WO2021198965A1 (en) * 2020-03-31 2021-10-07 Orum Therapeutics, Inc. Neodegrader conjugates

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2822575T (pt) * 2012-03-03 2020-07-02 Immungene Inc Moléculas de fusão anticorpos-mutante de interferão modificadas
JP2018516950A (ja) * 2015-06-12 2018-06-28 イミュンジーン, インコーポレイテッドImmunGene, Inc. がん治療のための集中インターフェロン免疫療法
CN104994263B (zh) * 2015-06-30 2016-12-28 广东欧珀移动通信有限公司 一种摄像装置及具有该摄像装置的终端

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010053732A1 (en) * 2008-10-29 2010-05-14 Celgene Corporation Isoindoline compounds for use in the treatment of cancer
WO2021198965A1 (en) * 2020-03-31 2021-10-07 Orum Therapeutics, Inc. Neodegrader conjugates

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOSHUA D. HANSEN, KEVIN CONDROSKI, MATTHEW CORREA, GEORGE MULLER, HON-WAH MAN, ALEXANDER RUCHELMAN, WEIHONG ZHANG, FAN VOCANSON, T: "Protein Degradation via CRL4 CRBN Ubiquitin Ligase: Discovery and Structure–Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 61, no. 2, 25 January 2018 (2018-01-25), US , pages 492 - 503, XP055757970, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b01911 *
JOSHUA D. HANSEN, MATTHEW CORREA, MARK A. NAGY, MATT ALEXANDER, VERONIQUE PLANTEVIN, VIRGINIA GRANT, BRANDON WHITEFIELD, DEHUA HUA: "Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, US , XP055678492, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b01928 *
SPERLING ADAM S.; BURGESS MICHAEL; KESHISHIAN HASMIK; GASSER JESSICA A.; BHATT SHRUTI; JAN MAX; SłABICKI MIKOłAJ; SELLAR: "Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 134, no. 2, 11 July 2019 (2019-07-11), US , pages 160 - 170, XP086697677, ISSN: 0006-4971, DOI: 10.1182/blood.2019000789 *
ZHAO MIN; HU MIN; CHEN YONG; LIU HEYI; CHEN YULU; LIU BIN; FANG BAIJUN: "Cereblon modulator CC-885 induces CRBN-dependent ubiquitination and degradation of CDK4 in multiple myeloma", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ELSEVIER, AMSTERDAM NL, vol. 549, 3 March 2021 (2021-03-03), Amsterdam NL , pages 150 - 156, XP086523660, ISSN: 0006-291X, DOI: 10.1016/j.bbrc.2021.02.110 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023221975A1 (zh) * 2022-05-18 2023-11-23 苏州宜联生物医药有限公司 包含蛋白降解剂类生物活性化合物的抗体药物偶联物及其制备方法和用途
WO2024169913A1 (zh) * 2023-02-15 2024-08-22 石药集团巨石生物制药有限公司 一种度胺类分子胶衍生物及其用途
WO2024222841A1 (zh) * 2023-04-27 2024-10-31 石药集团巨石生物制药有限公司 一种抗体药物偶联物
WO2024249235A1 (en) * 2023-06-01 2024-12-05 Abbvie Inc. Anti-human cd33 bet degrader antibody-drug conjugates
WO2025085489A1 (en) * 2023-10-17 2025-04-24 Bristol-Myers Squibb Company Gspt1-degrading compounds, anti-cd33 antibodies and antibody-drug conjugates and uses thereof

Also Published As

Publication number Publication date
JP2024521919A (ja) 2024-06-04
AU2022284372A9 (en) 2024-01-11
CL2026000399A1 (es) 2026-03-20
MX2023014282A (es) 2024-02-27
TW202313022A (zh) 2023-04-01
CO2023016712A2 (es) 2024-02-26
IL308812A (en) 2024-01-01
AU2022284372A1 (en) 2023-12-14
EP4346910A4 (en) 2026-05-06
US20240252671A1 (en) 2024-08-01
PE20250159A1 (es) 2025-01-22
EP4346910A1 (en) 2024-04-10
CA3222185A1 (en) 2022-12-08
CL2023003605A1 (es) 2024-05-03
KR20240042598A (ko) 2024-04-02

Similar Documents

Publication Publication Date Title
US20240252671A1 (en) Neodegrader-anti-cd33 antibody conjugates
JP7735526B2 (ja) リンカー、薬物リンカーおよびそのコンジュゲートならびにそれらの使用方法
JP7573685B2 (ja) 抗体－ａｌｋ５阻害剤コンジュゲートおよびその使用
JP6567551B2 (ja) 抗体−薬物複合体および癌の処置のためのその使用
KR20230051120A (ko) 신규분해약물 접합체
CA3139180A1 (en) Combination of antibody-pyrrolobenzodiazepine derivative conjugate and parp inhibitor
KR102911341B1 (ko) 튜불리신 및 단백질-튜불리신 접합체
KR20160142392A (ko) 튜부리신 유도체
KR20220006519A (ko) 항체 약물 접합체
KR20230154892A (ko) 항-her2 항체-약물 접합체 및 이의 용도
CN113166764A (zh) 抗cdh6抗体-吡咯并苯并二氮杂环庚三烯衍生物缀合物
CN118201641A (zh) 新降解剂－抗cd33抗体缀合物
US20250304563A1 (en) Activators of effector t cells
KR20250093370A (ko) Cd70 항체 약물 접합체 및 그의 사용 방법
EA051016B1 (ru) Конъюгаты неодеградер-анти-cd33 антитело
AU2023358091A1 (en) Neodegrader conjugates
WO2026069278A1 (en) Anti-cd123 antibodies and neodegrader conjugates
RU2846388C1 (ru) Конъюгаты неодеструкторов

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22815474

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 308812

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 806004

Country of ref document: NZ

Ref document number: 2022284372

Country of ref document: AU

Ref document number: AU2022284372

Country of ref document: AU

Ref document number: 2301007785

Country of ref document: TH

WWE Wipo information: entry into national phase

Ref document number: MX/A/2023/014282

Country of ref document: MX

Ref document number: P6003130/2023

Country of ref document: AE

WWE Wipo information: entry into national phase

Ref document number: NC2023/0016712

Country of ref document: CO

Ref document number: 2023574587

Country of ref document: JP

Ref document number: 003198-2023

Country of ref document: PE

Ref document number: 3222185

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 202280039908.6

Country of ref document: CN

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023025348

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2022284372

Country of ref document: AU

Date of ref document: 20220602

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 202317087599

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 202393514

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 11202309130V

Country of ref document: SG

WWE Wipo information: entry into national phase

Ref document number: 1020247000100

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2022815474

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022815474

Country of ref document: EP

Effective date: 20240103

WWE Wipo information: entry into national phase

Ref document number: 523451790

Country of ref document: SA

WWP Wipo information: published in national office

Ref document number: NC2023/0016712

Country of ref document: CO

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: 112023025348

Country of ref document: BR

Free format text: COM BASE NA PORTARIA/INPI/NO 48/2022, APRESENTE NOVO CONTEUDO DE LISTAGEM POIS O CONTEUDO DA LISTAGEM APRESENTADA NA PETICAO NO 870230106360 DE 01/12/2023 POSSUI O CAMPO 110 DIVERGENTE DO PEDIDO EM QUESTAO. TAMBEM DEVERA SER ATUALIZADO NA LISTAGEM OS CAMPOS 140 UMA VEZ QUE O DEPOSITANTE JA POSSUI O NUMERO DO PEDIDO NO BRASIL. A EXIGENCIA DEVE SER RESPONDIDA EM ATE 60 (SESSENTA) DIAS DE SUA PUBLICACAO E DEVE SER REALIZADA POR MEIO DA PETICAO GRU CODIGO DE SERVICO 207.

ENP Entry into the national phase

Ref document number: 112023025348

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20231201

WWE Wipo information: entry into national phase

Ref document number: 523451790

Country of ref document: SA

WWE Wipo information: entry into national phase

Ref document number: 523451790

Country of ref document: SA