WO2022125908A1 - Anti-pd-l1 immunoconjugates, and uses thereof - Google Patents

Anti-pd-l1 immunoconjugates, and uses thereof Download PDF

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Publication number
WO2022125908A1
WO2022125908A1 PCT/US2021/062824 US2021062824W WO2022125908A1 WO 2022125908 A1 WO2022125908 A1 WO 2022125908A1 US 2021062824 W US2021062824 W US 2021062824W WO 2022125908 A1 WO2022125908 A1 WO 2022125908A1
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WIPO (PCT)
Prior art keywords
seq
alkyldiyl
immunoconjugate
cancer
antibody
Prior art date
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Ceased
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PCT/US2021/062824
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English (en)
French (fr)
Inventor
Shelley Erin ACKERMAN
Michael N. ALONSO
David Dornan
Marcin KOWANETZ
Romas Kudirka
Arthur Lee
William Mallet
Brian Safina
Matthew ZHOU
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Bolt Biotherapeutics Inc
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Bolt Biotherapeutics Inc
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Filing date
Publication date
Application filed by Bolt Biotherapeutics Inc filed Critical Bolt Biotherapeutics Inc
Priority to US18/038,910 priority Critical patent/US20240033370A1/en
Priority to AU2021398552A priority patent/AU2021398552A1/en
Priority to CA3200168A priority patent/CA3200168A1/en
Priority to EP21840291.5A priority patent/EP4259209A1/en
Priority to JP2023534646A priority patent/JP2023552790A/ja
Priority to KR1020237022941A priority patent/KR20230118149A/ko
Priority to CN202180080177.5A priority patent/CN116723866A/zh
Priority to IL303491A priority patent/IL303491A/en
Publication of WO2022125908A1 publication Critical patent/WO2022125908A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K16/2827—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 against B7 molecules, e.g. CD80, CD86

Definitions

  • a heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • Heterocycles are described in Paquette, Leo A.; "Principles of Modem Heterocyclic Chemistry" (W.A.
  • the immunoglobulin heavy chain polypeptide comprises a HCDR1 comprising or consisting of SEQ ID NO: 4, a HCDR2 comprising or consisting of SEQ ID NO: 27, and a HCDR3 comprising or consisting of SEQ ID NO: 61; and/or the immunoglobulin light chain polypeptide comprises a LCDR1 comprising or consisting of SEQ ID NO: 99, a LCDR2 comprising or consisting of SEQ ID NO: 130, and a LCDR3 comprising or consisting of SEQ ID NO: 155;
  • the immunoglobulin heavy chain polypeptide comprises a HCDR1 comprising or consisting of SEQ ID NO: 8, a HCDR2 comprising or consisting of SEQ ID NO: 32, and a HCDR3 comprising or consisting of SEQ ID NO: 66; and/or the immunoglobulin light chain polypeptide comprises a LCDR1 comprising or consisting of SEQ ID NO: 104, a LCDR2 comprising or consisting of SEQ ID NO: 134, and a LCDR3 comprising or consisting of SEQ ID NO: 158;
  • the immunoglobulin heavy chain polypeptide comprises a HCDR1 comprising or consisting of SEQ ID NO: 19, a HCDR2 comprising or consisting of SEQ ID NO: 49, and a HCDR3 comprising or consisting of SEQ ID NO: 85; and/or the immunoglobulin light chain polypeptide comprises a LCDR1 comprising or consisting of SEQ ID NO: 120, a LCDR2 comprising or consisting of SEQ ID NO: 146, and a LCDR3 comprising or consisting of SEQ ID NO: 155;
  • the immunoglobulin heavy chain polypeptide comprises a HCDRl comprising or consisting of SEQ ID NO: 2, a HCDR2 comprising or consisting of SEQ ID NO: 53, and a HCDR3 comprising or consisting of SEQ ID NO: 89; and/or the immunoglobulin light chain polypeptide comprises a LCDR1 comprising or consisting of SEQ ID NO: 97, a LCDR2 comprising or consisting of SEQ ID NO: 147, and a LCDR3 comprising or consisting of SEQ ID NO: 172;
  • the immunoglobulin heavy chain polypeptide comprises a HCDR1 comprising or consisting of SEQ ID NO: 21, a HCDR2 comprising or consisting of SEQ ID NO: 38, and a HCDR3 comprising or consisting of SEQ ID NO: 90; and/or the immunoglobulin light chain polypeptide comprises a LCDR1 comprising or consisting of SEQ ID NO: 109, a LCDR2 comprising or consisting of SEQ ID NO: 150, and a LCDR3 comprising or consisting of SEQ ID NO: 165;
  • the PD-L1 binding agent (Type B) can comprise:
  • the CDRs of a given heavy or light chain Ig sequence can be determined in accordance with any of the various known Ig numbering schemes (e.g., Kabat, Chothia, Martin (Enhanced Chothia), IGMT, AbM).
  • the PD-L1 binding agent comprises one or more of the following CDRs: a HCDR1 comprising or consisting of any one of SEQ ID NOs: 308-321 or a sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% identical to SEQ ID NOs: 308-321; a HCDR2 comprising or consisting of any one of SEQ ID NOs: 322-338 or a sequence that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about
  • the antibodies in the immunoconjugates are glycosylated.
  • PEG has the formula: -(CH 2 CH 2 O) n -(CH 2 ) m -; m is an integer from 1 to 5, and n is an integer from 2 to 50;
  • Treatment with PD-L1 IC-51 resulted in improved anti -turn or efficacy even in the absence of PD-L1 expression on tumor cells, demonstrating an immunoconjugate of the invention can induce an anti -turn or response through PD-L1 on immune cells.
  • R 5 is independently selected from the group consisting of H, C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryldiyl, C 1 -C 12 alkyl, and C 1 -C 12 alkyldiyl, or two R 5 groups together form a 5- or 6-membered heterocyclyl ring;
  • R 5a is selected from the group consisting of C 6 -C 20 aryl and C 1 -C 20 heteroaryl; where the asterisk * indicates the attachment site of L, and where one of R 1 , R 2 , R 3 and R 4 is attached to L;
  • An exemplary embodiment of the immunoconjugate of Formula I includes wherein R 2 is CH 2 CH 2 CH 3 and R 3 is OCH 2 CH 3 .
  • An exemplary embodiment of the immunoconjugate of Formula I includes wherein R 2 or R 3 is attached to L.
  • An exemplary embodiment of the immunoconjugate of Formula I includes wherein, for the PEG, m is 1 or 2, and n is an integer from 2 to 10.
  • a homogeneous immunoconjugate with a single loading value may be isolated from the conjugation mixture by electrophoresis or chromatography.
  • a composition comprising the immunoconjugate compounds comprises a mixture of the immunoconjugate compounds, wherein the average drug (Hx) loading per antibody in the mixture of immunoconjugate compounds is about 2 to about 5.
  • a composition of immunoconjugates of the invention can have an average adjuvant to antibody construct ratio (DAR) of about 0.4 to about 10.
  • DAR average adjuvant to antibody construct ratio
  • the number of 8-cyclyl-2-aminobenzazepine adjuvants conjugated to the antibody construct may vary from immunoconjugate to immunoconjugate in a composition comprising multiple immunoconjugates of the invention and thus the adjuvant to antibody construct (e.g., antibody) ratio can be measured as an average which may be referred to as the drug to antibody ratio (DAR).
  • the adjuvant to antibody construct (e.g., antibody) ratio can be assessed by any suitable means, many of which are known in the art
  • the composition further comprises one or more pharmaceutically or pharmacologically acceptable excipients.
  • the immunoconjugates of the invention can be formulated for parenteral administration, such as IV administration or administration into a body cavity or lumen of an organ.
  • the immunoconjugates can be injected intra-tumorally.
  • Compositions for injection will commonly comprise a solution of the immunoconjugate dissolved in a pharmaceutically acceptable carrier.
  • acceptable vehicles and solvents that can be employed are water and an isotonic solution of one or more salts such as sodium chloride, e.g., Ringer's solution.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • the immunoconjugate of the present invention may be used to treat various hyperproliferative diseases or disorders, e.g. characterized by the overexpression of a tumor antigen.
  • hyperproliferative disorders include benign or malignant solid tumors and hematological disorders such as leukemia and lymphoid malignancies.
  • Carcinomas are malignancies that originate in the epithelial tissues. Epithelial cells cover the external surface of the body, line the internal cavities, and form the lining of glandular tissues.
  • carcinomas include, but are not limited to, adenocarcinoma (cancer that begins in glandular (secretory) cells such as cancers of the breast, pancreas, lung, prostate, stomach, gastroesophageal junction, and colon) adrenocortical carcinoma; hepatocellular carcinoma; renal cell carcinoma; ovarian carcinoma; carcinoma in situ; ductal carcinoma; carcinoma of the breast; basal cell carcinoma; squamous cell carcinoma; transitional cell carcinoma; colon carcinoma; nasopharyngeal carcinoma; multilocular cystic renal cell carcinoma; oat cell carcinoma; large cell lung carcinoma; small cell lung carcinoma; non-small cell lung carcinoma; and the like.
  • adenocarcinoma cancer that begins in glandular (secretory) cells such as cancers of the breast, pancreas, lung
  • Melanoma is a form of cancer that begins in melanocytes (cells that make the pigment melanin). Melanoma may begin in a mole (skin melanoma), but can also begin in other pigmented tissues, such as in the eye or in the intestines.
  • cells are first enriched by using a ROSETTESEPTM Human CD3 Depletion Cocktail (Stem Cell Technologies, Vancouver, Canada) to remove T cells from the cell preparation.
  • eDCs are then further enriched via negative selection using an EASYSEPTM Human Myeloid DC Enrichment Kit (Stem Cell Technologies).

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  • General Chemical & Material Sciences (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
PCT/US2021/062824 2020-12-11 2021-12-10 Anti-pd-l1 immunoconjugates, and uses thereof Ceased WO2022125908A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US18/038,910 US20240033370A1 (en) 2020-12-11 2021-12-10 Anti-pd-l1 immunoconjugates, and uses thereof
AU2021398552A AU2021398552A1 (en) 2020-12-11 2021-12-10 Anti-pd-l1 immunoconjugates, and uses thereof
CA3200168A CA3200168A1 (en) 2020-12-11 2021-12-10 Anti-pd-l1 immunoconjugates, and uses thereof
EP21840291.5A EP4259209A1 (en) 2020-12-11 2021-12-10 Anti-pd-l1 immunoconjugates, and uses thereof
JP2023534646A JP2023552790A (ja) 2020-12-11 2021-12-10 抗ｐｄ－ｌ１イムノコンジュゲート、及びそれらの使用
KR1020237022941A KR20230118149A (ko) 2020-12-11 2021-12-10 항-pd-l1 면역접합체, 및 그의 용도
CN202180080177.5A CN116723866A (zh) 2020-12-11 2021-12-10 抗pd-l1免疫缀合物和其用途
IL303491A IL303491A (en) 2020-12-11 2021-12-10 Anti-pd-l1 immunoconjugates, and uses thereof

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US63/124,396 2020-12-11

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KR (1) KR20230118149A (https=)
CN (1) CN116723866A (https=)
AU (1) AU2021398552A1 (https=)
CA (1) CA3200168A1 (https=)
IL (1) IL303491A (https=)
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WO2023076599A1 (en) * 2021-10-29 2023-05-04 Bolt Biotherapeutics, Inc. Tlr agonist immunoconjugates with cysteine-mutant antibodies, and uses thereof
WO2024173384A1 (en) 2023-02-14 2024-08-22 Bolt Biotherapeutics, Inc. Aza-benzazepine immunoconjugates, and uses thereof

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023076599A1 (en) * 2021-10-29 2023-05-04 Bolt Biotherapeutics, Inc. Tlr agonist immunoconjugates with cysteine-mutant antibodies, and uses thereof
WO2024173384A1 (en) 2023-02-14 2024-08-22 Bolt Biotherapeutics, Inc. Aza-benzazepine immunoconjugates, and uses thereof
WO2024173387A1 (en) 2023-02-14 2024-08-22 Bolt Biotherapeutics, Inc. Aza-benzazepine immunoconjugates, and uses thereof

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