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WO2025163120A1 - CONJUGUÉS ANTICORPS-MÉDICAMENT COMPRENANT UN ANTICORPS DE LIAISON ANTI-INTÉGRINE ΑVβ6 - Google Patents

CONJUGUÉS ANTICORPS-MÉDICAMENT COMPRENANT UN ANTICORPS DE LIAISON ANTI-INTÉGRINE ΑVβ6

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Publication number
WO2025163120A1
WO2025163120A1 PCT/EP2025/052491 EP2025052491W WO2025163120A1 WO 2025163120 A1 WO2025163120 A1 WO 2025163120A1 EP 2025052491 W EP2025052491 W EP 2025052491W WO 2025163120 A1 WO2025163120 A1 WO 2025163120A1
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WIPO (PCT)
Prior art keywords
antibody
seq
hetero
antigen
linker
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.)
Pending
Application number
PCT/EP2025/052491
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English (en)
Inventor
Jack DR. ELANDS
Xavier DR. PREVLLE
Camille LE GUILCHER
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Adcytherix Sas
Original Assignee
Adcytherix Sas
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Filing date
Publication date
Priority claimed from EP24155282.7A external-priority patent/EP4595981A1/fr
Application filed by Adcytherix Sas filed Critical Adcytherix Sas
Publication of WO2025163120A1 publication Critical patent/WO2025163120A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • A61K47/6801—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
    • A61K47/6801—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
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • 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
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • 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
    • 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

Definitions

  • Antibody-Drug conjugates comprising an anti -Intearin avP6 binding antibody
  • the present invention relates to novel antibody-drug conjugates comprising a monoclonal antibody or an antigen-binding fragment thereof wherein the monoclonal antibody or the antigen-binding fragment thereof binds specifically to the Integrin avp6.
  • the payload of this novel antibody-drug conjugate is preferably a topoisomerase I inhibitor.
  • Integrin avp6 a heterodimeric transmembrane protein, plays a crucial role in various cellular processes including cell adhesion, migration, and signal transduction.
  • Integrins are a family of cell surface receptors that mediate cell-cell and cell- extracellular matrix interactions. Among them, Integrin avp6 has garnered attention due to its selective expression in pathological conditions and its involvement in the activation of transforming growth factor-beta (TGF-P), a key player in tissue repair and fibrosis.
  • TGF-P transforming growth factor-beta
  • Integrin avp6 is composed of av and p6 subunits.
  • the av subunit is shared with other integrins, but the p6 subunit is unique, conferring specific properties to the heterodimer.
  • the expression of Integrin avp6 is typically low in healthy adult tissues but is upregulated in certain pathological conditions, including cancer, chronic inflammation, and fibrotic diseases.
  • Integrin avp6 mediates adhesion to extracellular matrix proteins like fibronectin and tenascin-C. It plays a pivotal role in wound healing by facilitating cell migration and tissue remodeling.
  • Integrin avp6 activates intracellular signaling pathways influencing cell survival, proliferation, and differentiation.
  • a critical function of Integrin avp6 is the activation of latent TGF-p. This has significant implications in tissue repair, fibrosis, and immune regulation.
  • Integrin avp6 In various cancers, overexpression of Integrin avp6 correlates with tumor aggressiveness, metastasis, and poor prognosis. It modulates the tumor microenvironment, influencing cancer cell invasion and immune evasion.
  • Integrin avp6 Given its selective expression in pathological states and its role in disease progression, Integrin avp6 is a promising target for therapeutic intervention. Strategies include the development of monoclonal antibodies and antibody-drug conjugates targeting Integrin avp6.
  • ADCs Antibody-Drug Conjugates
  • ADCs represent a novel class of therapeutic agents that combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs.
  • ADCs are designed to selectively deliver cytotoxic agents to cancer cells, thereby minimizing the systemic toxicity often associated with conventional chemotherapy.
  • the present invention relates to an antibody-drug conjugate according to formula (I),
  • AB is an antibody or antigen-binding fragment thereof that binds to the Integrin avp6,
  • M is a linker conjugating AB and D
  • D is an active agent or drug.
  • the antibodies used in the ADCs according to the present invention are antibodies that bind to the Integrin avp6
  • the antibodies of the invention are monoclonal antibodies (mAb) or monoclonal antibody fragments. If not indicated differently, the term “monoclonal” refers to a single species, i.e. , single amino acid composition of antibodies or antibody fragments.
  • the antibodies provided herein show preferably specific binding to Integrin avp6 and no essential or no cross-reactivity to other proteins.
  • the antigen-binding site of an inventive antibody comprises heavy chain variable domains/regions (VH) and/or antibody light chain variable domains/regions (VL), or pairs of VH/VL.
  • An anti Integrin avp6 antibody comprising a VH domain having the amino acid sequence of SEQ ID NO:1 and a VL domain having the amino acid sequence of SEQ ID NO:2 is particularly preferred, and/or antibodies or antigen-binding fragments thereof which show at least 90 % amino acid sequence identity, preferably 95%, or bind the same epitope as the respective antibody.
  • An anti Integrin avp6 antibody comprising a VH domain having the amino acid sequence of SEQ ID NO:91 and a VL domain having the amino acid sequence of SEQ ID NO:96, SEQ ID NO:97 or SEQ ID NO:98 is particularly preferred, and/or antibodies or antigen-binding fragments thereof which show at least 90 % amino acid sequence identity, preferably 95%, or bind the same epitope as the respective antibody.
  • An anti Integrin avp6 antibody comprising a VH domain having the amino acid sequence of SEQ ID NO:92 and a VL domain having the amino acid sequence of SEQ ID NO:96, SEQ ID NO:97 or SEQ ID NO:98 is particularly preferred, and/or antibodies or antigen-binding fragments thereof which show at least 90 % amino acid sequence identity, preferably 95%, or bind the same epitope as the respective antibody.
  • An anti Integrin avp6 antibody comprising a VH domain having the amino acid sequence of SEQ ID NO:93 and a VL domain having the amino acid sequence of SEQ ID NO:96, SEQ ID NO:97 or SEQ ID NO:98 is particularly preferred, and/or antibodies or antigen-binding fragments thereof which show at least 90 % amino acid sequence identity, preferably 95%, or bind the same epitope as the respective antibody.
  • binding and “specific binding” refer to the binding of the inventive antibody or fragment thereof to an epitope of the antibodies described herein.
  • the measure of the binding strength of an antibody is referred to as affinity.
  • Methods for determining such a binding and/or affinity using in vitro assays are known to the person skilled in the art. According to the present invention, detection with flow cytometry by fluorescence, immuno-histochemistry and/or surface plasmon resonance are described and particularly preferred herein.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, E, y and p, respectively.
  • an antibody of the class particularly of the human class IgG, IgA or IgM or a fragment thereof is particularly suitable.
  • an antibody of the invention is selected from class IgG, particularly from the class of human IgG, e.g., of subclass lgG1 , lgG2, lgG3 of lgG4, of class IgM, of class IgA or an antigen-binding fragment thereof.
  • the antibody comprises a constant domain, particularly a heavy chain constant domain, more particularly a heavy chain constant domain of the class IgG, particularly of the class human IgG, e.g., of subclass lgG1 , lgG2, lgG3 of lgG4, of class IgM, of class IgA, which has a reduced effector function compared to a wild-type sequence of the same subclass, e.g., which has a reduced binding to the Fc receptor.
  • a constant domain particularly a heavy chain constant domain, more particularly a heavy chain constant domain of the class IgG, particularly of the class human IgG, e.g., of subclass lgG1 , lgG2, lgG3 of lgG4, of class IgM, of class IgA, which has a reduced effector function compared to a wild-type sequence of the same subclass, e.g., which has a reduced binding to the Fc receptor.
  • heavy chain constant domains with reduced effector functions may contain at least one of the mutations D265C/A, L234A/F, L235A/E, P329G, P331S, and/or N297A/S/G of human IgG, e.g., lgG1 or lgG4 sequences.
  • Constant domains comprising a L234A and a L235A mutation are in particular preferred.
  • Such alanine insertions are for limiting the ability of the mAb to interact with Fc receptors
  • antibodies described herein may comprise cysteine insertions for the sitespecific coupling of linker payloads.
  • S239C and/or S442C mutations with a kappa LC are preferred.
  • the term also encompasses a fusion protein, e.g., a fusion protein with a non-immunoglobulin peptide or polypeptide, and a conjugate with a non-proteinaceous structure, e.g., a label or a toxin.
  • a fusion protein e.g., a fusion protein with a non-immunoglobulin peptide or polypeptide
  • a conjugate with a non-proteinaceous structure e.g., a label or a toxin.
  • the antibody or the antigen-binding fragment may be mono- or multivalent, i.e. , it may comprise a single antigen-binding site or multiple antigen-binding sites.
  • Fab fragments have single antigen-binding site
  • antibodies of the IgG class or Fv or scFv fragments have two antigen-binding sites
  • antibodies of the IgM class have 5 antigen-binding sites.
  • antibody also encompasses hetero-specific antibodies, e.g., hetero-bispecific antibodies, which have different antigen-binding sites, particularly antibodies, which are directed to two different epitopes on the antigen.
  • epitopes epitope
  • epitope is a region of an antigen that is bound by an antibody.
  • epipe includes any polypeptide determinant capable of specific binding to an antibody.
  • Percent (%) amino acid sequence identity with respect to a peptide or polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST.
  • Another aspect of the present invention is a combination of at least 2 different monoclonal antibodies or fragments as described herein.
  • the present invention relates to a nucleic acid molecule, e.g. a DNA molecule, encoding an antibody VH region, or an antibody VL region, or encoding a complete antibody or an antibody fragment as indicated above, a vector or vector system, i.e. a plurality of vectors, comprising said nucleic acid molecule(s) as indicated above, preferably in operative linkage with an expression control sequence, particularly with a heterologous expression control sequence.
  • a nucleic acid molecule e.g. a DNA molecule, encoding an antibody VH region, or an antibody VL region, or encoding a complete antibody or an antibody fragment as indicated above
  • a vector or vector system i.e. a plurality of vectors, comprising said nucleic acid molecule(s) as indicated above, preferably in operative linkage with an expression control sequence, particularly with a heterologous expression control sequence.
  • the invention relates to a cell comprising a nucleic acid molecule or a vector or vector system as described above.
  • vector refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked.
  • the vector is an expression vector.
  • An “expression vector” is a vector capable of directing the expression of nucleic acids to which they are operatively linked. Vectors, in particular expression vectors, for the recombinant production of antibodies are well known in the art.
  • the cell may be a known host cell for producing antibodies or antibody fragments, e.g. a prokaryotic cell such as an E. coli cell, a yeast cell, an insect cell or a mammalian cell, e.g. a CHO cell or a hybridoma cell.
  • a prokaryotic cell such as an E. coli cell, a yeast cell, an insect cell or a mammalian cell, e.g. a CHO cell or a hybridoma cell.
  • An antibody-drug conjugate of the present invention comprises a monoclonal antibody or antigen-binding fragment thereof as defined above, and a drug conjugated to a reactive amino acid residue on the antibody or antigen-binding fragment, e.g., an amino acid residue having a side chain comprising an amino, hydroxy or thiol group, or a reactive group in the antibody glycan structure.
  • the drug of the antibody-drug conjugate of the invention is preferably selected from topoisomerase I inhibitors, antimitotic agents, cytotoxic agents and/or corticosteroids.
  • a topoisomerase I inhibitor is a compound, which is capable of forming a ternary complex with topoisomerase I and DNA, thereby preventing DNA re-ligation and introducing DNA strand breaks in the cellular genome.
  • the topoisomerase I inhibitor may be e.g., selected from camptothecin or analogs thereof, indenoisoquinolines and indolocarbazoles.
  • the topoisomerase-l-inhibitor is camptothecin or an analog thereof, i.e. a compound comprising the pentacyclic basic structure of camptothecin and modified substituents optionally resulting in the presence of a further ring.
  • camptothecin topotecan, irinotecan, SN-38, belotecan, exatecan including derivatives thereof such as deruxtecan, lurtotecan or ati ratecan.
  • the drug e.g. the topoisomerase-l-inhibitor, such as exatecan
  • the drug may be conjugated to any suitable position of the monoclonal antibody or antigen-binding fragment thereof, particularly to any position, which does not abolish the binding of the antibody to Integrin avp6.
  • the drug e.g. the topoisomerase-l- inhibitor, such as exatecan
  • the drug e.g.
  • the topoisomerase-l-inhibitor such as exatecan
  • the topoisomerase I inhibitor is exatecan or a derivative thereof represented by formula (II)
  • Exatecan is typically conjugated to an antibody via its NH 2 group.
  • the topoisomerase-l-inhibitor is belotecan or a derivative thereof being represented by formula (III) wherein R 2 is -(CH 2 )2NR 1 CH(CH 3 )2
  • R 1 is H or -SO 2 CH 3
  • R 3 is H, amino, or Ci-Ce alkyl, preferably H.
  • R 1 is H.
  • antimitotic agents are auristatin and derivatives thereof, in particular Monomethyl auristatin E (MMAE) or Monomethyl auristatin F (MMAF).
  • a preferred cytotoxic agent is maytansine and/or derivatives thereof, the so-called maytansinoids.
  • Preferred examples of maytansinoids are Ansamitocin .Mertansine/emtansine (DM1) or Ravtansine/soravtansine (DM4).
  • Corticosteroids refer to a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two preferred main classes of corticosteroids, glucocorticoids and mineralocorticoids,
  • corticosteroids are Progesteron Cortisol, Corticosterone, Cortisone and Aldosterone and synthetic analogues thereof.
  • Preferred synthetic analogues of the Progesteron-type are:
  • the antibody drug conjugate comprises has a molar drug- antibody/antibody fragment ratio (DAR) of greater than 1 , i.e., more than one drug molecule is attached to an antibody/antibody fragment.
  • DAR molar drug- antibody/antibody fragment ratio
  • the conjugate has a DAR of about 2:1 to about 16:1 , particularly of about 4:1 to about 10:1 and more particularly of about 6:1 to about 8:1.
  • the DAR may be calculated from a statistical distribution according to known methods.
  • the drug can be conjugated to the antibody or antigen-binding fragment thereof via a linker M.
  • the linker is a cleavable linker, i.e., a linker cleavable under physiological conditions, e.g., by physiological enzymes.
  • cleavable linkers are peptide-based linkers, which may be subject to cleavage by a protease, or glycoside-based linkers, which may be subject to cleavage by a glycosidase.
  • Another specific example are branched tandem-cleavage linkers that combine moieties that can be cleaved under different conditions or by different enzymes, e.g. protease-cleavable dipeptide and glycosidase-cleavable sugar moieties. In this way, several identical or different payloads can be connected to the antibody.
  • the linker is a hydrophilic polysarcosine linker e.g., as described by Conilh et at. “Exatecan antibody drug conjugates based on a hydrophilic polysarcosine drug-linker platform” (Pharmaceuticals 14 (2021), 247).
  • Further preferred linkers include linkers comprising at least one ethylene glycol unit, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more ethylene glycol units, e.g., the linker of the antibodydrug conjugate MEDI7247, an mcc-triazole spacer-PEG7-x-Lys-PABC glycol linker from T rodelvy®,
  • linkers include oligopeptide, particularly di- to decapeptide, e.g., tetrapeptide sequences such as glycine-glycine-phenylalanine-glycine from Enhertu®.
  • Further preferred linkers include highly polar spacers such as an acyl group, carbamoyl group and/or sulfamide group added to at least at least one ethylene glycol unit, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more ethylene glycol units, e.g., the linker technology called HydraspaceTM.
  • a particularly preferred linker is a glucuronide linker.
  • the linker is a hydrophilic polysarcosine linker comprising, e.g., up to 15 sarcosine units, and at least one ethylene glycol unit, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more ethylene glycol units, wherein the linker is subject to cleavage by a glycosidase, and particularly subject to cleavage by a glucuronidase.
  • the linker is a hydrophilic polysarcosine linker comprising, e.g., about 8-12 sarcosine units, and at least one ethylene glycol unit, e.g., up to 10 ethylene glycol units, and wherein the linker is subject to cleavage by a glycosidase, and particularly subject to cleavage by a glucuronidase.
  • the linker is a hydrophilic polysarcosine linker comprising 10 sarcosine units, and 2 ethylene glycol units, and wherein the linker is subject to cleavage by a glucuronidase.
  • a further aspect of the invention relates to a linker-drug conjugate comprising:
  • a hydrophilic polysarcosine linker comprising, e.g., about 8-12 sarcosine units, and at least one ethylene glycol unit, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more ethylene glycol units, wherein the linker is subject to cleavage by a glycosidase, and particularly subject to cleavage by a glucuronidase, and wherein the linker comprises a thiolreactive group, e.g., a maleimide group capable of reacting with cysteine residues on an antibody or antigen-binding fragment thereof, and
  • the linker-drug conjugate comprises:
  • a hydrophilic polysarcosine linker comprising 10 sarcosine units, and 2 ethylene glycol units, wherein the linker is subject to cleavage by a glycosidase, and particularly subject to cleavage by a glucuronidase, and wherein the linker comprises a maleimide group capable of reacting with cysteine residues on an antibody or antigen-binding fragment thereof, and
  • a further aspect of the invention relates to a linker-drug conjugate comprising a aminobenzyl spacer, preferably a p-aminobenzyl (PAB) spacer, in particular a p- aminobenzyl carbamate (PABC) spacer.
  • a linker-drug conjugate comprising a aminobenzyl spacer, preferably a p-aminobenzyl (PAB) spacer, in particular a p- aminobenzyl carbamate (PABC) spacer.
  • PAB p-aminobenzyl
  • PABC p- aminobenzyl carbamate
  • linker-drug conjugate comprising
  • GGGS peptide in particular a propionyl GGGS peptide
  • the linker M is a maleimide-propionyl- Gly-Gly-Gly-Ser-p-glucuronide-PABC-linker.
  • the linker M of the inventive antibody drug conjugate may be characterized by formula (V):
  • L is -(Ci-C6-alkylene)-(O-CH 2 )m-NR 1 -,
  • A is a peptide comprising 2 to 8 amino acids, preferably 2 to 4 amino acids, wherein A is substituted with at least one polyol, wherein polyol is -(Ci-Ce alkylene)-X a -Y b , wherein:
  • Y b is -CH 2 -(C*i-C*5-alkyl)-, each C* substituted with a OH group,
  • R c is -H, Ci-Ce-alkyl, Ci-Ce fluoroalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or benzyl, and
  • alkylene refers to a saturated linear or branched divalent hydrocarbon radical.
  • cycloalkyl refers to the radical of a saturated carbocyclic ring. Suitable cycloalkyls include cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.
  • aryl as used herein, includes substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • Aryl groups include, but are not limited to, phenyl, phenol, aniline, etc.
  • the terms “aryl” also includes “polycyclyl”, “polycycle”, and “polycyclic” ring systems having two or more rings in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings,” wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, or aromatic rings.
  • the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
  • Aryl groups include, but are not limited to, phenyl, phenol, aniline, and the like.
  • Heteroaryl refers to substituted or unsubstituted aromatic single ring structures, preferably 6- to 18-member rings, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom (e.g., O, N, or S).
  • heteroaryl refers to substituted or unsubstituted aromatic single ring structures, preferably 6- to 18-member rings, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom (e.g., O, N, or S), preferably one to four or one to three heteroatoms, more preferably one or two heteroatoms.
  • heteroatom e.g., O, N, or S
  • heteroaryl moieties include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, quinoline, pyrimidine, indolizine, indole, indazole, benzimidazole, benzothiazole, benzofuran, benzothiophene, cinnoline, phthalazine, quinazoline, carbazole, phenoxazine, quinoline, purine and the like.
  • references to chemical moieties herein are understood to also include substituted variants, i.e. can be substituted with one or more (e.g., 2, 3, 4, 5, 6 or more) substituents.
  • substituted variants i.e. can be substituted with one or more (e.g., 2, 3, 4, 5, 6 or more) substituents.
  • alkyl group or moiety implicitly includes both substituted and unsubstituted variants.
  • the amino acids of peptide A may be selected independently.
  • the amino acids may be independently L or D amino acids. According to one preferred embodiment at least one amino acid is an L amino acid. According to other preferred embodiments all amino acids are D or L amino acids.
  • the amino acids alanine (Ala), valine (Vai), or glycine (Gly) are in particular preferred.
  • Such flexible linkers include, but are not limited to -Gly-Gly-Ser-Gly-, -Gly-Gly-Ser-Gly-Gly- , -Gly-Ser-Gly-Ser-Gly-, -Gly-Ser-Gly-Gly-Gly-, -Gly-Gly-Gly-Ser-Gly-, -Gly-Ser-Ser- Ser-Gly-, and the like.
  • antibody coupling groups are well known to the person skilled in the art.
  • the antibody coupling group is preferably a maleimide group.
  • Y b is Cs-alkyl substituted with 5 OH groups.
  • AB is the antibody or functional fragment thereof as shown in formula (I) and herein defined,
  • Fuc is fucose
  • GIcNAc is N-acetylglucosamine
  • S is a sugar or sugar derivative
  • M is -N(H)C(O)CH 2 -, -N(H)C(O)CF 2 -, -CH 2 -, -CF 2 - or a 1 ,4- phenylene containing 0-4 fluorine substituents, preferably 2 fluorine substituents which are preferably positioned on 02 and 06 or on 03 and 05 of the phenylene;
  • R 1 is independently selected from the group consisting of hydrogen, halogen, -OR 8 , -NO2, -CN, S(O)2R 8 , C1-C24 alkyl groups, C6-C24 (hetero)aryl groups, C7-C24 alkyl(hetero)aryl groups and C7-C24 (hetero)arylalkyl groups, preferably hydrogen, and wherein the alkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally substituted, wherein two substituents R 8 may be linked together to form an annelated cycloalkyl or an annelated (hetero)arene substituent, and wherein R 8 is independently selected from the group consisting of hydrogen, halogen, C1-C24 alkyl groups, C6-C24 (hetero)aryl groups, C7-C24 alkyl(hetero)aryl groups and C7
  • R 2 and are R 3 are independently selected from the group consisting of hydrogen, halogen, C1-C24 alkyl groups, C6-C24 (hetero)aryl groups, C7-C24 alkyl(hetero)aryl groups and C7-C24 (hetero)arylalkyl groups, preferably hydrogen;
  • R 4 is selected from the group consisting of hydrogen, halogen, C1-C24 alkyl groups, C6-C24 (hetero)aryl groups, C7-C24 alkyl(hetero)aryl groups and C7-C24 (hetero)arylalkyl groups, preferably hydrogen, the alkyl groups optionally being interrupted by one of more hetero-atoms selected from the group consisting of O, N and S, wherein the alkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are independently optionally substituted;
  • Y is O, S or NR 7 , wherein R 7 is independently selected from the group consisting of hydrogen, halogen, -OR 8 , -NO2, -CN, S(O)2R 8 , C1-C24 alkyl groups, Ce- C24 (hetero)aryl groups, C7-C24 alkyl(hetero)aryl groups and C7-C24 (hetero)arylalkyl groups and wherein the alkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally substituted, wherein two substituents R 8 may be linked together to form an annelated cycloalkyl or an annelated (hetero)arene substituent and wherein R 8 is independently selected from the group consisting of hydrogen, halogen, C1-C24 alkyl groups, C6-C24 (hetero)aryl groups, C7-C24 alkyl(hetero
  • L is a linking group, preferably a sulfamide based linking group, a is O or l ; x is 1 or 2, preferably 1 ; y is 1 , 2, 3 or 4, preferably 1 , r is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20, preferably 1 or 2; nn is 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 2, in particular 1 ; pp is 0 or 1 , preferably 1 ;
  • D is the drug or active agent as shown in formula (I) and herein defined.
  • glucose Glc
  • galactose Gal
  • Man mannose
  • Fuc fucose
  • sugar derivative is herein used to indicate a derivative of a monosaccharide sugar, i.e. a monosaccharide sugar comprising substituents and/or functional groups.
  • sugar derivatives examples include amino sugars and sugar acids, e.g. glucosamine (GICNH2), galactosamine (GalNH2) N-acetylglucosamine (GIcNAc), N- acetylgalactosamine (GalNAc), sialic acid (Sia) which is also referred to as N- acetylneuraminic acid (NeuNAc), and N-acetylmuramic acid (MurNAc), glucuronic acid (GlcA) and iduronic acid (IdoA).
  • GOCNH2 glucosamine
  • GalNH2 galactosamine
  • GalNH2 galactosamine
  • GalNAcNAc N-acetylglucosamine
  • GalNAc N- acetylgalactosamine
  • Sia sialic acid
  • NeNAc N- acetylneuraminic acid
  • MurNAc N-acetylmuramic
  • GIcNAc moieties as shown in Formula (I) are preferably present at a native N- glycosylation site in the Fc-fragment anti-lntegrin avp6 antibody or functional fragment thereof.
  • said GIcNAc moieties are attached to an asparagine amino acid in the region 290-305 of the antibody.
  • the antibody is an IgG type antibody, and depending on the particular IgG type antibody, said GIcNAc moieties are present on amino acid asparagine 297 (Asn297 or N297) of the antibody.
  • attachment sites i.e. “attachment amino acids” are also possible.
  • b is 1.
  • x is 1 .
  • R 1 , R 2 , R 3 and R 4 are hydrogen.
  • M is -CH2-, particular pp being 1 .
  • x is 1
  • R 1 , R 2 , R 3 and R 4 are hydrogen and nn is 1.
  • x is 1
  • R 1 , R 2 , R 3 and R 4 are hydrogen and nn is 1 and Y is O.
  • R 5 is selected from the group consisting of hydrogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24(hetero)arylalkyl groups, preferably hydrogen, the C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24(hetero)arylalkyl groups optionally substituted and/or optionally interrupted by one or more heteroatoms selected from O, S or NR 6 , wherein R 6 is hydrogen or C1-C4 alkyl, preferably hydrogen; wherein D is optionally connected to N via a spacer moiety.
  • x is 1
  • R 1 , R 2 , R 3 and R 4 are hydrogen
  • Y is O
  • nn is 1
  • M is -CH2- with pp being 1
  • L comprises Formula (VII), wherein in particular preferred R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen.
  • the spacer moiety is represented by Formula (VIII)
  • A is of Formula (II) as defined above;
  • L 1 is a -CH 2 -CH 2 -O-, -CH 2 -CH 2 -O-C(O)-, -O-CH 2 -CH 2 -, or -(CH 2 -CH 2 - O)ni-CH 2 -CH 2 - moiety, wherein n1 is an independently selected integer in the range of 1-10, preferably -CH 2 -CH 2 -O- or -CH 2 -CH 2 -O-C(O)-,
  • L 2 is a peptide spacer, preferably a dipeptide wherein L 2 is represented by general structure (IX): wherein R 9 is hydrogen, CH3 or CH2CH2CH2NHC(O)NH2, preferably R 9 is hydrogen;
  • L 3 is self-immolative spacer, preferably aminobenzyloxycarbonyl (PABC) derivative, more preferably a para-aminobenzyloxycarbonyl (PABC) derivative according to structure (X) wherein R 10 is hydrogen, R 11 or C(O)R 11 , wherein R 11 is selected from C1-C24 (hetero)alkyl groups, C3-C10 (hetero)cycloalkyl groups, C2-C10 (hetero)aryl groups, C3-C10 alkyl(hetero)aryl groups and C3-C10 (hetero)arylalkyl groups, which are optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR 12 wherein R 12 is independently selected from the group consisting of hydrogen and C1-C4 alkyl groups, R 10 preferably being hydrogen or C(O)R 11 wherein R 11 is preferably 4- methyl-piperazine or morpholine, most preferably wherein R 10 being hydrogen;
  • L 4 is an aminoalkanoic acid spacer according to the structure -N-(C X - alkylene)-C(O)-, wherein x is an integer in the range 1-10, or L 4 is an ethyleneglycol spacer according to the structure -N-(CH2-CH2-O) X I- (CH2)X2-C(O)-, wherein x1 is an integer in the range 1-10 and x2 is an integer in the range 1-3; and n, o, p, q are independently selected from 0 or 1.
  • at least one of d and f is 1.
  • R 5 of A 1 is of -(L 1 ) n -(CO)-(L 2 ) o -(L 3 )p-(L 4 ) q - as defined herein, i.e. the corresponding N atom is substituted by two residues of Formula
  • the peptide spacer L2 is represented by general formula (IX).
  • R 9 is hydrogen
  • R 10 is hydrogen
  • x is 1
  • R 1 , R 2 , R 3 and R 4 are hydrogen and L 2 is represented by general structure (IX).
  • x is 1
  • R 1 , R 2 , R 3 and R 4 are hydrogen and L 2 is represented by general structure (IX) and R 9 is hydrogen.
  • x is 1
  • R 1 , R 2 , R 3 and R 4 are hydrogen and L 2 is represented by general structure (IX), R 9 is hydrogen and Y is O.
  • x is 1 , R 1 , R 2 , R 3 and R 4 and are hydrogen and L 3 is a PABC derivative as herein defined.
  • x is 1 , R 1 , R 2 , R 3 and R 4 and are hydrogen, Y is O, L 2 is represented by general structure (IX), and L 3 is a PABC derivative as herein defined.
  • x is 1 , R 1 , R 2 , R 3 , R 4 and R 9 are hydrogen.
  • x is 1 , R 1 , R 2 , R 3 , R 4 and R 10 are hydrogen.
  • x is 1 , R 1 , R 2 , R 3 , R 4 , R 9 and R 10 are hydrogen.
  • x is 1, R 1 , R 2 , R 3 , R 4 and R 10 are hydrogen and
  • x is 1
  • R 1 , R 2 , R 3 , R 4 and R 10 are hydrogen
  • Y is O
  • L 3 is a PABC derivative as herein defined.
  • x is 1
  • R 1 , R 2 , R 3 , R 4 and R 10 are hydrogen
  • Y is O
  • L 3 is a PABC derivative as herein defined
  • M is -CH2- with pp being 1 .
  • x is 1
  • R 1 , R 2 , R 3 , R 4 , R 9 and R 10 are hydrogen and Y is O.
  • x is 1
  • R 1 , R 2 , R 3 , R 4 , R 9 and R 10 are hydrogen
  • L 2 is represented by general structure (XV)
  • Y is O
  • L 3 is a PABC derivative as herein defined.
  • x is 1
  • R 1 , R 2 , R 3 , R 4 , R 9 and R 10 are hydrogen
  • L 2 is represented by general structure (XV)
  • Y is O
  • L 3 is a PABC derivative as herein defined
  • M is -CH2- with pp being 1.
  • a "self-immolative group” as used herein is a part of a linker in an antibody-drug conjugate with a function to conditionally release a free drug at the site targeted by the ligand unit.
  • the activatable self-immolative moiety may comprise an activatable group (AG) and a self-immolative spacer unit.
  • AG activatable group
  • a self-immolative spacer unit Upon activation of the activatable group, for example by enzymatic conversion of an amide group to an amino group or by reduction of a disulfide to a free thiol group, a self-immolative reaction sequence is initiated that leads to release of free drug by one or more of various mechanisms.
  • the self-immolative group is not an inherent part of the chemical spacer, but branches off from the chemical spacer connecting the antibody and the payload.
  • the linker described herein is, for example, described in WO 2021/144313, WO 2016/053107 as well as WO 2017/137456.
  • Methods for attaching the described linkers to antibodies are, for example, described in WO 2011/136645, WO 2022/2022049211 , WO 2014/065661 , WO 2016/270186, WO 2017/137459 and WO 2021/015622.
  • linker-drug conjugates described herein are particularly suitable for attachment to an anti-lntegrin avp6 antibody as described herein. It should be noted, however, that the linker-drug conjugates are also suitable for attachment to any antibody or antigen-binding fragment thereof, e.g., an antibody binding to a tumor antigen or an antigen-binding fragment thereof.
  • the antibody-drug conjugate of the present invention may be prepared by known methods.
  • the antibody or the antigen-binding fragment thereof may be produced in a suitable host cell comprising a nucleic acid molecule, e.g., a DNA molecule, encoding an antibody VH region, or an antibody VL region, or encoding a complete antibody or an antibody fragment, or a vector or vector system, i.e. a plurality of vectors, comprising said nucleic acid molecule(s), preferably in operative linkage with an expression control sequence, particularly with a heterologous expression control sequence.
  • the host cell may be any known host cell for producing antibodies or antibody fragments, e.g., a prokaryotic cell such as an E. coli cell, a yeast cell, an insect cell, or a mammalian cell, e.g., a CHO cell or a hybridoma cell.
  • the antibody or antigen-binding fragment thereof may be reacted with a linker-drug conjugate to obtain the antibody-drug conjugate.
  • the linker-drug conjugate comprises a drug molecule, e.g., having attached thereto a suitable linker, wherein the linker comprises a reactive group capable of reacting with desired attachment positions on the antibody or antigen-binding fragment thereof.
  • the linker-drug conjugate comprises a thiol-reactive group, e.g., a maleimide group.
  • binding of the conjugating linker to the antibody can take place, for example, via aldehyde groups that may have been previously introduced into the antibody.
  • the ligand may include a Hydrazine- iso-Picted-Spengler (HIPS) chemistry, the binding of which to the aldehyde group leads to the formation of a stable C-C bond.
  • HIPS Hydrazine- iso-Picted-Spengler
  • This HIPS chemistry can be combined with any of the linker types described above.
  • a further aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an active agent, which is an antibody-drug conjugate as herein described and a pharmaceutically acceptable carrier and/or excipient.
  • Suitable carriers and excipients for formulating antibodies and antibody drug conjugates include saline and aqueous buffer solutions and are well known in the art.
  • the pharmaceutical composition is adapted for parenteral administration, e.g., for subcutaneous, intramuscular, or intravenous injection or by infusion.
  • the pharmaceutical composition is adapted for local administration, e.g., for intravesical instillation into the bladder.
  • the pharmaceutical composition may be administered once or several times in a therapeutically effective dose to a subject in need thereof, particularly to a human subject.
  • a therapeutically effective dose to a subject in need thereof, particularly to a human subject.
  • it may be administered once or several times daily, each second day, two times weekly or weekly for a suitable period, e.g., of at least one week, or at least one month.
  • the antibody-drug conjugate or pharmaceutical composition as described above is used in medicine, including human and veterinary medicine, particularly in human medicine.
  • the antibody-drug conjugate or pharmaceutical composition as described above is used in a method for the prevention and/or treatment of a Integrin avp6 associated disorder such as cancer, in particular solid cancers e.g. carcinomas such as breast-, lung-, prostate-, colorectal, ovarian-, pancreatic- cancer, or carcinoid tumors such as hepatocellular carcinoma, renal cell carcinoma or other carcinomas of the gastrointestinal tract, or sarcomas of connective or supportive tissues, such as bone, cartilage, fat, muscle, or blood vessels, or neurological or neuroendocrine tumors such as astrocytoma, glioblastoma, multiforme, or hematologic malignancies which affect blood, bone marrow, and/or the lymphatic system such as Leukemias, in particular acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), or
  • ALL acute lymph
  • Integrin avp6 expression is also associated with autoimmune diseases, fibrosis, chronic obstructive pulmonary disease (COPD), wound healing disorders, and asthma. Therefore, the ADCs and pharmaceutical compositions disclosed herein are in a preferred embodiments envisaged for the treatment and prevention of these conditions.
  • Autoimmune diseases are conditions where the immune system mistakenly attacks the body's own cells and tissues. In a healthy immune system, the body defends against foreign substances like bacteria and viruses. However, in autoimmune diseases, this system malfunctions, leading to inflammation and damage in various parts of the body. These diseases can affect almost any part of the body, including the heart, brain, nerves, muscles, skin, eyes, joints, lungs, kidneys, glands, the digestive tract, and blood vessels.
  • the active agent is administered in an effective amount to a subject in need thereof, particularly to a human subject.
  • the dose will depend on the specific type of agent, e.g., type of antibody or antibody fragment, the type of disease, and the mode of administration, e.g., locally or systemically.
  • a therapeutic dose of an antibody or antibody drug conjugate is typically from about 0.3 mg/kg to about 10 mg/kg.
  • the antibody-drug conjugate may be administered alone or together with a further active agent, which may be selected from chemotherapeutic agents, e.g., antimetabolites, alkylating agents, intercalating agents, or anti-mitotic agents), inhibitors of specific kinases e.g., tyrosine kinase inhibitors, serine/threonine kinase inhibitors or phosphoinositide kinase inhibitors, immunotherapeutic compounds, e.g., immune checkpoint inhibitors, CAR-T cells, bi- or multi-specific immune cell engager such as NK- or T-cell engagers, or therapeutic vaccines or oncolytic viruses.
  • chemotherapeutic agents e.g., antimetabolites, alkylating agents, intercalating agents, or anti-mitotic agents
  • inhibitors of specific kinases e.g.,
  • a preferred aspect of the present invention refers to an antibody-drug conjugate or a pharmaceutical composition as herein described for use in the treatment of an Integrin avp6 associated disorder of a patient who has relapsed or is refractory to prior Integrin avp6 directed treatment, in particular prior treatment based on monomethyl auristatin E (MMAE).
  • MMAE may have been administered to the patient as first- line, second-line or third-line treatment.
  • Another aspect relates to a method of treating an Integrin avp6 associated disorder of a patient who has relapsed or is refractory to prior Integrin avp6 directed treatment, comprising administering to the patient a therapeutically effective amount of the antibody-drug conjugate or a pharmaceutical composition as herein described.
  • 264RAD_EX is an Exatecan conjugated, lgG1 based, Fc-silenced ADC comprising the heavy and light chain variable regions according to SEQ ID NOs: 1 and 2).
  • L0 unconjugated light chain
  • L1 Light chain conjugated to one molecule of linker-payload
  • HO unconjugated heavy chain
  • H1 Heavy chain conjugated to one molecule of linker-payload
  • H2 Heavy chain conjugated to two molecules of linker-payload
  • H3 Heavy chain conjugated to three molecules of linker-payload.
  • MW molecular weight.
  • QC control quality of ADC after production
  • TO ADC after thawing
  • T2W ADC after two weeks at 40°C
  • T4W ADC after four weeks at 40°C
  • FT ADC after five freeze/thaw cycles.
  • FIG. 4 ADC binding and ECso compared to parental antibody on human cell lines 1 E5 cells/well of human cell lines Detroit 562, SW-780, HPAF-II and BxPC-3 were incubated with dilute parental antibody or ADC for 1 hour at 4°C, washed and incubated with Anti human secondary antibody (30min at 4°C). MFI were obtained by flux cytometry. ECso was determined using Mean fluorescence intensity (MFI) correlated to concentration (A) with GraphPad PrismIO Nonlinear regression dose response Asymmetric (five parameter), X is concentration (four parameters). ICT (Isotype ConTrol). (B) Table summarizing the result
  • IC50 was determined using Mean fluorescence intensity (MFI) correlated to concentration with GraphPad PrismIO Nonlinear regression [Inhibitor] vs. response -- Variable slope (four parameters)
  • Figure 5 ADC in vivo efficacy in cancerous cell derived xenografts
  • A) Graphs represent Mean tumor volume over time for each group, the mean tumor volume is plotted (+/- SEM) over time.
  • the mean tumor volume is no longer plotted as the curve could mechanically inflect when larger tumors are removed, independently of the effect of the treatment.
  • Antibodies generation, production, purification and control are antibodies generation, production, purification and control:
  • Antibodies are produced in CHO expression system, under a under modified human lgG1 bearing L234A/L235A/ S239C/S442C mutations with a kappa LC. Cysteine insertions are for the site-specific coupling of linker payloads. Alanine insertions are for limiting the ability of the mAb to interact with Fc receptors. Light and heavy chain expression vectors were co-transfected into suspension cells Light and heavy chain expression vectors were co-transfected into suspension cells. 5 L of cells were transiently transfected and grown in animal-component free and serum-free medium. Feeds were added during the production process following a defined feeding strategy and cells were kept in culture for at least 12 days.
  • the mass of the antibodies was determined in a Xevo G2-S Q-Tof mass spectrophotometer (Waters) using a reversed-phase column (PLRP-S 4000A, Agilent technologies). All samples were analyzed after deglycosylation with PNGase F glycosidase (New England Biolabs) at 37°C, according to the manufacturer’s instructions. Fragmentation and/or aggregation of the final material was evaluated by SDS-PAGE. Endotoxin load was determined using a chromogenic LAL-kinetic assay (Charles River Endosafe).
  • ADCs were purified and supplied in solution.
  • ADC solutions were prepared on the day of injection in aseptic conditions by dilution into sterile 1X PBS at 6 mpk for administration by intravenous route in NMRI mice.
  • Blood collection was performed on individual mice at : TO, 3 min, 3 h, 6 h, 24 h, 96 h.
  • Blood samples were taken from the submandibular vein of vigilant mice. Plasma samples were recovered by centrifugation and stored at -80°C. Three independent blood samples were collected for each time points, each corresponding to one individual mouse.
  • paramagnetic streptavidin beads (Dynabeads M-280 streptavidin, Thermofisher Scientific) were prepared and washed using magnet and mixed with biotinylated Human anti-LC-kappa-biot (CaptureSelect Biotin Anti-LC-kappa, Thermofisher Scientific) or anti-Fc-biot (Mouse Anti-Human IgG Fc-Biot, Southern BioTech) to form ADC-capturing complexes.
  • ADC Capture from plasma samples were performed with a specific magnet, adapted to a 96 deep well plate format at room temperature. Samples were washed twice to eliminate plasma protein and salt. ADC were eluted from ADC-capturing complexes with acid solution: 70:30 H2O/ACN +0.1 % AF (pH ⁇ 2.7). DAR was evaluated under reduced and deglycosylation conditions by LC-MS mass spectrometry (XevoG2-S Q-Tof mass spectrophotometer, Waters) to evaluate payload conjugation stability over time.
  • E5 cells expressing ITGb6 were incubated with dose range of the indicated antibodies or ADC (25 nM to 0,0004 nM) 1 hour at 4°C, washed and incubated with Anti human secondary antibody (Goat Anti human Fc-Alexa 647, Thermo Fisher Scientific) 30min a 4°C. After cells fixation (4% PFA for 15min), MFI were obtained by flux cytometry. EC50 was determined using Mean fluorescence intensity (MFI) correlated to concentration with GraphPad Prism 10 Nonlinear regression dose response Asymmetric (five parameters).
  • MFI Mean fluorescence intensity
  • IC50 was determined using Mean fluorescence intensity (MFI) correlated to concentration with GraphPad PrismIO Nonlinear regression [Inhibitor] vs. response -- Variable slope (four parameters)
  • mice 6-8-week-old female BALB/c nude mice were subcutaneously inoculated with, 5E6 cells /0.2 mL DPBS with 50% Matrigel.
  • animals were randomly divided into groups according to the tumor volume, with 10 mice per group. Animals in all groups were administered intravenously weekly x 3 dose. The tumor volume and body weight were measured twice a week. Tumor xenografts were measured with calipers and tumor volume in mm 3 was determined by multiplying height x width x length.
  • the mean tumor volume is plotted (+/- SEM) overtime using GraphPad Prism 10 software. When a mouse dies in a group, the mean tumor volume and weight is no longer plotted, independently of the effect of the treatment.

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Abstract

La présente invention concerne de nouveaux conjugués anticorps-médicament comprenant un anticorps monoclonal ou un fragment de liaison à l'antigène de celui-ci, l'anticorps monoclonal ou le fragment de liaison à l'antigène de celui-ci se liant à l'intégrine αvβ6.
PCT/EP2025/052491 2024-02-01 2025-01-31 CONJUGUÉS ANTICORPS-MÉDICAMENT COMPRENANT UN ANTICORPS DE LIAISON ANTI-INTÉGRINE ΑVβ6 Pending WO2025163120A1 (fr)

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EP24155282.7A EP4595981A1 (fr) 2024-02-01 2024-02-01 Conjugués anticorps-médicament comprenant un anticorps anti-intégrine v 6 se liant
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WO2003100033A2 (fr) 2002-03-13 2003-12-04 Biogen Idec Ma Inc. Anticorps anti-$g(a)v$g(b)6
US20080057063A1 (en) * 2006-08-03 2008-03-06 Julie Rinkenberger Antibodies Directed to AlphaVBeta6 and Uses Thereof
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