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WO2025061971A1 - Peptides fonctionnalisés pour l'adressage in vivo de l'expression de pd-l1 - Google Patents

Peptides fonctionnalisés pour l'adressage in vivo de l'expression de pd-l1 Download PDF

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Publication number
WO2025061971A1
WO2025061971A1 PCT/EP2024/076472 EP2024076472W WO2025061971A1 WO 2025061971 A1 WO2025061971 A1 WO 2025061971A1 EP 2024076472 W EP2024076472 W EP 2024076472W WO 2025061971 A1 WO2025061971 A1 WO 2025061971A1
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formula
radiotracer
trap
dotpi
conjugate compound
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Johannes NOTNI
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Trimt GmbH
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Trimt GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/008—Peptides; Proteins

Definitions

  • the invention relates to the field of molecular imaging, in particular, to the area of imaging of the expression of immune checkpoint inhibitor receptors by means of nuclear imaging modalities, such as positron emission tomography.
  • Background Cancer cells can modulate their interaction with and recognition by the immune system by overexpression of certain cell surface proteins.
  • One such protein, PD-L1 is recognized by a receptor expressed by immune cells, PD-1, which prevents them from attacking the cancer cells. By this mechanism, cancer cells can evade the actions of the immune system.
  • PD-1 and PD-L1 expression are known predictive biomarkers in the context of ICI treatment. While the presence/absence of PD-1 expression did not have any predicitive effect, tumoral (and inflammatory intratumoral) PD-L1 expression was found to be a reliable response predictor in many clinical scenarios and different tumor entities.[2] Currently, the determination of the PD-L1 status for therapy decision is done by means of histological methods using tissue material (usually biopsies, occasionally resection specimen). However, a biopsy (usually measuring not more than 1 mm) in many instances is obviously not fully representative for a metastatic tumor with multiple lesions measuring several centimeters in diameter.
  • PD-L1 expression in tumors can be quite heterogeneous, which is why the actual position of a biopsy specimen can have a strong and unpredictable influence on the overall result of the analysis. These factors will lead to a considerable fraction of wrong therapy decisions, when treatment is based on tumoral expression of PD-L1 measured in tissue specimen. And finally, obtaining a biopsy (or a resection specimen) is an invasive procedure. Nevertheless, since no other technical approaches are available right now, assessing PD-L1 status in biopsy specimen prior to treatment is currently the standard of care in a variety of important tumor entities such as lung, head and neck, and kidney/urinary bladder cancer just to name a few.
  • the respective radiotracers however showed unsatisfactory properties. In particular, they exhibited unwanted and very high uptakes in several organs, such as liver, lungs, and/or intestines, and a slow and/or incomplete clearance from the blood pool, rendering them unsuitable for clinical translation.
  • the present invention has the objective of providing a conjugate compound and radiotracer and/or radiopharmaceutical containing the same, which exhibit better suitability for clinical translation and especially higher enrichment in tumor tissue, which inter alia means avoidance of high uptake in several organs, such as liver, lungs, and/or intestines, and/or faster or more efficient clearance from the blood pool.
  • the above objective is accomplished by the conjugate compound of appended claim 1, the radiotracer of appended claim 3 and the radiopharmaceutical of appended claim 6.
  • kits comprising the conjugate compound of the invention according to appended claim 10 is provided.
  • the invention provides the radiotracer of the invention or pharmaceutical composition of the invention for use in the imaging of cells carrying PD-L1, as specified in appended claim 11, for use in determining susceptibility of a cancer patient for treatment with immune checkpoint inhibitors as specified in appended claim 12, or for use in a method of treating cancer patients as specified in appended claim 13.
  • the present invention further provides the radiopharmaceutical of the invention for use in a method for treating cancer patients as specified in appended claim 14.
  • the present invention further provides methods for treating cancer patients with immune checkpoint inhibitors, said methods comprise a step to determining susceptibility for treatment with immune checkpoint inhibitors by means of the radiotracer of the present invention, followed by administering the cancer patient with immune checkpoint inhibitor therapy or administering the radiopharmaceutical of the present invention.
  • the present invention provides an intermediate suitable for synthesizing the conjugate compound of the present invention, as well as a corresponding manufacturing method.
  • the present invention further provides closely related conjugate compounds, radiotracers, radiopharmaceuticals, pharmaceutical compositions, kits, uses, treatments, intermediates, and manufacturing methods as specified hereinbelow with respect to the specific embodiment of the invention.
  • Figure 2 shows the tumor-to-organ ratios (data expressed as mean ⁇ standard deviation) for Ga-68- TRAP-WL12 in MDA-MB231 tumor-bearing SCID mice, 60 and 120 min after injection, calculated from ex-vivo biodistribution data.
  • Figures 4(A) and 4(B) show representative examples of positron emission tomography (PET) scans (maximum intensity projections) for MDA-MB231 tumor-bearing SCID mice, 60 and 120 min after injection of Ga-68-TRAP-WL12.
  • Figures 5(A) and 5(B) show a comparison of the ex-vivo biodistribution data, and calculated tumor-to- organ ratios thereof, for Ga-68-TRAP-WL12 and Ga-68-DOTAGA-WL12 in MDA-MB231 tumor- bearing mice, 60 min after injection. Data for Ga-68-DOTAGA-WL12 were collected from the literature (De Silva et al., Molecular Pharmaceutics 2018, 15, 3946 ⁇ 3952).
  • radiotracer is used for chemical compounds comprising radionuclides which emit gamma radiation or positrons, for application as imaging agents using the techniques single-photon emission computed tomography (SPECT) or positron emission tomography. Said radionuclides may also emit other radiation types, but the respective radiolabelled compounds are, in the context of this document, nonetheless referred to as radiotracers since it is the emission of gamma photons or positrons that is relevant for the application.
  • SPECT single-photon emission computed tomography
  • positron emission tomography positron emission tomography
  • radiopharmaceutical is used herein, for a better distinction from “radiotracer”, for chemical compounds comprising radionuclides that emit alpha- or beta radiation (typically, ⁇ 10 alpha or beta particles per 100 disintegrations). Such compounds are commonly used for radionuclide therapy. Said radionuclides may also emit other radiation types, but the respective radiolabelled compounds are, in the context of this document, nonetheless referred to as radiopharmaceuticals since it is the emission of alpha or beta radiation that is relevant for the application.
  • radionuclide While it is possible that a radionuclide emits alpha- or beta radiation and additionally gamma radiation or positrons, so that this radionuclide would theoretically qualify as radiotracer and as radiopharmaceutical, such a dual use is of little practical relevance: emission of alpha- or beta radiation in therapeutically useful doses will normally preclude any imaging applications of such radionuclides. Accordingly, such radionuclides would primarily qualify as radiopharmaceuticals. If, on the other hand, alpha- or beta radiation doses are so low that imaging is practically feasible, this will preclude therapeutic applications.
  • radionuclide emits alpha- or beta radiation and additionally gamma radiation or positrons
  • the term “radionuclide” is used herein to characterize a radioactive isotope of an element, which emits at least one of positrons, gamma radiation, alpha radiation or beta radiation.
  • the half-life of the radionuclides to be used for the present invention is typically in the range of from 30 min to 12 days, more preferably 45 min to 10 days.
  • the term "patient” as used herein refers to a human or animal subject.
  • the patient is a human.
  • the human may be an adult or child.
  • the patient is characterized by a condition, typically cancer, in which PD-L1 expression is upregulated or is at least suspected to be upregulated.
  • treatment and “administering a treatment” or the like are meant to specify the treatment of a patient, typically a patient in need thereof such as a cancer patient, which comprises administration of a radiopharmaceutical of the present invention, or a pharmaceutical composition or kit containing the radiopharmaceutical of the present invention to the patient.
  • Administration type, formulation, dosage and administration intervals are not particularly restricted any may be suitable determined by the skilled person relying on literature information and/or using routine experimentation, optionally taking one or more of the specific patient’s condition, weight, age, sex, further medications, and the like into account.
  • all disclosures of conjugate compounds, radiotracers, radiopharmaceuticals, intermediate compounds of the invention should also be understood as disclosures of the respective compounds in the form of a pharmaceutically acceptable salt, solvate and/or polymorph.
  • the invention is not limited in this respect as long as the compounds are suitable for use in the field of medicine, i.e., are pharmaceutically acceptable (this requirement of being pharmaceutically acceptable applies to the intermediate compounds only indirectly insofar as they must be suitable for manufacturing a pharmaceutically acceptable conjugate compound, radiotracer and/or radiopharmaceutical. Unless specified otherwise, all terms should be given their usual meaning as reflected by standard textbooks, encyclopedias and the like. For instance, the term “peptide” is used to characterize a compound in which at least two amino acids are joined via a peptide (amide) bond. In the context of the present specification, the singular forms “a”, “an” and “the” are meant to include also the corresponding plural forms unless the context dictates otherwise.
  • references to “a compound” or “the compound” includes two or more compounds.
  • the words “comprise,” “comprises” and “comprising” are to be interpreted inclusively rather than exclusively.
  • the terms “contain”, “containing”, “include,” “including” and “or” should all be construed to be inclusive, i.e. as permitting additional unmentioned items, unless the context dictates otherwise.
  • the use of these terms should also be understood as a disclosure of the possibility of no further items being present.
  • a disclosure of an embodiment using the term “comprising” is in one aspect to be understood as a disclosure of “consisting essentially of” or “consisting of” the listed items.
  • the methods disclosed herein may contain one or more additional steps that are not specifically disclosed herein, but in one aspect, such additional steps are absent in accordance with the terms “consisting essentially of” or “consisting of”.
  • the term “and/or” used in the context of “X and/or Y” should be interpreted as “X,” or “Y,” or “X and Y.”
  • the terms “example” and “such as,” particularly when followed by a listing of terms, are merely exemplary and illustrative and should not be deemed to be exclusive or comprehensive.
  • the invention relates to conjugates of PD-L1 binding peptides such as WL12 and derivatives thereof with the radionuclide chelators and other functional moieties to form compounds such as TRAP (TRAP- WL12) or DOTPI (DOTPI-WL12) for labelling with the positron emitter Gallium-68 or other potentially useful radionuclides or for accomplishing other useful diagnostic or therapeutic effects.
  • TRAP- WL12 TRAP- WL12
  • DOTPI-WL12 DOTPI
  • Formula X0 wherein in Formula Y0 and Formula X0, FM represents a functional moiety selected from imaging-active moieties and therapeutically-active moieties.
  • h can adopt 0 or 1;
  • i can adopt 0 or 1;
  • k can adopt the values 1, 2, or 3;
  • g can adopt the values 1, 2, or 3;
  • A represents a group selected from *–(CH2)n-**, *–(CH2CH2O)m-(CH2)p-** or *–(OCH2CH2)m-**, wherein * indicates binding to the cyclic peptide moiety and ** indicates binding to B, and wherein n is selected from the range of from 1 to 6, and m is selected from the range of from 1 to 6, preferably 1 to 4 or preferably 3 to 5, and p is 1 or 2;
  • B represents a group selected such that the moiety
  • A-B-C is C represents a group selected from ⁇ –(CH 2 ) n’ - ⁇ , ⁇
  • the functional moiety FM is derived from the chelating group TRAP, so that a possible conjugate compound of the present invention is characterized by the following Formula Y1: Formula Y1, wherein the meanings of A, B, C, D, E, g, h, i, k, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , and X 18 are the same as specified above for Formula Y0.
  • n and n’ can be selected independently of each other. It is however preferred that n and n’ are selected such that n+n’ is in the range of from 3 to 7 and more preferably 4 to 6. Likewise, m and m’ can be selected independently of each other. It is however preferred that m and m’ are selected such that m+m’ is in the range of from 2 to 12 and more preferably 4 to 8. It is also possible to have a mix of an alkylene group on one side of B and a polyoxyethylene group on the other side of B.
  • the conjugate compound of the present invention (TRAP- WL12) is characterized by the following Formula Y1a:
  • the conjugate compound is characterized by the following Formula Y1b: .
  • Formula Y1b In a further preferred aspect of the first embodiment, the conjugate compound is characterized by the following Formula Y1c:
  • the conjugate compound is characterized by the following Formula Y1d: Formula Y1d.
  • the positron-emitting nuclides 68 Ga, 64 Cu, 66 Ga, or 18 F preferably in the form of a metal complex with a highly charged cation like Al 3+ , as described for instance in W.J. McBride et al. in EJNMMI Res.
  • the radionuclides are preferably used in aqueous solutions in their most stable ionic forms, such as Ga 3+ and Cu 2+ , with suitable counterions, preferably chloride.
  • the radiotracer of this aspect is sometimes referred to as Ga-68-TRAP-WL12.
  • a suitable non-metal radionuclide emitting positrons or gamma radiation is for example 123 I, 124 I or 125 I.
  • a suitable non-metal radionuclide emitting alpha- or beta radiation is for example 131 I or 211 At.
  • All conjugates of the present invention can also be labelled with suitable radionuclides directly by mixing the radionuclide solution and the conjugate in a single vial, preferably containing other necessary excipients such as buffer substances, or radiolysis protection compounds, or stabilizers.
  • a single vial preferably containing other necessary excipients such as buffer substances, or radiolysis protection compounds, or stabilizers.
  • Such vials are sometimes referred to as kits or single-vial kits.
  • the compounds of the invention and the necessary buffers, radiolysis protectors, and stabilizers can also be provided in separate vials, whose contents are then transferred into one vial where the labeling reaction takes place.
  • Such combinations of ready-to-use vials are sometimes referred to as multi-vial kits.
  • the present invention also relates to such kits containing the conjugate compound of the invention, including single- vial kits and multi-vial kits.
  • radionuclide chelate complex formation reactions are conducted preferably between 20 and 120 °C, and preferably within times of 1–15 minutes for 68 Ga, or 1–60 minutes for other radionuclides. These preferred temperatures and times also apply if complexation is carried out without relying on a kit.
  • the handling of such kits before, during and/or after complex formation with the radionuclide can be performed manually, or by using automated procedures.
  • all components for using the conjugate compounds of the present inventions for preparation of radiolabelled compounds can be placed in a combination of vials, tubing, manifolds, and separation cartridges, sometimes referred to as cassette, preferably to be used with a robotic system for radiolabeling, frequently referred to as synthesis module.
  • cassettes are preferably provided as single-use, sterile, ready-to-use packages.
  • the resulting chelate complex may be further used without purification, or be further purified by conventional purification means and methods such as RP-HPLC or solid-phase extraction.
  • 68 Ga can be provided by elution from a 68 Ge/ 68 Ga generator, preferably with nominal activity 1-4 GBq, e.g., as supplied from Eckert&Ziegler (Berlin, Germany), ITM (Garching, Germany), Monrol (Turkey), Rosatom/Isotope ( Russia), PARS Isotopes (Iran), iTHEMBA (South Africa), or IRE Elit (Belgium).
  • the pH of the 68 Ga aqueous solutions may be adjusted with suitable buffers to values ranging from 1 to 7, preferably 2–3, prior to complexation.
  • 68 Ga can also be provided by synthesizing it using a cyclotron, either using a solid target or a liquid target.
  • the activity of the resulting chelate complex can be very high, for instance up to 300 GBq when using a solid target.
  • the conjugate compound of the present invention contains the DOTPI chelating moiety instead of the TRAP moiety.
  • DOTPI is a larger homologue of TRAP with one additional binding unit. It therefore prefers the binding of alternative radionuclides of larger size.
  • the conjugate compound of the second embodiment is characterized by the following Formula Y2: Formula Y2 wherein the meanings of A, B, C, D, E, g, h, i, k, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , and X 18 are the same as specified above for Formula Y0.
  • n and n’ can be selected independently of each other.
  • n and n’ are selected such that n+n’ is in the range of from 3 to 7 and more preferably 4 to 6.
  • m and m’ can be selected independently of each other. It is however preferred that m and m’ are selected such that m+m’ is in the range of from 2 to 12 and more preferably 4 to 8. It is also possible to have a mix of an alkylene group on one side of B and a polyoxyethylene group on the other side of B. In this case, m or m’ and n or n’ are selected such that m+n’ or m’+n is preferably in the range of from 3 to 9 and more preferably 4 to 7.
  • the conjugate compound is characterized by the following Formula Y2a, Y2b, Y2c, or Y2d:
  • the conjugate compound of the second embodiment can be used to form a chelate complex with a radionuclide selected from Al 18 F, 43 Sc, 44 Sc, 99m Tc, 111 In, 155 Tb, or another suitable radionuclide that emits positrons or gamma radiation, to form a radiotracer of the second embodiment of the present invention.
  • a radionuclide selected from Al 18 F, 43 Sc, 44 Sc, 99m Tc, 111 In, 155 Tb, or another suitable radionuclide that emits positrons or gamma radiation
  • a suitable non-metal radionuclide emitting positrons or gamma radiation is for example 123 I, 124 I or 125 I.
  • the conjugate compound of the second embodiment can be used to form a chelate complex with a metal cation of a radionuclide selected from 47 Sc, 90 Y, 149 Tb, 161 Tb, 177 Lu, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, or another suitable metal ion or non-metal radionuclide that emits alpha- or beta radiation, to form the radiopharmaceuticals of the second embodiment of the present invention.
  • a suitable non-metal radionuclide emitting alpha- or beta radiation is for example 131 I or 211 At.
  • radiotracers and radiopharmaceuticals of the second embodiment of the present invention may be prepared and further used as described above for the radiotracers and radiopharmaceuticals of the first embodiment, but wherein the conjugate compound of Formulae Y1, Y1a or Y1b is replaced by that of Formulae Y2, Y2a or Y2b.
  • the conjugate compound is characterized by one of the following Formulae Y3-1 and Y4-1,
  • Formula Y4-1 wherein D and E have the same meanings as defined above with respect to Formula Y0; X 18 is selected from –O–, –S–, or a covalent bond; g can adopt the values 1 or 2; k can adopt the values 1, 2, or 3; and C represents –(CH2)n’-, wherein n’ is selected from the range of from 1 to 6, preferably 1 to 3, more preferably 1 to 2, most preferably 1.
  • D represents a group selected from –CH3, and –CH2–COOH
  • E represents a group selected from –CH(CH3)2, and –CH2–COOH
  • X 18 is selected from –O–, –S–, or a covalent bond
  • g can adopt the values 1 or 2
  • k can adopt the values 1, 2, or 3
  • C represents –(CH2)n’-, wherein n’ is selected from the range of from 1 to 3, preferably 1 to 2, more preferably 1.
  • D represents a –CH3 group and E represents a –CH2–COOH group, or D represents a –CH2–COOH group and E represents a – CH(CH 3 ) 2 group;
  • X 18 is selected from –O–, –S–, or a covalent bond;
  • g can adopt the values 1 or 2;
  • k can adopt the values 1, 2, or 3;
  • C represents –(CH 2 ) n’ -, wherein n’ is selected from the range of from 1 to 3, preferably 1 to 2, more preferably 1.
  • the conjugate compound is characterized by the following Formulae Y3a, Y3b, Y3c, Y3d, Y3e, Y3f, Y3g, Y3h, Y4a, Y4b, Y4c, Y4d, Y4e, Y4f, Y4g, or Y4h: Formula Y3b,
  • the conjugate compound is represented by Formula Y0 and Formula X0 above and functional moiety FM represents a functional moiety selected from imaging-active moieties and therapeutically-active moieties other than those specified in the first to third embodiment above, such as moieties containing one or more of the following: chromophors and particularly fluorescent or luminescent groups; radiolabelled prosthetic groups; chelators; magnetic resonance imaging agents; enzyme inhibitors; chemotherapeutics and particularly cytostatics, topoisomerase inhibitors, alkylating agents, antimetabolites, anti-microtubule agents, cytotoxic antibiotics, taxanes, intercalating agents, platinum compounds, mitosis inhibitors, tyrosine kinase inhibitors; peptides and particularly peptide receptor ligands; functional building blocks for surface grafting, particularly on medical devices, nanoparticles, micelles, magnetic particles, or quantum dots; functional proteins such as antibodies, antibody fragments, nanobodies, or affi
  • the cyclopeptide moiety, linker and functional moiety FM are as described above, but with the proviso that the functional moiety FM has a structure including a moiety as described above for FM, such as TRAP or DOTPI or another imaging- active moiety or therapeutically-active moiety, but which additionally has one or more moieties, which is capable of undergoing chemical reactions that result in formation of one or more covalent bonds to other chemical moieties.
  • compounds according to Formula Y0 and Formula X0 may serve as "building blocks" for instance for the preparation of multimers as described hereinbelow.
  • FM represents a moiety as described above that can undergo coupling reactions widely referred to as "click chemistry” (such as described in Bauer D, et al., Nat Protocols 2023;18:1659; and Bauer D, et al., Bioconjugate Chem.2023;34:1925), in particular terminal alkynes; terminal azides; strained alkynes such as dibenzoazacyclooctyne [DBCO or DIBAC; also occasionally referred to as azadibenzocyclooctyne (ADIBO)], 4-dibenzocyclooctynol (DIBO), bicyclo[6.1.0]nonyne (BCN), difluorobenzocyclooctyne (DIFO), and 4,8-diazacyclononyne (DACN); tetrazines; trans-cyclooctenes; pinacolyl boranes.
  • click chemistry such as described in Bauer D, et al., Nat
  • the moiety capable of undergoing chemical reactions can be attached to any position of the remaining FM moiety.
  • the remaining FM moiety comprises TRAP or DOTPI and one or two, or in the case of DOTPI three moieties capable of undergoing chemical reactions are bonded to the remaining FM moiety via a corresponding number of the free carboxyl groups of TRAP or DOTPI.
  • the cyclopeptide moiety, linker and functional moiety FM are as described above, but with the proviso that the functional moiety FM has a structure including a moiety as described above for FM, such as TRAP or DOTPI or another imaging- active moiety or therapeutically-active moiety, but which additionally has one or more moieties, each of which containing structural elements of type A, B and/or C and a cyclic peptide, which are all according to the above definitions.
  • Said one or more additional moieties each of which containing cyclic peptide and structural elements of type A, B and/or C, may be the same or differ from each other, provided they are all in accordance with the above definitions.
  • TRAP moiety is contained in FM
  • one or two such further moieties may be attached to the central chelating moiety via amide bond formation with a corresponding number of free carboxyl groups
  • DOTPI moiety is contained in FM
  • one, two or three such further moieties may be attached via amide bond formation with a corresponding number of free carboxyl groups.
  • Such structures referred to as multimers, therefore contain more than one of the cyclic peptides described above. Preferred numbers of cyclic peptide moieties in such multimers are 2, 3, and 4.
  • a seventh embodiment relates to the synthesis of the conjugate of the invention as well as intermediates that can be used in the synthesis.
  • the peptide is provided in a modified form suitable for attaching the chelating moiety TRAP or DOTPI via Click chemistry.
  • Said modified form is the intermediate suitable for the manufacturing method of the present invention.
  • These intermediates of the invention are specified in the following Formulae Y5, Y6, Y7, Y8, X5, X6, X7, and X8: Formula Y6,
  • Formula X8 wherein the meanings of A, D, E, g, k, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , and X 18 in Formulae Y5, Y6, Y7, Y8, X5, X6, X7, and X8 are, if present, the same as specified above in the definition of Formula Y0 and Formula X0.
  • Preferred intermediates are characterized by the following Formulae Y5a, Y5b, Y5c, Y5d, Y6a, Y6b, Y6c, Y6d, Y7a, Y7b, Y7c, Y7d, Y8a, Y8b, Y8c, and Y8d: Formula Y5a,
  • the intermediates of the invention according to Formulae Y5, Y5a, Y5b, Y5c, Y5d, Y6, Y6a, Y6b, Y6c, or Y6d can be obtained by reacting the peptide WL12 or a suitable derivative thereof with suitable azido group-containing agents and alkyne group-containing agents, respectively.
  • the above intermediates of Formulae Y5a and Y6a can be prepared using 5-azidopentanoic acid or pent-4-ynoic acid, respectively. Suitable reaction conditions are indicated in Example 1 below.
  • WL12 is shown below as Formula 9. It is commercially available.
  • Suitable derivatives of WL12 with E other than isopropyl and D other than methyl can be obtained by standard peptide synthesis methods (Fmoc strategy), using however suitably modified amino acid monomers instead of leucine and N-methyl tryptophane.
  • Formula 9 Said intermediates of Formula Y5, X5, Y5a, Y5b, Y5c, Y5d, Y7, X7, Y7a, Y7b, Y7c, and Y7d can be reacted with alkyne group-containing TRAP- or DOTPI-intermediates hereinafter referred to as TRAP- alkyne and DOTPI-alkyne, respectively.
  • TRAP-alkyne is characterized by the formula TRAP-NH-C- C ⁇ CH
  • DOTPI-alkyne is characterized by the formula DOTPI-NH-C-C ⁇ CH.
  • TRAP and DOTPI are the molecules as described for instance in Figure 1 of A. Wurzer et al. in Front. Chem.2018 Apr 10;6:107. doi: 10.3389/fchem.2018.00107. Bonding of the C-alkyne and C-azide moieties takes place by amide bond formation of a terminal nitrogen atom bonded to C with one of the carboxyl groups of TRAP and DOTPI, respectively.
  • C is as defined above in relation to Formula Y0.
  • Preferred variants of the TRAP- alkyne and DOTPI-alkyne intermediates are shown below:
  • Intermediates according to Formula Y7, X7, Y7a, Y7b, Y7c, and Y7d are of particular interest because they can be synthesized from commercially available amino acid building blocks via standard peptide synthesis methods (Fmoc strategy).
  • intermediates of Formulae Y7a, Y7b, Y7c, and Y7d can be obtained using the commercially available, non-natural amino acid azidolysine (CAS No. 159610-92-1), or a suitable derivative for use in peptide synthesis reactions such as Fmoc-azidolysine (CAS 159610-89-6), during peptide synthesis.
  • TRAP-azide is characterized by the formula TRAP-NH-C-N3, and DOTPI-azide is characterized by the formula DOTPI-NH-C-N3, wherein bonding of the C-azide moieties takes place by amide bond formation of a terminal nitrogen atom bonded to C with one of the carboxyl groups of TRAP and DOTPI, respectively.
  • C is as defined above with respect to Formula Y0.
  • Intermediates according to Formulae Y8, X8, Y8a, Y8b, Y8c, and Y8d are of particular interest because they can be synthesized from commercially available amino acid bulding blocks via standard peptide synthesis methods (Fmoc strategy). Specifically, intermediates of Formulae Y8a, Y8b, Y8c, and Y8d can be obtained using commercially the available amino acid building block O-propargyl-serine (CAS No.
  • chromophors and particularly fluorescent or luminescent molecules include radiolabeled prosthetic groups; chelators; magnetic resonance imaging agents; enzyme inhibitors; chemotherapeutics and particularly cytostatics, topoisomerase inhibitors, alkylating agents, antimetabolites, anti-microtubule agents, cytotoxic antibiotics, taxanes, intercalating agents, platinum compounds, mitosis inhibitors, tyrosine kinase inhibitors; peptides and particularly peptide receptor ligands; functional building blocks for surface grafting, particularly on medical devices, nanoparticles, micelles, magnetic particles, or quantum dots; functional proteins such as antibodies, antibody fragments, nanobodies, or affibodies; pharmacokinetic modifiers and particularly albumin binders, sugars, oligo- and polysaccarides; metal- containing or metal-free compounds suitable for photodynamic therapy, specifically compounds that generate reactive oxygen species upon irradiation with light (visible or near-infrared
  • composition of the invention further provides pharmaceutical compositions comprising the radiotracer or radiopharmaceutical of the invention as described herein.
  • Said pharmaceutical compositions further comprise one or more excipients. These excipients can be selected by the skilled person as appropriate in view of the intended use, type of administration, and so forth.
  • Excipients that are typically used in the pharmaceutical compositions of preferred embodiments of the present invention are buffer substances, radiolysis protection compounds, and/or stabilizers.
  • the radiotracer of the preferred aspect of the first embodiment of the present invention Ga-68-TRAP-WL12
  • the conjugate compound of the first embodiment can be radiolabelled faster and the resulting radiotracer has higher molar activity than corresponding antibody-based radiotracers and their precursors.
  • the radiotracer of the first embodiment of the present invention such as Ga-68-TRAP-WL12
  • the precursor conjugate compound represent a peptide-based PD-L1 imaging agent with advantageous properties.
  • the present invention also provides the radiotracer of the first embodiment of the present invention for use in the imaging of cells carrying PD-L1.
  • Said imaging can be accomplished using Positron Emission Tomography (PET), single-photon emission computed tomography (SPECT), or planar scintigraphy. It can be carried out in vivo on a patient in need thereof. This is typically a cancer patient and more specifically a cancer patient for which treatment with immune checkpoint inhibitor (ICI) therapy is considered, especially ICI therapy addressing the PD-1/PD-L1 axis.
  • Said imaging is preferably carried out in order to assess the expression status of PD-L1 in that patient, by quantification of the uptake of the radiotracer in the tumor tissue and other tissues.
  • ICI therapy in the context of the present invention includes in particular therapy with an agent selected from pembrolizumab, nivolumab, cemiplimab, spartalizumab, atezolizumab, durvalumab, avelumab or any other substance interfering with the PD-1/PD-L1 interaction, including antibodies or small molecules, for instance as described in WO 2014/151634 A1, WO 2017/176608 A1 or WO 2018/237153 A1.
  • it includes in particular melanoma and especially metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, small cell lung cancer, esophageal carcinoma, malignant pleural mesothelioma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, endometrial cancer, squamous cell carcinoma, bladder cancer, breast cancer and basal cell carcinoma.
  • the present invention further provides the radiotracer of the present invention for use in determining susceptibility of a cancer patient for treatment with ICI therapy and especially ICI therapy addressing the PD-1/PD-L1 axis.
  • Susceptibility can be determined by a procedure comprising the following steps: (i) Administering the radiotracer to the patent. This can be done by intravenous infusion or intravenous injection. (ii) Performing a PET scan, a SPECT scan, or a scintigraphy on the patient. (iii) Comparing the quantitative uptake values obtained in said scan with reference uptake values. In particular, the signal strength in the patient scan according to (ii) may be quantified in one or more regions of interest.
  • the obtained signal strength values may then be compared with reference values, and preferably reference values for the same regions of interest, that are predetermined such that similar or higher signal strengths are indicative of susceptibility for ICI treatment.
  • the reference value is to be determined empirically for a particular radiotracer of interest, based on measurements with cancer patients for which susceptibility (or non- susceptibility) for ICI treatment is known.
  • Confirming susceptibility for ICI treatment if the signal strength of the patient’s scan in at least one region of interest is equal or higher than that of the reference scan in the same region.
  • susceptibility for ICI treatment may be confirmed if the quantified signal strength value of the patient’s scan in at least one region of interest is equal or higher than that of the reference scan in the same region.
  • the radiotracer administered in step (i) is a radiotracer based on a conjugate compound of the first embodiment according to Formula Y1 or Y3, and preferably Formula Y1a, Y1b, Y1c, Y1d, Y3a, Y3b, Y3c, Y3d, Y3e, Y3f, Y3g or Y3h and a radionuclide selected from 68 Ga, 66 Ga, 64 Cu, Al 18 F or a radiotracer based on a conjugate compound of the second embodiment according to Formula Y2 or Y4, and preferably Formula Y2a, Y2b, Y2c, Y2d, Y4a, Y4b, Y4c, Y4
  • the dose of the radiotracer is not particularly limited.
  • the person skilled in the art can determine a suitable dose taking into account the known characteristics of the radionuclide of interest as well as the sensitivity of the scanner. As an example, at present, it is common to use a dose of 80–300 MBq for 68 Ga, but it is expected that the next generation PET scanners will have a higher sensitivity so that doses as low as 5 MBq may be sufficient. Possible doses may thus range from 0.1 to 6000 MBq, such as 1- 1000 MBq, 2-500 MBq, 4-400 MBq or 5-300 MBq. The present invention is however not limited to any of these ranges.
  • Step (ii) is typically started to be carried out 15-90 min after step (i), preferably 30-60 min after completion of step (i).
  • the present invention provides the radiotracer of the invention for use in a method of treating cancer patients with ICI therapy and especially ICI therapy addressing the PD-1/PD-L1 axis.
  • This method comprises the following steps: a first step of determining susceptibility of a cancer patient for treatment with ICI therapy as specified above; a second step of administering treatment involving an immune checkpoint inhibitor only if susceptibility of the cancer patient for treatment with ICI therapy has been confirmed in the first step.
  • Further applications of the radiotracers of the present invention are for use in monitoring efficacy of anticancer therapy.
  • This use involves carrying out the above steps (i) and (ii) one or more times after initiation of anticancer therapy.
  • the obtained scan images (or quantitative data derived from the scans) may then be compared to determine that (a) disease has progressed in spite of the anticancer treatment if the detected tissue with upregulation of PD-L1 increases during therapy in terms of volume and/or signal intensity; (b) there is disease remission if the detected tissue with upregulation of PD-L1 decreases during therapy in terms of volume and/or signal intensity; or (c) disease is stable if there is no clear trend in the images or quantitative data derived therefrom.
  • the conjugate compound of Formula Y1 or Y3, and preferably Formula Y1a, Y1b, Y1c, Y1d, Y3a, Y3b, Y3c, Y3d, Y3e, Y3f, Y3g or Y3h forms a chelate complex with 68 Ga.
  • 68 Ga-containing radiotracers are positron emitters and may therefore be used as peptide-based PD-L1 imaging agents in the same manner as described above relying on PET imaging.
  • this aspect of the first embodiment of the present invention provides the uses for imaging PD-L1 expression, determining susceptibility of a cancer patient for treatment with ICI therapy, monitoring efficacy of anticancer therapy and use in a method of treating cancer patients with ICI therapy as described above.
  • the conjugate compound of Formula Y1 or Y3, and preferably Formula Y1a, Y1b, Y1c, Y1d, Y3a, Y3b, Y3c, Y3d, Y3e, Y3f, Y3g or Y3h forms a chelate complex with 64 Cu, Al 18 F or 66 Ga.
  • this aspect of the second embodiment of the present invention provides the same uses for PET-based imaging PD-L1 expression, determining susceptibility of a cancer patient for treatment with ICI therapy, monitoring efficacy of anticancer therapy and use in a method of treating cancer patients with ICI therapy as described above for the first embodiment, the sole difference being the use of the Al 18 F, 43 Sc-or 44 Sc-containing radiotracers together with the conjugate compound of the second embodiment.
  • this aspect of the second embodiment of the present invention provides the same uses for imaging PD-L1 expression, determining susceptibility of a cancer patient for treatment with ICI therapy, monitoring efficacy of anticancer therapy and use in a method of treating cancer patients with ICI therapy as described above for the first embodiment, the sole difference being the use of the 111 In, 155 Tb, or 99m Tc-containing radiotracers of the second embodiment.
  • the conjugate compound of Formula Y1 or Y3, and preferably Formula Y1a, Y1b, Y1c, Y1d, Y3a, Y3b, Y3c, Y3d, Y3e, Y3f, Y3g or Y3h forms a chelate complex with 67 Cu, or another suitable metal ion radionuclide that emits alpha- or beta radiation, to provide a radiopharmaceutical having therapeutic utility. That is, the radiopharmaceutical of this further aspect of the first embodiment is suitable for use in the treatment of cancer patients and especially patients having cancer that is associated with a high level of PD-L1 expression.
  • the conjugate compound of Formula Y2 or Y4, and preferably Formula Y2a, Y2b, Y2c, Y2d, Y4a, Y4b, Y4c, Y4d, Y4e, Y4f, Y4g or Y4h forms a chelate complex with 47 Sc, 90 Y, 149 Tb, 161 Tb, 177 Lu, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, or another suitable metal ion radionuclide that emits alpha- or beta radiation, to provide a radiopharmaceutical having therapeutic utility.
  • the radiopharmaceutical of this further aspect of the second embodiment is suitable for use in the treatment of cancer patients and especially patients having cancer that is associated with a high level of PD-L1 expression.
  • Said treatment involves the administration of the radiopharmaceutical to the cancer patient.
  • the cancer types that can be treated are as defined above and they are preferably selected from the above-mentioned list.
  • the invention relates to conjugates of PD-L1 binding peptides such as WL12 and derivatives thereof with the radionuclide chelators and other functional moieties to form compounds such as TRAP (TRAP-WL12) or DOTPI (DOTPI-WL12) for labelling with the positron emitter Gallium-68 or other potentially useful radionuclides or for accomplishing other useful diagnostic or therapeutic effects.
  • TRAP TRAP-WL12
  • DOTPI DOTPI
  • the functional moiety FM is derived from the chelating group TRAP, so that the conjugate compound of the specific embodiment of the present invention is characterized by the following Formula 1: Formula 1 wherein in Formula 0 and/or 1: A represents a group selected from *–(CH2)n-**, *–(CH2CH2O)m-(CH2)p-** or *–(OCH2CH2)m-**, wherein * indicates binding to the cyclic peptide moiety and ** indicates binding to B, and wherein n is selected from the range of from 1 to 6, and m is selected from the range of from 1 to 6, preferably 1 to 4 or preferably 3 to 5, and p is 1 or 2 ; B represents a group selected such that the moiety A-B-C is C represents a group selected from ⁇ –(CH2)n’- ⁇ , ⁇ –(CH2CH2O)m’- ⁇ or ⁇ -(CH2)p’–(OCH2CH2)m’- ⁇ , where
  • n and n’ can be selected independently of each other.
  • n and n’ are selected such that n+n’ is in the range of from 3 to 7 and more preferably 4 to 6.
  • m and m’ can be selected independently of each other. It is however preferred that m and m’ are selected such that m+m’ is in the range of from 2 to 12 and more preferably 4 to 8. It is also possible to have a mix of an alkylene group on one side of B and a polyoxyethylene group on the other side of B. In this case, m or m’ and n or n’ are selected such that m+n’ or m’+n is preferably in the range of from 3 to 9 and more preferably 4 to 7.
  • the conjugate compound of the specific embodiment of the present invention is characterized by the following Formula 1a: .
  • Formula 1a is characterized by the following Formula 1b:
  • the conjugate compound is characterized by the following Formula 1c: Formula 1c. In a further preferred aspect of the first embodiment, the conjugate compound is characterized by the following Formula 1d:
  • the radionuclides are preferably used in aqueous solutions in their most stable ionic forms, such as Ga 3+ and Cu 2+ , with suitable counterions, preferably chloride.
  • kits before, during and/or after complex formation with the radionuclide can be performed manually, or by using automated procedures.
  • all components for using the conjugate compounds of the specific embodiment of the present invention for preparation of radiolabelled compounds can be placed in a combination of vials, tubing, manifolds, and separation cartridges, sometimes referred to as cassette, preferably to be used with a robotic system for radiolabeling, frequently referred to as synthesis module.
  • cassettes are preferably provided as single-use, sterile, ready-to-use packages.
  • 68 Ga can be provided by elution from a 68 Ge/ 68 Ga generator, preferably with nominal activity 1-4 GBq, e.g., as supplied from Eckert&Ziegler (Berlin, Germany), ITM (Garching, Germany), Monrol (Turkey), Rosatom/Isotope ( Russia), PARS Isotopes (Iran), iTHEMBA (South Africa), or IRE Elit (Belgium).
  • the conjugate compound of the second embodiment is characterized by the following Formula 2: Formula 2 wherein the meanings of A, B, C, D, E, and k are the same as specified above for the first embodiment.
  • the conjugate compound is characterized by the following Formula 2a, 2b, 2c, or 2d: Formula 2b,
  • the conjugate compound of the second embodiment can be used to form a chelate complex with a radionuclide selected from Al 18 F, 43 Sc, 44 Sc, 99m Tc, 111 In, 155 Tb, or another suitable radionuclide that emits positrons or gamma radiation, to form a radiotracer of the second embodiment of the specific embodiment of the present invention.
  • a radionuclide selected from Al 18 F, 43 Sc, 44 Sc, 99m Tc, 111 In, 155 Tb, or another suitable radionuclide that emits positrons or gamma radiation
  • the conjugate compound of the second embodiment can be used to form a chelate complex with a metal cation of a radionuclide selected from 47 Sc, 90 Y, 149 Tb, 161 Tb, 177 Lu, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, or another suitable metal ion radionuclide that emits alpha- or beta radiation, to form the radiopharmaceuticals of the second embodiment of the specific embodiment of the present invention.
  • a radionuclide selected from 47 Sc, 90 Y, 149 Tb, 161 Tb, 177 Lu, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, or another suitable metal ion radionuclide that emits alpha- or beta radiation
  • the radiotracers and radiopharmaceuticals of the second embodiment of the specific embodiment of the present invention may be prepared and further used as described above for the radiotracers and radiopharmaceuticals of the first embodiment, but wherein the conjugate compound of Formulae 1, 1a or 1b is replaced by that of Formulae 2, 2a or 2b. Unless specified otherwise or the context dictates otherwise, all information provided herein for the first embodiment, for instance with respect to kits or purification, applies in an analogous manner to the second embodiment, and vice versa.
  • the conjugate compound is characterized by the following Formulae 3a, 3b, 4a, or 4b: Formula 3b,
  • the conjugate compound is represented by Formula 0 above and functional moiety FM represents a functional moiety selected from imaging-active moieties and therapeutically- active moieties other than those specified in the first to third embodiment above, such as moieties containing one or more of the following: chromophors and particularly fluorescent or luminescent groups; radiolabelled prosthetic groups; chelators; magnetic resonance imaging agents; enzyme inhibitors; chemotherapeutics and particularly cytostatics, topoisomerase inhibitors, alkylating agents, antimetabolites, anti-microtubule agents, cytotoxic antibiotics, taxanes, intercalating agents, platinum compounds, mitosis inhibitors, tyrosine kinase inhibitors; peptides and particularly peptide receptor ligands; functional building blocks for surface grafting, particularly on medical devices, nanoparticles, micelles, magnetic particles, or quantum dots; functional proteins such as antibodies, antibody fragments, nanobodies, or affibodies; pharmacokinetic modifier
  • the peptide is provided in a modified form suitable for attaching the chelating moiety TRAP or DOTPI via Click chemistry.
  • Said modified form is the intermediate suitable for the manufacturing method of the specific embodiment of the present invention.
  • Formula 7 wherein the meanings of A, D, E, and k in Formulae 5, 6 and 7 are the same as specified above for the first embodiment.
  • Preferred intermediates are characterized by the following Formulae 5a, 5b, 6a, 6b, 7a, and 7b:
  • Suitable derivatives of WL12 with E other than isopropyl and D other than methyl can be obtained by standard peptide synthesis methods (Fmoc strategy), using however suitably modified amino acid monomers instead of leucine and N-methyl tryptophane.
  • Formula 8 Said intermediates of Formula 5, 5a, 5b, 7, 7a, and 7b are reacted with alkyne group-containing TRAP- or DOTPI-intermediates hereinafter referred to as TRAP-alkyne and DOTPI-alkyne, respectively.
  • TRAP-alkyne is characterized by the formula TRAP-NH-C-C ⁇ CH
  • DOTPI-alkyne is characterized by the formula DOTPI-NH-C-C ⁇ CH.
  • TRAP and DOTPI are the molecules as described for instance in Figure 1 of A. Wurzer et al. in Front. Chem. 2018 Apr 10;6:107. doi: 10.3389/fchem.2018.00107. Bonding of the C-alkyne and C-azide moieties takes place by amide bond formation of a terminal nitrogen atom bonded to C with one of the carboxyl groups of TRAP and DOTPI, respectively.
  • C is as defined above in relation to Formula 1.
  • Preferred variants of the TRAP-alkyne and DOTPI-alkyne intermediates are shown below:
  • Intermediates according to formula 7, 7a, and 7b are of particular interest because they can be synthesized from commercially available amino acid bulding blocks via standard peptide synthesis methods (Fmoc strategy). Specifically, 7a and 7b can be obtained using the commercially available, non-natural amino acid azidolysine (CAS No. 159610-92-1), or a suitable derivative for use in peptide synthesis reactions such as Fmoc-azidolysine (CAS 159610-89-6), during peptide synthesis.
  • Intermediates according to Formula 7, 7a and 7b can be directly functionalized via Click Chemistry (CuAAC) without the necessity of attaching a separate functional linker, e.g., as outlined above for synthesis of the intermediates according to formula 5a and 5b from WL12 or suitable derivatives thereof.
  • Said intermediates of Formula 6, 6a, and 6b are reacted with azide group-containing TRAP- or DOTPI- intermediates hereinafter referred to as TRAP-azide and DOTPI-azide, respectively.
  • TRAP-azide is characterized by the formula TRAP-NH-C-N3, and DOTPI-azide is characterized by the formula DOTPI-NH-C-N3, wherein bonding of the C-azide moieties takes place by amide bond formation of a terminal nitrogen atom bonded to C with one of the carboxyl groups of TRAP and DOTPI, respectively.
  • C is as defined above with respect to Formula 1.
  • chromophors and particularly fluorescent or luminescent molecules include radiolabeled prosthetic groups; chelators; magnetic resonance imaging agents; enzyme inhibitors; chemotherapeutics and particularly cytostatics, topoisomerase inhibitors, alkylating agents, antimetabolites, anti- microtubule agents, cytotoxic antibiotics, taxanes, intercalating agents, platinum compounds, mitosis inhibitors, tyrosine kinase inhibitors; peptides and particularly peptide receptor ligands; functional building blocks for surface grafting, particularly on medical devices, nanoparticles, micelles, magnetic particles, or quantum dots; functional proteins such as antibodies, antibody fragments, nanobodies, or affibodies; pharmacokinetic modifiers and particularly albumin binders, sugars, oligo- and polysaccarides; metal-containing or metal-free compounds suitable for photodynamic therapy, specifically compounds that generate reactive oxygen species upon irradiation with light (visible or near- infrared wavelength
  • Said alkyne- or azide-containing building blocks used for CuAAC coupling to intermediates 5, 5a, 5b, 6, 6a, 6b, 7, 7a, and 7b may also be equipped with a branched linker, or a functional linker that is selectively cleaved depending on tissue-specific parameters such as presence of enzymes, pH value, oxygen partial pressure, or similar, between its alkyne moiety and the bioactive or otherwise functional part of the molecule.
  • Pharmaceutical composition of specific embodiment of the invention further provides pharmaceutical compositions comprising the radiotracer or radiopharmaceutical of the specific embodiment of the invention as described herein. Said pharmaceutical compositions further comprise one or more excipients.
  • excipients can be selected by the skilled person as appropriate in view of the intended use, type of administration, and so forth.
  • Excipients that are typically used in the pharmaceutical compositions of preferred embodiments of the specific embodiment of the present invention are buffer substances, radiolysis protection compounds, and/or stabilizers.
  • the radiotracer of the preferred aspect of the first embodiment of the specific embodiment of the present invention Ga-68-TRAP-WL12, showed a higher uptake in the tumor tissue, a markedly lower uptake in many organs, and markedly accelerated blood clearance in comparison to the prior art structures Ga-68-DOTAGA-WL12 or Cu-64-DOTAGA-WL12.
  • the conjugate compound of the first embodiment can be radiolabelled faster and the resulting radiotracer has higher molar activity than corresponding antibody-based radiotracers and their precursors.
  • the radiotracer of the first embodiment of the specific embodiment of the present invention such as Ga-68-TRAP-WL12
  • the precursor conjugate compound represent a peptide-based PD-L1 imaging agent with advantageous properties.
  • the specific embodiment of the present invention also provides the radiotracer of the first embodiment of the specific embodiment of the present invention for use in the imaging of cells carrying PD-L1. Said imaging can be accomplished using Positron Emission Tomography (PET), single-photon emission computed tomography (SPECT), or planar scintigraphy.
  • PET Positron Emission Tomography
  • SPECT single-photon emission computed tomography
  • planar scintigraphy planar scintigraphy.
  • ICI immune checkpoint inhibitor
  • Said imaging is preferably carried out in order to assess the expression status of PD-L1 in that patient, by quantification of the uptake of the radiotracer in the tumor tissue and other tissues.
  • ICI therapy in the context of the specific embodiment of the present invention includes in particular therapy with an agent selected from pembrolizumab, nivolumab, cemiplimab, spartalizumab, atezolizumab, durvalumab, avelumab or any other substance interfering with the PD-1/PD-L1 interaction, including antibodies or small molecules, for instance as described in WO 2014/151634 A1, WO 2017/176608 A1 or WO 2018/237153 A1.
  • the cancer type that can be treated, imaged, assessed for treatment susceptibility or in any other way subjected to the uses and methods of the specific embodiment of the invention is naturally any cancer type for which ICI therapy is authorized and/or tested in clinical trials and/or otherwise published in the scientific or patent literature and/or employed in clinical practice. It includes in particular any cancer for which upregulation of PD-L1 at the surface of the cancer cells is present or at least suspected.
  • it includes in particular melanoma and especially metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, small cell lung cancer, esophageal carcinoma, malignant pleural mesothelioma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, endometrial cancer, squamous cell carcinoma, bladder cancer, breast cancer and basal cell carcinoma.
  • the specific embodiment of the invention further provides the radiotracer of the specific embodiment of the invention for use in determining susceptibility of a cancer patient for treatment with ICI therapy and especially ICI therapy addressing the PD-1/PD-L1 axis.
  • Susceptibility can be determined by a procedure comprising the following steps: (v) Administering the radiotracer to the patent. This can be done by intravenous infusion or intravenous injection. (vi) Performing a PET scan, a SPECT scan, or a scintigraphy on the patient. (vii) Comparing the quantitative uptake values obtained in said scan with reference uptake values. In particular, the signal strength in the patient scan according to (ii) may be quantified in one or more regions of interest.
  • the obtained signal strength values may then be compared with reference values, and preferably reference values for the same regions of interest, that are predetermined such that similar or higher signal strengths are indicative of susceptibility for ICI treatment.
  • the reference value is to be determined empirically for a particular radiotracer of interest, based on measurements with cancer patients for which susceptibility (or non- susceptibility) for ICI treatment is known.
  • Confirming susceptibility for ICI treatment if the signal strength of the patient’s scan in at least one region of interest is equal or higher than that of the reference scan in the same region.
  • susceptibility for ICI treatment may be confirmed if the quantified signal strength value of the patient’s scan in at least one region of interest is equal or higher than that of the reference scan in the same region.
  • the radiotracer administered in step (i) is a radiotracer based on a conjugate compound of the first embodiment according to Formula 1 or 3, and preferably Formula 1a, 1b, 1c, 1d, 3a, or 3b, and a radionuclide selected from 68 Ga, 66 Ga, 64 Cu, Al 18 F or a radiotracer based on a conjugate compound of the second embodiment according to Formula 2 or 4, and preferably Formula 2a, 2b, 2c, 2d, 4a, or 4b, and a radionuclide selected from Al 18 F, 43 Sc or 44 Sc, and step (ii) is carried out by performing a PET scan.
  • the radiotracer administered in step (i) is a radiotracer based on a conjugate compound of the first embodiment according to Formula 1 or 3, and preferably Formula 1a, 1b, 1c, 1d, 3a, or 3b, and a radionuclide selected from 67 Ga or 99m Tc or a radiotracer based on a conjugate compound of the second embodiment according to Formula 2 or 4, and preferably Formula 2a, 2b, 2c, 2d, 4a, or 4b, and a radionuclide selected from 111 In, 155 Tb or 99m Tc, and step (ii) is carried out by performing a SPECT scan or scintigraphy.
  • the dose of the radiotracer is not particularly limited.
  • Step (ii) is typically started to be carried out 15-90 min after step (i), preferably 30-60 min after completion of step (i).
  • the specific embodiment of the present invention provides the radiotracer of the specific embodiment of the invention for use in a method of treating cancer patients with ICI therapy and especially ICI therapy addressing the PD-1/PD-L1 axis.
  • This method comprises the following steps: a first step of determining susceptibility of a cancer patient for treatment with ICI therapy as specified above; a second step of administering treatment involving an immune checkpoint inhibitor only if susceptibility of the cancer patient for treatment with ICI therapy has been confirmed in the first step.
  • Further applications of the radiotracers of the specific embodiment of the present invention are for use in monitoring efficacy of anticancer therapy. This use involves carrying out the above steps (i) and (ii) one or more times after initiation of anticancer therapy.
  • the obtained scan images may then be compared to determine that (d) disease has progressed in spite of the anticancer treatment if the detected tissue with upregulation of PD-L1 increases during therapy in terms of volume and/or signal intensity; (e) there is disease remission if the detected tissue with upregulation of PD-L1 decreases during therapy in terms of volume and/or signal intensity; or (f) disease is stable if there is no clear trend in the images or quantitative data derived therefrom.
  • the conjugate compound of Formula 1 or 3 and preferably Formula 1a, 1b, 1c, 1d, 3a, or 3b forms a chelate complex with 68 Ga.
  • this aspect of the first embodiment of the specific embodiment of the present invention provides the uses for imaging PD-L1 expression, determining susceptibility of a cancer patient for treatment with ICI therapy, monitoring efficacy of anticancer therapy and use in a method of treating cancer patients with ICI therapy as described above.
  • the conjugate compound of Formula 1 or 3, and preferably Formula 1a, 1b, 1c, 1d, 3a, or 3b forms a chelate complex with 64 Cu, Al 18 F or 66 Ga.
  • these 64 Cu, Al 18 F or 66 Ga-containing radiotracers are also positron emitters and may therefore be used as peptide-based PD-L1 imaging agents as described above for the first embodiment of the specific embodiment of the invention.
  • this aspect of the first embodiment of the specific embodiment of the present invention provides the same uses for imaging PD-L1 expression, determining susceptibility of a cancer patient for treatment with ICI therapy, monitoring efficacy of anticancer therapy and use in a method of treating cancer patients with ICI therapy as described above, the sole difference being the use of the 64 Cu-, Al 18 F- or 66 Ga-containing radiotracers of the first embodiment.
  • the conjugate compound of Formula 2 or 4 forms a chelate complex with Al 18 F, 43 Sc or 44 Sc.
  • Al 18 F, 43 Sc or 44 Sc-containing radiotracers are also positron emitters and may therefore be used as peptide-based PD-L1 imaging agents in the same manner as described above for the first embodiment of the specific embodiment of the invention.
  • this aspect of the second embodiment of the specific embodiment of the present invention provides the same uses for PET-based imaging PD-L1 expression, determining susceptibility of a cancer patient for treatment with ICI therapy, monitoring efficacy of anticancer therapy and use in a method of treating cancer patients with ICI therapy as described above for the first embodiment, the sole difference being the use of the Al 18 F, 43 Sc-or 44 Sc-containing radiotracers together with the conjugate compound of the second embodiment.
  • the conjugate compound of Formula 1 or 3 and preferably Formula 1a, 1b, 1c, 1d, 3a, or 3b forms a chelate complex with 67 Ga or 99m Tc.
  • These 67 Ga or 99m Tc-containing radiotracers are gamma emitters and may therefore be used as a peptide-based PD-L1 imaging agent in the same manner as described above for the radiotracer of the first embodiment of the specific embodiment of the invention, with the difference being that imaging is done by SPECT or planar scintigraphy.
  • this aspect of the first embodiment of the specific embodiment of the present invention provides the same uses for imaging PD-L1 expression, determining susceptibility of a cancer patient for treatment with ICI therapy, monitoring efficacy of anticancer therapy and use in a method of treating cancer patients with ICI therapy as described above, the sole difference being the use of the 67 Ga- or 99m Tc-containing radiotracer of the first embodiment as well as the use of SPECT or planar scintigraphy.
  • the conjugate compound of Formula 2 or 4 and preferably Formula 2a, 2b, 2c, 2d, 4a, or 4b, forms a chelate complex with 111 In, 155 Tb, or 99m Tc.
  • These 111 In, 155 Tb, or 99m Tc-containing radiotracers are gamma emitters and may therefore be used as a peptide-based PD-L1 imaging agent in the same manner as described above for the radiotracer of the first embodiment of the specific embodiment of the invention, with the difference being the use of the conjugate compound of the second embodiment and that imaging is done by SPECT or planar scintigraphy.
  • this aspect of the second embodiment of the specific embodiment of the present invention provides the same uses for imaging PD-L1 expression, determining susceptibility of a cancer patient for treatment with ICI therapy, monitoring efficacy of anticancer therapy and use in a method of treating cancer patients with ICI therapy as described above for the first embodiment, the sole difference being the use of the 111 In, 155 Tb, or 99m Tc-containing radiotracers of the second embodiment.
  • the conjugate compound of Formula 1 or 3, and preferably Formula 1a, 1b, 1c, 1d, 3a, or 3b forms a chelate complex with 67 Cu, or another suitable metal ion radionuclide that emits alpha- or beta radiation, to provide a radiopharmaceutical having therapeutic utility.
  • the radiopharmaceutical of this further aspect of the first embodiment is suitable for use in the treatment of cancer patients and especially patients having cancer that is associated with a high level of PD-L1 expression. Said treatment involves the administration of the radiopharmaceutical to the cancer patient.
  • the conjugate compound of Formula 2 or 4, and preferably Formula 2a, 2b, 2c, 2d, 4a, or 4b forms a chelate complex with 47 Sc, 90 Y, 149 Tb, 161 Tb, 177 Lu, 212 Pb, 212 Bi, 213 Bi, 225 Ac, 227 Th, or another suitable metal ion radionuclide that emits alpha- or beta radiation, to provide a radiopharmaceutical having therapeutic utility. That is, the radiopharmaceutical of this further aspect of the second embodiment is suitable for use in the treatment of cancer patients and especially patients having cancer that is associated with a high level of PD-L1 expression.
  • Said treatment involves the administration of the radiopharmaceutical to the cancer patient.
  • the cancer types that can be treated are as defined above and they are preferably selected from the above-mentioned list.
  • the individual patient’s susceptibility for treatment with the radiopharmaceuticals of this further aspect of the first or second embodiment can be determined using the radiotracer of the first or second embodiment, i.e., the radiotracers containing Al 18 F, 43 Sc, 44 Sc, 64 Cu, 66 Ga, 67 Ga, 68 Ga, 111 In, 155 Tb, or 99m Tc as described hereinabove, and applying the method described above for the first embodiment.
  • the above-mentioned therapeutic use of the radiopharmaceutical of this further aspect of the first and second embodiments comprises a first step, in which the patient’s susceptibility is determined as described hereinabove, and a second step in which the radiopharmaceutical of this further aspect of the first or second embodiment is administered to the patient.
  • the above descriptions of the radiotracers and/or radiopharmaceuticals of the specific embodiment of the invention for use in various methods, and especially imaging methods, methods for determining treatment susceptibility, methods for monitoring treatment efficacy, therapeutic methods, and the like are also to be understood as descriptions of the respective methods as such.
  • Formula 4 wherein in each of Formula 0, Formula 1, Formula 2, Formula 3 and Formula 4, if present, FM represents a functional moiety selected from imaging-active moieties and therapeutically-active moieties; i can adopt 0 or 1;
  • A represents a group selected from *–(CH 2 ) n -**, *–(CH 2 CH 2 O) m -(CH 2 ) p -** or *–(OCH 2 CH 2 ) m -**, wherein * indicates the position of binding to the moiety at the left-hand-side of Formula 0, 1 or 2 above, and ** indicates the position of binding to B;
  • B represents a group selected such that the moiety A-B-C is C represents a group selected from ⁇ –(CH2)n’- ⁇ , ⁇ –(CH2CH2O)m’- ⁇ or ⁇ -(CH2)p’–(OCH2CH2)m’- ⁇ , wherein ⁇ indicates the position of binding to B and ⁇ indicates the position of binding to
  • the radiotracer according to embodiment 3 comprising the conjugate compound or pharmaceutically acceptable salt thereof of embodiment 1 or 2 having a Formula 2, 2a, 2b, 2c or 2d and a radionuclide selected from Al 18 F, 43 Sc, 44 Sc, 99m Tc, 111 In, and 155 Tb. 6.
  • Radiopharmaceutical comprising the conjugate compound or pharmaceutically acceptable salt thereof of embodiment 1 or 2 and a metal ion radionuclide that emits alpha- or beta radiation.
  • the radiopharmaceutical according to embodiment 6 comprising the conjugate compound or pharmaceutically acceptable salt thereof of embodiment 1 or 2 having a Formula 1, 1a, 1b, 1c or 1d and 67 Cu. 8.
  • the radiopharmaceutical according to embodiment 6 comprising the conjugate compound or pharmaceutically acceptable salt thereof of embodiment 1 or 2 having a Formula 2, 2a, 2b, 2c or 2d and a radionuclide selected from 47 Sc, 90 Y, 149 Tb, 161 Tb, 177 Lu, 212 Pb, 212 Bi, 213 Bi, 225 Ac, or 227 Th.
  • Pharmaceutical composition comprising either the radiotracer of any one of embodiments 3, 4 or 5 or alternatively the radiopharmaceutical of any one of embodiments 6, 7 or 8, together with one or more excipients, preferably including one or more excipients selected from buffer substances, radiolysis protection compounds, and stabilizers. 10.
  • the radiotracer according to embodiments 3, 4 or 5 or the radiotracer-containing pharmaceutical composition of embodiment 9 for use in a method of treating cancer patients comprising: a first step of determining susceptibility of a cancer patient for treatment with immune checkpoint inhibitors using the radiotracer of embodiments 3, 4 or 5 or the radiotracer-containing pharmaceutical composition of embodiment 9; and a second step of administering treatment involving an immune checkpoint inhibitor only if susceptibility of the cancer patient for treatment with ICI therapy has been confirmed in the first step.
  • the radiopharmaceutical according to embodiments 6, 7 or 8 or the radiopharmaceutical- containing pharmaceutical composition of embodiment 9 for use in a method of treating cancer patients. 15.
  • Cu(OAc)2 ⁇ H2O, 4-pentynoic acid, diisopropylamine (DIPEA) and sodium ascorbate were purchased from Sigma Aldrich (Darmstadt, Germany).
  • 1,4,7- triazacyclononane-1,4,7-triacetic acid (NOTA) was purchased from Macrocyclics, Inc. (Plano, Texas, USA).
  • HATU was obtained from Bachem Holding AG (Bubendorf, Switzerland).
  • WL12 was purchasd from CPC Scientific Inc. (Sunnyvale, CA, USA). The structure of the employed TRAP-alkyne is shown below.
  • Example 2 Experimental procedures for assessment of compound Metal complexation and Radiochemistry Radiometal incorporation and radiochemical purity of labeled compounds was determined by radio-TL on ITLC silica impregnated chromatography paper (Agilent, Santa Clara, USA; eluents: 0.1 M trisodium citrate or a 1:1 (v/v) mixture of 1 M ammonium acetate and methanol), analyzed using a scan-RAM radio-TLC detector by LabLogic systems Inc. (Brandon, USA).
  • 68 Ga-labelling was performed using a fully-automated on-site system (GallElut + by Scintomics, Lindach, Germany) as described previously.[7] Briefly, t * 68 Ge/ 68 -Ga *with SnO 2 matrix (by IThemba LABS, SA; 1.25 mL, eluent: 1 M aq. HCl, containing approx. 500 MBq 68 Ga) was adjusted to pH 2 by addition of aq. HEPES buffer (450 ⁇ L, 2.7 M) and applied for labeling of 5 nmol of TRAP-WL12 for 2 min at 95 °C.
  • aq. HEPES buffer 450 ⁇ L, 2.7 M
  • the radiolabeled peptides were trapped on -SepPak ® C8 light solid phase extraction (SPE) cartridges, which were purged with water (10 mL). The product was eluted with 2 mL aq. EtOH (50%). After evaporation of the ethanol, the labeling efficiency was determined by radio-TLC and was always found to be ⁇ 98%. Determination of log D value For the determination of n-octanol-PBS distribution coefficients (log D7.4), 500 ⁇ L 1-octanol and 500 ⁇ L phosphate buffered saline were combined in a 1.5 mL Eppendorf tube.
  • mice 6- to 10-wk-old female CB17 severe combined immunodeficiency mice (Charles River) were inoculated with 5 ⁇ 10 6 MDA-MB-231 cells in Matrigel (CultrexBME, type 3 PathClear; Trevigen, GENTAUR GmbH). Mice were used for biodistribution or PET studies when tumors had grown to a diameter of 10–14 mm (10–14 wk after inoculation). PET imaging Mice were anaesthesized with isoflurane for intravenous administration of Ga-68-TRAP-WL12. The administered activity per mouse ranged between 12–16 MBq (200–400 pmol, depending on variations in timing of production and administration).
  • PET imaging was performed on a Siemens Inveon small- animal PET system, either dynamic under isoflurane anaesthesia for 90 min, or as single frames 60 or 120 min p.i. with an acquisition time of 15 min. Data were reconstructed using Siemens Inveon Research Workspace software, employing a three-dimensional ordered subset expectation maximum (OSEM3D) algorithm without scatter and attenuation correction. For kinetic analyses, regions of interest (ROIs) were defined manually. Biodistribution For biodistribution studies, 3–6 MBq (between 70–180 pmol) of 68 Ga-TRAP-WL12 was injected into the tail vein. The mice were sacrificed 60 or 120 min after injection, a blood sample was taken and the organs of interest were dissected.
  • OEM3D ordered subset expectation maximum
  • Example 3 Results of testing The biodistribution of Ga-68-TRAP-WL12 in SCID mice bearing subcutaneous xenografts of the PD- L1 expressing MDA-MB231 human mamillary carcinoma cell line (see) shows highest uptake in the tumor (apart from the excretion-related precence of activity in the kidneys). Tumor uptake is blockable, indicating target specificity.
  • PET images of MDA-MB231 tumor xenografted mice with Ga-68-TRAP-WL12 as the radiotracer show that the tumor is clearly delineated. Focal uptakes are observed in the kidneys and urinary bladder due to renal excretion, and in the liver due to unspecific accumulation. Because of clearance from the non-target tissues, tumor delineation and image contrast are improved at 120 min p.i. as compared to 60 min p.i..
  • Ga-68-TRAP-WL12 compare favourably to the previously published gallium-68 labelled derivative of WL12, Ga-68-DOTAGA-WL12.[4]
  • the intention of the replacement of the DOTAGA with the TRAP chelator for gallium-68 complexation was to increase the hydrophilic character of the resulting radiopharmaceutical.
  • a lower extent of excretion via the hepatobiliary pathway and a higher fraction via the renal route was expected.
  • a more rapid blood clearance was furthermore expected to result in a lower uptake in all tissues, including the tumor.
  • Figure 5(A) (left), all non-target-related uptakes (except kidneys) indeed were reduced.
  • Ga-68-TRAP-WL12 appears to be more useful for in-vivo imaging of PD-L1 expression, and hence represents a PD-L1 imaging agent with markedly improved market potential.

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Abstract

La présente invention concerne des composés conjugués ainsi que des radiotraceurs et des produits radiopharmaceutiques les comprenant ainsi que leur utilisation dans l'imagerie de l'expression de PD-L1. Ceci permet de déterminer si un traitement par une thérapie par inhibiteur de point de contrôle immunitaire est appropriée pour un patient d'intérêt. L'invention concerne également des compositions pharmaceutiques, un kit, des méthodes de traitement ainsi que des procédés de synthèse.
PCT/EP2024/076472 2023-09-20 2024-09-20 Peptides fonctionnalisés pour l'adressage in vivo de l'expression de pd-l1 Pending WO2025061971A1 (fr)

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WO2014151634A1 (fr) 2013-03-15 2014-09-25 Bristol-Myers Squibb Company Inhibiteurs macrocycliques des interactions protéine-protéine pd-1/pd-l1 et cd80(b7-1)/pd-l1
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