WO2025061801A1 - Combinaison thérapeutique d'une protéine de fusion il2 ou il12 d'anticorps du domaine de la fibronectine anti-edb et d'un radioconjugué lutétium-177 - Google Patents

Combinaison thérapeutique d'une protéine de fusion il2 ou il12 d'anticorps du domaine de la fibronectine anti-edb et d'un radioconjugué lutétium-177 Download PDF

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WO2025061801A1
WO2025061801A1 PCT/EP2024/076164 EP2024076164W WO2025061801A1 WO 2025061801 A1 WO2025061801 A1 WO 2025061801A1 EP 2024076164 W EP2024076164 W EP 2024076164W WO 2025061801 A1 WO2025061801 A1 WO 2025061801A1
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combination
dosage form
antibody
interleukin
conjugate
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Samuele CAZZAMALLI
Andrea Galbiati
Aureliano ZANA
Matilde BOCCI
Tony Georgiev
Ettore GILARDONI
Dario Neri
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Philochem AG
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Philochem AG
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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
    • A61K47/6801—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
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
    • 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
    • A61K47/6843—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 material from animals or humans
    • 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
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • 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
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5434—IL-12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Definitions

  • the invention relates to the field of immunoconjugates.
  • Cytokines are key mediators of innate and adaptive immunity. Many cytokines have been used for therapeutic purposes in patients with advanced cancer, but their administration is typically associated with severe toxicity, hampering dose escalation to therapeutically active regimens and their development as anticancer drugs. To overcome these problems, the use of ‘immunocytokines’ (i.e. cytokines fused to antibodies or antibody fragments) has been proposed, with the aim to concentrate the immune-system stimulating activity at the site of disease while sparing normal tissues (Neri & Bicknell, 2005). However, genetically fusing a cytokine to an antibody or to an antibody fragment creating an “immunocytokine”, does not always result in an immunocytokine that retains the ability to target the tumor of the antibody.
  • immunocytokine i.e. cytokines fused to antibodies or antibody fragments
  • Interleukin-2 is a four a helix bundle cytokine produced by T helper 1 cells and plays an essential role in the activation phases of both specific and natural immune responses.
  • IL2 promotes proliferation and differentiation of activated T and B lymphocytes and of natural killer (NK) cells and induces cytotoxic T cell (CTL) activity and NK/lymphokine-activated killer (LAK) cell antitumor cytotoxicity.
  • CTL cytotoxic T cell
  • LAK NK/lymphokine-activated killer
  • IL2 has been approved for the treatment of several human cancers.
  • Administration of recombinant IL2 (rIL2) alone or in combination with adoptively transferred lymphoid cells has been shown to result in the regression of established tumors in both animal models and patients.
  • the in vivo therapeutic efficacy of IL2 is limited by its rapid clearance and, at high doses severe toxicity mainly related to a vascular leak syndrome.
  • Interleukin- 12 is a heterodimeric cytokine with multiple biological effects on the immune system. It is made up of two subunits, p35 and p40, both of which are required for the secretion of the active form of IL12, p70. Interleukin- 12 acts on dendritic cells (DC), leading to increased maturation and antigen presentation, which can allow for the initiation of a T cell response to tumor specific antigens. It also drives the secretion of IL12 by DCs, creating a positive feedback mechanism to amplify the response.
  • DC dendritic cells
  • IL12 plays a fundamental role in directing the immune system towards a Thl cytokine profile, inducing CD4+ T cells to secrete interferon-gamma (IFN-y) and leading to a CD8+ cytotoxic T cell response.
  • IFN-y interferon-gamma
  • IL12 is also a strong pro-inflammatory cytokine that leads to the secretion of other cytokines including tumor necrosis factor-alpha (TNF-a) which, combined with IFN-y, is a prerequisite for the development of CD4+ cytotoxic T lymphocytes (CTL).
  • TNF-a tumor necrosis factor-alpha
  • CTL cytotoxic T lymphocytes
  • IL12 can promote the activation of innate immune cells such as macrophages and eosinophils through its induction of IFN-y and other cytokines. This activation then leads to IL12 secretion by these cells and further amplification of both the innate and acquired responses.
  • high levels of IL12, and consequently IFN-y have also been associated with induction of antagonistic molecules such as IL-10 and the depletion of signaling molecules downstream of IL12, such as STAT4.
  • IL2 or IL12 delivery of IL2 or IL12 to the tumor site by means of an antibody directed against tumor-associated marker to increase local concentrations of IL2 or IL12 at the tumour site, as well as reduce toxicities associated with systemic administration of IL2 or IL12 has been proposed.
  • concentration of cytokines at the level of tumour blood vessels is an attractive therapeutic strategy as the tumour neovasculature is more accessible to intravenously administered therapeutic agents than tumour cells, which helps avoid problems associated with the interstitial hypertension of solid tumours.
  • angiogenesis is characteristic of most aggressive solid tumours. Angiogenesis describes the growth of new blood vessels from existing blood vessels.
  • Tumours can induce angiogenesis through secretion of various growth factors (e.g. Vascular Endothelial Growth Factor).
  • Tumour angiogenesis allows tumours to grow beyond a few millimetres in diameter and is also a prerequisite for tumour metastasis.
  • New blood vessels formed as the result of angiogenesis form the neovasculature of the tumour or the tumour metastases.
  • Targeting IL2 or IL 12 to the neovasculature should allow the immunotherapy of a variety of different tumour types.
  • ED-B extra domain B of fibronectin
  • ED-B extra domain B of fibronectin
  • WO2011/015333 described treating leukaemia, including acute myeloid leukaemia, by targeting the bone marrow neovasculature.
  • immunocytokines based on LI 9 are currently being investigated in Phase I, Phase II and Phase III clinical trials in patients with cancer. These immunocytokines include several cytokines, comprising IL2 or IL 12.
  • Fig. 2 The tolerability of the different treatments reported in Fig. 1 was assessed by the evaluation of changes (%) in body weight during the experiment in mice bearing SK-RC- 52.hFAP tumors.
  • Fig. 3 The therapeutic activity of 177Lu-ESV6-DOTAGA, 177Lu-Bi-ESV6-DOTAGA, L19- IL2, 177Lu-ESV6-DOTAGA + L19-IL2, 177Lu-Bi-ESV6-DOTAGA + L19-IL2 or saline was further confirmed in a second tumor model.
  • Fig. 4 Volcano plots representing up- and down-regulated proteins for each treatment group compared the treatment with saline in the HT-1080.hFAP tumor model.
  • A. Treatment with 177Lu-Bi-ESV6-DOTAGA resulted in the identification of 1 statistically significant down- regulated protein and 8 statistically significant up-regulated proteins.
  • B. Treatment with L19- IL2 resulted in the identification of 179 statistically significant down-regulated proteins and 178 statistically significant up-regulated proteins.
  • C. Treatment with “177Lu-Bi-ESV6- DOTAGA + L19-IL2” resulted in the identification of 634 statistically significant down- regulated proteins and 804 statistically significant up-regulated proteins.
  • Fig. 5 Specific protein intensities expressed as relative abundance compared the saline group in the HT-1080.hFAP tumor model.
  • FAP Fibroblast Activation Protein
  • CAIX Carbonic Anhydrase IX
  • A-B Expression of proteins involved in NK cells activity as Perforin- 1 (C) and different Granzymes (G).
  • C Perforin- 1
  • G Granzymes
  • D immune cells chemotactic protein pro-IL16
  • marker of lymphatic cells as B
  • marker of macrophages CD68 F.
  • Data are reported as mean ⁇ SEM.
  • Fig. 6 Ex vivo immunofluorescence analysis on SK-RC-52.hFAP tumor sections following administration of vehicle (saline), 177Lu-Bi-ESV6-DOTAGA (250 nmol/kg, 250 MBq/kg), L19-IL2 (2.5 mg/kg), or 177Lu-Bi-ESV6-DOTAGA (250 nmol/kg, 250 MBq/kg) + L19-IL2 (2.5 mg/kg) or with the schedule indicated in Figure 1.
  • Fig. 6 A Original color reproduction.
  • Fig. 6B Grey scale reproduction of the NKp46 staining only.
  • Fig. 6C Grey scale reproduction of the DAPI staining only.
  • Fig. 7 Radio-HPLC profile of 177Lu-PSMA-617 after radiolabelling.
  • Fig. 8 In vivo therapy experiment with 177Lu-PSMA-617 (black arrow) and L19-IL2 (white arrows) in Balb/c nude mice bearing HT-1080.hPSMA xenografts.
  • Graph (A) compares the therapeutic activity of the single agent (L19-IL2 or 177Lu-PSMA-617), combination, and vehicle groups.
  • Graph (B) outlines the percentage change in body weight over the course of the experiment. The study was performed with randomized groups of 4 tumor-bearing mice.
  • Fig. 9 A. Volcano plot representing the up- and down- regulated proteins in comparison with the vehicle treatment in the HT-1080.hPSMA tumor model treated with L19-IL2, 177Lu- PSMA-617, or the combination of the two.
  • Fig. 10 In vivo therapy experiment with 177Lu-PSMA-617 (black arrow) and L19-murineIL12 (grey arrows) in C57BL/6J mice bearing MC38.hPSMA tumors.
  • the graph compares the therapeutic activity of the single agent (L19-murineIL12 or 177Lu-PSMA-617), the combination of the two, and the vehicle groups.
  • the combination with L19-murineIL12 strongly potentiates the in vivo anti-cancer activity of 177Lu-PSMA-617.
  • Fig. 11 A. Volcano plot representing the up- and down- regulated proteins in comparison with the vehicle treatment in the MC38.hPSMA tumor model treated with L19-murineIL12, 177Lu- PSMA-617, or the combination of the two.
  • compositions comprising LI 9-IL2 or L19- IL12 in combination with Lutetium 177-labelled radioconjugates.
  • a pharmaceutical composition comprising
  • interleukin-2 IL2
  • interleukin- 12 IL 12
  • Lutetium 177 is a gamma and beta emitter with a half-life of 6.7 days and low energy beta- particles emissions with a mean range of 0.7 mm and maximum range of 2.1 mm in soft tissue. It finds application in several therapies, most notably radiolabelled somatostatin analogues for neuroendocrine tumors and PMSA-ligands prostate cancer and it is particularly suitable for radiolabelling of biologically active tracer molecules.
  • interleukin-2 IL2
  • interleukin- 12 IL 12
  • an antibody binding the extra-domain B ED-B
  • fibronectin or a target binding fragment or derivative thereof, which antibody or fragment or derivative comprises a set of three heavy chain and three light chain complementarity determining regions (CDR) as set forth in SEQ ID NOs 7-12, and
  • PSMA-617 a human prostate-specific membrane antigen (PSMA)-targ eting ligand, conjugated to the beta-emitting radioisotope Lutetium 177, and has antineoplastic activity against PSMA-expressing tumor cells.
  • PSMA prostate-specific membrane antigen
  • the conjugate Upon intravenous administration of lutetium, the conjugate targets and binds to PSMA-expressing tumor cells. Upon binding, the PSMA expressing cells are destroyed by Lutetium 177 through the specific delivery of beta particle radiation.
  • the inventors have found that the two components given together are better tolerated in terms of body weight change, than the single agents.
  • the inventors have found that the recombinant protein comprising interleukin-2 (IL2) or interleukin- 12 (IL 12) and an antibody binding the extra-domain B (ED- B) and a conjugate radiolabelled with 177Lutetium given together activate the immune system better than the recombinant protein comprising interleukin-2 (IL2) or interleukin- 12 (IL 12) and an antibody binding the extra-domain B (ED-B) of fibronectin alone.
  • IL2 interleukin-2
  • ED- B antibody binding the extra-domain B
  • CDR complementarity determining regions
  • a dosage form comprising
  • interleukin-2 IL2
  • interleukin- 12 IL 12
  • a combination comprising at least
  • interleukin-2 IL2
  • interleukin- 12 IL 12
  • kits of dosage forms comprising at least:
  • Darleukin is an antibody-cytokine fusion protein consisting of a singlechain Fv (scFv) antibody fragment directed against the extra-domain B (ED-B) of fibronectin, called LI 9, and human IL-2.
  • the antibody binds to the tumor and deliver IL-2 into the tumor vasculature and microenvironment, thereby directly stimulating immune effector cells at the tumor site.
  • Interleukin-2 IL2
  • L19-IL12 is disclosed in WO2019/154986 by the current applicants, the content of which is incorporated herein by reference in its entirety, and has been tested in a variety of therapeutic regimens, modalities, molecular formats and combinations for treatment of different types of cancer. These embodiments are disclosed in inter alia in WO2021/209452, WO2023/131611 the content of which is incorporated herein by reference in its entirety, with good results.
  • the complete amino acid sequence of L19-IL12 is given in SEQ ID NO: 14.
  • the complete amino acid sequence of L19-murineIL12 used in the examples below is given in SEQ ID NO: 15.
  • Example 1 Therapy Studies in mice on SK-RC-52.hFAP cancer model
  • mice were treated with SK-RC-52.hFAP (cancer cells expressing FAP) in mice.
  • SK-RC-52.hFAP cells were grown to 80% confluence in RPMI-1640 medium with 10% fetal bovine serum (FBS) and 1% antibiotic-antimycotic and detached with Trypsin-EDTA (ethylenediaminetetraacetic acid) 0.05%. Tumour cells were resuspended in Hanks’ Balanced Salt Solution medium. Aliquots of 5 million cells (100 pL of suspension) were injected subcutaneously in the right flank of female athymic Balb/c AnNRj-Foxnl mice (6 to 8 wk of age).
  • FBS fetal bovine serum
  • Trypsin-EDTA ethylenediaminetetraacetic acid
  • Radiolabeling of ESV6-DOTAGA and Bi-ESV6-DOTAGA with lutetium- 177 was performed as follows: precursors (25 nmol) were dissolved in 25 pL of milliQ water, then sodium acetate buffer (75 pL, 1 M in water, pH 4.5) and 25 MBq of 177Lu solution were added. The mixture was heated at 90°C for 1 minutes followed by dilution with 400 pL of PBS to afford a final volume of 500 pL (5 doses of 100 pL each). Quality control of radiosynthesis was performed using radio-HPLC.
  • the anti-cancer efficacy of 177Lu-ESV6-DOTAGA, 177Lu-Bi-ESV6-DOTAGA, L19-IL2 and of the combinations 177Lu-ESV6-DOTAGA + L19-IL2 and 177Lu-Bi-ESV6-DOTAGA + L19-IL2 was assessed in athymic Balb/c AnNRj-Foxnl mice bearing SK-RC-52.hFAP tumor in the right flank.
  • HT-1080.hFAP cells were grown to 80% confluence in DMEM with 10% fetal bovine serum (FBS) and 1% antibiotic-antimycotic and detached with Trypsin-EDTA (ethylenediaminetetraacetic acid) 0.05%. Tumour cells were resuspended in Hanks’ Balanced Salt Solution medium. Aliquots of 2 million cells (50 pL of suspension) were injected subcutaneously in the right shoulder of female athymic Balb/c AnNRj-Foxnl mice (6 to 8 wk of age).
  • FBS fetal bovine serum
  • Trypsin-EDTA ethylenediaminetetraacetic acid
  • Radiolabeling of ESV6-DOTAGA and Bi-ESV6-DOTAGA with lutetium- 177 was performed as follows: precursors (-650 nmol) were dissolved in 34.3 mL of sodium acetate buffer (34.3 mL, 0.5 M in water, pH 5.2), then 700 pL of a sterile filtered ascorbic acid solution (250 g/L in ultrapure water) were added. 700 pL of above solutions were separately added to 1 GBq of 177LUC13. The mixture was heated to 90°C for 20 min. After cooling, radiochemical purity was verified by radio-HPLC to confirm complete Lutetium- 177 incorporation.
  • the anti-cancer efficacy of 177Lu-ESV6-DOTAGA, 177Lu-Bi-ESV6-DOTAGA, L19-IL2 and of the combinations 177Lu-ESV6-DOTAGA + L19-IL2 and 177Lu-Bi-ESV6-DOTAGA + L19-IL2 was assessed in athymic Balb/c AnNRj-Foxnl mice bearing HT-1080.hFAP tumor in the right shoulder.
  • 177Lu-ESV6-DOTAGA and of 177Lu-Bi-ESV6-DOTAGA as monotherapy or administered in combination with L19-IL2 was assessed in mice bearing HT- 1080.hFAP tumors on the right flank ( Figure 3).
  • Systemic administration of 177Lu-ESV6- DOTAGA and of 177Lu-Bi-ESV6-DOTAGA (5 MBq/mouse, 250 nmol/kg) and of L19-IL2 (2.5 mg/kg) resulted in selective and potent anti-cancer activity against the growth of HT- 1080.
  • hFAP as compared to mice injected with saline.
  • L19-IL2 potently synergizes with radioligand therapeutics (177Lu-ESV6-DOTAGA and 177Lu-Bi-ESV6-DOTAGA).
  • the most active treatment in the therapy study was 177Lu-Bi-ESV6-DOTAGA in combination with LI 9- IL2, which showed superior anti-cancer activity compared to monotherapies based on single agents (177Lu-Bi-ESV6-DOTAGA at 5 MBq/mouse, or L19-IL2 at 2.5 mg/kg). All mice administered with 177Lu-Bi-ESV6-DOTAGA + L19-IL2 were cured after treatment.
  • Samples were homogenized with a tissue lyser (TissueLyser II, QIAGEN) for 1 minutes at 30 Hz two times at 4 °C. The homogenised samples were sonicated for 2 minutes at 50 % intervals and 36 % intensity. After sonication samples were centrifugated for 10 minutes at 15000 g and protein concentration of the supernatant was measured with BCA kit following kit instructions.
  • Ionization was carried out in positive ion mode, with 2 kV of spray voltage, 250 °C of capillary temperature, 60 S-lens RF level.
  • the mass spectrometer was working in a data-dependent mode. MS 1 scan range was set from 350 to 1650 m/z, the 10 most abundant peptides were subjected to HCD fragmentation with NCE of 25. A dynamic exclusion was set at 20 seconds.
  • Raw files were processed with Proteome Discoverer 2.5 (Thermo Fisher) for quantitative analysis.
  • Figure 6B shows only the NKp46 staining.
  • NKp46 stains NK cells. It can be seen how the staining increases for the treatment with 177Lu-Bi-ESV6-DOTAGA and L19-IL2.
  • Figure 6C shows only the DAPI staining. As DAPI stains cell nuclei, one can appreciate nuclei, how the treatment with 177Lu-Bi-ESV6-DOTAGA and L19-IL2 or with L19-IL2 alone results in a reduction of the size of the nuclei, which means less tumor cells and more NK-cells.
  • PSMA-617 (10 mL, ImM solution in mQ Water, 2% DMSO, 10 nmol) was added to a 1.5 mL Eppendorf tube and diluted with IM NaOAc buffer (pH 4.5, 170 mL). 177LuC13 (20 mL, aqueous solution, 50 MBq) was added, and the mixture was incubated in a thermomixer for 10 min at 95 °C. The 177Lu incorporation was followed by HPLC using a radiometric detector. Complete incorporation was afforded as evidenced by radio-HPLC analysis as shown in Figure 7.
  • HT-1080.hPSMA tumor cells were grown to 90% confluence and detached with Trypsin- EDTA 0.05%. Cells were resuspended in Hank’s Balanced Salt Solution (HBSS) at a 5 x 10 7 cells/mL density. 100 pL of HT1080.hPSMA cells (5 x 10 6 cells) were injected subcutaneously in the right flank of female athymic Balb/c AnNRj-Foxnl mice (6 to 8 weeks of age). Tumors were grown until volumes of -100 mm 3 .
  • HBSS Hank’s Balanced Salt Solution
  • mice were randomized into groups of 4 and 0.15 mL of a 6.7 pM solution (0.03% DMSO, 9% Acetate Buffer pH 4.5, PBS, 50 nmol/kg, 250 MBq/kg ) of 177Lu- PSMA-617, 0.1 mL solution of L19-IL2 (0.5 mg/mL, 2.5 mg/kg), 0.1 mL PBS solution, or 0.1 mL L19-IL2 buffer (NaH 2 PO 4 6.7 mM, NaCl 20 mM, KC1 1.8 mM, Mannitol 133 mM, Tween80 0.1% v/v, Glycerol 1% w/v) was injected intravenously (i.e., systemic administration through tail-vein) with the following schedule:
  • 177Lu-PSMA-617 group 1 injection (day 9 after tumor implantation).
  • L19-IL2 group 3 injections with a 1-day break in between (days 10, 12, and 14 after tumor implantation).
  • Combination therapy group 1 injection of 177Lu-PSMA-617 (day 9) and 3 injections of L19- IL2 with a 1-day break in between (days 10, 12, and 14 after tumor implantation).
  • Raw files were processed with Proteome Discoverer 2.5 (Thermo Fisher) for quantitative analysis.
  • Database searches were performed with Sequest as a search engine using a FASTA file containing the Mus musculus and Homo sapiens reference proteomes.
  • Carbamidomethylation of cysteines was set as a fixed modification, methionine oxidation as a variable modification, and trypsin as cleavage specificity allowing a maximum of 2 missed cleavages.
  • a rescoring of PSM was carried out with the Inferys node.
  • Data filtering was performed using a percolator, resulting in 1% false discovery rate (FDR).
  • FDR false discovery rate
  • Data mining was carried out with an in-house built Python script. Briefly, only identified and not quantified proteins were filtered out.
  • Proteins without abundance values in at least 2 replicates for at least one condition were removed. Abundances were median- normalised, NaNs were imputed to the absolute minimum and finally abundances were log2 transformed. Fold change analysis was carried out to compare protein abundances in all treatment groups against the saline. The statistical significance of the fold change was evaluated with multiple Welch t-test corrected for multiple comparisons (using the Benjamini -Hochberg correction with 5% FDR). The abundances of selected proteins involved in inflammatory and immune processes were compared among groups on the log 10 transformed protein abundances normalized on the Saline condition. Samples were analyzed in quadruplicates (2 biological plus 2 tryptic digestion replicas).
  • Figure 8A presents changes in tumor volume over the course of the combination therapy, outlining the therapeutic efficacy of 177Lu-PSMA-617 and its therapeutic synergy with L19- IL2.
  • Monotherapy with 177Lu-PSMA-617 was efficacious but did not lead to complete and long-lasting cancer regression in all treated animals, with only 1 out of 4 mice cured at the end of the experiment.
  • all mice administered with the 177Lu-PSMA-617 + L19-IL2 combination treatment showed complete responses (cancer cures) after treatment.
  • L19-IL2 single agent induced modest tumor-growth retardation.
  • Figure 8B presents body weight changes (%) of the therapy groups associated with single agent (L19-IL2 or 177Lu-PSMA-617), combination, and the vehicle-treated groups. In the combination no significant body weight loss was observed unlike in the other three arms.
  • Fig. 9A L19-IL2 and the combination therapy produce an alteration of the proteome.
  • Many proteins associated with the immune system are upregulated, highlighting the activation of the host defense mechanisms.
  • granzyme B (Gzmb), Cdl6a, Cd90, and Sppl are significantly upregulated in the combination therapy compared to the single agents alone. (Fig. 9B).
  • 177Lu-PSMA-617 was produced as described in Example 5.1
  • MC38.hPSMA tumor cells were grown to 90% confluence and detached with Trypsin-EDTA 0.05%. Cells were resuspended in Hank’s Balanced Salt Solution (HBSS) at a 5 x 10 7 cells/mL density. 100 pL of MC38.hPSMA cells (5 x 10 6 cells) were injected subcutaneously in the right flank of female C57BL/6J mice (6 to 8 weeks of age). Tumors were grown until volumes of -100 mm 3 .
  • HBSS Hank’s Balanced Salt Solution
  • - L19-murineIL12 group 3 injections with a 1-day break in between (days 6, 8, and 10 after tumor implantation).
  • - Vehicle group 4 injections of saline (day 5, 6, 8, and 10 after tumor implantation).
  • Chromatographic separation was carried out at room temperature on an Acclaim PepMap RSLC column (50 pm x 15 cm, particle size 2 pm, pore size, 100 A), using a 60 min linear gradient with 5-35% solvent B (0.1% formic acid in acetonitrile) at a flow rate of 300 nL/min. Ionization was carried out in positive ion mode, with 2 kV of spray voltage, 250 °C capillary temperature, and 60 S-lens RF level. The mass spectrometer was working in a data- dependent (DDA) top 12 mode with the following parameters: MSI scan range: from 350 to 1650 m/z, HCD NCE: 25, Dynamic exclusion: 15 sec.
  • DDA data- dependent
  • Raw files were processed with Proteome Discoverer 2.5 (Thermo Fisher) for quantitative analysis.
  • Database searches were performed with Sequest as a search engine using a FASTA file containing the Mus musculus reference proteomes.
  • Carb amidomethylation of cysteines was set as a fixed modification, methionine oxidation as a variable modification, and trypsin as cleavage specificity allowing a maximum of 2 missed cleavages.
  • a rescoring of PSM was carried out with the Inferys node.
  • Data filtering was performed using a percolator, resulting in 1% false discovery rate (FDR).
  • FDR false discovery rate
  • Data mining was carried out with an in-house built R script. Briefly, only identified and not quantified proteins were filtered out.
  • Figure 10 presents changes in tumor volume over the course of the combination therapy, outlining the therapeutic efficacy of 177Lu-PSMA-617 and its therapeutic synergy with L19- IL12.
  • Monotherapy with 177Lu-PSMA-617 induced modest tumor-growth retardation, while L19-IL12 was efficacious but did not lead to complete cancer regression.
  • mice administered with the 177Lu-PSMA-617 + L19-IL12 combination treatment showed potent responses.
  • Markers of cell apoptosis i.e., Caspl and Adamtsl4
  • immune response i.e., Cd38, Cdl80, granzyme F (Gzmf), and granzyme C (Gzmc)
  • a pharmaceutical composition comprising

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Abstract

L'invention concerne une combinaison comprenant (i) une protéine recombinante comprenant de l'interleukine-2 (IL2) ou de l'interleukine-12 (IL12) et un anticorps liant l'extra-domaine B (ED-B) de la fibronectine, ou un fragment de liaison cible ou un dérivé de celle-ci, et (ii) un conjugué radiomarqué au Lutétium-177, le conjugué en question étant 177Lu-PSMA-617, et son utilisation pour le traitement du cancer. Dans un mode de réalisation préféré, l'anticorps est L19.
PCT/EP2024/076164 2023-09-19 2024-09-18 Combinaison thérapeutique d'une protéine de fusion il2 ou il12 d'anticorps du domaine de la fibronectine anti-edb et d'un radioconjugué lutétium-177 Pending WO2025061801A1 (fr)

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