WO2019185792A1 - Traitement du cancer à l'aide d'immunoconjugués et d'inhibiteurs du point de contrôle immunitaire - Google Patents

Traitement du cancer à l'aide d'immunoconjugués et d'inhibiteurs du point de contrôle immunitaire Download PDF

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WO2019185792A1
WO2019185792A1 PCT/EP2019/057854 EP2019057854W WO2019185792A1 WO 2019185792 A1 WO2019185792 A1 WO 2019185792A1 EP 2019057854 W EP2019057854 W EP 2019057854W WO 2019185792 A1 WO2019185792 A1 WO 2019185792A1
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fibronectin
antibody
therapeutic combination
combination according
seq
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PCT/EP2019/057854
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English (en)
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Roberto DE LUCA
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Philogen S.P.A
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Priority claimed from GBGB1805138.3A external-priority patent/GB201805138D0/en
Priority claimed from GBGB1812127.7A external-priority patent/GB201812127D0/en
Application filed by Philogen S.P.A filed Critical Philogen S.P.A
Publication of WO2019185792A1 publication Critical patent/WO2019185792A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • C07K14/525—Tumour necrosis factor [TNF]
    • 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
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the present invention relates to the use of immunocytokines in combination with immune check-point inhibition to treat cancer.
  • Immune check-point inhibitors are rapidly changing the clinical management of patients with cancer [1 ,2].
  • Ipilimumab (blocking CTLA-4), Nivolumab or Pembrolizumab (blocking PD-1 ) and Avelumab (Blocking PD- L1 ) [3-6] have gained marketing authorization for the treatment of different types of malignancies, on the basis of an impressive clinical benefit offered to a subset of patients.
  • the therapeutic activity of immune check-point inhibitors often correlates with the quantity and quality of lymphocyte infiltrate into the solid tumor mass [2].
  • the nature of tumor rejection antigens presented by the tumor influences the anti-cancer activity of specific cytotoxic T cells [8,9].
  • a growing body of experimental evidence indicates that both mutational load and HLA class I genotype potently influence response to immunotherapy in patients [10]
  • various experimental strategies are under development, with the aim to turn“cold” tumors“hot”, by increasing the density of lymphocytes in the neoplastic lesions and by tilting the cytokine balance towards a more inflammatory phenotype [11].
  • cytokines e.g., IL2, TNF, IFNy
  • IL2 Treatment with recombinant IL2 mediates a long-term survival for a relatively small proportion of patients with metastatic melanoma and renal cell carcinoma [12].
  • TNF has received marketing authorization in Europe for the treatment of soft-tissue sarcoma with isolated limb perfusion procedures [13], while recombinant IFNy has been used for decades to treat various types of cancer [14].
  • the clinical use of anti-cancer cytokines is often limited to substantial toxicity (sometimes even at sub-milligram dose levels), preventing escalation to therapeutically active regimens [12-15].
  • immunomodulatory payloads In order to improve the therapeutic index of pro-inflammatory cytokines for oncological applications, the fusion of these immunomodulatory payloads with tumor-targeting monoclonal antibodies has been proposed [16-18]. Both intact immunoglobulins and antibody fragments have been used to generate fusion proteins with cytokines (“immunocytokines”). Some of these products have moved to clinical trials [19], on the basis of promising preclinical results.
  • L19-IL2 and L19-TNF Two antibody-cytokine fusion proteins (L19-IL2 and L19-TNF) are currently being investigated by the present applicant in Phase III clinical trials [EudraCT number 2015-002549-72], after having shown encouraging activity in Phase II clinical studies [20-22] These products recognize the alternatively-spliced EDB domain of fibronectin, a marker of tumor angiogenesis [23].
  • the simultaneous delivery of two cytokine payloads to the tumor environment may exhibit a synergistic anticancer effect.
  • the combination of IL2- and TNF-based immunocytokine products was able to eradicate lesions in immunocompetent mouse models [24] and to induce complete responses in patients with stage IIIB/C melanoma [22].
  • L19-TNF also known as "FIBROMUN”
  • FIBROMUN is an immunocytokine developed by the present applicant, consisting of three polypeptides each of which is composed of TNFalpha (TNFa) fused at its N-terminus, via a linker, to the C-terminus of recombinant monoclonal antibody L19.
  • L19 is an antibody molecule in the scFV format, which recognizes the alternatively spliced extra-domain B (EDB) of fibronectin (FN), a marker of tumor angiogenesis.
  • EDB extra-domain B
  • FN fibronectin
  • the construction of L19-TNF is disclosed in W001/062298. Certain formulations of L19-TNF are disclosed in WO2018/011404.
  • L19-TNF has been studied in a number of pre-clinicai models of cancer, in particular:
  • bigger tumors were studied (140 mm 3 ) two out of five mice could be cured after first intratumoral injection and five mice out of six could be cured with a second intratumoral injection.
  • the present inventors have unexpectedly recognised that immune checkpoint inhibition potentiates the anticancer properties of IL2 and TNF targeted to fibronectin as immunocytokines.
  • the present inventors have found that when L19-TNF is administered in combination with an anti-PD-1 antibody, complete eradication of large tumors (volumes up to 250 mm 3 ) in mouse models was achieved. This result is surprising because previous combinations with L19-TNF at the same dose in preclinical models did not achieve completeeradication in 100% of the mice treated.
  • a first aspect of the invention provides a therapeutic combination comprising an immune check-point inhibitor and fibronectin-targeted IL2 and/or fibronectin-targeted TNF.
  • a second aspect of the invention provides a therapeutic combination comprising an immune check-point inhibitor and an im mu noconjugate comprising tumor necrosis factor (TNF) and an anti-fibronectin antibody.
  • TNF tumor necrosis factor
  • a third aspect of the invention provides a therapeutic combination comprising an anti-PD1 antibody and an immunoconjugate comprising tumor necrosis factor (TNF) and an anti-fibronectin antibody.
  • TNF tumor necrosis factor
  • a fourth aspect of the invention provides a therapeutic combination comprising an anti-PD1 antibody and an immunoconjugate comprising tumor necrosis factor (TNF) and an anti-ED-B antibody.
  • TNF tumor necrosis factor
  • a fifth aspect of the invention provides a therapeutic combination comprising an anti-PD1 antibody and an immunoconjugate comprising tumor necrosis factor (TNF) and the L19 antibody.
  • TNF tumor necrosis factor
  • a sixth aspect of the invention provides a therapeutic combination comprising an immune check-point inhibitor and an immunoconjugate comprising interleukin 2 (IL2) and an anti-fibronectin antibody.
  • IL2 interleukin 2
  • a seventh aspect of the invention provides a therapeutic combination comprising an immune check-point inhibitor; a first immunoconjugate comprising tumor necrosis factor (TNF) and an anti-fibronectin antibody and a second immunoconjugate comprising interleukin 2 (IL2) and an anti-fibronectin antibody.
  • TNF tumor necrosis factor
  • IL2 interleukin 2
  • An eight aspect of the invention provides a therapeutic combination comprising an immune check-point inhibitor and a dual immunoconjugate comprising IL2, TNF and an anti-fibronectin antibody.
  • a ninth aspect of the invention provides a therapeutic combination comprising a PD-L1 inhibitor and a dual immunoconjugate comprising IL2, TNF and an anti-fibronectin antibody.
  • a tenth aspect of the invention provides a therapeutic combination comprising a PD-L1 inhibitor and a dual immunoconjugate comprising IL2, TNF and an anti-ED-A antibody.
  • An eleventh aspect of the invention provides a therapeutic combination comprising a PD-L1 inhibitor and a dual immunoconjugate comprising IL2, TNF and an F8 antibody.
  • a twelfth aspect of the invention provides a method of treating cancer comprising administering to an individual in need thereof a therapeutic combination according to any of the first to eleventh aspects.
  • a thirteenth aspect of the invention provides a therapeutic combination any of the first to eleventh aspects for use in a method of treating cancer, for example a method of the twelfth aspect.
  • a fourteenth aspect of the invention provides an immunoconjugate comprising TNF and an anti-fibronectin antibody for use in a method of treating cancer comprising administering said immunoconjugate in combination with a check-point inhibitor to an individual in need thereof, for example a method of the twelfth aspect.
  • a fifteenth aspect of the invention provides an immunoconjugate comprising IL2 and an anti-fibronectin antibody for use in a method of treating cancer comprising administering said immunoconjugate in combination with a check-point inhibitor to an individual in need thereof, for example a method of the twelfth aspect.
  • a sixteenth aspect of the invention provides a first immunoconjugate comprising TNF and an anti-fibronectin antibody and a second immunoconjugate comprising IL2 and an anti-fibronectin antibody for use in a method of treating cancer comprising administering said first and second immunoconjugates and a check-point inhibitor to an individual in need thereof, for example a method of the twelfth aspect.
  • a seventeenth aspect of the invention provides a dual immunoconjugate comprising TNF, IL2 and an anti- fibronectin antibody for use in a method of treating cancer comprising administering said dual
  • Figure 1 shows reagents and tumor models characterization
  • (b) Microscopic fluorescence analysis of EDA expression on CT26, WEHI-164, LLC and F9 tumor sections detected with IL2-F8-TNF mut or IL2-KSF-TNF mut (green for anti-murine IL2, Alexa Fluor 488) and anti-CD31 (red, Alexa Fluor 594), 20x magnification, scale bars 100pm.
  • Figure 2 shows therapeutic performance of ll2-F8-TNF mut in combination with anti-PD-L1 treatment.
  • Data represent mean tumor volume ⁇ SEM.
  • mice were injected three times intravenously (black arrows) every 48 hours with either PBS, IL2-F8-TNFmut, 200pg anti-mouse PD-L1 or a combination of the two (IL2-F8-TNF mut six hours before anti-PD-L1 or the opposite)
  • n 5 mice per group (unless stated elsewhere)
  • CR complete response
  • n 4 for re-challenge group
  • c Therapy in Balb/c mice bearing WEHI-164 tumors. Treatment started when tumors reached a volume of 70 mm 3 , IL2-F8-TNF mut was dosed at 20pg.
  • IL2-F8-TNF mut was dosed at 20pg.
  • IL2-F8-TNF mut was dosed at 40pg.
  • n 4 from day 15 for groups IL2-F8-TNF mut + anti-PD-L1 and PBS, from day 16 for group anti-PD-L1 and from day 20 for groups anti-PD- L1 + IL2-F8-TNF mut and IL2-F8-TNF mut .
  • Figure 3 shows the body weight profiles. Weight change was monitoring during the therapy of subcutaneous CT26 (a), WEHI-164 (b), F9 (c) and LLC (d). Data represent mean % weight ( ⁇ SEM).
  • Figure 4 shows microscopic analysis of therapeutic performance of N2-F8-TNF mut in combination with anti- PD-L1 treatment
  • (a) Immunofluorescence analysis of tumor targeting properties of an anti-PD-L1 antibody 24 hours after IL2-F8-TNF mut + anti-PD-L1 treatment in mice bearing CT26 or LLC lesions, cryosections were stained with anti-rat IgG (green, Alexa Fluor 488) and anti-CD31 (red, Alexa Fluor 594), 20x magnification, scale bars 100pm.
  • Figure 6 shows the body weight profiles. Weight change was monitoring during the therapy of subcutaneous WEHI-164 tumors.
  • This invention relates to the treatment of cancer using a combination of an immune check-point inhibitor and fibronectin-targeted immunocytokines IL2 and/or TNF.
  • the combination may comprise an immune checkpoint inhibitor and one or more fibronectin-targeted immunoconjugates.
  • the one or more fibronectin-targeted immunoconjugates may comprise (i) a im mu noconjugate comprising IL2 and an anti-fibronectin antibody (ii) an immunoconjugate comprising TNF and an anti-fibronectin antibody; (iii) a first immunoconjugate comprising IL2 and an anti-fibronectin antibody and a second immunoconjugate comprising TNF and an anti- fibronectin antibody; or (iv) a single dual immunoconjugate comprising IL2, TNF and an anti-fibronectin antibody.
  • the therapeutic combination may comprise an immune check-point inhibitor and one or more fibronectin-targeted immunoconjugates, the one or more fibronectin-targeted immunoconjugates comprising an immunoconjugate comprising TNF and an anti-fibronectin antibody.
  • the one and more fibronectin-targeted immunoconjugates may comprise an immunoconjugate comprising TNF and an anti ED- B antibody.
  • the one and more fibronectin-targeted immunoconjugates may comprise an immunoconjugate comprising TNF and L19 antibody.
  • the therapeutic combination may comprise an immune check-point PD-1 inhibitor and one fibronectin-targeted immunoconjugate comprising an immunoconjugate comprising TNF and L19 antibody.
  • the therapeutic combination may comprise an immune check-point inhibitor and one and more fibronectin-targeted immunoconjugates, the one and more fibronectin-targeted immunoconjugates comprising a single dual immunoconjugate comprising IL2, TNF and an anti-fibronectin antibody.
  • the one and more fibronectin-targeted immunoconjugates may comprise a single dual immunoconjugate comprising IL2, TNF and an anti-EDA antibody.
  • the one and more fibronectin-targeted immunoconjugates comprise a single dual immunoconjugate comprising IL2, TNF and a F8 antibody.
  • the therapeutic combination may comprise an immune check-point PD-L1 inhibitor and one fibronectin-targeted immunoconjugate, the fibronectin-targeted immunoconjugate comprising a single dual immunoconjugate comprising IL2, TNF and a F8 antibody.
  • Immune checkpoint proteins negatively regulate the activation or function of T-cells. Immune checkpoint inhibition increases or promote T-cell activation or function by totally or partially inhibiting or reducing the expression or activity of an immune checkpoint protein.
  • An immune checkpoint inhibitor may for example inhibit or block the interaction of an immune checkpoint protein with one of its ligands or receptors.
  • Immune checkpoint proteins are known, including CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) and its ligands CD80 and CD86; PD-1 (Programmed Death 1 ) with its ligands PD-L1 and PD-L2 (Pardall, Nature Reviews Cancer 12: 252-264, 2012); TIM-3 (T-cell Immunoglobulin domain and Mucin domain 3); LAG-3 (Lymphocyte Activation Gene-3); BTLA (CD272 or B and T Lymphocyte Attenuator), KIR (Killer-cell Immunoglobulin-like Receptor); VISTA (V-domain immunoglobulin suppressor of T-cell activation); and A2aR (Adenosine A2A receptor). These proteins are responsible for down-regulating T-cell responses. Immune checkpoint proteins regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses.
  • CTLA-4 Cytotoxic T-lymphocyte associated antigen 4
  • CTLA-4 is an immune checkpoint protein that down-regulates pathways of T-cell activation (Fong et al., Cancer Res. 69(2):609-5 615, 2009; Weber Cancer Immunol. Immunother, 58:823-830, 2009).
  • CTLA-4 is a negative regulator of T-cell activation. Blockade of CTLA-4 has augment T-cell activation and proliferations.
  • Inhibitors of CTLA-4 include anti-CTLA-4 antibodies.
  • Anti-CTLA- 4 antibodies bind to CTLA-4 and block the interaction of CTLA-4 with its ligands CD80/CD86 expressed on antigen presenting cells and thereby blocking the negative down regulation of the immune responses elicited by the interaction of these molecules.
  • Anti-CTLA-4 antibodies include tremelimumab, (ticilimumab, CP-675,206), ipilimumab (also known as IODI, MDX-0010; marketed under the name YervoyTM and) a fully human monoclonal IgG antibody that binds to CTLA-4 approved for the treatment of unresectable or metastatic melanoma.
  • PD-1 Programmed cell death 1
  • CD279 is a type I membrane protein that mediates T cell exhaustion. It has two ligands, PD-L 1 and PD-L2.
  • the PD-1 pathway is a key immune-inhibitory mediator Blockade of this pathway leads to T-cell activation, expansion, and enhanced effector functions. As such, PD-1 negatively regulates T cell responses.
  • PD-1 has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1 :PD-L1 interactions has been shown to partially restore T cell function. (Sakuishi et al., JEMVol. 207, September 27, 2010, pp2187-2194).
  • PD-1 limits the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity.
  • PD-1 blockade in vitro enhances T-cell proliferation and cytokine production in response to a challenge by specific antigen targets or by allogeneic cells in mixed lymphocyte reactions.
  • a strong correlation between PD-1 expression and response was shown with blockade of PD-1 (Pardall, Nature Reviews Cancer, 12: 252-264,
  • PD-1 blockade can be accomplished by a variety of mechanisms including antibodies that bind PD-1 or its ligand, PD-L1 , or soluble PD-1 decoy receptors (e.g. sPD-1 , see Pan et al., Oncology Letters 5: 90-96,
  • PD-1 and PD-L1 blockers are described in US7488802; US7943743; US8008449; US8168757; US8217149, W02003042402, WO2008156712, W02010089411 , W02010036959,
  • PD-1 blockers include anti-PD-L 1 antibodies and proteinaceous binding agents.
  • Nivolumab (BMS-936558) is an anti-PD-1 antibody that was approved for the treatment of melanoma in Japan in July 2014. It is a fully human lgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-L 1 and PD-L2.
  • Other anti-PD-1 antibodies include lambrolizumab (pembrolizumab; MK-3475 or SCH 900475), a humanized monoclonal lgG4 antibody against PD-1 ; CT-01 1 a humanized antibody that binds PD-1.
  • AMP-224 is a fusion protein of 87-DC; an antibody Fe portion; BMS-936559 (MDX-1105-01 ) for PD-L 1 (87-HI) blockade.
  • Other anti-PD-1 antibodies are described in WO 2010/077634, WO 2006/121168, WO 2008/156712 and WO 2012/135408.
  • AUNP-12 (Aurigene) is a branched 29 amino acid peptide antagonist of the interaction of PD-1 with PD-L 1 or PD-L2 and has been shown to inhibit tumor growth and metastasis in preclinical models of cancer.
  • T cell immunoglobulin mucin 3 (TIM-3) is an immune regulator identified as being upregulated on exhausted coa+ T cells (Sakuishi et al., JEM (2010) 207 2187-2194 and Fourcade et al J. Exp. Med. (2010) 207:2175- 86).
  • TIM-3 was originally identified as being selectively expressed on IFN-y-secreting Th1 and Tc1 cells. Interaction of TIM-3 with its ligand, galectin-9, triggers cell death in TIM-3+ T cells.
  • Anti-TIM-3 antibodies are described for example in Ngiow et al (Cancer Res. 2011 May 15; 71 (10):3540-51 ) and in US8552156.
  • immune-checkpoint inhibitors include lymphocyte activation gene-3 (LAG-3) inhibitors, such as IMP321 , a soluble Ig fusion protein (Brignone et al., 2007, J. Immunol.179:4202-4211 ).
  • Other immune- checkpoint inhibitors include B7 inhibitors, such as B7-H3 and B7-H4 inhibitors.
  • the anti-B7-H3 antibody MGA271 (Loo et al. (2012) 5 Clin. Cancer Res. July 15 (18) 3834).
  • Preferred immune check-point inhibitors for use as described herein include anti-CTLA4 antibodies, such as ipilimumab; anti-PD-1 antibodies, such as nivolumab and pembrolizumab; and an anti-PD-L1 antibody, such as is atezolizumab, avelumab or durvalumab.
  • the immune check-point inhibitor is an anti-PD-L1 antibody.
  • the immune check-point inhibitor is an anti-PD-1 antibody.
  • Immune checkpoint inhibitors are administered as described herein in combination with the fibronectin- targeted immunocytokines IL2 and TNF.
  • the fibronectin-targeted immunocytokines may be contained in one or more immunoconjugates. In a preferred embodiment, the fibronectin-targeted immunocytokines may be contained in one immu noconjugate.
  • a fibronectin-targeted immunoconjugate specifically binds to fibronectin.
  • Fibronectin is subject to alternative splicing, and a number of alternative isoforms of fibronectin are known, including alternatively spliced isoforms A-FN and B-FN, comprising domains ED-A or ED-B respectively, which are known markers of angiogenesis and are selectively expressed in the neovasculature.
  • a fibronectin-targeted immunoconjugate may selectively bind to one or more isoforms of fibronectin that are selectively expressed in the neovasculature.
  • an immunoconjugate may specifically bind to fibronectin isoform A-FN, e.g. it may bind the extra domain A (ED-A); or fibronectin isoform B-FN, e.g. it may bind extra domain B (e.g. ED- B).
  • the one or more fibronectin-targeted immunoconjugates may comprise an immunoconjugate comprising IL2 and an anti-fibronectin antibody or an immunoconjugate comprising TNF and an anti-fibronectin antibody.
  • the fibronectin-targeted immunoconjugates may comprise an immunoconjugate comprising IL2 and an anti-fibronectin antibody or an immunoconjugate comprising TNF and an anti-fibronectin antibody.
  • the fibronectin-targeted immunoconjugates may comprise an immunoconjugate comprising IL2 and an anti-fibronectin antibody or an immunoconjugate comprising TNF and an anti-fibronectin antibody.
  • the fibronectin-targeted may comprise an immunoconjugate comprising IL2 and an anti-fibronectin antibody or an immunoconjugate comprising TNF and an anti-fibronectin antibody.
  • immunoconjugates may comprise an immunoconjugate comprising TNF and an anti-fibronectin antibody.
  • the fibronectin-targeted immunoconjugates may comprise an immunoconjugate comprising TNF and an anti ED-B antibody.
  • the one and more fibronectin-targeted immunoconjugates may comprise an immunoconjugate comprising TNF and L19 antibody.
  • the one or more fibronectin-targeted immunoconjugates may comprise a combination of a first immunoconjugate comprising IL2 and an anti-fibronectin antibody and a second immunoconjugate comprising TNF and an anti-fibronectin antibody.
  • the one or more fibronectin-targeted immunoconjugates may comprise a dual immunoconjugate comprising IL2, TNF and an anti-fibronectin antibody.
  • the one and more fibronectin-targeted immunoconjugates may comprise a single dual immunoconjugate comprising IL2, TNF and an anti-EDA antibody.
  • the one and more fibronectin-targeted immunoconjugates may comprise a single dual immunoconjugate comprising IL2, TNF and a F8 antibody.
  • an immunoconjugate as described herein may be targeted to fibronectin through the presence of an anti- fibronectin antibody.
  • antibody describes an immunoglobulin whether natural or partly or wholly synthetically produced.
  • the term also relates to any polypeptide or protein comprising an antibody antigen-binding site.
  • Antibodies may have been isolated or obtained by purification from natural sources, or else obtained by genetic recombination, or by chemical synthesis, and that they may contain unnatural amino acids.
  • An antigen binding site is the part of a molecule that recognises and binds to all or part of a target antigen.
  • an antibody molecule it is referred to as the antibody antigen-binding site or paratope, and comprises the part of the antibody that recognises and binds to all or part of the target antigen. Where an antigen is large, an antibody may only bind to a particular part of the antigen, which part is termed an epitope.
  • An antibody antigen-binding site may be provided by one or more antibody variable domains.
  • An antibody antigenbinding site preferably comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).
  • An antigen binding site may be provided by means of arrangement of complementarity determining regions (CDRs).
  • CDRs complementarity determining regions
  • the structure for carrying a CDR or a set of CDRs will generally be an antibody heavy or light chain sequence or substantial portion thereof in which the CDR or set of CDRs is located at a location corresponding to the CDR or set of CDRs of naturally occurring VH and VL antibody variable domains encoded by rearranged immunoglobulin genes.
  • the structures and locations of immunoglobulin variable domains may be determined by reference to Kabat et al. (1987) (Sequences of Proteins of Immunological Interest. 4 th Edition. US Department of Health and Human Services.), and updates thereof, now available on the Internet (at immuno.bme.nwu.edu or find“Kabat” using any search engine).
  • CDR region or CDR it is intended to indicate the hypervariable regions of the heavy and light chains of the immunoglobulin as defined by Kabat et al. (1987) Sequences of Proteins of Immunological Interest, 4 th Edition, US Department of Health and Human Services (Kabat et al., (1991a), Sequences of Proteins of Immunological Interest, 5 th Edition, US Department of Health and Human Services, Public Service, NIH, Washington, and later editions).
  • An antibody typically contains 3 heavy chain CDRs and 3 light chain CDRs.
  • CDR or“CDRs” may indicate, according to the case, one of these regions or several, or even the whole, of these regions which contain the majority of the amino acid residues responsible for the binding by affinity of the antibody for the antigen or the epitope which it recognizes.
  • HCDR3 the third CDR of the heavy chain (HCDR3) has a greater size variability (greater diversity essentially due to the mechanisms of arrangement of the genes which give rise to it). It can be as short as 2 amino acids although the longest size known is 26. Functionally, HCDR3 plays a role in part in the determination of the specificity of the antibody (Segal et al., (1974), PNAS, 71 :4298- 4302; Amit et al., (1986), Science, 233:747-753; Chothia et al., (1987), J. Mol.
  • antibody should be construed as covering any specific binding member or substance having an antibody antigen-binding site with the required specificity and/or binding, for example to fibronectin or an immune checkpoint inhibitor.
  • this term covers antibody fragments, in particular antigen-binding fragments, and derivatives, including any polypeptide comprising an antibody antigen-binding site, whether natural or wholly or partially synthetic.
  • Chimeric molecules comprising an antibody antigen-binding site, or equivalent, fused to another polypeptide (e.g. belonging to another antibody class or subclass) are therefore included. Cloning and expression of chimeric antibodies are described in EP-A-0120694 and EP-A-0125023, and a large body of subsequent literature.
  • fragments of a whole antibody can perform the function of binding an antigen.
  • binding fragments are (i) the Fab fragment consisting of VL, VH, CL and CH1 domains; (ii) the Fd fragment consisting of the VH and CH1 domains; (iii) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward et al. (1989) Nature 341 , 544-546; McCafferty et a!., (1990) Nature, 348, 552-554; Holt et al.
  • a single chain Fv may be comprised within a mini-immunoglobulin or small immunoprotein (SIP), e.g. as described in (Li et al., (1997), Protein Engineering, 10: 731-736).
  • SIP small immunoprotein
  • a SIP may comprise an scFv molecule fused to the CH4 domain of the human IgE secretory isoform lgE-S2 (E S2 -CH4; Batista et al., (1996), J. Exp. Med., 184: 2197- 205) forming a homo-dimeric mini-immunoglobulin antibody molecule.
  • Minibodies comprising a scFv joined to a CH3 domain may also be made (Hu et al. (1996), Cancer Res., 56(13):3055-61 ).
  • Other examples of binding fragments are Fab’, which differs from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region, and Fab’-SH, which is a Fab’ fragment in which the cysteine residue(s) of the constant domains bear a free thiol group.
  • An immunoconjugate is a molecule comprising an anti-fibronectin antibody and one or more cytokines selected from IL2 and TNF (e.g. IL2, TNF or IL2 and TNF).
  • cytokines selected from IL2 and TNF (e.g. IL2, TNF or IL2 and TNF).
  • the cytokines present in an immunoconjugate may be referred to as immunocytokines.
  • a fibronectin targeted immunoconjugate as described herein may comprise an antibody that specifically binds to fibronectin (i.e. an anti-fibronectin antibody), preferably a single chain Fv (scFv), diabody or single chain diabody that binds fibronectin.
  • an anti-fibronectin antibody preferably a single chain Fv (scFv), diabody or single chain diabody that binds fibronectin.
  • Diabodies and scFvs do not comprise an antibody Fc region, thus potentially reducing the effects of anti-idiotypic reaction.
  • the anti-fibronectin antibody for use in the immunoconjugates described herein is a scFv.
  • the VH and VL domains of the antibody are preferably linked by a 10 to 20 amino acid linker, by a 14 to 20 amino acid linker, preferably by a 10 to 14 amino acid linker.
  • Suitable linkers are known in the art and available to the skilled person.
  • the VH and VL domains may be linked by a 5 to 12 amino acid linker.
  • a diabody comprises two VH-VL molecules which associate to form a dimer.
  • the VH and VL domains of each VH-VL molecule may be linked by a 5 to 12 amino acid linker.
  • An immunoconjugate described herein may specifically bind to the ED-A of fibronectin, and thus also A-FN.
  • Suitable anti-ED-A antibodies are known in the art (see for example Villa et al Int J Cancer. (2008)
  • an anti-fibronectin antibody as described herein may comprise the complementarity determining regions (CDRs) of antibody F8 set forth in SEQ ID NOs 1 to 6. More preferably, an antibody for use as described herein may comprise the VH and/or VL domains of antibody F8 set forth in SEQ ID NOs 7 and 8, respectively or variants thereof.
  • an antibody for use as described herein comprises the VH and VL domains of antibody F8 set forth in SEQ ID NOs 7 and 8, respectively or variants thereof.
  • the F8 antibody is preferably in scFv or diabody format, most preferably in scFv format.
  • the antibody molecule for use as described herein preferably has the amino acid sequence set forth in SEQ ID NO: 9 or a variant thereof.
  • An anti-fibronectin antibody for use as described herein may bind the A-FN and/or the ED-A of fibronectin, with the same affinity as anti-ED-A antibody F8 e.g. in scFv format, or with a higher affinity.
  • An anti-fibronectin antibody for use as described herein may bind to the same epitope on A-FN and/or the ED-A of fibronectin as anti-ED-A antibody F8.
  • An immunoconjugate described herein may specifically bind to the ED-B of fibronectin, and thus also B-FN.
  • Suitable anti-ED-B antibodies and conjugates comprising anti-EDB antibodies such as the L19 antibody are known in the art (see for example W01999/058570, W02001/062298, WO2007/128563, WO2013/045125, and W02018/011404).
  • An anti-fibronectin antibody for use as described herein may comprise the CDRs of antibody L19 set forth in SEQ ID NOs 10-15. More preferably, an antibody for use as described herein may comprise the VH and/or VL domains of antibody L19 set forth in SEQ ID NOs 16 and 17 or variants thereof.
  • an antibody for use as described herein comprises the VH and VL domains of antibody L19 set forth in SEQ ID Nos 16 and 17 or variants thereof.
  • the L19 antibody is preferably in scFv or diabody format, most preferably in scFv format.
  • the antibody molecule for use as described herein preferably has the amino acid sequence set forth in SEQ ID NO: 18 or a variant thereof.
  • An anti-fibronectin antibody for use as described herein may bind the B-FN and/or the ED-B of fibronectin, with the same affinity as anti-ED-B antibody L19 e.g. in scFv format, or with a higher affinity.
  • An anti-fibronectin antibody for use as described herein may bind to the same epitope on B-FN and/or the ED-B of fibronectin as anti-ED-B antibody L19 as described by Fattorusso et al., Structure 1999, 7, 381-390.
  • Variants of an antibody disclosed herein may be produced and used as an anti-fibronectin antibody as described herein.
  • the techniques required to make substitutions within amino acid sequences of CDRs, antibody VH or VL domains, in particular the framework regions of the VH and VL domains, and antibody molecules generally are available in the art.
  • Variant sequences may be made, with substitutions that may or may not be predicted to have a minimal or beneficial effect on activity, and tested for ability to bind antigen, such as A-FN and/or the ED-A of fibronectin, B-FN and/or the ED-B of fibronectin, and/or for any other desired property.
  • amino acid alterations may be made in one or more of the CDRs and/or the VH and/or the VL domain of an antibody molecule as described herein.
  • anti-fibronectin antibody may comprise the CDRs and/or the VH and/or the VL domain of antibody F8 or L19 described herein with 5 or fewer, for example, 5, 4, 3, 2 or 1 amino acid alterations within the CDRs and/or the VH and/or the VL domain.
  • an antibody which binds the FN-A or FN-B may comprise the VH and/or the VL domain of antibody F8 or L19 described herein with 5 or fewer, for example, 5, 4, 3, 2 or 1 amino acid alterations within the framework region of the VH and/or VL domain.
  • Such an antibody molecule may bind the ED-A isoform or ED-A of fibronectin with the same or substantially the same, affinity as an antibody molecule comprising the VH domain shown in SEQ ID NO: 7 and the VL domain shown in SEQ ID NO: 8 or may bind the ED-A isoform or ED-A of fibronectin with a higher affinity than an antibody molecule comprising the VH domain shown in SEQ ID NO: 7 and the VL domain shown in SEQ ID NO: 8.
  • An antibody that binds the FN-B or ED-B of fibronectin thus may comprise the VH domain shown in SEQ ID NO: 16 and/or the VL domain shown in SEQ ID NO: 17 with 5 or fewer, for example, 5, 4, 3, 2 or 1 amino acid alterations within the framework region of the VH and/or VL domain.
  • Such an antibody molecule may bind the ED-B isoform or ED-B of fibronectin with the same or substantially the same, affinity as an antibody molecule comprising the VH domain shown in SEQ ID NO: 16 and the VL domain shown in SEQ ID NO: 17 or may bind the ED-B isoform or ED-B of fibronectin with a higher affinity than an antibody molecule comprising the VH domain shown in SEQ ID NO: 16 and the VL domain shown in SEQ ID NO: 17.
  • An anti-fibronectin antibody as described herein may comprise a VH and/or VL domain that has at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, sequence identity to the F8 antibody VH and/or VL domains set forth in SEQ ID NOs 7 and 8, respectively, or the L19 antibody VH and/or VL domains set forth in SEQ ID NOs 16 and 17, respectively.
  • An anti-fibronectin antibody as described herein may have at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, sequence identity to the VH or VL amino acid sequence of the F8 or L19 antibodies set forth in SEQ ID NOs 7, 8, 16 and 17, respectively.
  • the anti- fibronectin antibody may comprise the VH and VL CDR sequences of the F8 or L19 antibodies set forth in SEQ ID NOs 1-6 and 10-15, respectively i.e. the variation may be in the framework regions.
  • An immunoconjugate, second immunoconjugate or a dual im mu noconjugate described herein may comprise TNF.
  • TNF is preferably human TNF.
  • the tumour necrosis factor is TNFa
  • the TNFa is preferably human TNFa.
  • Human TNFa consists of a 35 amino acid cytoplasmic domain, a 20 amino acid transmembrane domain and a 177 amino acid extracellular domain. The 177 amino acid extracellular domain is cleaved to produce a 157 amino acid soluble form, which is biologically active, and which forms a non-covalently linked trimer in solution.
  • Human TNFa is preferably the soluble form of the extracellular domain of human TNFa, or the extracellular domain of human TNFa.
  • the sequence of the soluble form of the extracellular domain of human TNFa is shown in SEQ ID NO: 19.
  • the TNFa thus preferably comprises or consist of the sequence set forth in SEQ ID NO: 19.
  • TNFa has at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO: 19.
  • the sequence of the extracellular domain of human TNFa is shown in SEQ ID NO: 20.
  • the TNFa may comprise or consist of the sequence set forth in SEQ ID NO: 20.
  • the TNFa may have at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO: 20.
  • TNFa in conjugates of the invention retains a biological activity of human TNFa, e.g. the ability to inhibit cell proliferation.
  • TNF may be a wild type human TNF or a TNF mutant which retains biological function of human TNF, e.g. the ability to inhibit cell proliferation but has a reduced activity relative to the wild-type human TNF.
  • the TNF mutant may comprise one or more mutations which reduce activity relative to the wild-type TNF which lacks the one or more mutations i.e. the TNF mutant is less potent than wild-type TNF.
  • the TNF mutant may comprise a mutation at the position corresponding to position 32 in SEQ ID NO: 19 or position 52 of SEQ ID NO: 20.
  • the R at said position may be substituted for a different amino acid, preferably an amino acid other than G, for example a non-polar amino acid, preferably A, F, or V, most preferably A.
  • a mutant TNFa may comprise or consist of the sequence shown in SEQ ID NO: 19 or 20, except that the residue at position 32 of SEQ ID NO: 19 or at position 52 of SEQ ID NO: 20 is an alanine residue rather than an arginine residue.
  • This sequence is shown in SEQ ID NO: 21 or 22.
  • the mutant of TNFa thus preferably comprises or consist of the sequence set forth in SEQ ID NO: 21.
  • the mutant of TNFa has at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO: 21 with an A at the position corresponding to position 32 in SEQ ID NO: 21.
  • the TNFa may comprise or consist of the sequence set forth in SEQ ID NO: 22.
  • the TNFa may have at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO: 22 with an A at the position corresponding to position 52 in SEQ ID NO: 22.
  • a dual immunoconjugate as described herein may comprise a TNF mutant.
  • An immunoconjugate, first immunoconjugate or a dual immunoconjugate described herein may comprise IL2.
  • the IL2 may be human IL2.
  • the IL2 preferably comprises or consist of the sequence set forth in SEQ ID NO: 38 or a variant thereof.
  • IL2 has at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, sequence identity to the amino acid sequence set forth in SEQ ID NO: 38.
  • IL2 in an immunoconjugate described herein may retain a biological activity of human IL2, e.g. the ability to inhibit cell proliferation.
  • the anti-fibronectin antibody may be connected to IL2 and/or TNF in an immunoconjugate through linkers, for example peptide linkers.
  • the anti-fibronectin antibody and IL2 and/or TNF may be connected directly, e.g. through a chemical bond.
  • the chemical bond may be, for example, a covalent or ionic bond. Examples of covalent bonds include peptide bonds (amide bonds) and disulphide bonds.
  • the anti-fibronectin antibody and IL2 and/or TNF may be covalently linked, for example by peptide bonds (amide bonds).
  • the antibody molecule, in particular a scFv portion of an antibody molecule, and IL2 and/or TNF may be produced as a fusion protein.
  • fusion protein is meant a polypeptide that is a translation product resulting from the fusion of two or more genes or nucleic acid coding sequences into one open reading frame (ORF).
  • IL2 and/or TNF may be conjugated as a fusion protein with one or more polypeptide chains in the anti-fibronectin antibody.
  • the peptide linkers connecting the anti-fibronectin antibody and IL2 and/or TNF in an immunoconjugate described herein may be a flexible peptide linker. Suitable examples of peptide linker sequences are known in the art.
  • the linker may be 10-20 amino acids, preferably 10-15 or 15-18 amino acids in length. Most preferably, the linker is 1 1-15 or 16-18 amino acids in length, for example 17 amino acids in length.
  • the linker may have the sequence set forth in SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25 or SEQ ID NO: 41.
  • the IL2 may be linked to the N-terminus of the VH domain of the scFv via a peptide linker and TNF may be linked to the C- terminus of the VL domain of the scFv via a peptide linker.
  • the TNF may be linked to the N- terminus of the VH domain of the scFv via a peptide linker and the IL2 may be linked to the C-terminus of the VL domain of the scFv via a peptide linker.
  • the IL2 and TNF may be linked to the C-terminus of the VL domain or the N-terminus of the VH domain of the antibody, e.g. in scFv format, via a peptide linker.
  • the IL2 and TNF may be in any order and/or may optionally be linked to one another via a peptide linker. Suitable peptide linkers are described herein.
  • the IL2 and the TNF may be linked to the anti-fibronectin antibody by the linkers set forth in SEQ ID NO: 23 and SEQ ID NO: 24, respectively; or the linkers set forth in SEQ ID NO: 24 and SEQ ID NO: 25, respectively.
  • An immunoconjugate or first immunoconjugate as described herein may comprise or consist of the sequence shown in SEQ ID NO: 26 or 32 or may be a variant thereof.
  • immunoconjugate as described herein may comprise or consist of the sequence shown in SEQ ID NO: 27 or 33 or may be a variant thereof. Suitable first and second immunoconjugates are described, for example in W02001/062298, WO2013/045125, Hemmerle et al. (2013) Br. J. Cancer 109, 1206-1213; Frey et al. (2008) J. Urol. 184, 2540-2548.
  • the immunoconjugate or second immunoconjugate comprises or consists of the sequence shown in SEQ ID NO: 33.
  • a dual immunoconjugate as described herein may comprise the amino acid sequence of any one of SEQ ID NOs: 28 to 31 and 34 to 37 or a variant of any one of these sequences.
  • a dual cytokine may be a potency matched immunoconjugate, for example an immunoconjugate comprising the sequence of any one of SEQ ID NOs: 30 to 31 and 34 to 35 or a variant of any one of these sequences.
  • Suitable dual immunoconjugates are described in W02016/180715 and PCT/EP2017/078652, De Luca R, et al (2017), Molecular Cancer Therapeutics 16 (1 1 ):2442
  • a variant of a reference sequence such as an antibody or immunoconjugate sequence set out herein may have an amino acid sequence having at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to the reference amino acid sequence.
  • Suitable reference amino acid sequences for anti-fibronectin antibodies, IL2, TNF, linkers and immunoconjugates are provided herein.
  • GAP GCG Wisconsin PackageTM, Accelrys, San Diego CA.
  • GAP uses the Needleman & Wunsch algorithm (J. Mol. Biol. (48): 444-453 (1970)) to align two complete sequences that maximizes the number of matches and minimizes the number of gaps.
  • Use of GAP may be preferred but other algorithms may be used, e.g. BLAST, psiBLAST or TBLASTN (which use the method of Altschul et al. (1990) J. Mol. Biol.
  • Particular amino acid sequence variants may differ from a reference sequence by insertion, addition, substitution or deletion of 1 amino acid, 2, 3, 4, 5-10, 10-20 or 20-30 amino acids.
  • a variant sequence may comprise the reference sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more residues inserted, deleted or substituted. For example, up to 15, up to 20, up to 30 or up to 40 residues may be inserted, deleted or substituted.
  • a variant may differ from a reference sequence by 1 , 2, 3, 4, 5, 6, 7, 8, 9,
  • amino acids 10 or more substitutions, preferably conservative substitutions.
  • Conservative substitutions involve the replacement of an amino acid with a different amino acid having similar properties. For example, an aliphatic residue may be replaced by another aliphatic residue, a non-polar residue may be replaced by another nonpolar residue, an acidic residue may be replaced by another acidic residue, a basic residue may be replaced by another basic residue, a polar residue may be replaced by another polar residue or an aromatic residue may be replaced by another aromatic residue.
  • Conservative substitutions may, for example, be between amino acids within the following groups:
  • Fibronectin-targeted immunoconjugates and immune check-point inhibitors will usually be administered in the form of pharmaceutical compositions, which may comprise at least one component in addition to the active agent.
  • Fibronectin-targeted immunoconjugates and immune check-point inhibitors may be formulated into a single combined composition or any formulated into separate compositions. Separate compositions preparations may be useful, for example, to facilitate separate and sequential or simultaneous administration, and allow administration of the components by different routes.
  • compositions may comprise, in addition to an active ingredient described herein, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be by injection, e.g. intravenous or subcutaneous.
  • the therapeutic combination of the present invention is administered intravenously.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives may be employed, as required.
  • Many methods for the preparation of pharmaceutical formulations are known to those skilled in the art. See e.g. Robinson ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York, 1978.
  • a therapeutic combination as described herein may be for use in a method of treatment of the human or animal body, for example a method of treating cancer.
  • a method of treating cancer as described herein may comprise administering a first immunoconjugate comprising IL2 and an anti-fibronectin antibody and/or a second immunoconjugate comprising TNF and an anti-fibronectin antibody and an immune check-point inhibitor to an individual in need thereof.
  • Some preferred methods of treating cancer as described herein may comprise administering an immunoconjugate comprising TNF and an anti-fibronectin antibody and an immune check-point inhibitor to an individual in need thereof.
  • a method of treating cancer may comprise administering antibody to an individual in need thereof an immune checkpoint inhibitor and a dual immunoconjugate that comprises IL2, TNF and an anti-fibronectin.
  • Other aspects of the invention provide a therapeutic combination; a first immunoconjugate; a second immunoconjugate; a first immunoconjugate and a second immunoconjugate; or a dual immunoconjugate for use in the above methods of treating cancer; and the use of a therapeutic combination; a first immunoconjugate; a second immunoconjugate; a first immunoconjugate and a second immunoconjugate; or a dual immunoconjugate in the manufacture of a medicament for use in the above methods of treating cancer.
  • Cancer may be a cancer which expresses, or has been shown to express, an antigen, such as an extracellular matrix component, that is associated with neoplastic growth and/or angiogenesis.
  • an antigen such as an extracellular matrix component
  • the cancer is a cancer which expresses, or has been shown to express, the ED-A or ED-B isoform of fibronectin. More preferably, the cancer expresses the ED-B isoform of fibronectin.
  • the cancer may be any type of solid or non-solid cancer or malignant lymphoma.
  • the cancer may be selected from the group consisting of skin cancer (in particular melanoma), head and neck cancer, kidney cancer, sarcoma, germ cell cancer (such as teratocarcinoma), liver cancer, lymphoma (such as Hodgkin's or non-Hodgkin's lymphoma), leukaemia (e.g. acute myeloid leukaemia), skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colorectal cancer, cervical cancer, oesophageal cancer, pancreatic cancer, stomach cancer, and cerebral cancer. Cancers may be familial or sporadic.
  • Cancers may be metastatic or non-metastatic.
  • the cancer is a cancer selected from the group consisting of a melanoma, head and neck cancer, kidney cancer, and a sarcoma.
  • the reference to a cancer as mentioned above normally refers to a malignant transformation of the cells in question.
  • kidney cancer for example, refers to a malignant transformation of cells in the kidney.
  • the cancer may be located at its primary location, such as the kidney in the case of kidney cancer, or at a distant location in the case of metastases.
  • a tumour as referred to herein may be the result of any of the cancers mentioned above.
  • a tumour is the result of a melanoma, head and neck cancer, kidney cancer, or a sarcoma.
  • a tumour which is the result of a particular cancer includes both a primary tumour and tumour metastases of said cancer.
  • a tumour which is the result of head and neck cancer for example, includes both a primary tumour of head and neck and cancer and metastases of head and neck cancer found in other parts of a patient’s body.
  • Administration of the immune check-point inhibitor and the immunoconjugate(s) can include coadministration, either in a single pharmaceutical formulation or using separate formulations, or consecutive administration in either order but generally within a time period such that all active agents can exert their biological activities simultaneously.
  • Examples of sequential administration of IL2-based immunocytokines and anti-CTLA-4 checkpoint inhibitors include W02013/010749.
  • compositions provided may be administered to mammals, preferably humans. Administration may be in a "therapeutically effective amount", this being sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom. Thus“treatment” of a specified disease refers to amelioration of at least one symptom.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the composition, the type of conjugate, the method of administration, the scheduling of administration and other factors known to medical practitioners. Prescription of treatment, e.g.
  • a therapeutically effective amount or suitable dose of a conjugate for use in the invention can be determined by comparing its in vitro activity and in vivo activity in an animal model.
  • mice and other test animals to humans are known.
  • the precise dose will depend upon a number of factors, including whether the antibody is for diagnosis, prevention or for treatment, the size and location of the area to be treated, the precise nature of the conjugate.
  • a typical conjugate dose will be in the range 100 pg to 1 g for systemic applications.
  • An initial higher loading dose, followed by one or more lower doses, may be administered. This is a dose for a single treatment of an adult patient, which may be proportionally adjusted for children and infants, and also adjusted according to conjugate format in proportion to molecular weight. Treatments may be repeated at daily, twice-weekly, weekly or monthly intervals, at the discretion of the physician.
  • Treatments may be every two to four weeks for subcutaneous administration and every four to eight weeks for intravenous administration. Treatment may be periodic, and the period between administrations is about two weeks or more, e.g. about three weeks or more, about four weeks or more, or about once a month. In some embodiments, treatment may be given before, and/or after surgery, and may be administered or applied directly at the anatomical site of surgical treatment.
  • a therapeutic combination as described herein may be administered alone or in combination with other cancer treatments, concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of cancer.
  • a therapeutic combination of the invention may be used in combination with an existing therapeutic agent for cancer.
  • Example 1- Therapeutic activity of IL2-F8-TNF mut in combination with an anti-PD-L1 antibody
  • WEHI-164 fibrosarcoma cells, F9 teratocarcinoma cells, CT26 colon carcinoma cells and LLC Lewis lung carcinoma cells were grown according to the supplier’s protocol and kept in culture for no longer than 14 passages. Authentication of the cell lines also including check of post-freeze viability, growth properties and morphology, test for mycoplasma contamination, isoenzyme assay and sterility test were performed by the cell bank before shipment.
  • IL2-F8-TNF mut has the amino acid sequence set forth in SEQ ID NO 39.
  • the commercial anti-PD-L1 was purchased at BioXCell (clone 10F.9G2; BE0101 ). Tumor models and therapy studies
  • Tumor cells were implanted subcutaneously in the flank of BALB/c mice using 4 x 10 ® cells (CT26), 5 x 10 ® cells (WEHI-164). 15 x 10 ® cells (F9) in 129/ScEv mice and 2 x 10 ® cells (LLC) in C57BL/6 mice.
  • PBS phosphate buffered saline
  • IL2-F8-TNF mut was administered at 50pg, 20pg, 40pg and 40pg for the therapy in CT26, WEHI-164, F9 and LLC, respectively.
  • the commercial anti-PD-L1 antibody was administered at 200pg (Mosely et al. (2017) Cancer Immunol Res. 5: 29-41 ).
  • IL2-F8-TNF mut was administered 6 hours before anti-PD-L1
  • anti-PD-L1 was administered 6 hours before IL2-F8-TNF mut .
  • mice with complete responses were injected subcutaneously with 4 x 10 ® CT26 cells in the flank.
  • EDA expression was assessed on ice-cold acetone fixed 8- pm cryostat sections of WEHI-164, CT26, F9 and LLC stained with IL2-F8-TNF mut (final concentration 5pg/mL), as negative control IL2-KSF-TNF mut (specific for an irrelevant antigen) was used. Both antibodies were detected with rat anti-IL2 and anti-rat
  • AlexaFluor488 For vascular staining goat anti-CD31 and anti-goat AlexaFluor594 antibodies were used.
  • mice bearing CT26 or LLC lesions were injected once with IL2- F8-TNF muf + anti-PD-L1 or saline according to the therapy schedule and sacrificed 24h after injection.
  • Tumors were excised and embedded in cryoembedding medium and cryostat sections (8pm) were stained using the following antibodies: rabbit anti-CD4, rabbit anti-CD8, rabbit anti-FoxP3, rabbit anti-NCR1 , goat anti-CD31 and detected with anti-rat AlexaFluor488, anti-rabbit AlexaFluor488, anti-goat AlexaFluor594. Slides were mounted with fluorescent mounting medium and analysed with Axioskop2 mot plus microscope.
  • Fig. 1 describes the reagents used for therapy experiments and provides information about the murine tumor models used in the study.
  • IL2-F8-TNF mut assembled into a stable non-covalent homotrimeric structure [Fig. 1a], was produced and purified as previously described [25], while a commercial antibody specific to murine PD-L1 was used as a surrogate for clinically-approved anti-PD-L1 products [11].
  • the IL2-F8-TNF mut product strongly stained the neo-vasculature of F9 teratocarcinomas [Fig. 1 b], while the three other models used in our study (CT26, WEHI-164 and LLC) displayed a more diffuse stromal staining pattern.
  • IL2-KSF- TNF mut (a fusion protein with identical format but specific to hen egg lysozyme) was used as negative control in immunofluorescence procedures, no detectable staining was observed in addition to the CD31 signal.
  • IL2-F8-TNF mut administered at a dose of 50pg
  • an anti-mouse PD-L1 antibody used at 200pg
  • Treatment with the anti-PD-L1 antibody resulted in a tumor growth profile similar to the one obtained in the saline control group (PBS).
  • a tumor growth inhibition was observed in the IL2-F8-TNF mut group, as well as in the combination group where the anti-PD-L1 antibody had been administered six hours before IL2-F8-TNF mut .
  • the tumor-targeting properties of the commercial anti-PD-L1 antibody were investigated by analyzing sections of CT26 (a tumor that could be cured) or LLC (a tumor that could not be cured in our experimental setting) 24 hours after intravenous administration of 200 pg of this product.
  • a similar analysis, performed in sections of LLC tumors [Fig. 4c] revealed a distinct increase in the intratumoral density of NK cells, CD4+ T cells and CD8+ T cells after combination therapy. Only a small reduction in the density of FoxP3-positive lymphocytes was observed.
  • cytokine fusion protein IL2-F8-TNF mut
  • the product was used alone or in combination with an anti-PD-L1 antibody (a surrogate for the human-specific PD-L1 blockers Avelumab, Durvalumab and Atezolizumab, which have gained marketing authorization for cancer therapy) [6,43,44]
  • an anti-PD-L1 antibody a surrogate for the human-specific PD-L1 blockers Avelumab, Durvalumab and Atezolizumab, which have gained marketing authorization for cancer therapy
  • a potent tumor growth inhibition was observed when F9 tumors were treated with IL2-F8-TNF mut , alone or in combination with anti-PD-L1. However, only one mouse could be cured in the combination group. For LLC tumors, no cures were observed and the potency-matched immunocytokine product could mediate only a partial tumor growth inhibition. No apparent benefit was observed in the combination therapy group.
  • Example 2- Therapeutic activity of L19-TNF in combination with an anti-PD-1 antibody
  • L19-mTNF was dissolved in phosphate buffered saline (PBS), and administered at 2pg/mouse into the lateral tail vein three times every 48h.
  • PBS phosphate buffered saline
  • the commercial anti- PD-1 antibody (clone 29F.1A12, BioXCell, Catalog # BE0273) was administered at 200pg/mouse into the lateral tail vein three times every 48h, together with L19-mTNF. Weight of the mice was also recorded during the therapy and expressed as percent of weight change.
  • Amino acid sequence of the hulL2-F8-huTNFa [soluble forml conjugate (SEQ ID NO: 28)
  • the amino acid sequence of the hull_2-F8-huTNFa [soluble form] conjugate (human IL2 - linker - F8 VH - linker - F8 VL - linker - human TNFa [soluble form]) is shown below. The linker sequences are underlined.
  • the human TNFa in this conjugate is the soluble form of the extracellular domain of TNFa.
  • the amino acid sequence of the hull_2-F8-huTNFa [extracellular domain] conjugate (human IL2 - linker - F8 VH - linker - F8 VL - linker - human TNFa [extracellular domain]) is shown below. The linker sequences are underlined. The human TNFa in this conjugate is the extracellular domain of TNFa.
  • the amino acid sequence of the hulL2-F8-huTNFa (R32A) mutant [soluble form] conjugate (human IL2 - linker - F8 VH - linker - F8 VL - linker - human TNFa (R32A) mutant [soluble form]) is shown below.
  • the linker sequences are underlined and the R32A is underlined in bold.
  • the mutant of human TNFa (R32A) in this conjugate is the soluble form of the extracellular domain of TNFa.
  • the amino acid sequence of the hulL2-F8-huTNFa (R52A) mutant [extracellular domain] conjugate (human IL2 - linker - F8 VH - linker - F8 VL - linker - human TNFa (R52A1 mutant [extracellular domain]) is shown below. The linker sequences are underlined and the R52A is in underlined in bold. The human TNFa (R52A) mutant in this conjugate is the extracellular domain of TNFa.
  • the amino acid sequence of the hull_2-L19-huTNFa (R32A1 mutant [soluble form] conjugate (human IL2 - linker - L19 VH - linker - L19 VL - linker - human TNFa (R32A) mutant [soluble form]) is shown below.
  • the linker sequences are underlined and the R32A is underlined in bold.
  • the human TNFa mutant in this conjugate is the soluble form of the extracellular domain of TNFa.
  • the amino acid sequence of the hulL2-L19-huTNFa (R52A) mutant [extracellular domain] conjugate (human IL2 - linker - L19 VH - linker - L19 VL - linker - human TNFa (R52A) mutant) is shown below. The linker sequences are underlined and the R52A is underlined in bold. The human TNFa mutant in this conjugate is the extracellular domain of TNFa.
  • the amino acid sequence of the hull_2-L19-huTNFa [soluble form] conjugate (human IL2 - linker - L19 VH - linker - L19 VL - linker - human TNFa [soluble form]) is shown below. The linker sequences are underlined. The human TNFa in this conjugate is the soluble form of the extracellular domain of TNFa.
  • VL - linker - mTNFal is shown below.
  • the linker sequences are underlined.
  • the murine TNFa in this conjugate is the soluble form of the extracellular domain of TNFa.

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Abstract

La présente invention concerne des combinaisons thérapeutiques comprenant un inhibiteur du point de contrôle, tel qu'un anticorps anti-PD1 ou anti-PD-L1 et soit (i) un immunoconjugué comprenant le facteur de nécrose tumorale (TNF) et un anticorps anti-fibronectine et/ou un immunoconjugué comprenant l'interleukine 2 (IL2) et un anticorps anti-fibronectine ; soit (ii) un immunoconjugué double comprenant IL2, TNF et un anticorps anti-fibronectine. L'invention concerne également des combinaisons thérapeutiques et des procédés d'utilisation dans le traitement du cancer.
PCT/EP2019/057854 2018-03-29 2019-03-28 Traitement du cancer à l'aide d'immunoconjugués et d'inhibiteurs du point de contrôle immunitaire WO2019185792A1 (fr)

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WO2020249757A1 (fr) 2019-06-14 2020-12-17 Philogen S.P.A Immunoconjugués comprenant un dianticorps à chaîne unique et de l'interleukine-15 ou l'interleukine-15 et un domaine sushi du récepteur alpha de l'interleukine-15
WO2021029318A1 (fr) * 2019-08-13 2021-02-18 国立大学法人東北大学 Inhibiteur de point de contrôle immunitaire, agent thérapeutique pour maladie liée au point de contrôle immunitaire, immunosuppresseur, anticorps anti-fibronectine ou dérivé de celui-ci, analogue de la fibronectine, kit pour détecter la fibronectine ou protéine partielle de celle-ci, et procédé pour détecter la fibronectine ou une protéine partielle de celle-ci
WO2021147886A1 (fr) * 2020-01-21 2021-07-29 张晋宇 Composition pharmaceutique et son utilisation
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US11760802B2 (en) 2019-12-19 2023-09-19 Ngm Biopharmaceuticals, Inc. ILT3-binding agents and methods of use thereof
WO2023175077A1 (fr) 2022-03-17 2023-09-21 Philogen S.P.A Anticorps anti-ed-a pour traitement d'hypertension pulmonaire
WO2023180341A1 (fr) 2022-03-21 2023-09-28 Philogen S.P.A PRÉPARATION D'IMMUNOCONJUGUÉS DE TNFα
WO2023180409A1 (fr) 2022-03-23 2023-09-28 Philogen S.P.A Preparation d'immunoconjugués d'il2
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