EP3475415A1 - System zur ausgabe von zellulären, gerichteten, pharmazeutisch aktiven substanzen oder etiketten - Google Patents
System zur ausgabe von zellulären, gerichteten, pharmazeutisch aktiven substanzen oder etikettenInfo
- Publication number
- EP3475415A1 EP3475415A1 EP16836211.9A EP16836211A EP3475415A1 EP 3475415 A1 EP3475415 A1 EP 3475415A1 EP 16836211 A EP16836211 A EP 16836211A EP 3475415 A1 EP3475415 A1 EP 3475415A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino acid
- delivery system
- cell
- macrophage
- pharmaceutically active
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Definitions
- the present invention relates to an isolated cellular targeted delivery system comprising a CD45 + leukocyte cell comprising within said cell a complex of one or more iron binding proteins and an active pharmaceutically active substance and/or label as well as methods for producing such isolated cellular targeted delivery system and uses of such system for prophylaxis, therapy, diagnosis or theragnosis, in particular for prophylactic or therapeutic vaccination, therapy of cancer, particularly metastatic cancer or inflammatory diseases.
- micrometastases hidden within a large population of normal cells presents a unique challenge since access to the micrometastases is impeded by several bio-barriers, poor blood supply, further obstacles are presented by small size of the micrometastases and their dispersion to organs.
- micrometastases are often refractive to therapy. While the solid tumours from which the micrometastases have originated often respond well to conventional therapy there is often regrowth at the site of the primary tumour or at sites of metastasis. This constitutes a serious problem in clinical oncology (Muthana, et al. 2012, Cancer Res; 73(2); 490-495). It is related to characteristics of the microenvironment of solid tumours that limit drug penetration, thereby exposing the tumour to lower than efficacious concentrations of drugs (Hobbs, et al. 1998, Proc Natl Acad Sci USA: 4607-4612).
- CD45 + leukocyte cells in particular activated macrophages, their precursors monocytes, lymphocytes and granulocytes can uptake pharmaceutically active substances, labels or pharmaceutically active substances and labels complexed with one or more iron binding proteins in vitro and deliver these complexes to or into cells, preferably to or into tumour cells in vivo or other cells undergoing stress (e.g. oxidative stress).
- stress e.g. oxidative stress
- the targeted delivery system of the present invention provides inta alia one or more of the following advantages: (i) specific delivery of one or more pharmaceutically active substances, labels or pharmaceutically active substances and labels to tissues that attract above mentioned CD45 + leukocytes, preferably into diseased cells, (ii) protection of pharmaceutically active substances, labels or pharmaceutically active substances and labels from inactivation in the blood circulation or clearance from the body, (iii) delivery of pharmaceutically active substances, labels or pharmaceutically active substances and labels to, preferably into cells of poorly or non-vascularized areas of disease, e.g.
- metastases hypoxic areas within larger tumours, rheumatic lesions, inflamed lymph nodes, avascular wounds, skin
- reduced toxicity of pharmaceutically active substances, labels or pharmaceutically active substances and labels (v) delivery of pharmaceutically active substances, labels or pharmaceutically active substances and labels with poor pharmacokinetics, (vi) reduced side effects of the drugs due to their targeted delivery, (vii) higher treatment efficacy with lower doses of the drugs due to targeted delivery; and/or (viii) lower risk of local tissue injury at the site of drug administration due to administration of the drug linked with iron-binding protein, which is loaded inside the CD45 + leukocyte; and/or (ix) possibility to detect highly hypoxic small metastases; and/or (x) early detection of inflammatory diseases.
- the present invention relates to an isolated targeted delivery system comprising a CD45 + monocyte-macrophage, CD45 + lymphocyte, in particular CD45 + natural killer cells (NK cells), precursors of any of these cell types, preferably MDSC, and/or CD45 + granulocyte, ("CD45 + leukocyte cell”), , or their precursors, preferably MDSC, comprising within said cell a complex of one or more iron binding proteins and a pharmaceutically active substance, label or pharmaceutically active substance and label.
- NK cells natural killer cells
- the present invention relates to an isolated targeted delivery label system comprising a CD45 + leukocyte cell, preferably capable of being labelled, comprising one or more labels, preferably radiolabels or their conjugates and combinations.
- the present invention relates to a method of preparation of the isolated targeted delivery system of claims 1 to 25 comprising steps of
- step b) incubating the CD45 + leukocyte cell in the presence of the iron binding protein produced in step b) until the CD45 + leukocyte cell is at least partially loaded with the complex of the iron binding protein and the a pharmaceutically active substance, label or pharmaceutically active substance and label produced in step b); and/or
- the present invention relates to an isolated targeted delivery system of the first aspect or second aspect of the invention or producible according to the method of the third aspect of the invention for use as a medicament or diagnostic.
- the present invention relates to a pharmaceutical or diagnostic composition
- a pharmaceutical or diagnostic composition comprising the isolated targeted delivery system of the first or second aspect of the present invention or producible according to the method of the third aspect of the invention and a pharmaceutically acceptable carrier and/or suitable excipient(s).
- the present invention relates to an isolated targeted delivery system of the first aspect or second aspect of the present invention or producible according to the method of the third aspect of the invention for use in preventing, treating or diagnosing a disease characterized by hypoxic areas within the diseases tissue and/or by areas of oxidative stress; tumours, preferably solid tumours and/or its metastases, preferably breast cancer, pancreatic cancer, bladder cancer, lung cancer, colon cancer, or a tumour having hypoxic areas, an inflammatory disease, inflamed tissue, preferably inflamed joints or arthritic joints, inflamed lung, inflamed intestine or other inflamed tissue; lymph nodes, preferably inflamed lymph nodes, or other non-physiological lymph nodes that develop during disease preferably but not only during infection, cancer, or autoimmune disease; or ischemic areas, in particular in skin wounds or after organ infarctus (heart) or ischemic retina or for prophylactic or therapeutic vaccination, in particular to prevent or treat an infectious
- targeted pharmaceutically active substance delivery refers to the delivery of a pharmaceutically active substance to a patient which results in an increased concentration of the pharmaceutically active substance in a particular region of the body when compared to other regions of the body of that patient.
- the relative concentrations are compared between the diseased region(s) of the body and other regions of the body having similar access to the blood circulation.
- the concentration of the pharmaceutically active substance in a given number of cells or a given biopsy volume from the diseased region is at least 10% higher, if compared to the identical number of cells or biopsy volume from a non-diseased region after administration of the targeted pharmaceutically active substance delivery system of the present invention, preferably after 2-24 hrs.
- the concentration of the pharmaceutically active substance in the diseased region of the body of a patient is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%), more preferably at least 1000%) higher than in a non-diseased region of the body after administration of the targeted pharmaceutically active substance delivery system of the present invention, preferably after 2-24 hrs.
- At least 5% of the pharmaceutically active substance administered to a patient is delivered to the diseased region of the body, preferably at least 10%), more preferably at least 15%.
- the targeted delivery of the pharmaceutically active substance limits the potential deleterious effects of a pharmaceutically active substance to the diseased region of the body.
- targeted label delivery or “targeted contrast agent delivery” refers to the delivery of a label, in particular a contrast agent to a patient or a person to be diagnosed which results in an increased concentration of the label, in particular the contrast agent in a particular region of the body when compared to other regions of the body of that patient.
- the relative concentrations are compared between the diseased region(s) of the body and other regions of the body having similar access to the blood circulation.
- the concentration of the label, in particular a contrast agent in a given number of cells or a given biopsy volume from the diseased region is at least 10% higher, if compared to the identical number of cells or biopsy volume from a non-diseased region after administration of the targeted delivery system of the present invention, preferably after 1-24 hrs.
- the concentration of the label, in particular the contrast agent in the diseased region of the body of a patient is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%), more preferably at least 1000%) higher than in a non-diseased region of the body after administration of the targeted delivery system of the present invention, preferably after 2-24 hrs.
- the label in particular the contrast agent administered to a patient or a person to be diagnosed is delivered to the diseased region of the body, preferably at least 10%, more preferably at least 15%).
- the targeted delivery of the label, in particular the contrast agent limits the potential deleterious effects of an label, in particular the contrast agent to the diseased region of the body.
- targeted theragnostic delivery has a similar meaning as set out above for "targeted pharmaceutically active substance” and “targeted label delivery, however instead of only delivering a pharmaceutical active substance or a label the complex of the iron binding protein comprises in this embodiment both a pharmaceutically active substance and a label, thereby allowing the concomitant delivery of both a pharmaceutically active substance and a label.
- targeted pharmaceutically active substance delivery system is used in the present application to refer to a system that is capable of delivering a pharmaceutically active substance to the targeted region, i.e. capable of targeted delivery within the body of a patient, preferably to a diseased region.
- targeted label delivery system is used in the present application to refer to a system that is capable of delivering a label to the targeted region, i.e. capable of targeted delivery within the body of a patient, preferably to a diseased region.
- targeted theragnostic delivery system is used in the present application to refer to a system that is capable of delivering a complex of a pharmaceutically active substance and at the same time a label to the targeted region, i.e. capable of targeted delivery within the body of a patient, preferably to a diseased region and thus allows simultaneous treatment and diagnosis and/or treatment monitoring.
- targeted delivery system is used to commonly refer to “targeted pharmaceutically active substance delivery system”, “targeted label delivery system” and “targeted theragnostic delivery system”
- pharmaceutically active substance is used in the context of the present invention to refer to a substance that modifies or modulates cell activity, preferably a cell activity that leads to a disease in a patient.
- the term encompasses both substances which are already pharmaceutically active or which are capable of being activated, i.e. a prodrug.
- pharmaceutically active substances include so called (i) "small molecules", (ii) polynucleotides and (iii) peptide or proteins.
- small molecule is used in the context of the present invention to refer to a hydrocarbon with a molecular mass of below 1.500 g/mol or to pharmaceutically active radioactive isotopes.
- drugs that can be used comprise anti-cancer drugs, pharmaceutically active radioactive isotopes or ferrihydrite.
- prodrug refers to any active ingredient that, after administration, is metabolized or otherwise converted to a biologically active or more active ingredient (or drug) with respect to at least one property.
- a prodrug is modified chemically in a manner that makes it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered to the patient.
- a prodrug may for example have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
- a prodrug may be synthesized using reactants other than the corresponding drug.
- nucleic acid molecules include but are not limited to ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and mixtures thereof such as e.g.
- RNA-DNA hybrids The nucleic acids, can e.g. be synthesized chemically, e.g. in accordance with the phosphotriester method (see, for example, Uhlmann, E. & Peyman, A. (1990) Chemical Reviews, 90, 543-584).
- "Aptamers” are nucleic acids which bind with high affinity to a polypeptide. Aptamers can be isolated by selection methods such as SELEmirl46-a (see e.g. Jayasena (1999) Clin. Chem., 45, 1628-50; Klug and Famulok (1994) M. Mol. Biol. Rep., 20, 97-107; US 5,582,981) from a large pool of different single-stranded RNA molecules.
- Aptamers can also be synthesized and selected in their mirror-image form, for example as the L-ribonucleotide (Nolte et al. (1996) Nat. Biotechnol., 14, 1116-9; Klussmann et al. (1996) Nat. Biotechnol., 14, 1112-5). Forms which have been isolated in this way enjoy the advantage that they are not degraded by naturally occurring ribonucleases and, therefore, possess greater stability.
- peptide or “polypeptide” is used interchangeably in the context of the present invention to refer to a chain of at least two amino acids linked by peptide bonds.
- peptide in the context of the present invention is also used to refer to amino acid chains with more than 50, more than 100 or more than 150 amino acids.
- antibody refers to a glycoprotein belonging to the immunoglobulin superfamily; the terms antibody and immunoglobulin are often used interchangeably.
- An antibody refers to a protein molecule produced by plasma cells and is used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, its antigen.
- antibody fragment refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen.
- antibody fragment examples include a fragment antigen binding (Fab) fragment, a Fab' fragment, a F(ab') 2 fragment, a heavy chain antibody, a single-domain antibody (sdAb), a single-chain fragment variable (scFv), a fragment variable (Fv), a V H domain, a V L domain, a single domain antibody, a nanobody, an IgNAR (immunoglobulin new antigen receptor), a di-scFv, a bispecific T-cell engager (BITEs), a dual affinity re-targeting (DART) molecule, a triple body, a diabody, a single-chain diabody, an alternative scaffold protein, and a fusion protein thereof.
- Fab fragment antigen binding
- Fab' fragment fragment antigen binding
- F(ab') 2 fragment a heavy chain antibody
- sdAb single-domain antibody
- scFv single-chain fragment variable
- Fv fragment variable
- V H domain a V L
- diabody refers to a fusion protein or a bivalent antibody which can bind different antigens.
- a diabody is composed of two single protein chains which comprise fragments of an antibody, namely variable fragments.
- Diabodies comprise a heavy chain variable domain (V H ) connected to a light-chain variable domain (V L ) on the same polypeptide chain (V H -V L , or V L -V H ). By using a short peptide connecting the two variable domains, the domains are forced to pair with the complementary domain of another chain and thus, create two antigen-binding sites.
- Diabodies can target the same (monospecific) or different antigens (bispecific).
- single domain antibody refers to antibody fragments consisting of a single, monomeric variable domain of an antibody. Simply, they only comprise the monomeric heavy chain variable regions of heavy chain antibodies produced by camelids or cartilaginous fish. Due to their different origins they are also referred to VHH or VNAR (variable new antigen receptor)-fragments.
- single-domain antibodies can be obtained by monomerization of variable domains of conventional mouse or human antibodies by the use of genetic engineering. They show a molecular mass of approximately 12-15 kDa and thus, are the smallest antibody fragments capable of antigen recognition. Further examples include nanobodies or nanoantibodies.
- antibody mimetic refers to compounds which can specifically bind antigens, similar to an antibody, but are not structurally related to antibodies.
- antibody mimetics are artificial peptides or proteins with a molar mass of about 3 to 20 kDa which comprise one, two or more exposed domains specifically binding to an antigen. Examples include inter alia the LACI-D1 (lipoprotein-associated coagulation inhibitor); affilins, e.g.
- Trans-bodies e.g. human transferrin; tetranectins, e.g. monomeric or trimeric human C-type lectin domain; microbodies, e.g. trypsin-inhibitor-II; affilins; armadillo repeat proteins.
- Nucleic acids and small molecules are sometimes considered antibody mimetics as well (aptamers), but not artificial antibodies, antibody fragments and fusion proteins composed from these. Common advantages over antibodies are better solubility, tissue penetration, stability towards heat and enzymes, and comparatively low production costs.
- antigen is used to refer to a substance, preferably an immunogenic peptide that comprises at least one epitope, preferably an epitope that elicits a B or T cell response or B cell and T cell response.
- an “epitope”, also known as antigenic determinant, is that part of a substance, e.g. an immunogenic polypeptide, which is recognized by the immune system. Preferably, this recognition is mediated by the binding of antibodies, B cells, or T cells to the epitope in question.
- binding preferably relates to a specific binding.
- Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics.
- the term “epitope” comprises both conformational and non-conformational epitopes. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
- An immunogenic polypeptide according to the present invention is, preferably, derived from a pathogen selected from the group consisting of viruses, bacteria and protozoa. In particular embodiments.
- the immunogenic polypeptide is a tumor antigen, i.e. polypeptide or fragment of a polypeptide specifically expressed by a cancer.
- sequence identity is used throughout the specification with regard to polypeptide and nucleotide sequence comparisons. In case where two sequences are compared and the reference sequence is not specified in comparison to which the sequence identity percentage is to be calculated, the sequence identity is to be calculated with reference to the longer of the two sequences to be compared, if not specifically indicated otherwise. If the reference sequence is indicated, the sequence identity is determined on the basis of the full length of the reference sequence indicated by SEQ ID, if not specifically indicated otherwise.
- a polypeptide sequence consisting of 200 amino acids compared to a reference 300 amino acid long polypeptide sequence may exhibit a maximum percentage of sequence identity of 66.6 % (200/300) while a sequence with a length of 150 amino acids may exhibit a maximum percentage of sequence identity of 50 % (150/300). If 15 out of those 150 amino acids are different from the respective amino acids of the 300 amino acid long reference sequence, the level of sequence identity decreases to 45 %.
- the similarity of nucleotide and amino acid sequences, i.e. the percentage of sequence identity can be determined via sequence alignments. Such alignments can be carried out with several art- known algorithms, preferably with the mathematical algorithm of Karlin and Altschul (Karlin & Altschul (1993) Proc. Natl.
- Sequence matching analysis may be supplemented by established homology mapping techniques like Shuffle-LAGAN (Brudno M., Bioinformatics 2003b, 19 Suppl 1 :154-162) or Markov random fields. Structure based alignments for multiple protein sequences and/or structures using information from sequence database searches, available homologs with 3D structures and user-defined constraints may also be used (Pei J, Grishin NV: PROMALS: towards accurate multiple sequence alignments of distantly related proteins.
- label as used in the context of the present invention refers to any kind of compound being suitable for diagnostic purposes. Preferred compounds are selected from a fluorescent dye, a radioisotope and a contrast agent.
- a contrast agent is a dye or other substance that helps to show abnormal areas inside the body.
- the term label refers to a compound that comprises a chelating agent which forms a complex with divalent or trivalent metal cations.
- Preferred radioisotopes/fluorescence emitting isotopes are selected from the group consisting of alpha radiation emitting isotopes, gamma radiation emitting isotopes, Auger electron emitting isotopes, X-ray emitting isotopes, fluorescent isotopes, such as 65 Tb, fluorescence emitting isotopes, such as 18 F, 51 Cr, 67 Ga, 68 Ga, U 1 ln, 99m Tc, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y, 89 Zr, 90 Y, 149 Pm, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 72 As, 72 Se, 97 Ru, 109 Pd,
- fluorescent dyes are selected from the following classes of dyes: Xanthens (e.g. Fluorescein), Acridines (e.g. Acridine Yellow), Oxazines (e.g. Oxazine 1), Cynines (e.g. Cy7 / Cy 3), Styryl dyes (e.g. Dye-28), Coumarines (e.g. Alexa Fluor 350), Porphines (e.g. Chlorophyll B), Metal-Ligand-Complexes (e.g.
- PtOEPK Fluorescent proteins (e.g APC, R- Phycoerythrin), Nanocrystals (e.g QuantumDot 705), Perylenes (e.g. Lumogen Red F300) and Phtalocyanines (e.g. IRDYETM700DX) as well as conjugates and combinations of these classes of dyes or fluorescent 65 Tb emitting.
- Preferred contrast agents are selected from paramagnetic agents, e.g. Gd, Eu, W and Mn, preferably complexed with a chelating agent. Further options are superparamagnetic iron (Fe) complexes and particles, compounds containing atoms of high atomic number, i.e. iodine for computer tomography (CT), microbubbles and carriers such as liposomes that contain these contrast agents.
- CT computer tomography
- leukocyte is used in the context of the present invention to refer to cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All leukocytes are produced and derived from multipotent cells in the bone marrow known as a hematopoietic stem cells. Leukocytes are found throughout the body, including the blood and lymphatic system. All leukocytes have nuclei, which distinguishes them from the other blood cells, the anucleated red blood cells (RBCs) and platelets. Types of leukocyte can be classified in standard ways. Two pairs of the broadest categories classify them either by structure (granulocytes or agranulocytes) or by cell division lineage (myeloid cells or lymphoid cells).
- neutrophils neutrophils
- eosinophils neutrophils
- basophils lymphocytes
- monocytes neutrophils
- monocytes neutrophils
- monocytes neutrophils
- neutrophils neutrophils
- B cells B cells
- T cells T cells
- NK cells cytoplasm granules
- Myeloid cells neutrils, monocytes, eosinophils and basophils
- lymphoid cells lymphoid cells
- hematopoietic lineage cellular differentiation lineage
- CD45 + expression is characteristic of a subgroup of leukocyte cells, i.e. monocyte, monocyte-macrophages, lymphocytes, granulocytes, NK cells that are suitable to be used in the context of the targeted delivery system of the present invention, in particular since CD45 + leukocyte cells are attracted to particular tissues and cells within the body and are capable of delivering complexes of one or more iron binding proteins and one or more pharmaceutically active substances, labels or pharmaceutically active substances and labels to or into cells.
- This subgroup of leukocytes is in the following referred to as "CD45 + leukocyte cells" or "CD45 + leukocytes”.
- the monocyte is not a dendritic cell which differentiation is controlled by one or more of the following transcription factors: IFN-regulatory factor 8 (IRF8), nuclear factor interleukin (IL)-3 -regulated protein (NFIL3), basic leucine zipper transcriptional factor ATF-like 3 (BATF3) or Transcription Factor RelB (NF-KB Subunit) - RELB, Spi-1 Proto- Oncogene (PU/1), recombining binding protein suppressor of hairless (RBPJ), IFN- regulatory factor 4 (IRF4) or transcription factor E2-2 (also known as (TCF4).
- IRF8 IFN-regulatory factor 8
- IL nuclear factor interleukin
- BATF3 basic leucine zipper transcriptional factor ATF-like 3
- PU/1 Spi-1 Proto- Oncogene
- RBPJ recombining binding protein suppressor of hairless
- IRF4 IFN- regulatory factor 4
- transcription factor E2-2 also known as (TCF4).
- CD45 + leukocyte cells as defined above unless of clonal origin are a mixed population of different leukocytes which share the common property of expressing CD45 + surface antigen. Accordingly, subpopulations of cells within the diverse group of CD45 + leukocyte cells as defined above are characterized throughout the specification by further functional and/or structural characteristics.
- the term "CD45 + " indicates that the majority of cells within a population of cells or essentially all cells express the CD45 + surface antigen.
- the term “expresses” indicates that the surface antigen is produced within the cell and detectably exposed on the surface of a cell.
- the level of expression and, thus the number of surface antigens detectably exposed on the surface of a cell can vary greatly among different leukocytes.
- a cell is considered to be positive, i.e. is indicated to be " ", for a cellular surface antigen, if at least 5, preferably at least 10 copies of the surface antigen are detectably exposed on the surface of the cell.
- Preferred methods include Fluorescence Activated Cell Sorting (FACS).
- fluorescently labelled antibodies are used to bind to cellular surface antigens of a population of cells, the cells are subsequently isolated into single cells and based on fluorescence intensity measured for the single cell, characterized as being positive or negative for the given cellular surface antigen.
- the expression of a given protein is high or low. This means that the protein is detectably expressed in both instances, i.e. is " + ", however, at different levels. High and low expression, respectively, will mean different absolute numbers of proteins per cell for different proteins.
- a given protein may be considered to be expressed at high levels if there are more than 500 detectable copies of that protein per cell and to be expressed at low levels if there are between 1 to 50 detectable copies of that protein per cell.
- another protein may be considered to be expressed at high levels, if there are more than 5000 detectable copies and expressed at low levels, if there are between 1 to 500 detectable copies per cell. It is well known in the art how to quantify the number of proteins expressed or produced in a cell using flow cytometry and Becton Dickinson QuantibriteTM bead method (see e.g. Pannu, K.K., 2001, Cytometry. 2001 Dec 1;45(4):250- 8) or mass spectrometry (see, e.g.
- the term "high expression” of a given protein refers to detectable expression of that protein that is at least 70% of the highest expression level found, i.e. number of copies per cell, in a population of healthy CD45 + leukocytes.
- the term “low expression” of a given protein refers to detectable expression of that protein that is 30% or less of the highest expression level found, i.e. number of copies of that protein per cell, in a population of healthy CD45 + leukocytes.
- the "highest expression level" is determined as the average of the highest expression levels found in healthy CD45 + leukocytes of different subjects.
- preferred subpopulations of cells are characterized as "producing" a given protein. This is understood to mean that the protein is not necessarily detectable on the surface of the cell but may only be present inside the cell.
- the skilled person is well aware how to detect and/or quantify production of a protein inside a cell and/or select cells producing such proteins.
- cell populations can be defined by expression of specific transcription factors. It is well known in the art how to determine expression of a given protein or its encoding mRNA in a population of cells or even in single cells, e.g. using in vivo labeling with antibodies, FISH assays, in vivo single molecule fluorescent microscopy (Crawford, R. et al. Biophys J. (2013) 105(11): 2439) alone or in combination with Fluorescent Activated Cell Sorting (FACS), or by the PrimeFlow technique (e Bioscience), (Adam S. Venable, et. al, (2015) Methods in Molecular Biology).
- differentiated monocyte is used in the context of the present invention to refer to a monocyte differentiated from the committed precursor termed macrophage-DC precursor (MDP) mainly resident in bone marrow (but could be also in the spleen) and differentiate into either dendritic cells or macrophages.
- MDP macrophage-DC precursor
- mice consist of two main subpopulations: (i) CDl lb + cell with high expression of CX3CR1, low expression of CCR2 and Ly6C " and (ii) CDl lb + cell with low expression of CX3CR1, high expression of CCR2 and Ly6C + .
- mouse Ly6C + monocytes differentiate into Ly6C " monocytes in circulation.
- the differentiated monocyte is not a dendritic cell, which differentiation is controlled by one or more of the following transcription factors: IRF8, FIL3, BATF3, RELB, PU/1, RBPJ, IIRF4, and/or TCF4, and more preferably is not a dendritic cell.
- Macrophages are tissue-resident professional phagocytes and antigen-presenting cells
- activated macrophage which differentiate from circulating peripheral blood monocytes (PBMs).
- PBMs peripheral blood monocytes
- activated macrophage is used in the context of the present invention to refer to any macrophage that is polarized. Macrophage activation is in general achieved by incubation with interleukins, cytokines and/or growth factors. In particular IL-4 and M-CSF can be used as activating agents. Activated macrophages of different phenotypes are classified into Ml- macrophages, classically activated macrophages (CAM) and M2-macrophages, alternatively activated macrophages (AAM). The classically activated Ml -macrophages comprise immune effector cells with an acute inflammatory phenotype.
- CAM classically activated macrophages
- AAM alternatively activated macrophages
- M2-macrophages can be separated into at least three subgroups. These subtypes have various different functions, including regulation of immunity, maintenance of tolerance and tissue repair/wound healing.
- Ml inducer is used in the context of the present invention to refer to a compound that directs differentiation of PBMs to macrophages of the Ml type.
- M2 inducer is used in the context of the present invention to refer to a compound that directs differentiation of PBMs to macrophages of the M2 type. The skilled person is aware of a large number of ways to promote differentiation into either Ml or M2 macrophages.
- phagocytosis by macrophages is the process by which a macrophage engulfs a solid particle to form an internal vesicle known as a phagosome.
- iron binding protein refers to a protein that non-covalently binds an iron ion.
- examples of such proteins comprise ferritin, haemoglobin, transferrin; and lactoferrin. Iron binding proteins are bound by cellular surface receptors which facilitate the internalization of these proteins into cells.
- the present invention relates to an isolated targeted delivery system comprising a CD45 + monocyte, CD45 + monocyte-macrophage, CD45 + lymphocyte, CD45 + K cell and/or CD45 + granulocyte (hereinafter referred to as "CD45 + leukocyte cell”) comprising within said cell a complex of one or more iron binding proteins and a pharmaceutically active substance, label or pharmaceutically active substance and label.
- CD45 + monocyte is not a dendritic cell, which differentiation is controlled by one or more of the following transcription factors: IRF8, FIL3, BATF3, RELB, PU/1, RBPJ, IIRF4, and/or TCF4, and more preferably is not a dendritic cell.
- CD45 + leukocyte cells preferably activated macrophages, preferably Ml macrophages, more preferably M2 macrophages acquire pharmaceutically active substances, labels or pharmaceutically active substances and labels and deliver the pharmaceutically active substances, labels or pharmaceutically active substances and labels in the amount sufficient (i) to be detected using imaging systems to allowing them to be used to trace their location in the body.
- activated macrophages preferably Ml macrophages, more preferably M2 macrophages acquire pharmaceutically active substances, labels or pharmaceutically active substances and labels and deliver the pharmaceutically active substances, labels or pharmaceutically active substances and labels in the amount sufficient (i) to be detected using imaging systems to allowing them to be used to trace their location in the body.
- Ml macrophages preferably M2 macrophages
- a label 18 F-FDG, 89 Zr-oxide
- a label 18 F-FDG, 89 Zr-oxide
- a radioactive label can visualize organ with accumulation of the labelled cells preferably by positron emission tomography (PET) imaging, (ii) to elicit a prophylactic or therapeutic effect or to allow a therapy and diagnosis of a disease at the same time.
- PET positron emission tomography
- the present invention relates to an isolated targeted label delivery system comprising a CD45 + leukocyte cell, preferably capable of being labelled with one or more labels, preferably radiolabels or their conjugates and combinations. It is a preferred embodiment of the second aspect of the present invention that the cell is directly linked to or labelled with label.
- the label maybe within said cell, or on its surface, preferably it is on the surface of the cell.
- CD45 + leukocyte cell or cell population The ability of a given CD45 + leukocyte cell or cell population to internalize iron binding proteins depends on the expression of receptors involved in this internalization process.
- Receptors that lead to internalization of ferritin comprise, e.g. TfR, CXCR4, CD163, and TIM-2.
- TfR Receptors that lead to internalization of ferritin
- CXCR4 CXCR4, CD163, and TIM-2.
- the skilled person is well aware how to measure the amount of uptake of an iron binding protein and preferred method of measuring the uptake are described in the Example Section below.
- subpopulations of CD45 + leukocyte cells have a certain propensity to internalize one iron binding protein over another iron binding protein and, thus can attain higher complex concentrations and/or show less leakage of the complex from the cells.
- Such CD45 + leukocyte subpopulations are described in more detail below.
- complex of one or more iron binding proteins and a pharmaceutically active substance, label or pharmaceutically active substance and label refers to a composition in which one or more molecules of the pharmaceutically active substance, label or pharmaceutically active substance and label are covalently or non-covalently bound to one or more iron binding proteins.
- the covalent or non-covalent binding between the one or more iron binding proteins and the one more pharmaceutically active substance, label or pharmaceutically active substance and label can be direct or indirect. In the latter case the pharmaceutically active substance, label or pharmaceutically active substance and label is linked to the iron binding protein via a linker or spacer.
- Linker or spacers are known to the skilled artisan, such as polyalanine, polyglycin, carbohydrates, (CH 2 )n groups or polypeptide linkers. The skilled artisan will, thus, be able to select the respective suitable linker(s) or spacer(s) depending on the respective application.
- the iron binding proteins form cages like, e.g. ferritin
- the term "complex” also encompasses the enclosure of pharmaceutically active substances, labels or pharmaceutically active substances and labels within the cage even in the absence of a covalent or non-covalent bond between the protein(s) and the active compound(s). The formation of the complex allows the transport of the pharmaceutically active substance, label or pharmaceutically active substance and label into the cell when the cell is internalizing the iron binding protein.
- the pharmaceutically active substances, labels or pharmaceutically active substances and labels are bound to the iron binding protein in a way that does not interfere with the transport mechanism. This can be easily tested by the skilled person using uptake assays known in the art and described in the Example Section below. It is preferred that the complex is sufficiently stable to survive the transport within the cell to the target region within the body. Thus, it is preferred that the complex rather than the pharmaceutically active substance, label or pharmaceutically active substance and label alone is delivered to the cells or into the cells in the target region. This property also reduces possible deleterious effects, e.g. cytotoxicity, of the pharmaceutically active substance, label or pharmaceutically active substance and label to the CD45 + leukocyte cell.
- iron binding proteins used in the context of the present invention can form stable non-covalently bound complexes with a wide variety of pharmaceutically active substances, labels or pharmaceutically active substances and labels.
- the pharmaceutically active substance or label is a peptide, e.g. an antigenic peptide it is preferred that it is not expressed as a fusion with the iron binding protein, since in this case release of the peptide from the iron binding protein will require endosomal processing of the entire iron binding protein peptide fusion protein.
- the CD45 + leukocyte cells originate from the patient to be treated in such case the cell loaded with the complex would be autologous to the patient. It is also envisioned that patients are MHC typed prior to treatment with the targeted delivery of the present invention and that the leukocyte cell type used for a given patient is MHC matched to the patient. In these two preferred embodiments the CD45 + leukocyte cell is a primary cell or derived by a low number of differentiation steps from a primary cell. Alternatively, the CD45 + leukocyte cell may be from an immortalized but preferably non-transformed CD45 + leukocyte cell line. Thus the blood used for CD45 + leukocyte cells, i.e.
- CD45 + monocyte, CD45 + monocyte- macrophage, CD45 + granulocyte, or CD45 + lymphocyte, in particular CD45 + NK cell, isolation is preferably obtained from the patient to be treated or from a healthy donor.
- the blood can be obtained from the blood bank.
- Use of umbilical cord blood is also considered herein.
- the skilled person is well aware how to select CD34 + hematopoietic precursor cells and how to differentiate such cells into leukocytes.
- CD45 + leukocyte cell is used throughout this specification to refer to a CD45 + monocyte, CD45 + monocyte-macrophage, CD45 + lymphocyte and/or CD45 + .
- the monocyte is not a dendritic cell, which differentiation is controlled by one or more of the following transcription factors: IRF8, FIL3, BATF3, RELB, PU/1, RBPJ, IIRF4, and/or TCF4, and more preferably is not a dendritic cell.
- Preferred subpopulations in these general categories of leukocytes are defined in the following by structural parameters, e.g. presence or absence of a given protein, functional properties and/or method of their production/differentiation.
- the targeted delivery system of the present invention still provides the advantages outlined above, if in a population of cells not every cell has a particular property in as long as the majority of cells within that population has that property.
- the property of one preferred cell of the targeted delivery system of the present invention is described. It is appreciated by the skilled person that a pharmaceutical composition of the present invention will comprises millions of cells and that not every cell within the population will have the functional and/or structural properties outlined herein but that the pharmaceutical composition can nevertheless be used to treat a disease, if the majority of cells share the respective functional and/or structural properties.
- the present inventors have recognized that subpopulations of CD45 + leukocyte cells have particular advantageous properties including among others efficiency and/amount of complex uptake in general, ability to retain the complex within the cell, i.e. to avoid leakage and of target release of the pharmaceutically active substance, label or pharmaceutically active substance and label, efficiency of uptake of a particular iron binding protein and/or targeting to particular tissues or cells and, thus suitability to treat or ameliorate a particular disease.
- the present inventors have, e.g. observed that CD45 + leukocyte cells, which express one or more of the following antigens: CD204, CD206, CD200R, CCR2 have a preference for ferritin uptake over the uptake of other iron binding proteins.
- iron binding protein in the complex is ferritin it is preferred to select CD45 + leukocyte cells that express one or more of the following antigens: CD204, CD206, CD200R, CCR2. Accordingly, in a preferred embodiment of the present invention
- the monocyte is a CD1 lb + monocyte, preferably selected from the group consisting of a CDl lb + CD14 + monocyte, a CDl lb + CD16 + monocyte, a CDl lb + CD14 + CD16 + monocyte, a CDl lb + CD14 + MHClf monocyte, a CDl lb + CD14 + CD115 + monocyte, CDl lb + CD114 + monocyte, CDl lb + CD116 + monocyte, CDl lb + CCR1 + monocyte, CDl lb + CCR2 + monocyte, CDl lb + CX3CR + monocyte, CDl lb + CXR4 + monocyte, CD1 lb + CXR6 + monocyte and a CD1 lb + CD14 + CD33 + monocyte,
- the monocyte is not a dendritic cell, which differentiation is controlled by one or more of the following transcription factors: IRF8, FIL3, BATF3, RELB, PU/1, RBPJ, IIRF4, and/or TCF4, and more preferably is not a dendritic cell.;
- the differentiated monocyte or monocyte-macrophage is differentiated by M-CSF and selected from the group consisting of a macrophage, an activated macrophage, preferably a CDl lb + macrophage, more preferably a CDl lb + CD16 + macrophage, CDl lb + CD32 + macrophage, CDl lb + CD64 + macrophage, CDl lb + CD68 + macrophage, preferably a CDl lb + CD86 + Ml macrophage, preferably producing inducible nitric oxide synthetase (iNOS) and/or secreting interleukin 12 (IL-12) or preferably CDl lb + CCR2 + M2 macrophage, CDl lb + CD204 + M2 macrophage, CDl lb + CD206 + M2 macrophage, CDl lb + CD204 + CD206 + M2 macrophage, CDl lb + Major Histocompatibility Complex II +
- a foam cell is a type of macrophage that localize to fatty deposits on blood vessel walls, where they ingest low-density lipoproteins and become loaded with lipids giving them a foamy appearance. These cells secrete various substances involved in plaque growth and their death promotes inflammation, thereby contributing to cardiovascular disease;
- monocyte-macrophage or activated monocyte-macrophage is differentiated by M-CSF and is preferably expressing at least one chemokine receptor, preferably selected from the group consisting of CCR1, CCR2, CXCR4, and CXCR6, or at least one growth factor receptor, preferably selected from the group consisting of macrophage colony stimulating factor Receptor (CD 115), granulocyte colony stimulating factor Receptor (CD114), and granulocyte-macrophage colony stimulating factor Receptor (consisting of CD116 and CD131); monocytes of these characteristics are particular suitable to treat inflammatory conditions and cancer; (iv) the lymphocyte is selected from the group consisting of a CD3 + and CD4 + or CD8 + T lymphocyte, or a CD19 + , CD20 + , CD21 + , CD19 + CD20 + , CD19 + CD21 + , CD20 + CD21 + , or CD19 + CD20 + CD21 + B lymphocyte; or a
- the granulocyte is selected from the group consisting of a neutrophil, preferably a CD66b + neutrophil, an eosinophil and a basophil, preferably a CD193 + eosinophil.
- a factor capable of altering the macrophages ability to secrete cytokines preferably IL-10 and IL-12, chemokines and/or to produce iNOS, arginase or other immunomodulating enzymes; examples of such factors are: activated platelets, IL-4, IL-10, IL-13, immune complex of an antigen and antibody, IgG, heat activated gamma-globulin, glucocorticosteroid, tumour growth factor- ⁇ (TGF- ⁇ ), IL-1R, CC-chemokine ligand 2 (CCL-2), IL-6, Macrophage colony- stimulating factor (M-CSF), peroxisome proliferator-activated receptor ⁇ (PPARy) agonist, leukocyte inhibitory factor (LIF), adenosine, helminth and fungal infection, lipopolysaccharide (LPS), interferon ⁇ (INF- ⁇ ), viral and bacterial infection; in this respect it was observed that activation of cytokines,
- (ii) is characterized by expression of at least one of following antigens: CD64, CD86, CD16, CD32, high expression of MHCII, and/or production of iNOS and/or IL-12;
- (iii) is producible by in vitro incubation of a monocyte or macrophage with a factor capable of inducing the ability of the macrophage to phagocytose, e.g. IL-18, opsonins (for example complement-derived proteins such as iC3b, immunoglobulin G), calcitonin gene-related peptide (CGRP), lipopolysaccharide (LPS), interferon ⁇ (INF- ⁇ ), , viral infection and/or bacterial infection;
- a monocyte or macrophage with a factor capable of inducing the ability of the macrophage to phagocytose, e.g. IL-18, opsonins (for example complement-derived proteins such as iC3b, immunoglob
- (iv) is characterized by expression of at least one of following antigens: CD204, CD206, CD200R; CCR2, transferrin receptor (TfR), CXC-motive chemokine receptor 4 (CXCR4), CD163, and/or T cell immunoglobulin-domain and mucin-domain 2 (TFM- 2), and/or show low expression of MHCII; activated macrophages having these properties are particularly suitable for complexes comprising ferritin as the iron binding protein;
- cytokine secretion preferably of IL-12, or IL-10, or production of inducible nitric oxide synthetase (iNOS) (or other pro-inflammatory compounds), arginase or other immunosuppressive/anti-inflammatory compounds.
- iNOS inducible nitric oxide synthetase
- the Ml inducer for differentiating macrophages into Ml macrophages is selected from the group consisting of lipopolysaccharide (LPS), interferon ⁇ (INF- ⁇ ), and viral and bacterial infection and the M2 inducer for differentiating macrophages into M2 macrophages is selected from the group consisting of IL-4, IL-10, IL-13, immune complex of an antigen and antibody, IgG, heat activated gamma-globulin, glucocorticosteroid, tumour growth factor- ⁇ (TGF- ⁇ ), IL-IR, CC-chemokine ligand 2 (CCL-2), IL-6, Macrophage colony-stimulating factor (M-CSF), peroxisome proliferator-activated receptor ⁇ (PPARy) agonist, leukocyte inhibitory factor (LIF), adenosine, helminth and fungal infection.
- LPS lipopolysaccharide
- IFN- ⁇ interferon ⁇
- both complex loaded Ml macrophages and M2 macrophages are suitable for targeted active agent delivery into hypoxic tissues, preferably a tumour or its metastasis.
- hypoxic tissues preferably a tumour or its metastasis.
- 3 to 5% of the administered Ml macrophages localized at the tumour site while about 35% of the M2 macrophages showed tumour specific targeting.
- this general advantage of M2 macrophages were offset when using a complex comprising haemoglobin and drug, since significantly larger amounts of this complex could be loaded into Ml macrophages than into M2 macrophages.
- this specific tropisms makes M2 macrophages more suitable for treating tumour and diseases characterized by hypoxic tissue.
- CCL2-activated macrophages are particularly suitable to target lymph nodes, preferably inflamed lymph nodes.
- target lymph nodes preferably inflamed lymph nodes.
- the use of such macrophages is preferred in all uses in which the targeting of lymph nodes is desired, in particular for prophylactic or therapeutic vaccination as well as for diagnosis of inflamed lymph nodes. Accordingly, the loading of CCL2-activated macrophages with complexes of iron binding proteins and antigens is preferred.
- (ii) is producible by in vitro incubation of monocytes with at least one inducer, preferably Ml or M2 inducer, more preferably at least one M2 inducer;
- (iii) is characterized by expression of at least one of the following antigens: TfR, CD163, TIM-2, CD 14, CD 16, CD33, and/or CD 115;
- (iv) is characterized by expression of at least one of the following antigens: TfR, CD163, TIM-2, CXCR4, CD 14, and/or CD 16; and/or
- (vi) is not a dendritic cell which differentiation is controlled by one or more of the following transcription factors: IRF8, FIL3, BATF3 or RELB, PU/1, RBPJ, IRF4 or TCF4.
- the Ml inducer for differentiating monocyte-macrophage cells is selected from the group consisting of LPS, INF- ⁇ or viral or bacterial infection or the M2 inducer for differentiating monocytes is selected from the group consisting of IL-4, IL-10, IL-13, immune complex of an antigen and antibody, IgG, heat activated gamma-globulins, Glucocorticosteroids, TGF- ⁇ , IL-IR, CCL-2, IL-6, M-CSF, PPARy agonist, Leukocyte inhibitory factor (LIF), cancer-conditioned medium, cancer cells, adenosine and helminth or fungal infection.
- LPS LPS
- M2 inducer for differentiating monocytes is selected from the group consisting of IL-4, IL-10, IL-13, immune complex of an antigen and antibody, IgG, heat activated gamma-globulins, Glucocorticoster
- monocytes are suitable for targeted active agent delivery into hypoxic tissues, preferably the tumour or its metastasis while monocytes treated with M2 activators are more suitable for targeted active agent delivery into hypoxic tissues, preferably the tumour or its metastasis.
- This specific tropisms make monocytes treated with M2 activators more suitable to targeting tumour and hypoxic sites, e.g. sites of inflammation.
- the lymphocyte in a preferred embodiment of the targeted delivery system of the present invention the lymphocyte:
- (i) is obtainable from blood, spleen, or bone marrow or is producible from a CD34 + precursor cell as known to the skilled person and also described in the, e.g. Lefort and Kim, 2010, J Vis Exp 40: 2017; Tassone and Fidler, 2012, Methods in Molecular Biology 882: 351-357; Kouro et al. 2005, Current Protocols in Immunology, 66:F22F.1 :22F.1.1-22F.1.9.;
- (iv) is characterized by expression of at least one of the following antigens: (a) CD3 and CD4 or CD 8 or (b): CD 19, CD20, CD21, CD 19 CD20, CD 19 CD21, CD20 CD21, or CD 19 CD20 CD21 antigen, and is preferably capable of producing immunoglobulins
- the CD45+ lymphocytes is a K cell, which
- (ii) is characterized by the lack of CD3 expression and expression of at least one of the following CD56 + and/or CD94 + , CD158a + CD158f CD314 + CD335 + .
- (i) is obtainable from blood, spleen or bone marrow or producible from a CD34 + precursor cell as described, e.g. in Kuhs et al. 2015, Curr Protoc Immunol 111 :7.23-1-7.23.16; Coquery et al. 2012, Cytometry A 81(9): 806-814; Swemydas and Lionakis 2013, J Vis Exp 77: 50586.;
- (ii) is characterized by expression of at least one of the following CD66b and/or CD 193;
- (iii) is a polymorphonuclear leukocyte characterized by the presence of granules in its cytoplasm;
- (iii) is characterized by expression of at least one of the following: TfR, CD163, TIM-2, and/or CXCR4.
- the iron binding protein is selected from the group consisting of ferritin, preferably heavy (H) type ferritin, light (L) ferritin and/or mitochondrial ferritin; haemoglobin, preferably haemoglobin A, haemoglobin AS, haemoglobin SC, haemoglobin C, haemoglobin D, haemoglobin E, haemoglobin F, haemoglobin H; haemoglobin-haptoglobin complex, haemopexin, transferrin; and lactoferrin.
- ferritin preferably heavy (H) type ferritin, light (L) ferritin and/or mitochondrial ferritin
- haemoglobin preferably haemoglobin A, haemoglobin AS, haemoglobin SC, haemoglobin C, haemoglobin D, haemoglobin E, haemoglobin F, haemoglobin H
- haemoglobin preferably haemoglobin A, haemoglobin AS, haemoglobin SC, haemoglobin C, haemoglobin D, haemoglobin E, haemoglobin F, haemoglobin H; haemoglobin-haptoglobin complex, hemopexin, transferrin; and lactoferrin encompass structural variants of the naturally occurring proteins and, thus relates to proteins that have at least 70 %, preferably at least 75 %, more preferably at least 80 %, more preferably at least 85 %, more preferably at least 90 %, more preferably at least 95 % more preferably at least 100 % of the ability of the respective wild-type protein to bind iron ion(s).
- the iron binding proteins used in the context of the present invention are preferably of mammalian, more preferably mouse, rat, dog, ape, in particular, chimpanzee, or human, most preferably of human origin. Consensus sequences of the preferred iron binding proteins used in the context of the present invention are shown in Fig. 1 below. Preferred structural variants are based on the sequences indicated in Fig. 1. The residues marked with X vary among different mammalian ferritins, transferrins, and haemoglobins. The alteration of these residues is not crucial for the ability of the proteins to bind to iron ions. Accordingly, it is preferred that amino acid mutations or deletions effect one or more of the residues marked with an X.
- Plasma proteins have always been privileged carriers for the delivery of active pharma ingredients in cancer therapy.
- albumin the most abundant plasma protein, is currently used in therapeutic protocols for the delivery of taxane molecules and doxorubicin derivatives (Larsen MT et al. 2016, Mol Cell Ther 27;4:3).
- Ferritin has a cage architecture and capability of iron-binding which could be used to encapsulate pharmaceutically active substances and/or labels inside its cavity.
- Ferritins are not abundant in plasma, but can be readily produced in high yield as recombinant proteins in common protein expression vectors such as Escherichia coli cells.
- Ferritins H- or L ⁇ chains are encoded as small protein monomer (21 kDa and 19 KDa for H and L chains, respectively) capable of a 24-mer assembly into a cage-like structure, delimiting a 8 nm diameter cavity.
- H -ferritin homopoiymers represent a preferred protein construct in order to specifically deliver encapsulated drugs to CD45 leukocyte cells expressing TfR. Furthermore H-ferritin targets complex pharmaceutically active substances, labels or pharmaceutically active substances and labels to the cell nucleus (and therefore directly delivers DNA-binding proteins into the nucleus.
- Transferrin can be efficiently conjugated to various molecueis including anticancer drugs through covalent linkers that are appropriately released inside the cells (Beyer U et al . 1998, J Med Chem 41 (15):2701-2708). In case of transferrin, only lysine groups on the protein surface are ready available for covalent attachment.
- Haemoglobin has been considered in the past as a possible drug carrier, due to its versatility in chemical conjugation with drugs, its abundance and relative stability in the blood (Somatogen, 1993, WO1993008842 Al). Nevertheless, the lack of receptor targeting properties did not foster biomedical applications other than blood substitutes or antisickling agent. As a matter of fact. Fib can only be recognized by CD 163 (haptoglobin haemogiobin receptor) epitopes on the leukocytes, especially monocyte-macrophage origin.
- CD 163 haptoglobin haemogiobin receptor
- the 0345 ⁇ leukocyte, in particular macrophage based protein delivery, described in this application moved haemoglobin center stage as a target specific carrier of pharmaceutically active substances and/or labels.
- Haemoglobin can be readily covalently linked to appropriate pharmaceutically active substances and/or labels, host hydrophobic pharmaceutically active substances and/or labels within the heme binding pocket or even transport small molecules, e.g. cytotoxic molecules linked to the heme iron. Hb can be easily modified by selective attachment of the appropriate drug conjugate to the beta93 cysteine residue, the only titratabie cystein on the protein surface.
- Maleimido functionaiized drugs such as the tubuline inhibitor MonomethylAuri statin (MMAE) or the DNA crosslink! ng drug Pyrrolobenzodiazepme dimer (PBD) are most notable examples of extremely potent cytotoxics that can be readily and specifically attached to the relevant cys beta93 residue.
- lysine residues on the Hb surface may be easily amenable to drug conjugation through cleavable succinimide linkers.
- Haemoglobin also offers a unique capability of releasing non covalently bound heme group at acidic pH values. Apo-haemoglobin thus obtained is capable of hosting several hydrophobic molecules within the empty heme pocket, as shown in the case of paclitaxel (Meng Z et al. 2015 J Pharm Sci 104(3): 1045-55) or for labels with fluorescent properties (e.g. chlorine e6, hyperycin, phtalocyanine derivatives) (Dong J et al. J Photochem Photobiol B 2014, 140: 163-172).
- haemoglobin (Hb), transferrin (Tf) and ferritins were shown by the present inventors to be privileged carriers of pharmaceutically active substances and labels, once loaded into appropriate cell systems with tumour targeting properties, e.g. activated macrophages.
- tumour targeting properties e.g. activated macrophages.
- the easy, fast, cheap and safe purification procedure of these protein also provide a tremendous added value.
- H-type ferritins Based on sequences of mammalian H-type ferritins, L-type ferritins, haemoglobin alpha chains, haemoglobin beta chains and transferrins a consensus sequence was determined for each of these proteins. These are shown in Fig. 1 in SEQ ID NO: 2, 7, 9, 14, 16, 20, and 25, respectively). On this basis but also on the basis of deletion and structural analysis disclosed in the prior art a minimal fragment was determined for H-type ferritins, L-type ferritins, haemoglobin alpha chains, and haemoglobin beta chains sufficient for uptake by CD45 + leukocytes.
- Transferrin comprises a N-terminally located domain and a C-terminally located domain that are necessary for binding iron and uptake by CD45 + leukocytes, if comprised in one polypeptide and positioned between 100 to 450 amino acids apart, preferably between 150 to 400, more preferably between 200 to 350 amino acids and more preferably 250 to 320 amino acids apart.
- the N-terminal domain comprises amino acids 1 to 82 of full length consensus transferrin (SEQ ID NO: 25) or full length human transferrin (SEQ ID NO: 28).
- the C- terminal domain comprises amino acids 396 to 510 of full length consensus transferrin (SEQ ID NO: 25) or full length human transferrin (SEQ ID NO: 28).
- an X is indicated in the consensus sequence it independently stands for any amino acid and characterizes an amino acid not or only poorly conserved among mammalian H-type ferritins, which can be mutated without or little detriment to the iron binding properties of the respective iron binding protein. It is preferred that X in each case takes on the meaning of the amino acid of the respective human iron binding protein aligning with X. This information can be taken, e.g. from Fig. 1, which shows alignments of the consensus sequences with human an in some instances mouse proteins.
- Preferred H-type ferritins comprise or consist of the amino acid sequence indicated in SEQ ID NO: 1 and variants thereof having at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a H-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 1 to be taken up by CD45 + leukocytes, preferably M2 leukocytes.
- X at position 5 may be present or absent, if present it means any amino acid, preferably He, X at position 6 means any amino acid, preferably Asn, X at position 14 means any amino acid, preferably Tyr, X at position 24 means any amino acid, preferably Tyr or Cys, X at position 66 means any amino acid, preferably Phe, X at position 68 means any amino acid, preferably Gin, X at position 75 means any amino acid, preferably Arg or Cys, X at position 90 means any amino acid, preferably His, X at position 94 means any amino acid, preferably Ser or Asn, X at position 120 may be present or absent, if present it means any amino acid, preferably His or Tyr, more preferably His, X at position 123 means any amino acid, preferably Asn or Ser, more preferably Asn, X at position 128 means any amino acid, preferably Ala or Ser, more preferably Ala.
- the H-type ferritin comprises or consists of murine ferritin according to SEQ ID NO: 3.
- preferred structural variants have at least 70% amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70% of the ability of a H-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 3 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the H-type ferritin comprises or consists of human ferritin according to SEQ ID NO: 5.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a H-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 5 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the H-type ferritin comprises or consists of a mammalian consensus sequence derived from aligning full length H-type ferritins according to SEQ ID NO: 2 or 7, with 2 being preferred.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a H-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 2 or 7, with 2 being preferred to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- X at position 6 can be any naturally occurring amino acid, preferably Pro
- X at position 14 can be any naturally occurring amino acid, preferably His
- X at position 16 can be any naturally occurring amino acid, preferably Asp
- X at position 21 may be present or absent, if present it means any amino acid, preferably He
- X at position 22 means any amino acid, preferably Asn
- X at position 30 can be any naturally occurring amino acid, preferably Tyr
- X at position 40 can be any naturally occurring amino acid, preferably Tyr or Cys, more preferably Tyr
- X at position 82 can be any naturally occurring amino acid, preferably Phe
- X at position 84 can be any naturally occurring amino acid, preferably Gin
- X at position 91 can be any naturally occurring amino acid, preferably Arg or Cys, more preferably Cys
- X at position 106 can be any naturally occurring amino acid, preferably His
- X at position 110 can be any naturally occurring amino acid, preferably Asn or Ser, more preferably Asn,
- X at position 6 can be any naturally occurring amino acid, preferably Pro X at position 14 can be any naturally occurring amino acid, preferably His, X at position 16 can be any naturally occurring amino acid, preferably Asp, X at position 21 may be present or absent, if present it means any amino acid, preferably He, X at position 29 can be any naturally occurring amino acid, preferably Tyr, X at position 81 can be any naturally occurring amino acid, preferably Phe, X at position 83 can be any naturally occurring amino acid, preferably Gin, X at position 105 can be any naturally occurring amino acid, preferably His, X at position 144 can be any naturally occurring amino acid, preferably Ala or Ser, more preferably Ala, X at position 180 is absent or any naturally occurring amino acid, preferably Asn, X at position 181 is absent or any naturally occurring amino acid, preferably Glu, X at position 182 is absent or any naturally occurring amino acid, preferably Ser.
- the H-type ferritin comprises or consists of murine full length ferritin according to SEQ ID NO: 4 being preferred.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a murine H-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 4 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the H-type ferritin comprises or consists of human full length ferritin according to SEQ ID NO: 6 being preferred.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70% of the ability of a human H-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 6 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- Preferred L-type ferritins comprise or consist of the amino acid sequence indicated in SEQ ID NO: 8 and variants thereof having at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85% amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70% of the ability of a L-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 8 to be taken up by CD45 + leukocytes, preferably M2 leukocytes.
- X at position at position 5 can be any naturally occurring amino acid, preferably Asp or Glu, more preferably Asp, X at position 12 can be any naturally occurring amino acid, preferably Arg or Ser, more preferably Ser, X at position 17 can be any naturally occurring amino acid, preferably Ser or Arg, more preferably Ser, X at position 19 can be any naturally occurring amino acid, preferably Arg or Gin, more preferably Gin, X at position 29 can be any naturally occurring amino acid, preferably Phe, X at position 30 can be any naturally occurring amino acid, preferably Tyr or Phe, more preferably Tyr, X at position 42 can be any naturally occurring amino acid, preferably Ser or Gly, more preferably Ser, X at position 56 can be any naturally occurring amino acid, preferably Ala or Tyr, more preferably Tyr, X at position 61 can be any naturally occurring amino acid, preferably Glu or Lys, more preferably Lys, X at position 62 can be any naturally occurring amino acid, preferably Met or Phe, more
- the L-type ferritin comprises or consists of murine L-type ferritin according to SEQ ID NO: 10.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a L-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 10 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the L-type ferritin comprises or consists of human ferritin according to SEQ ID NO: 12.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a L-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 12 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the L-type ferritin comprises or consists of a mammalian consensus sequence derived from aligning full length H-type ferritins according to SEQ ID NO: 9 or 14, with 9 being preferred.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a L-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 9 or 14, with 9 being preferred to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- X at position 12 can be any naturally occurring amino acid, preferably Asp or Glu, more preferably Asp, X at position 19 can be any naturally occurring amino acid, preferably Ser or Arg, more preferably Ser, X at position 24 can be any naturally occurring amino acid, preferably Ser or Arg, more preferably Ser, X at position 26 can be any naturally occurring amino acid, preferably Arg or Gin, more preferably Gin, X at position 36 can be any naturally occurring amino acid, preferably Phe, X at position 37 can be any naturally occurring amino acid, preferably Tyr or Phe, more preferably Tyr, X at position 47 can be any naturally occurring amino acid, preferably Ser or Gly, more preferably Ser, X at position 63 can be any naturally occurring amino acid, preferably Ala or Tyr, more preferably Tyr, X at position 68 can be any naturally occurring amino acid, preferably Glu or Lys, more preferably Lys, X at position 69 can be any naturally occurring amino acid, preferably Met or P
- X at position 36 can be any naturally occuring amino acid, preferably Phe
- X at position 37 can be any naturally occurring amino acid, preferably Tyr or Phe, more preferably Tyr
- X at position 94 can be any naturally occurring amino acid, preferably Pro or Gin, more preferably Pro
- X at position 126 can be any naturally occurring amino acid, preferably Leu
- X at position 137 can be any naturally occurring amino acid, preferably Lys or Glu, more preferably Glu
- X at position 147 can be any naturally occurring amino acid, preferably Asp or Asn, more preferably Asp
- X can be any naturally occurring amino acid
- X at position 163 can be absent or any naturally occurring amino acid, preferably Thr
- X at position 166 can be absent or any naturally occurring amino acid, preferably Pro
- X at position 168 can be any naturally occurring amino acid, preferably Gly or Ala, more preferably Ala.
- the L-type ferritin comprises or consists of murine full length ferritin according to SEQ ID NO: 11 being preferred.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a murine L-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 11 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the L-type ferritin comprises or consists of human full length ferritin according to SEQ ID NO: 13 being preferred.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a human L-type ferritin consisting of the amino acid sequence according to SEQ ID NO: 13 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the alpha haemoglobin comprises or consists of a minimal mammalian consensus sequence derived from aligning full length alpha haemoglobins according to SEQ ID NO: 15
- Preferred comprise or consist of the amino acid sequence indicated in SEQ ID NO: 15 and variants thereof having at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of an alpha haemoglobin consisting of the amino acid sequence according to SEQ ID NO: 15 to be taken up by CD45 + leukocytes, preferably Ml macrophages.
- the alpha haemoglobin comprises or consists of a minimal human amino acid sequence derived of human alpha haemoglobin according to SEQ ID NO: 17.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of an alpha haemoglobin consisting of the amino acid sequence according to SEQ ID NO: 17 to be taken up by CD45 + leukocytes, preferably Ml macrophages.
- the alpha haemoglobin comprises or consists of a mammalian consensus sequence derived from aligning full length alpha haemoglobins according to SEQ ID NO: 16.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of an alpha haemoglobins consisting of the amino acid sequence according to SEQ ID NO: 16 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the alpha haemoglobin comprises or consists of human full length alpha haemoglobin according to SEQ ID NO: 18.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95% amino acid identity and in each case at least 70 % of the ability of a human full length alpha haemoglobin consisting of the amino acid sequence according to SEQ ID NO: 18 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the alpha haemoglobin comprises or consists of a minimal mammalian consensus sequence derived from aligning full length beta haemoglobins according to SEQ ID NO: 19 and variants thereof having at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a beta haemoglobin consisting of the amino acid sequence according to SEQ ID NO: 19 to be taken up by CD45 + leukocytes, preferably Ml macrophages.
- the alpha haemoglobin comprises or consists of a minimal human amino acid sequence derived of human beta haemoglobin according to SEQ ID NO: 21.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a beta haemoglobin consisting of the amino acid sequence according to SEQ ID NO: 21 to be taken up by CD45 + leukocytes, preferably Ml macrophages.
- the beta haemoglobin comprises or consists of a mammalian consensus sequence derived from aligning full length beta haemoglobins according to SEQ ID NO: 20.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of an beta haemoglobins consisting of the amino acid sequence according to SEQ ID NO: 20 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the beta haemoglobin comprises or consists of human full length beta haemoglobin according to SEQ ID NO: 22.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a human full length beta haemoglobin consisting of the amino acid sequence according to SEQ ID NO: 22 to be taken up by CD45 + leukocytes, preferably M2 macrophages.
- the transferrin comprises or consists of a mammalian consensus sequence derived from aligning full length alpha haemoglobins according to SEQ ID NO: 25.
- preferred transferrins comprise or consist of the amino acid sequence indicated in SEQ ID NO: 25 and of variants thereof having at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a transferrin consisting of the amino acid sequence according to SEQ ID NO: 25 to be taken up by CD45 + leukocytes preferably Ml macrophages.
- the transferrin comprises or consists of human transferrin according to SEQ ID NO: 28.
- preferred structural variants have at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a transferrin consisting of the amino acid sequence according to SEQ ID NO: 28 to be taken up by CD45 + leukocytes, preferably Ml macrophages.
- the transferrin used in the present invention comprises at least the N-terminal domain according to SEQ ID NO: 23 and the C-terminal domain according to SEQ ID NO: 24.
- Preferred transferrin comprise proteins that comprise the amino acid sequence indicated in SEQ ID NO: 23 and 24 as well as variants thereof having at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a transferrin consisting of the amino acid sequence according to SEQ ID NO: 23 and 24 to be taken up by CD45 + leukocytes, preferably Ml macrophages.
- SEQ ID NO: 23 or 24 indicates a consensus sequence of mammalian transferrins.
- the transferrin used in the present invention comprises at least the N-terminal domain according to SEQ ID NO: 26 and the C-terminal domain according to SEQ ID NO: 27.
- Preferred transferrin comprise proteins that comprise the amino acid sequence indicated in SEQ ID NO: 26 and 27 as well as variants thereof having at least 70 % amino acid identity, more preferably at least 75 % amino acid identity, more preferably at least 80 % amino acid identity, more preferably at least 85 % amino acid identity, more preferably at least 90 % amino acid identity, more preferably at least 95 % amino acid identity and in each case at least 70 % of the ability of a transferrin consisting of the amino acid sequence according to SEQ ID NO: 26 and 27, respectively, to be taken up by CD45 + leukocytes, preferably Ml macrophages.
- Preferred ferritins also comprise proteins that, irrespective of the given amino acid sequence, conform to the 24-mer subunit assembly of a four helix bundle protein module, falling within given sequence alignments of distantly related proteins as defined by 3D structure based alignments.
- monocytes, macrophages and preferably M2 macrophages are able to uptake the amount of label enough to make them visible using imaging methods at the site of their accumulation (e.g. in the tumour or its metastasis, hypoxia site).
- lymphocytes and M2 macrophages are better in uptake of complexes comprising one or more ferritin and one or more pharmaceutically active substance, label or pharmaceutically active substance and label, that Ml macrophages are better in uptake of complexes comprising one or more haemoglobin and one or more pharmaceutically active substance, label or pharmaceutically active substance and label and that macrophages are better in uptake of complexes comprising one or more transferrin and one or more pharmaceutically active substance, label or pharmaceutically active substance and label.
- CD45 + leukocytes monocytes, Ml and M2 macrophages, granulocytes and lymphocytes, described above complexes comprising one or more ferritin and one or more pharmaceutically active substance, label or pharmaceutically active substance and label are used to load M2 macrophages, lymphocytes or monocytes if the tropism of M2 macrophages, lymphocytes or monocytes is desired and complexes comprising one or more haemoglobin and one or more pharmaceutically active substance, label or pharmaceutically active substance and label are used to load Ml macrophages, if the tropism of Ml macrophages is desired.
- the pharmaceutically active substance, label or pharmaceutically active substance and label is selected from the group consisting of a protein, a nucleic acid, a chemical non-protein non- nucleic acid compound with a molecular weight of less than 1.5 kD, more preferably less than 1 kD, preferably an anticancer drug, in particular a cytostatic drug, cytotoxic drug and prodrugs thereof; an anti arteriosclerotic drug; and anti-inflammatory drug; and photosensitizing compound; a virus, in particular oncolytic virus; and a a or ⁇ radiation emitting radioisotope, which also emit a cell damaging amount of ⁇ radiation, preferably selected from the group consisting of lutetium-177, ytterbium-90, iodine-131, samarium-153, phosphorus-32, caesium-131, palladium- 103, radium-233, iodine-125, and boro
- Preferred anticancer drugs are selected from an apoptosis/autophagy or necrosis- inducing drug.
- An apoptosis/autophagy or necrosis-inducing drug can be any drug that is able to induce apoptosis/autophagy or necrosis effectively even in cells having an abnormality in cell proliferation.
- These drugs are preferably used in complexes with one or more ferritins.
- Preferred anticancer drugs are selected from the group consisting of an apoptosis- inducing drug, an alkylating substance, anti-metabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, an anti-androgene, an anti-estrogen, a platinum compound, a hormone, a antihormone, an interferon, an inhibitor of cell cycle-dependent protein kinases (CDKs), an inhibitor of cyclooxygenases and/or lipoxygenases, a biogeneic fatty acid, a biogenic fatty acid derivative, including prostanoids and leukotrienes, an inhibitor of protein kinases, an inhibitor of protein phosphatases, an inhibitor of lipid kinases, a platinum coordination complex, an ethyleneimine, a methylmelamine, a triazine, a vinca alkaloid, a pyrimidine analog, a purine analog, an alkyl sulfonate, a folic acid
- acediasulfone aclarubicine
- ambazone aminoglutethimide
- L-asparaginase azathioprine
- banoxantrone bendamustine
- bleomycin busulfan
- calcium folinate carboplatin
- carpecitabine carmustine
- celecoxib chlorambucil
- cis-platin cladribine
- cyclophosphamide cytarabine
- dacarbazine dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel
- doxorubicin enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine,
- the anticancer drug is a proliferation inhibiting protein, preferably a cell cycle inhibitor or an antibody or antibody like binding protein that specifically binds to a proliferation promoting protein or a nucleic acid, preferably encoding a proliferation inhibiting protein or an antibody or antibody like binding protein that specifically binds to a proliferation promoting protein or a siRNA or DNAzym.
- Preferred immunomodulatory drugs that activate or inhibit activity of immune cells.
- These can be natural or synthetic ligands or antagonists of Pattern Recognition Receptors, particularly Toll-like Receptors, NOD-like receptors ( LR), RIG-I-like receptors (RLR).
- PAMPs pathogen-associated molecular patterns
- DAMPs damage-associated molecular patterns
- Preferred examples of antibodies to be used in the context of the present invention are single chain antibodies, antibody fragments, nanobodies, light or heavy chains, variable light or variable heavy chains, or diabodies.
- Preferred antibody fragments comprise a fragment antigen binding (Fab) fragment, a Fab' fragment, a F(ab')2 fragment, a heavy chain antibody, a single-domain antibody (sdAb), a single-chain fragment variable (scFv), a fragment variable (Fv), a VH domain, a VL domain, a single domain antibody, a nanobody, an IgNAR (immunoglobulin new antigen receptor), a di-scFv, a bispecific T-cell engager (BITEs), a dual affinity re-targeting (DART) molecule, a triple body, a diabody, a single-chain diabody, and a fusion protein thereof.
- Fab fragment antigen binding
- Fab' fragment fragment antigen binding
- inflamed joints are targeted by macrophage-monocytes, preferably activated macrophages.
- macrophage-monocytes are preferably loaded with a label or a complex comprising an iron binding protein and a label.
- the complex comprises a pharmaceutically active substance with anti-inflammatory activity to deliver the anti-inflammatory substance to the inflamed tissue.
- the targeted delivery system of the present invention targets lymph nodes, which makes it particularly suitable for delivery of antigens to dendritic cells residing in the lymph nodes.
- the lymph node targeting is particularly pronounced, if the cells loaded with the complex are macrophages in particular activated macrophages, even more preferably CCL-2 activated bone marrow derived activated macrophages, or lymphocytes, in particular B cells or T cells.
- the targeted delivery system is used to deliver one or more antigens in order to elicit a prophylactic and/or therapeutic immune response against the one or more antigens.
- Preferred antigens are derived from pathogens, i.e. bacteria or viruses or are tumour specific antigens.
- tumour specific antigens refers to proteins or epitopes (including peptides with altered glycosylation patterns) that are higher expressed on tumour cells in comparison to non-tumour cells, preferably to antigens or epitopes only expressed on tumour cells.
- Preferred antigens are selected from the group consisting of epidermal growth factor receptor (EGFR, ErbB-1, HER1), ErbB-2 (HER2/neu), ErbB-3/HER3, ErbB-4/HER4, EGFR ligand family; insulin-like growth factor receptor (IGFR) family, IGF-binding proteins (IGFBPs), IGFR ligand family; platelet derived growth factor receptor (PDGFR) family, PDGFR ligand family; fibroblast growth factor receptor (FGFR) family, FGFR ligand family, vascular endothelial growth factor receptor (VEGFR) family, VEGF family; HGF receptor family; TRK receptor family; ephrin (EPH) receptor family; AXL receptor family; leukocyte tyrosine kinase (LTK) receptor family; TIE receptor family, angiopoietin 1,2; receptor tyrosine kinase-like orphan receptor (ROR) receptor family; discoidin domain receptor (
- HLA-A*201-R170I HLA-A11
- HLA-A11 heat shock protein 70-2 mutated
- HSP70-2M heat shock protein 70-2 mutated
- KIAA0205 MART2
- melanoma ubiquitous mutated 1, 2, 3 MUM-1, 2, 3
- prostatic acid phosphatase PAP
- neo-PAP Myosin class I, NFYC, OGT, OS-9
- pml-RARalpha fusion protein PRDX5, PTPRK, K-ras (KRAS2), N-ras (NRAS), HRAS, RBAF600, SIRT2, SNRPD1, SYT-SSX1 or -SSX2 fusion protein, Triosephosphate Isomerase, BAGE, BAGE-1, BAGE- 2,3,4,5, GAGE-1, 2,3, 4,5, 6,7,8, GnT-V (aberrant N
- the pharmaceutically active substance is a nucleic acid it is preferred that it is a miRNA, siRNA, chemically modified-RNA, DNAzyme or a nucleic acid encoding a pharmaceutically active protein, e.g. an antibody, an antibody mimetic, a cytokine, a prodrug- converting enzyme, an immunogenic peptide or the like.
- a pharmaceutically active protein e.g. an antibody, an antibody mimetic, a cytokine, a prodrug- converting enzyme, an immunogenic peptide or the like.
- the label is selected from a fluorescent dye, a fluorescence emitting isotope, a radioisotope, a detectable polypeptide or nucleic acid encoding such a detectable polypeptide and a contrast agent.
- the label comprises a chelating agent which forms a complex with divalent or trivalent metal cations.
- the chelating agent is selected from the group consisting of 1, 4,7,10-tetraazacy clododecane- N,N',N,N'-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7- triazacyclononane-l,4,7-triacetic acid (NOTA), tnethylenetetramine (TETA), iminodiacetic acid, Diethylenetriamine-N,N,N',N',N"-pentaacetic acid (DTP A) and 6-Hydrazinopyridine-3- carboxylic acid (HYNIC).
- DTP A Diethylenetriamine-N,N,N',N',N"-pentaacetic acid
- HYNIC 6-Hydrazinopyridine-3- carboxylic acid
- the contrast agent comprises a paramagnetic agent, preferably selected from Gd, Eu, W and Mn, or ferrihydride.
- the radioisotope/fluorescence emitting isotope is selected from the group consisting of alpha radiation emitting isotopes, gamma radiation emitting isotopes, Auger electron emitting isotopes, X-ray emitting isotopes, fluorescence emitting isotopes, such as 18 F, 51 Cr, fluorescent 65 Tb, 67 Ga, 68 Ga, m In, 99m Tc, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y, 90 Y, 149 Pm, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 72 As, 72 Se, 97 Ru, 109 Pd, 105 Rh, 101ml5 Rh, 119 Sb, 128 Ba, 123 I, 124 I, 131 I, 197 Hg, 211 At, 169 Eu, 203 Pb, 212 Pb, 64 Cu, 89 Zr,
- the fluorescence dye is selected from the group consisting of the following classes of fluorescent dyes: Xanthens, Acri dines, Oxazines, Cynines, Styryl dyes, Coumarines, Porphines, Metal - Ligand-Complexes, Fluorescent proteins, Nanocrystals, Perylenes and Phtalocyanines as well as conjugates and combinations of these classes of dyes.
- the detectable polypeptide is an autofluorescent protein, preferably green fluorescent protein or any structural variant thereof with an altered adsorption and/or emission spectrum.
- the targeted delivery system of the present invention has particular suitability to deliver pharmaceutically active substances, labels or pharmaceutically active substances and labels to hypoxic areas. Hypoxy is characteristic of various disease including cancer and inflammatory diseases and thus allows targeting such diseases.
- the pharmaceutically active substance, label or pharmaceutically active substance and label is a hypoxia-activated prodrug.
- the backbone of all the hypoxia-activated prodrugs is the presence of one of five different chemical moieties (nitro groups, quinines, aromatic and aliphatic N-oxides and transition metals) that are enzymatically reduced under hypoxic conditions in tissue.
- Hypoxia-activated prodrugs are any prodrug that is less active or inactive, relative to the corresponding drug, and comprises the drug and one or more bioreducible groups.
- Such hypoxia-activated prodrugs include all prodrugs activated by a variety of reducing agents and reducing enzymes, including without limitation single electron transferring enzymes (such as cytochrome P450 reductases) and two electron transferring (or hydride transferring) enzymes.
- hypoxia- activated prodrug is TH-302. Methods of synthesizing TH-302 are described in PCT application WO 07/002931 and WO 08/083101.
- prodrugs are selected from the class I group consisting of: benzotriazine N-oxides, apaziquone (E09), tirapazamine (TPN) and SN30000; or class II group consisting of: nitro compounds PR- 104 A, TH-302, TH-4000, and AQ4N.
- the bond(s) between the iron binding protein(s) and the pharmaceutically active substance, label or pharmaceutically active substance and label comprised in the complex are covalent and/or non-covalent; and/or the pharmaceutically active substance, label or pharmaceutically active substance and label comprised in the complex is entrapped/encapsulated by the iron binding protein, preferably ferritin or multimers thereof.
- the covalent and/or non-covalent coupling is indirect through a linker or spacer. If the formation of covalent bonds is desired, relevant thiol, amino or carboxyl groups of the iron binding proteins are used to covalently couple pharmaceutically active substances, labels or pharmaceutically active substances and labels directly or indirectly to the one or more iron binding protein.
- different pharmaceutically active substances, labels or pharmaceutically active substances and labels are comprised in the complex.
- one type of pharmaceutically active substance, label or pharmaceutically active substance and label may be bound to an iron binding protein (non-covalently bound), while another type is encapsulated.
- This approach utilizes different release rates of the pharmaceutically active substances, labels or pharmaceutically active substances and labels from the iron binding protein once delivered to the targeted tissue and/or cells.
- pharmaceutically active substance, label or pharmaceutically active substance and label can be covalently attached to ferritin molecule either on the surface of the 24-mer or within the internal cavity by exploiting the reactivity of relevant thiol, amino or carboxyl groups.
- the complex comprises both a label and a pharmaceutically active substance
- the label is covalently attached to the iron binding protein and the pharmaceutically active substance is non-covalently bound to the iron binding protein and/or entrapped in the internal cavity formed upon assembly of the iron binding proteins.
- the present invention relates to a method of preparation of the isolated targeted delivery system of the first or second aspect comprising the steps of
- step b) incubating the CD45 + leukocyte cell in the presence of the iron binding protein produced in step b) until the CD45 + leukocyte cell is at least partially loaded with the complex of the iron binding protein and the a pharmaceutically active substance, label or pharmaceutically active substance and label produced in step b); and/or
- the present invention relates to the isolated targeted delivery system producible by the method according to the third aspect of the present invention.
- the formation of the adduct between the protein and the pharmaceutically active substance and/or label is preferably by a non-covalent binding to the iron binding protein and can be described as follows:
- pharmaceutically active substances and/or labels can be typically encapsulated within the internal cavity (physical confinement) by exploiting the association dissociation properties of the ferritin macromolecule itself.
- pharmaceutically active substance and/or label molecules are held in place by non-covalent interactions with amino acid residues within the cavity internal surface.
- Haemoglobin macromolecules also offer the possibility of non-covalent binding of selected pharmaceutically active substances and/or labels molecules that may be hosted within the heme binding pocket of haemoglobin itself.
- the heme in the pocket can be displaced and be replaced by pharmaceutically active substances and/or labels with appropriate hydrophobicity profile.
- all proteins considered in the present invention may be covalently attached to pharmaceutically active substance and/or label molecules modified by specific active linker moieties reactive towards thiol or amino groups of the protein itself.
- ferritins or haemoglobin may be linked to cysteine thiol reactive pharmaceutically active substances and/or labels bearing a peptide based cleavable linker (e.g. cathepsin sensitive valine-citrulline sequence and para-aminobenzylcarbamate spacer).
- the antimitotic agent monomethyl auristatin E has been used.
- the peptide-based linker binds the protein to the cytotoxic compound in a stable manner so the drug is not easily released from the protein under physiologic conditions and help prevent toxicity to healthy cells and ensure dosage efficiency.
- the protein pharmaceutically active substance and/or label adduct thus generated is capable of attaching to the selected receptor types, i.e. CD163 for haemoglobin and TfR for ferritin or transferrin, respectively. Once bound the protein pharmaceutically active substance and/or label adduct is internalised by endocytosis and thus selectively taken up by targeted cells.
- the vesicle containing the drug is fused with lysosomes and lysosomal cysteine proteases, particularly cathepsin B start to break down valine-citrulline linker and MMAE is no longer bound to the iron binding protei and is released directly into the tumour environment.
- DM1-SMCC is an efficient mertansine derivative bearing a linker that specifically binds to lysine residues generating a covalent complex with ferritin, haemoglobin or transferrin in a reaction that has been successfully described for antibodies.
- haemoglobin, ferritin or transferrin can be reacted with DM1-SMCC thus providing a covalent protein-drug adduct that can be cleaved inside cells and releases the active drug in a time-dependent manner.
- the suppression of microtubule dynamics by DM1 induces mitotic arrest and cell death.
- full load is used in the context of the present invention to refer to the maximum amount of iron binding protein, preferably ferritin, complexed with a pharmaceutically active substance, label or pharmaceutically active substance and label that can be taken up by the CD45+ leukocyte cell, preferably macrophage more preferably activated macrophage.
- the present invention relates to an isolated targeted delivery system of the first aspect or second aspect of the invention or producible according to the method of the third aspect of the invention for use as a medicament or diagnostic.
- the present invention relates to a pharmaceutical or diagnostic composition
- a pharmaceutical or diagnostic composition comprising the isolated targeted delivery system of the first or second aspect of the present invention or producible according to the method of the third aspect of the invention and a pharmaceutically acceptable carrier and/or suitable excipient(s). Since the isolated targeted delivery system comprises living cells, it is preferred that carriers and excipients are chosen in such to keep the cells alive.
- “Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
- carrier refers to a pharmacologically inactive substance such as but not limited to a diluent, excipient, surfactants, stabilizers, physiological buffer solutions or vehicles with which the pharmaceutically active substance is administered.
- Such pharmaceutical carriers can be liquid or solid.
- Liquid carrier include but are not limited to sterile liquids, such as saline solutions in water and oils, including but not limited to those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
- a saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.
- Suitable pharmaceutical "excipients” include starch, glucose, lactose, sucrose, gelatine, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
- “Surfactants” include anionic, cationic, and non-ionic surfactants such as but not limited to sodium deoxycholate, sodium dodecyl sulfate, Triton X-100, and polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65 and polysorbate 80.
- Stabilizers include but are not limited to mannitol, sucrose, trehalose, albumin, as well as protease and/or nuclease antagonists.
- Physiological buffer solution include but are not limited to sodium chloride solution, demineralized water, as well as suitable organic or inorganic buffer solutions such as but not limited to phosphate buffer, citrate buffer, tris buffer (tris(hydroxymethyl)aminomethane), HEPES buffer ([4 (2 hydroxyethyl)piperazino]ethanesulphonic acid) or MOPS buffer (3 morpholino-1 propanesulphonic acid).
- phosphate buffer citrate buffer
- tris buffer tris(hydroxymethyl)aminomethane
- HEPES buffer [4 (2 hydroxyethyl)piperazino]ethanesulphonic acid
- MOPS buffer 3 morpholino-1 propanesulphonic acid
- adjuvant refers to agents that augment, stimulate, activate, potentiate, or modulate the immune response to the pharmaceutically active substance comprised in the composition at either the cellular or humoral level, e.g. immunologic adjuvants stimulate the response of the immune system to the actual antigen, but have no immunological effect themselves.
- adjuvants include but are not limited to inorganic adjuvants (e.g. inorganic metal salts such as aluminium phosphate or aluminium hydroxide), organic adjuvants (e.g. saponins or squalene), oil-based adjuvants (e.g. Freund's complete adjuvant and Freund's incomplete adjuvant), cytokines (e.g.
- particulate adjuvants e.g. immuno-stimulatory complexes (ISCOMS), liposomes, or biodegradable microspheres), virosomes, bacterial adjuvants (e.g. monophosphoryl lipid A, or muramyl peptides), synthetic adjuvants (e.g. non-ionic block copolymers, muramyl peptide analogues, or synthetic lipid A), or synthetic polynucleotides adjuvants (e.g polyarginine or polylysine).
- the present invention relates to an isolated targeted delivery system of the first aspect or second aspect of the present invention or producible according to the method of the third aspect of the invention for use in preventing, treating or diagnosing a disease characterized by hypoxic areas within the diseases tissue and/or by areas of oxidative stress (Fig.
- tumours preferably solid tumours and/or its metastases, preferably breast cancer, pancreatic cancer, bladder cancer, lung cancer, colon cancer, or a tumour having hypoxic areas, an inflammatory disease, inflamed tissue, preferably inflamed joints or arthritic joints, inflamed lung, inflamed intestine or other inflamed tissue; lymph nodes, preferably inflamed lymph nodes, or other non-physiological lymph nodes that develop during disease preferably but not only during infection, cancer, or autoimmune disease; or ischemic areas, in particular in skin wounds or after organ infarctus (heart) or ischemic retina or for prophylactic or therapeutic vaccination, in particular to prevent or treat an infectious disease or cancer.
- This aspect also includes also of antigens to physiological or non-physiological lymph nodes in order to vaccinate an individual or to induce immune memory.
- treatment includes all types of preventive and/or therapeutic interventions medically allowed for the purpose of cure, temporary remission, prevention, etc. for different purposes including delaying or stopping the progress of a disease, making a lesion regress or disappear, preventing onset, or inhibiting recurrence.
- the targeted delivery system enables tumour delivery of the pharmaceutically active substances, labels or pharmaceutically active substances and labels, which normally would not be able to reach the tumour (for example, due to solubility problems). It also enables the delivery of pharmaceutically active substances, labels or pharmaceutically active substances and labels to the hypoxic tumours or to the hypoxic areas of the tumour. This system also provides for delivery of pharmaceutically active substance, label or pharmaceutically active substance and label to any area within an organism subjected to hypoxic conditions, for example during ischaemic incidents, or undergoing an inflammatory process.
- the present invention provides also the method for targeted delivery into the tumour mass.
- This method comprises preparation of CD45 + leukocytes, preferably activated macrophages which enables highly efficient iron-binding protein (ferritin, haemoglobin and/or transferring) uptake by the macrophages, wherein said ferritin, haemoglobin and/or transferrin carry a pharmaceutically active substance, label or pharmaceutically active substance and label (for example a drug/prodrug), tumour targeting and iron-binding protein transfer to the cancer cell, where the pharmaceutically active substance, label or pharmaceutically active substance and label is released.
- a pharmaceutically active substance, label or pharmaceutically active substance and label for example a drug/prodrug
- the present invention exploits CD45 + leukocytes, preferably activated macrophages loaded with iron-binding proteins linked with a drug/prodrug as a delivery system to target the tumour.
- CD45 + leukocytes preferably activated macrophages loaded with iron-binding proteins linked with a drug/prodrug
- Unsatisfactory response of the tumours to chemotherapy or difficulties in their detection using imaging methods are mainly related to an altered penetration of the anticancer drugs to the hypoxic areas due to poor vasculature.
- these avascular regions attract CD45 + leukocytes, preferably activated macrophages to migrate even in areas far away from blood vessels. Therefore, they constitute a delivery system of particles to the tumour mass.
- a promising example of such particles is iron-binding protein.
- when used as single agents they do not reach hypoxic regions, similarly to other compounds and accumulate in other organs.
- CD45 + leukocytes monocytes, macrophages, lymphocytes and/or granulocytes
- activated macrophages treating cells with iron-binding protein solution as it is described in examples.
- Fig. 1 Panel (A) shows a minimal active fragment of a consensus amino acid sequence among mammalian ferritin H chains and two full length consensus sequences based on several mammalian ferritin H chains (see SEQ ID NO: 1, 2 and 7, respectively) as well as a minimal and full length amino acid sequence of mouse (SEQ ID NO: 3 and 4) and human (SEQ ID NO: 5 and 6) ferritin H chain.
- Panel (B) shows a a minimal active fragment of a consensus amino acid sequence among mammalian ferritin L chains and two full length consensus sequences based on several mammalian ferritin L chains (see SEQ ID NO: 8, 9 and 14, respectively) as well as a minimal and full length amino acid sequence of mouse (SEQ ID NO: 10 and 11) and human (SEQ ID NO: 12 and 13) ferritin L chain. .
- Panel (C) shows a minimal active fragment of a consensus amino acid sequence among mammalian haemoglobin alpha chains and one full length consensus sequences based on several mammalian haemoglobin alpha chain (see SEQ ID NO: 15 and 16, respectively) as well as a minimal and full length amino acid sequence of human (SEQ ID NO: 17 and 18) haemoglobin alpha chain.
- Panel (D) shows a minimal active fragment of a consensus amino acid sequence among mammalian haemoglobin beta chains and a full length consensus sequences based on several mammalian haemoglobin beta chain (see SEQ ID NO: 19 and 20, respectively) as well as a minimal and full length amino acid sequence of human (SEQ ID NO: 21 and 22) haemoglobin beta chain.
- Panel (E) shows a N- and C-terminal minimal active fragment of a consensus amino acid sequence among mammalian transferrins (SEQ ID NO: 23 and 24) and a full length consensus sequences based on several mammalian transferrins (SEQ ID NO: 25) as well as a N- and C-terminal minimal active fragment of a human transferrin (SEQ ID NO: 26 and 27) and full length amino acid sequence of human transferrin (SEQ ID NO: 28).
- X indicates a position that is variable and stands for any natural amino acid.
- X in dependently of other X stands for the amino acid present in the human protein.
- Fig. 2 Shows macrophage inside the mouse tumour mass (TRITC stained before injection, loaded with FITC-decorated ferritin).
- Fig. 3 Shows confocal microscopy image of tumour tissue mouse injected with mammary cancer cells and given i.v. macrophages loaded with FITC-ferritin (asterix) - it is clearly observed, not only in macrophages but also in cancer cells, that ferritin-FITC spread within all tumour mass.
- Fig. 4 Shows snapshots of one channel (in original green channel converted to the grey- scale picture) recording using confocal microscopy of macrophages (indicated with *; loaded with FITC-ferritin) and cancer cell (indicated with arrow; stained with red label and therefore not observed in green channel before ferritin uptake) in vitro taken at the starting time point (A) and after time long enough to fill cancer cell with ferritin (B).
- FITC-ferritin was dynamically transported to the cancer cell (accumulating firstly in the vesicles; then spreading to the whole cytoplasm as seen at this image (the cell appeared in green channel).
- Fig. 5 Shows survival of mice receiving placebo and macrophages loaded with ferritin- coupled melphalan and ferritin-coupled chlorambucil.
- Fig. 6 Shows tumour cells apoptosis caused by treatment with cyclophosphamide and cyclophosphamide encapsulated in ferritins loaded to macrophages (given at the same doses).
- Fig. 7 Shows MRI images of mouse mammary tumour.
- the mouse was treated (at time point 0 h) with macrophages (i.v. injection) loaded with ferritin Fh.
- macrophages i.v. injection
- ferritin Fh ferritin Fh.
- arrow blood vessels
- FIG. 8 Shows ferritin, haemoglobin and transferrin uptake by macrophages, ferritin and haemoglobin uptake by monocytes and ferritin uptake by lymphocytes and granulocytes.
- Fig. 9 Shows the stability of the ferritin storage by macrophages.
- Fig. 10 Shows transfer of ferritin, haemoglobin and transferrin from macrophage to various cancer cells.
- Fig. 11 Shows the transfer of ferritin from macrophage to cancer and non-cancer cells.
- Fig. 12 Shows the transfer of ferritin encapsulated with hypoxia activated prodrug from macrophage to cancer cells.
- Fig. 13 Shows the apoptosis in cancer cells that received ferritin with encapsulated various anticancer agents from co-cultured macrophages or soluble ferritin with the same agents.
- Fig. 14 Shows the transfer of ferritin, haemoglobin and transferrin from monocyte to various cancer cells.
- Fig. 15 Shows the transfer of ferritin and haemoglobin from granulocyte to various cancer cells.
- Fig. 16 Shows the transfer of ferritin and haemoglobin from lymphocyte to various cancer cells.
- Fig. 17 Shows the picture from two-photon microscopy showing tumour from a mouse that received pre-labeled (before administration) macrophages containing Ferritin-FITC.
- Fig. 18 Shows the whole body imaging of mice that intravenously received labeled macrophages, showing their accumulation in the tumour site and their distribution in other organs.
- Fig. 19 Shows the migration of macrophages to hypoxic tissue, a cross-section of the tumour from a mouse that was administered intravenously with pre-labeled macrophages, tumour hypoxic areas are visualized with a hypoxia marker - pimonidazolone.
- Fig. 20 Shows the presents localization of vesicles containing FITC-laded ferritin (round objects) in the microenvironment inside the tumour mass. Macrophages containing FITC-laded ferritin were administered intravenously to the mouse.
- Fig. 21 Shows the signal recorded by PET from a whole-body analysis of mice with the metastatic 4T1 cancer. Mice received intravenously macrophages loaded with 18 F- FDG. Signal accumulation is increased in the lungs of mice with micrometastases (confirmed by pathology examination). Mice receiving plain 18 F-FDG, or mice without 4T1 cancer had lower PET signal.
- MQ-FDG indicates mice with metastatic 4T1 tumour +intravenous macrophages loaded with 18 F-FDG.
- FDG indicates mice with metastatic 4T1 tumour +intravenous free 18 F-FDG.
- Naive mice MQ-FDG Indicates naive mice without tumour +intravenous macrophages loaded with 18 F- FDG.
- Fig. 22 Shows the tumour homing by different CD45+ leukocyte cell types usable in the targeted delivers systems of the invention. Mice with CT26 tumors (marked by the arrows) were intravenously injected with PBS or fluorescently labelled cells. Panel
- Panel A - PBS, no cells added
- Panel B. - shows homing of a CD45 + leukocyte subpopulation
- Panel C shows homing of activated CD4 + T lymphocytes
- Panel D shows homing of a macrophage-monocytic cell line. 24 hours after injection mice were anaesthetized and imaged.
- Panel E Shows the quantification of the tumour homing by different CD45+ leukocyte cells.
- Fig. 24 Shows targeting of intravenously administered cells to inflamed (arthritic) joints Control mouse (panel A.) or a mouse with severe inflammation of the joints (panel A.).
- Macrophage-monocyte cells are present with greater number in the inflamed than in control joints.
- Fig. 25 Shows targeting of intravenously administered cells to the lymph nodes.
- Control mouse panel A.
- a mouse with severe inflammation of the joints panel B.
- have been intravenously injected with activated macrophages with M-CSF and CCL2.
- Fig. 26 Shows radiolabeling of monocyte-macrophage cell line with plain Zr-oxinate, i.e. without iron binding protein (-1.85 MBq) for PET imaging. Radioactivity of cells after loading with 89 Zr is indicated in MBq.
- Fig. 27 Ferritin transfer was examined in cancer cells (EMT6) co-cultured with ferritin-loaded macrophages (RAW264.7) for 2 hrs.
- EMT6 cancer cells
- obviouslyEMT6 OS when EMT6 cells were subjected to the oxidative stress before co-culture and then co-cultured with macrophages at normoxic conditions and
- counselco-culture OS when both cell types were subjected to the oxidative stress before the co-culture.
- Results showed that cancer cells subjected to the oxidative stress received (from macrophages) more ferritins than control cells. The uptake was even more efficient when both cell types were subjected to the oxidative stress.
- Panel A shows: Ferritin uptake from macrophages (2 hrs co-culture) in oxidative stress (oxidative glucose treatment for 16 hrs).
- Panel B shows: Ferritin uptake from macrophages (2 hrs co-culture) in oxidative stress (oxidative glucose treatment for 16 hrs).
- Macrophages for use according to the present invention were obtained, differentiated and activated as follows.
- macrophages they are obtained firstly from bone marrow precursors (for example see paper: Weischenfeld and Porse, 2008, CSH Protoc, doi. 10.1101/pdb.prot.5080) or blood monocytes. Alternatively, they can be obtained from peritoneum.
- the methods of macrophage isolation, culture, differentiation and polarization/activation are well known for those skilled in the art. For example, they have been described in details by Murray et al. (Immunity, 2014, 41(1): 14-20).
- bone marrow derived macrophages were obtained from BALB/c or C57B1/6 mouse, however canine blood-monocyte-derived macrophages or commercially available macrophage cell lines (monocyte-macrophage lineage mouse cells: RAW 264.7, J744, human: THP-1, U937, or canine DH82 cell line).
- macrophage lineage mouse cells RAW 264.7, J744, human: THP-1, U937, or canine DH82 cell line.
- bone marrow derived macrophages are seeded in plastic Petri dish in 5 ml medium (3 ml cells per plate): DMEM:F12 + glutamine/glutamax + 10 % FBS + Penicillin/Streptomycin and 20 % of L929 conditioned medium or M-CSF (50 ng/ml).
- the medium is supplemented in growth factor and one of the activating compounds or their combinations as one cytokine cocktail.
- macrophages have been cultured in "M1/M2 Macrophage Generation Medium” (Promocell) or equivalent commercially available or self-made medium containing all the necessary cytokines and interleukins to consider them as activated.
- M1/M2 Macrophage Generation Medium Promocell
- equivalent commercially available or self-made medium containing all the necessary cytokines and interleukins to consider them as activated.
- Ml- or M2 -Macrophage Generation Medium DXF is added to the cells (e.g. 20 ml per T-75 flask) and cells are incubated for 6 days at 37°C and 5% C0 2 without medium change. In order to activate macrophages, the whole medium is replaced with medium supplemented with activating compound.
- Activating compounds used in this invention are as follows: IL-4 (20 ng/ml), IFN- ⁇ (at least 20 ng/ml), LPS (at least 10 ng/ml), IL-13 (at least 20 ng/ml), IL-10 (at least 20 ng/ml), dexamethason (at least 20 ⁇ g/ml), CCL2 (at least 20 ng/ml), oxLDL (at least 20 ng/ml), T F-a (20 ng/ml), TGF- ⁇ (20ng/ml), Cortisol (150-300 ng/ml) or their combinations as one cytokine cocktail. In order to obtain non-activated macrophages, the activating compound has not been added.
- Reverse of the polarization/activation of macrophages can be reached for example by culture of macrophages in appropriate cytokines listed above for at least 48 hours.
- monocytes bone marrow derived or spleen-derived monocytes were obtained from BALB/c or C57B1/6 mouse, however canine blood monocyte or commercially available monocyte cell lines were used (monocyte-macrophage lineage mouse cells: RAW 264.7, J744, human cells: THP-1, U937, or canine cells DH82).
- monocytes fresh blood (not older than 12 hours) cells were purified by centrifugation using Histopaque system 1.077 g/ml or equivalent and white blood cells are seeded in an appropriate amount of pre-warmed Monocyte Attachment Medium (or equivalent, e.g. DMEM/RPMI supplemented with 20 ng/ml M-CSF), e.g. 15 ml Medium per T-75 flask.
- pre-warmed Monocyte Attachment Medium or equivalent, e.g. DMEM/RPMI supplemented with 20 ng/ml M-CSF
- Alternatively, only white blood cells collected from the blood bank (buffy coat) may be used. After cell attachment, they are washed at least twice, and adherent cells are considered as monocytes.
- monocytes were obtained from BALB/c or C57B1/6 mouse. Shortly, such bone marrow derived precursors were isolated using Mouse Monocyte Enrichment Kit (StemCells) according to manufacturer's instructions.
- the spleen has been mechanically dissociated to obtain single cell suspension and passed through the 70 ⁇ cell strainer. Cells were centrifuged and supernatant was removed. Optionally erythrocyte lysis was performed prior to monocyte isolation by EasySepTM Mouse Monocyte Enrichment Kit (StemCells) according to manufacturer's instructions.
- IL-4 (20 ng/ml), IFN- ⁇ (at least 20 ng/ml), LPS (at least 10 ng/ml), IL-13 (at least 20 ng/ml), IL-10 (at least 20 ng/ml), dexamethason (at least 20 ⁇ g/ml), CCL-2 (at least 20 ng/ml), oxLDL (at least 20 ng/ml), T F-a (20 ng/ml), TGF- ⁇ (20 ng/ml), Cortisol (150-300 ng/ml) or their combinations as one cytokine cocktail.
- Example 3 Granulocyte isolation To obtain granulocyte cells from blood, 9 parts of blood were diluted with 1 part of
- ACD buffer (containing 0.17 M d-glucose, 0.10 M citric acid, 0.11 M trisodium citrate). Blood from this step was further diluted with PBS at the 1 : 1 ratio and centrifuged. After removing plasma and buffy coat, remaining cells were mixed with PBS to 80% of the original volume from the first step (ACD-blood) and then diluted with cold distillated water at the ratio of 4: 12. Then, 6 parts of 2.7 % of NaCl solution were added and centrifuged. After removal of supernatant cells were resuspended in RPMI-1640 medium. These cell were considered as granulocytes.
- the spleen has been mechanically dissociated to obtain single cell suspension and passed through the 70 ⁇ cell strainer. Cells were centrifuged and supernatant was removed. After erythrocyte lysis, lymphocytes were isolated using a negative cell isolation strategy with a help of EasySepTM CD4 + Enrichment Kit (Stemcell) according to manufacturer s instructions.
- Lymphocytes were activated by the 3-5 day culture in RPMI medium supplemented with glutamine/glutamax, 10% FBS, Penicillin/Streptomycin, in the presence of beads covered with anti-CD3 and anti-CD28 (Gibco) according to manufacturer's instructions.
- lymphocytes Activation of lymphocytes was confirmed with upregulation of CD25 and CD69 cell surface expression, that was monitored by flow cytometry.
- Example 5 Leukocyte (CD45 + cells) isolation
- fresh blood not older than
- ferritins with the anticancer drug (e.g. classic drugs like cyclophosphamide, chlorambucil, melphalan, bendamustine, banoxantrone or hypoxia- activated prodrug like TH-302) or with the "imaging contrast agents" (e.g. ferrihydride or isotope) ferritins have to be prepared before macrophage treatment.
- the anticancer drug e.g. classic drugs like cyclophosphamide, chlorambucil, melphalan, bendamustine, banoxantrone or hypoxia- activated prodrug like TH-302
- imaging contrast agents e.g. ferrihydride or isotope
- coli culture was grown at 37°C to OD600 0.6 in 1 L of Luria-Bertani broth (LB) added with ampicillin (100 mg/L). Protein expression was induced by addition of 1 mM isopropyl thio-b-D-galactoside (IPTG) and the culture was incubated overnight. Cells were harvested by centrifugation (15000g for 15 min) and suspended in 20 mM Hepes (pH 7.5), 150 mM NaCl, 0.1 mg/mL DNase, 10 mM MgCl 2 and disrupted by sonication.
- LB Luria-Bertani broth
- IPTG isopropyl thio-b-D-galactoside
- the lysate was centrifuged at 15000g for 30 min and the supernatant was treated 10 min at 50°C, centrifuged to remove denatured proteins and then at 70°C for 10 min and centrifuged again.
- the supernatant was added with 30% ( H) 4 S0 4 at 4°C stirring for lh and centrifuged at 15000g for 30 min.
- the supernatant was added with 70 % ( H) 4 S0 4 at 4°C stirring for 1 h and centrifuged at 15000g for 30 min.
- the pellet was resuspended in 20 mM Hepes (pH 7.5), 150 mM NaCl and dialysed overnight at 4°C against the same buffer.
- the protein was loaded on a HILOAD 26/600 SUPERDEX 200 gel-filtration column (GE-Healthcare) and then sterile filtered and stored at 4°C. (Fig. 9) Protein concentration was determined spectrophotometrically at 280 nm using a molar extinction coefficient of 21000 M "1 m "1 and by Bradford assay measuring the absorbance at 595 nm.
- Said ferritins include recombinant mammalian ferritin proteins H and/or L homopolymers.
- Ferritins obtained as previously described, are purified by standard methods in order to obtain an endotoxin free, pre-clinical grade product (see, for example: Ceci et al. 2011, Extremophiles 15(3):431-439; Vanucci et al. 2012, Int J Nanomed 7: 1489-1509). Shortly, the ferritin conserved sterile in a storage solution containing 20 mM Hepes pH 7.5 is diluted to a final concentration of 4 uM in 24-mer in acidic solution (final pH ⁇ 3.0) or, alternatively, at highly basic pH values (pH > 9.5) (see for example Pontillo et al., 2016), thus allowing the dissociation of multimer.
- phenylhydrazone derivative may breaks and liberates the drug from the ferritin surface
- lysine bound derivatives may become active after full protein degradation into aminoacids
- cysteine bound derivative may be liberated within the cell through reductive hydrolysis of the maleimede thioether link.
- Human haemoglobin is prepared from fresh red cells as described in Rossi-Fanelli et al. (Archives of biochemistry and biophysics 77:478-492, 1958). Shortly, the heparinized blood, obtained from healthy donors, was centrifuged at 1600 rpm for 30 minutes (4°C) to sediment the RBCs. Buffy coat was accurately removed by needle aspiration on the surface of the pellet. The plasma supernatant was discarded and the RBC pellet was washed three times by resuspending the RBCs in isotonic 0.9% saline solution and centrifuging at 1600 rpm for 30 minutes at 4°C.
- PB 5 mM potassium phosphate buffer
- Human Haemoglobin (SEQ ID NO: 18 or 22, see Fig. 1) can be readily covalently linked to appropriate drug conjugates, host hydrophobic drug molecules within the heme binding pocket or even transport small cytotoxic molecules linked to the heme iron. Hb can be easily modified by selective attachment of the appropriate drug conjugate to the cysteine residue in position 93 of the beta chains, the only titratable cystein on the protein surface.
- Maleimido functionalized drugs such as the tubuline inhibitor MonomethylAuristatin (MMAE) or the succinimide functionalized mertansine analogue (DM1-SMCC) are most notable examples of extremely potent cytotoxics that can be readily and specifically attached to the relevant cys beta93 residue (for maleimido functionalized drugs) or to one or more lysine residues (succinimide functionalized drug), respectively. These drugs have been conveniently conjugated to human haemoglobin according to the following procedures:
- MMAE MonomethylAuristatin
- DM1-SMCC succinimide functionalized mertansine analogue
- vcMMAE The auristatin E analogue, maleimidocaproyl-valine-citrulline-p- aminobenzoyloxycarbonyl-monomethyl auristatin E (vcMMAE) was obtained from MedChem Express (Princeton, NJ).
- the Haemoglobin vcMMAE adduct was prepared as follows. Human haemoglobin solution was adjusted to a concentration of 120 ⁇ heme with reaction buffer (50 mM phosphate buffer pH 6,8, containing 0, 1 mM EDTA) and conjugated with 10-fold molar excess of vcMMAE in the presence of 20% v/v acetonitrile solution at 4 °C overnight.
- the mertansin analogue DM1 SMCC (Alb Technology Ltd, Hederson, NV, USA), functionalized for lysine covalent attachment, was prepared as follows. Human haemoglobin solution was adjusted to a concentration of 400 ⁇ heme with reaction buffer (0.1 mM phosphate buffer pH 7.4, containing 0.5 mM EDTA) and conjugated with 20-fold molar excess of DM1 -SMCC in the presence of 10 % v/v DMSO solution at 4 °C for 16 hours. The amine-reactive succinimidyl ester couples to amines thus yielding a covalent adduct with lysine groups on the surface of the protein.
- reaction buffer 0.1 mM phosphate buffer pH 7.4, containing 0.5 mM EDTA
- DM1 -SMCC conjugate was confirmed by LC-MS analysis.
- concentrations of Hb-DMl-SMCC conjugates were determined by UV-vis spectroscopy analysis. Alternatively, the apo-protein solution must be kept on an ice bath for the duration of the reconstitution process.
- a 1.5-fold molar excess of CuT-CPP (Cu-TCPP 4,4',4",4"'- (Porphine-5,10, 15,20-tetrayl)tetrakis(benzoic acid) - Cu 67 ) in 0.1 M NaOH must be added dropwise to the apo-globin solution in 0.2 M KPi buffer at pH 7.0 vortexed quickly at room temperature and then placed back in ice bath for 30 minutes. The protein solution must then be filtered in a syringe filter before use.
- the serum was obtained from healthy donor and excess iron was added in the presence of citrate ions as a chelator and bicarbonate, which is facilitates for iron binding to transferrin.
- the mertansin analogue DM1 SMCC (Alb Technology Ltd, Hederson, NV, USA), functionalized for lysine covalent attachment, was prepared as follows. Taansferrin solution was adjusted to a concentration of 100 ⁇ heme with reaction buffer (0.1 mM phosphate buffer pH 7.4, no EDTA in this case due to possible iron chelation effects) and conjugated with 20-fold molar excess of DMl-SMCC in the presence of 8 % v/v DMSO solution at 4 °C for 16 hours. The amine-reactive succinimidyl ester couples to amines thus yielding a covalent adduct with lysine groups on the surface of the protein.
- DMl-SMCC conjugate was confirmed by LC-MS analysis. The concentrations of Transferrin-DMl-SMCC conjugates were determined by UV-vis spectroscopy analysis.
- the apo-protein solution is kept in an ice bath for the duration of the reconstitution process.
- a 1.5-fold molar excess of CuT-CPP (Cu-TCPP 4,4',4",4"'- (Porphine-5,10, 15,20-tetrayl)tetrakis(benzoic acid) - Cu 67 ) in 0.1 M NaOH must be added dropwise to the apo-globin solution in 0.2 M KPi buffer at pH 7.0 vortexed quickly at room temperature and then placed back in ice bath for 30 minutes.
- the protein solution must then be filtered in a syringe filter before use.
- Obtained cells are incubated in ferritin solution for a time and at the concentration sufficient to ensure proper ratio of ferritin/cell for their full load and also to ensure proper drug content to obtain therapeutic effect or contrast for proper imaging.
- the time and concentration may vary depending on the number of molecules encapsulated/adsorbed into the ferritin cage, status of cell activation, condition and number of their intended administration.
- ferritins For example, to ensure proper load with ferritins, cells are incubated for 1-4 hours in ferritin solution 0.8 mg/ml in standard culture conditions.
- the frame of ferritin concentration may vary at least between 0.01 and 4 mg/ml as well as incubation time (5 min - 6 hours or more). Adjusting time and concentration of ferritin load to cells, the influence of ferritin and treatment conditions on cell viability should be minded.
- Cells obtained as stated above very easily uptake ferritins in a relatively short time (in minutes; Fig. 8). Once they absorb ferritins, they do not release it to the culture medium (Fig. 9).
- Obtained cells are incubated in haemoglobin solution for a time and at the concentration sufficient to ensure proper ratio of haemoglobin/cell for their full load and also to ensure proper drug content to obtain therapeutic effect or contrast for proper imaging.
- the time and concentration may vary depending on the number of molecules linked with the haemoglobin molecule, status of cell activation, condition and number of their intended administration.
- haemoglobins For example, to ensure proper load with haemoglobins, cells are incubated for 1-4 hours in haemoglobin solution 0.1 mg/ml in standard culture conditions.
- the frame of haemoglobin concentration may vary at least between 0.01 and 0.2 mg/ml as well as incubation time (5 min - 4 hours or more). Adjusting time and concentration of haemoglobin load to cells, the influence of ferritin and treatment conditions on cell viability should be minded. Cells obtained as stated above very easily uptake haemoglobins in a relatively short time (in minutes; Fig. 8).
- Example 11 - Obtaining transferrin loaded cells Obtained cells are incubated in transferrin solution for a time and at the concentration sufficient to ensure proper ratio of transferrin/cell for their full load and also to ensure proper drug content to obtain therapeutic effect or contrast for proper imaging.
- the time and concentration may vary depending on the number of molecules linked with the transferrin molecule, status of cell activation, condition and number of their intended administration.
- transferrin solution 0.1 mg/ml in standard culture conditions.
- the frame of transferrin concentration may vary at least between 0.01 and 0.2 mg/ml as well as incubation time (5 min - 4 hours or more). Adjusting time and concentration of transferrin load to cells, the influence of transferrin and treatment conditions on cell viability should be minded. Cells obtained as stated above very easily uptake transferrin in a relatively short time (in minutes; Fig. 8).
- Example 11 Ferritin/haemoglobin/transferrin-macrophage complex as useful delivery tool to cancer cells
- Example 14 Ferritin/haemoglobin/transferrin-lymphocyte complex as useful delivery tool to cancer cells
- lymphocytes from Example 4 prepared as described in Examples 8, 9 and 10, very easily transport ferritins, haemoglobins, transferrins to the cancer cells (Fig. 16).
- the ratio of both cell types is crucial. The more lymphocytes the better and faster the transport is.
- the most efficient transfer to the cancer cells was observed when ratio of lymphocytes to cancer cells was 1 : 1 or more.
- cells were labeled with 18 F-FDG or 89 Zr-oxinate in order to become imaged on PET. Cells have been detached from the plate and incubated with 18 F-FDG or
- 89 18 89 Zr-oxinate solution in adequate concentration to ensure the most optimal F-FDG or Zr- oxinate uptake by cells allowing their radio-detection at the site of their accumulation.
- cells were incubated at room temperature for at least 90 min. in 89 Zr-oxinate solution containing 3-9 MBq per 5 mln of cells.
- the ratio of radioisotope and cells influences significantly the reaction efficacy (Fig. 26). After labeling, cells are be centrifuged and supernatant is removed. This step should be repeated until no radioactivity is detected in the supernatant.
- Example 16 Ferritin/haemoglobin/transferrin/label-leukocyte complex as useful delivery tool to tumor, arthritic joints and lymph nodes
- the macrophages from Example 1 prepared as described in Examples 9, 10, 11 and
- monocytes from Example 2 prepared as described in Examples 9, 10, 11 and 12, granulocytes from Example 3 prepared as described in Examples 9, 10, 11 and 12, and lymphocytes from Example 4 prepared as described in Examples 9, 10, 11 and 12, highly efficiently migrate to the tumors (Fig. 22 and Fig. 23), arthritic joints (Fig. 24), in this particular example monocytic-macrophage cell line was used) and inflamed lymph nodes (Fig. 25), in this particular example monocyte/young macrophages activated using M-CSF and CCL-2 were used). Once they migrate to the tumors or other tissues they very easily transport ferritins, haemoglobins, transferrins and labels to the tumor in the enough amount to be detected using imaging systems (Figs. 2, 3, 7, 17, and 18).
- Example 17 Leukocyte-protein carrier complex as useful targeted pharmaceutically active substance delivery system to hypoxic regions
- Macrophages prepared as above are injected into the tail vein of animal with the tumour (appropriate number of macrophages should be adjusted to the tumour size, stage of development and presence of metastases). As it is shown on Figs. 2, and 17 they specifically reach the tumour (after a few hrs) and also disperse in other organs of the whole animal (Fig. 18). Moreover, as it is shown on Fig. 19, in hypoxic model they are also able to migrate to the avascular and hypoxic sites and to transfer carrier proteins to cancer cells (Figs. 3, and 20).
- the targeting of the targeted delivery system described in present invention can be followed by coupling the ferritin to a contrast agent.
- a contrast agent in this case: ferrihydrite
- isotope e.g. I
- isotope in this case Zr-oxide or F-FDG
- Fig. 21 they can be easily detected by MRI, PET or SPECT.
- mammary-tumour bearing mice were imaged using MRI at 3, 22 and 24 hours after i.v. injection of macrophages loaded with ferritin Fh. The mouse was treated (at time point 0 h) with macrophages. Then increased diameter of blood vessels (arrow) filled with injected macrophages (giving significant T2-signal reduction) has been observed and afterword macrophages spread to the tissue (spot-like pattern; arrows). These changes (in the same time points) were observed in all examined mice.
- Macrophages were also labeled with 89 Zr-oxide or 18 F-FDG (5-50 mln) and their radioactivity was confirmed to be imaged using PET after i.v. administration to the tumour- bearing mice. These mice were inoculated with 4T1 metastatic cell line 3 weeks before the experiment and metastases in the lungs, liver and spleen were histopatologically confirmed. At Fig. 21 it is seen that macrophages migrated to the regions with metastatic tumours allowing their visualization at PET.
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