WO2017189899A1 - Méthode de traitement du cancer à l'aide d'une aphérèse thérapeutique pour éliminer le tgf-bêta par l'intermédiaire de ses complexes - Google Patents

Méthode de traitement du cancer à l'aide d'une aphérèse thérapeutique pour éliminer le tgf-bêta par l'intermédiaire de ses complexes Download PDF

Info

Publication number
WO2017189899A1
WO2017189899A1 PCT/US2017/029930 US2017029930W WO2017189899A1 WO 2017189899 A1 WO2017189899 A1 WO 2017189899A1 US 2017029930 W US2017029930 W US 2017029930W WO 2017189899 A1 WO2017189899 A1 WO 2017189899A1
Authority
WO
WIPO (PCT)
Prior art keywords
tgfp
blood
polypeptide
binding agent
tgfpi
Prior art date
Application number
PCT/US2017/029930
Other languages
English (en)
Inventor
Steven F. Josephs
Amir Jafri
Vijay Mahant
Original Assignee
Immunicom, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Immunicom, Inc. filed Critical Immunicom, Inc.
Publication of WO2017189899A1 publication Critical patent/WO2017189899A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption

Definitions

  • Embodiments of the invention relate to compositions, devices, systems and methods for selective removal of TGFp from blood or a blood product, and methods of using the same for treating a subject having, or suspected of having a disorder, symptom or disease.
  • Transforming growth factor beta is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes at least three different variant forms (i.e., TGFpl , TGF
  • 33 are highly pleiotropic cytokines that virtually all cell types secrete.
  • TGFp molecules are proposed to act as cellular switches that regulate processes such as immune function, proliferation, and epithelial-mesenchymal transition. Targeted deletions of these genes in mice show that each isoform has some non-redundant functions.
  • TGFpl is involved in hematopoiesis and endothelial differentiation
  • TGF$2 affects development of cardiac, lung, craniofacial, limb, eye, ear, and urogenital systems
  • 33 influences palatogenesis and pulmonary development.
  • TGF 1 , 2, and 3 have been found to be largely interchangeable in an inhibitory bioassay.
  • TGFp knockout mice die around 4 weeks of age due to extensive inflammatory cell infiltrates.
  • TGFp is an immune-suppressive cytokine that is elevated systemically in cancer patients. TGFpl is also expressed by tumors as a mechanism to suppress immune cell activity.
  • devices, compositions and methods for removing TGFp from blood or a blood product are provided.
  • Fig. 1 shows a schematic of one embodiment of an apheresis approach.
  • Fig. 2 shows a circulating plasma form of TGFp is the LLC (blue arrow) which is a therapeutic target for removal by apheresis. Since conventional antibodies to TGF do not recognize or bind to LLC, the binding agents, in some embodiments, bind specifically to the LLC for removal of this complex from the plasma of cancer patients.
  • Fig. 3 shows a diagram of an embodiment of a device with anti-TGF antibody conjugate beads.
  • the device housing comprises glass with polypropylene frits and tips and caps. The materials are all Class 6 quality. All housing components are sterilized by EtO or purchased sterile.
  • the beads comprising covalently linked anti-latent TGFpi are washed to remove uncoupled antibody, stored under bacteriostatic phosphate buffered saline with 0.9% benzyl alcohol (Bacteriostatic PBS).
  • Fig. 4 shows a bar graph illustrating amounts of TGFpi that were captured from latent TGFp complexes using the 7H4 antibody.
  • PBS/BSA was spiked with recombinant latent TGFp (R&D Systems) to 10 ng/mL.
  • the solution was run through a 1 mL column bead bed coupled to 5 mg of antibody to Latent TGFp (7H4, Biolegend).
  • the % capture of total TGFp at the successive indicated flow rates in imL/min was plotted.
  • a method for extracorporeal depletion or removal of a transforming growth factor beta (TGFp) polypeptide, or complex thereof, from blood or a blood product comprising: a) contacting the blood or blood product with a solid surface comprising a binding agent that specifically binds to a TGFp polypeptide; and b) separating the blood or blood product from the solid surface.
  • step a) removes or depletes TGFp polypeptide from the blood or blood product, or reduces or decreases the amount of TGFp polypeptide present in the blood or blood product.
  • the blood or blood product is introduced or re-introduced into a subject.
  • the blood or blood product is introduced or reintroduced into the subject from which the blood or blood product was obtained.
  • the blood or blood product is obtained from a subject.
  • the subject is a mammal or human.
  • the method of obtaining the blood or blood product from the subject and introducing the blood or blood product into the subject is by a process comprising apheresis or plasma exchange.
  • the solid substrate comprises a bead or particle and the binding agent is covalently linked to the bead or particle.
  • the solid substrate is housed in a column.
  • the TGFp polypeptide comprises a TGFpi polypeptide.
  • the complex thereof comprises a small latent complex (SLC) comprising a TGFpi polypeptide, or a large latent complex (LLC) comprising a TGFpi polypeptide.
  • a method of treating a subject having or suspected of having a disease or disorder comprising: a) contacting a blood or blood product obtained from the subject with a solid surface comprising a binding agent that specifically binds to a TGFp polypeptide or complex thereof; b) separating the blood or blood product from the solid surface and c) introducing the separated blood or blood product into the subject.
  • the process of obtaining the blood or blood product from the subject and introducing the blood or blood product comprises apheresis or plasma exchange.
  • step a) removes or depletes TGFp polypeptide from the blood or blood product, or reduces or decreases the amount of TGFp polypeptide present in the blood or blood product.
  • the disease is a cancer, tumor or metastasis.
  • the solid substrate comprises a bead or particle and the binding agent is covalently linked to the bead or particle. In some embodiments, the solid substrate is contained within a column.
  • the binding agent is an antibody.
  • the binding agent comprises a monoclonal antibody, humanized monoclonal antibody, aptamer, camelid, X-aptamer, single chain antibody, TGFp receptor, or binding fragment thereof.
  • the binding agent binds to a small latent complex (SLC) comprising a TGFp polypeptide, a large latent complex (LLC) comprising a TGFp polypeptide or a latency-associated peptide (LAP) portion of TGFpi .
  • SLC small latent complex
  • LLC large latent complex
  • LAP latency-associated peptide
  • the TGFp polypeptide comprises a TGFpi , TGFp2 or TGFp3 polypeptide.
  • the complex thereof comprises a small latent complex (SLC) comprising a TGFp polypeptide, or a large latent complex (LLC) comprising a TGFp polypeptide.
  • SLC small latent complex
  • LLC large latent complex
  • the device capable of removing a TGFp polypeptide, or complex thereof, from the blood or a blood product obtained from a subject, for example a human subject.
  • the device comprises a column containing a solid substrate comprising a binding agent that specifically binds to a TGFpi polypeptide, or complex thereof, wherein the column is configured for apheresis or plasma exchange.
  • the binding agent binds specifically to a LAP portion of a TGFp polypeptide.
  • the binding agent binds specifically to a small latent complex of TGFp or a large latent complex of TGFp.
  • the device comprises a column, cylinder or cartridge having an inflow port and an outflow port, a solid surface comprised with the column, cylinder or cartridge, and the binding agent is covalently attached to the solid surface.
  • a device described herein is used to treat a subject having, or suspected of having a cancer, tumor or metastasis.
  • TGFp polypeptides e.g., TGFpi , TGFp2, and TGFP3 are multifunctional secreted cytokines that play pivotal roles in diverse biological processes, including the regulation of cell growth and survival, cell and tissue differentiation, development, inflammation, immunity, hematopoiesis, and tissue remodeling and repair.
  • TGFpi plays a significant role in cancer ⁇ 1) : is essential for wound healing, stimulates matrix molecule deposition and angiogenesis, and is an essential mediator of pathologic scarring in fibrotic disorders.
  • TGFpi , TGFp2, and TGFP3 are initially synthesized as precursor proteins that undergo proteolytic cleavage by a similar process to form latent complexes.
  • TGFpi is synthesized as a single propeptide precursor of 390-amino acids with an N- terminal signal peptide of 29 amino acids, a 249 amino acid pro-region (LAP), and a 1 12 amino acid C-terminal region (TGFp).
  • Furin cleaves the protein at residue 278, yielding an N-terminal cleavage product which corresponds to the latency-associated peptide (LAP), and a 25-kD C-terminal portion.
  • the disulfide linked homodimers of LAP and homodimers of the TGFp C-terminal portion remain non-covalently associated, forming the small latent TGFp complex (SLC, 100kD).
  • This complex remains in the cell until it is bound by another protein called Latent TGF-p-Binding Protein (LTBP), forming a larger complex called Large Latent Complex (LLC, 235-260 kD). It is this LLC that gets secreted to the extracellular matrix (ECM).
  • ECM extracellular matrix
  • the TGFp homodimer can be activated and released from the LLC complex by a variety of different mechanisms. These activation mechanisms may involve proteases that degrade LAP, thrombospondin-1 , reactive oxygen species, and integrins avb6 and avb8, some of which are mechanisms are pH dependent.
  • Signaling begins with binding to a complex of the accessory receptor betaglycan (also known as Ri ll) and a type I I serine/threonine kinase receptor termed Rll.
  • the active TGFp dimer signals by bringing together two pairs of receptor serine/threonine kinases known as the type I and type II receptors, respectively.
  • the type II receptors phosphorylate and activate the type I receptors (either ALK-1 or Rl (also called ALK-5)) that then propagate the signal by phosphorylating Smad transcription factors.
  • Receptors of the TGFp branch of the cytokine family phosphorylate Smads 2 and 3, whereas those of the other branch such as BMP receptors phosphorylate Smads 1 , 5, and 8.
  • Use of other signaling pathways that are Smad-independent allows for distinct actions observed in response to in different contexts.
  • the receptor substrate Smads RSmads
  • Smads shuttle to the nucleus and form a complex with Smad4, a binding partner common to all RSmads ⁇ 2) .
  • RSmads receptor substrate Smads
  • a common TGFp stimulus can activate or repress hundreds of target genes at once.
  • Variant signaling branches and Smad-independent pathways coexist with the canonical Smad pathway in the response to TGFp. Seven type I receptors and five type II receptors paired in different combinations provide the receptor system for the entire TGFp family. Alterations and frame shifts are found at the level of the TGFp receptors in cancer.
  • TGFp inhibits the development, proliferation, and function of both the innate and the adaptive arms of the immune system.
  • Targets of TGFp include CD4 + effector T cells (Th1 and Th2), CD8 + cytotoxic T cells (CTLs), dendritic cells, NK cells, and macrophages. Additionally, TGFp stimulates the generation of regulatory T cells (Treg), which inhibit effector T cell functions, and IL17-producing Th17 cells, which regulate NK cells and macrophages.
  • TGFp is a potent inducer of Epithelial-mesenchymal transition (EMT).
  • EMT Epithelial-mesenchymal transition
  • Cells undergoing EMT lose expression of E-cadherin and other components of epithelial cell junctions. Instead, they produce a mesenchymal cell cytoskeleton and acquire motility and invasive properties.
  • TGFp in the tumor environment primes cells for metastasis through the angiopoietin-like 4 (ANGPTL4) expression pathway' 3 '.
  • TGFp can also enhance cell motility by cooperating with HER2 signals, as observed in breast cancer cells overexpressing HER2.
  • TGFp stimulates the generation of myofibroblasts from mesenchymal precursors' 4 '.
  • Myofibroblasts have features of fibroblasts and smooth muscle cells and are highly motile. Their presence in tumor stroma, partly as what are called “cancer-associated fibroblasts,” facilitates tumor development. Glioma cell cultures proliferate in response to TGFp through the induction of platelet-derived growth factor B (PDGF-B) through epigenetic processes.
  • PDGF-B platelet-derived growth factor B
  • Mutational inactivation of core pathway components occurs in large subsets of colorectal, pancreatic, ovarian, gastric, and head and neck carcinomas.
  • Breast cancers, prostate cancers, gliomas, melanomas, and hematopoietic neoplasias preferentially disable the tumor-suppressive action of TGFp by losing the tumor-suppressive arm of the signaling pathway.
  • lung adenocarcinomas and squamous cell carcinomas the loss of the TGFBRII results in aggressive tumor growth and reduced survival' 5 '.
  • TGFp tumor necrosis fibroblast growth factor receptor 4
  • ANGPTL4 functions to disrupt vascular endothelial cell junctions, to increase permeability of lung capillary walls and facilitates seeding of pulmonary metastases.
  • TGFp in addition to the role of TGFp in local tumor invasion, growing evidence implicates TGFp in the promotion of distal metastasis. Metastasis proceeds through a series of steps whereby cancer cells enter the circulatory system, disseminate to distal capillary beds, enter a parenchyma by extravasation, adapt to the new host microenvironment, and eventually grow into lethal tumor colonies in those distal organs ' 9, 10) . Metastasis follows characteristic organ distribution patterns that reflect distinct colonization aptitudes of cancer cells from different origins, different tumor-efferent circulation patterns, and distinct compatibilities between disseminated cells and the organ that they encounter.
  • metastasis requires extravasation and colonization functions that come into play once malignant cells disseminate. Such functions may be acquired in the primary tumor but become selected mainly during seeding and colonization distal metastases. Studies in model systems have described a broad range of potential and sometimes contradictory TGFp effects on metastasis.
  • Bone metastases are a significant problem in late stage breast cancer patients. Following their mobilization into marrow, cancer cells trigger osteoclasts to release which further influences cytokine release which in turn enhances metastatic invasiveness' 11 '.
  • Two genes that modulate bone metastases in ER " breast cancer cells are interleukin- 11 (IL- 11) and connective tissue growth factor (CTGF). These are TGFp target genes.
  • IL- 11 interleukin- 11
  • CTGF connective tissue growth factor
  • TGF connective tissue growth factor
  • TGFp Induction of IL-11 and CTGF expression by TGFp is mediated by the Smad pathway' 12 ' and has been confirmed in malignant cells isolated from patients with metastatic breast cancer ⁇ 13) . TGFp also induces IL-10 and IL-6 expression where IL-10 provides positive feedback for TGFp expression.
  • ER breast tumors that are positive for both the TGFp gene response signature and lung metastasis signature (LMS) are associated with the highest risk of relapse through lung metastases ⁇ 14) . Patients with these signatures showing enhanced function may be selective candidates for TGFp blocking therapy.
  • TGFp tumor mitogens
  • Smad7 a dominant-negative form of the TGFp receptor
  • PTHrP parathyroid hormone-related protein
  • TGFp RANK ligand
  • RTKL RANK ligand
  • Administration of anti-PTHrP neutralizing antibodies inhibits TGFp-dependent osteolytic bone metastasis in mice ⁇ 18) .
  • the role of TGFp in metastatic colony expansion may not be limited to bone metastasis.
  • a majority of metastases to lung, liver, and brain in breast cancer patients stain positive for phospho-Smad2, suggesting a widespread activation of this pathway in metastasis by locally released TGFp.
  • TGFp may facilitate tumor reinitiation through an aberrant induction of ID1 expression' 3 '.
  • Inhibitors of the TGFp pathway developed to date encompass several classes. They include antisense oligonucleotides, inhibitors of ligand-receptor interactions such as anti- TGFp antibodies' 19 ', anti-receptor antibodies, TGFp-trapping receptor ectodomain proteins, and small-molecule inhibitors that target TGFp receptor kinases. A few anti-TGFp compounds have shown efficacy in preclinical studies and several of these compounds are being evaluated in clinical trials ' 20, 21 ) . Clinical trials for each of these inhibitor classes have been initiated not only against cancers (glioma, melanoma, breast cancer) but also against fibrosis, scarring, and other conditions that result from excessive TGFp activity.
  • TGFp signaling might enhance the progression of premalignant lesions
  • offsetting potential clinical benefit exists especially for patients with TGFp promoted tumor growth.
  • systemic administration of TGFp blockers has not been reported to increase spontaneous tumor development in animal models with one possible exception.
  • Prolonged treatment with an antibody (1 D1 1 ) that binds to all three isoforms of TGFp was shown to give rise to carcinomas.
  • Such lesions are believed to be derived from pre-malignant foci that normally remain suppressed in the absence of antibody. Indeed, when antibody treatment is discontinued, the carcinomas resolve.
  • TGFp pathway targeting in tumors is based on the rationale that TGFp exerts strong
  • blocking or inhibiting TGFp function might empower the immune system against tumors.
  • Blocking or inhibiting TGFp action may also have additional tumor-specific benefits.
  • TGFp inhibition in gliomas may curtail the production of autocrine survival factors, such as PDGF.
  • Blocking or inhibiting TGFp in ER " breast cancer might prevent primary or metastatic tumors from seeding and reseeding metastasis' 22 '.
  • blocking or inhibiting TGFp might interrupt the cycle of TGFp-induced osteoclastogenic factors and halt tumor growth.
  • TGFp TGFp
  • Inhibition of TGFp might lead to chronic inflammatory and autoimmune reactions, although this problem has not yet materialized in the preclinical or clinical trials of systemic TGFp blockers. Inhibition of TGFp receptor function might also lead to runaway compensatory mechanisms by other activators of the Smad pathway, similar to what occurs in individuals with inactivating mutations in TGFBRI or TGFBRII ⁇ 23) .
  • TGFp gene expression prognostic tools and TGFp response biomarkers may provide the means to select patients for anti-TGFp intervention in addition to a way to assess effective pharmacological targeting of this pathway.
  • TGFp is an immunosuppressive cytokine that is elevated systemically in cancer patients. TGFpi is also expressed by tumors as a mechanism to suppress immune cell activity.
  • an affinity column for the removal or depletion of TGFp from the plasma, blood or blood product using any apheresis systems.
  • presented herein is a device to specifically remove or deplete TGFp as a treatment strategy for cancer, tumor or metastasis. In certain embodiments, this is accomplished by covalently linking an anti-TGFp antibody to circulating TGFp as a capture ligand to a support matrix.
  • patient plasma, blood or blood product is treated by placing a column (OEM components) containing the TGFp binding matrix into a plasma flow line of the apheresis system for plasma exchange to capture and thus remove or deplete the patient's TGFp.
  • a column OEM components
  • TGFp binding matrix As the TGFp is removed or depleted, the systemic reservoir concentration of TGFp is reduced to desuppress anti-cancer effects with ramifications at the tumor site(s).
  • the device performance is dependent on the efficiency of binding TGFp complexes by the immobilized binding agent (e.g., antibody).
  • the stable covalent linkage of the capture binding agent (e.g., antibody) on the matrix prevents its release into the patients being treated.
  • TGFp is a suppressor of immune responses
  • transitory inhibition or removal of TGFp by apheresis may stimulate immune responses to tumor cells in cancer patients and may provide therapeutic benefit alone or in combination with other anti-cancer therapies.
  • affinity cartridges that can be used in any apheresis setting for the removal of specific proteins from patient plasma, blood or blood product during apheresis.
  • TGFp Systemic elevation of TGFp is common to cancers.
  • This method is a novel approach to treat cancer patients through transient potentiation and systemic release from the immune suppressive effects of TGFp.
  • the approach is to remove or deplete TGFp using a blood filtration affinity column in conjunction with plasmapheresis (immunopheresis) to selectively capture circulating latent complexes from the plasma, blood or blood product.
  • the TGFp depleted plasma, blood or blood product is returned to the patient. This in turn can stimulate antitumor and anti-metastatic responses to reduce tumor burden and may lead to protective anti-tumor immunity.
  • the feasibility of subtractive targeting TGFp has several aspects that justify this approach:
  • Cancers have a high level of TGFp in the tumor microenvironment that is
  • Anti- TGFp approaches have potential for the clinic' 20 ' 21 ' 25) .
  • TGFp a pleiotropic cytokine whose inhibition has been shown to promote anti-cancer effects.
  • Use of an anti-TGF antibody, 1 D1 1 resulted in the reduction of tumor burden as well as increasing the survival rates in small animal studies and displayed overall beneficial responses in human clinical trials.
  • the administration of anti-TGF antibody serves to inhibit TGFp activity but does not reduce the overall systemic levels of circulating TGFp.
  • the methods herein enable the ability to reduce the levels of circulating TGFp.
  • One embodiment described herein is a method to remove circulating TGFp and thus control the overall systemic blood plasma concentration of the cytokine that is not readily achievable with antibody infusion. Additional robustness of treatment can be implemented since real time observations are complemented by the ability to immediately cease the cytokine removal process and then restart the process on demand.
  • the use of a plasmapheresis system compatible with a TGFp capture device allows treatment without the infusion of therapeutic agents.
  • anti-TGF antibodies recognize mature un-complexed TGFp, their inhibitory activity to TGFp is dependent on the dissociation of the TGFp polypeptide from LAP.
  • the infusion of anti-TGF antibodies is intended to inhibit the function of TGFp at sites where it is activated and released from the LTBP complex, for example at cellular receptor sites.
  • TGFp activation achieved by proteases at the site of action as a prelude to ligation of
  • TGFp 10 TGFp to its receptor.
  • the dissociation of TGFp from the complex is achieved by an acidification step to lower the pH to approximately 2 followed by a neutralization step.
  • the free TGFp protein can then be detected for instance, by an ELISA assay.
  • the method makes use of extracorporeal plasmapheresis/affinity chromatography systems such as those used for commercial plasma exchange.
  • the embodiment includes the use of a device that is compatible with such subtractive procedures for targeted reduction of systemic TGFp as a method for the treatment of cancer.
  • matrices are comprised in a column device through which patient plasma, blood or blood product is circulated such that the TGFp complex is captured on the matrix contained within the device.
  • the matrix is coupled to a binding agent that is specific for capture of circulating TGFp complexes.
  • the device outflow which is depleted of TGFp is then returned to the patient during the plasmapheresis or plasma exchange procedure. The resulting lowering of systemic levels of TGFp thus attenuates its immunosuppressive effects and activates anticancer, tumor or metastasis immune responses.
  • a TGFp polypeptide refers to polypeptide comprising an amino acid sequence of a mature TGFpi , a mature TGFp2, or mature TGFP3 peptide.
  • the mature form of TGFpi , 2 and 3 is that portion of the molecule that can bind to, and active a TGFp receptor.
  • a TGFp polypeptide comprises a TGFp leader sequence (e.g., a leader sequence of TGFpi , 2 or 3) and/or a TGFp LAP polypeptide (e.g., a LAP polypeptide of TGFpi , 2 or 3).
  • a TGFp polypeptide may comprise any known naturally occurring variant of a TGFp polypeptide.
  • a TGFp polypeptide is a mammalian TGFp polypeptide. In some embodiments a TGFp polypeptide is a primate TGFp polypeptide. In some embodiments a TGFp polypeptide is a human TGFp polypeptide. In some embodiments a TGFp polypeptide is a monkey TGFp polypeptide. In some embodiments a TGFp polypeptide is a rodent TGFp polypeptide (e.g., rat and/or mouse). In some embodiments a TGFp polypeptide is a canine TGFp polypeptide (e.g., a dog TGFp polypeptide).
  • a TGFp polypeptide comprises TGFpi or a mature peptide of TGFpi .
  • a TGFp polypeptide comprises TGFp2 or a mature peptide of TGFp2.
  • a TGFp polypeptide comprises TGFp3 or a mature peptide of TGFp3.
  • a TGFp polypeptide comprises a polypeptide sequence that is at least 80%, at least 85%, at least 90% or at least 95% to a TGFp polypeptide disclosed herein.
  • a TGFp polypeptide comprises a polypeptide sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% to SEQ ID Nos: 1 , 2 or 3. In some embodiments, a TGFp polypeptide comprises a polypeptide sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% to the mature TGFp peptide SEQ ID Nos: 1 , 2 or 3.
  • a binding agent disclosed herein binds specifically to a complex of a TGFp polypeptide.
  • a complex of a TGFp polypeptide comprises a TGFp LAP polypeptide.
  • a complex of a TGFp polypeptide comprises a TGFp latency-associated peptide (LAP).
  • LAP TGFp latency-associated peptide
  • a complex of a TGFp polypeptide is a small latent TGFp complex (SLC).
  • a complex of a TGFp polypeptide comprises a Latent TGF-p-Binding Protein (LTBP). In some embodiments, a complex of a TGFp polypeptide comprises a Latent TGF- ⁇ -Binding Protein (LTBP) and a LAP. In some embodiments, a complex of a TGFp polypeptide is a large latent TGFp complex (LLC). In certain embodiments, a complex of a TGFp polypeptide comprises a mature peptide of TGFpi , a LAP derived from TGFpi and/or an LTBP.
  • LLC latent TGFp complex
  • blood or a blood product comprises a TGFp polypeptide, or a complex thereof.
  • a method or device described herein removes a TGFp polypeptide, or complex thereof from blood or a blood product.
  • a method or device described herein removes at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% of a TGFp polypeptide, or a complex thereof, from the blood or blood product of a subject. In some embodiments, a method or device described herein reduces the amount of a TGFp polypeptide, or complex thereof, in the blood or a blood product obtained from a subject.
  • blood refers to whole blood. Non-limiting examples of a blood product include serum and plasma.
  • a method or device described herein is used for the treatment of a disease or disorder in a subject.
  • subject refers to a mammal. Any suitable mammal can be treated by a method or composition described herein.
  • mammals include humans, non-human primates (e.g., apes, gibbons, chimpanzees, orangutans, monkeys, macaques, and the like), domestic animals (e.g., dogs and cats), farm animals (e.g., horses, cows, goats, sheep, pigs) and experimental animals (e.g., mouse, rat, rabbit, guinea pig).
  • a mammal is a human.
  • a mammal can be any age or at any stage of development (e.g., an adult, teen, child, infant, or a mammal in utero).
  • a mammal can be male or female.
  • a subject is a human, such as a human having a tumor, cancer or metastasis.
  • a solid substrate or device described herein comprises one or more binding agents.
  • a binding agent binds specifically to a TGFp polypeptide, a complex thereof (e.g., an SLC or LLC), a portion thereof, or a fragment thereof.
  • a binding agent binds specifically to a LAP portion of a TGFp polypeptide.
  • a binding agent binds specifically to an SLC complex.
  • a binding agent binds specifically to TGFpi , or a complex thereof.
  • a binding agent binds specifically to TGFp2, or a complex thereof.
  • a binding agent binds specifically to TGFp3, or a complex thereof.
  • a binding agent sometimes comprises or consists of a suitable antibody, an antibody fragment and/or an antigen binding portion thereof (e.g., a binding fragment).
  • a binding agent is an antibody or an antigen binding portion thereof.
  • An antibody can refer to a natural antibody, polyclonal antibody, monoclonal antibody, non- naturally occurring antibody, recombinant antibody, chimeric antibody, and antibody binding fragments (e.g., an antigen binding portion of an antibody), a CDR-grafted antibody, a humanized antibody, a human antibody, or portions thereof.
  • a binding agent is a non-naturally occurring antibody, non-limiting examples of which include chimeric antibodies, recombinantly produced monoclonal antibodies, humanized antibodies, Fab, Fab', F(ab')2, Fv fragment, single-chain Fv (scFv), diabody (Dab), synbody, TandAbs, nanobodies, BiTEs, SMIPs, DARPins, DNLs, affibodies, camelid, Duocalins, adnectins, fynomers, Kunitz Domains Albu-dabs, DARTs, DVD-IG, Covx-bodies, peptibodies, scFv-lgs,
  • a binding agent is an aptamer.
  • a binding agent is a peptide aptamer.
  • a binding agent is an X-aptamer.
  • a binding agent is a nucleic acid based aptamer. Any suitable method can be used to make a binding agent that specifically binds to a TGFp polypeptide or complex thereof.
  • an antibody is derived, obtained, isolated, or purified from a suitable animal non-limiting examples of which include rabbit, goat, horse, ruminant (e.g., goats, sheep, giraffes, yaks, deer, antelope, cows and the like), rodent (rat, mouse, hamster), pig, fish, bird (e.g., chicken, e.g., bird eggs), llama, or the like.
  • ruminant e.g., goats, sheep, giraffes, yaks, deer, antelope, cows and the like
  • rodent rat, mouse, hamster
  • pig fish
  • bird e.g., chicken, e.g., bird eggs
  • llama or the like.
  • an antibody is derived, obtained, isolated, or purified from a suitable mammal.
  • a suitable mammal is a genetically altered mammal (e.g., a trans chromosomal or transgenic mammal) engineered to produce antibodies comprising human heavy chains and/or human light chains or portions thereof.
  • an antibody is derived, obtained, isolated, or purified from a rabbit, goat, horse, cow, rat, mouse, fish, bird, or llama, for example.
  • a binding agent that specifically binds to a TGFp polypeptide, or complex thereof can be made by any suitable method. Methods for generating antibodies, recombinant antibodies and/or antigen binding portions thereof are known. In some embodiments a binding agent is obtained from a suitable expression library. In some embodiments, a monoclonal binding agent is isolated from a phage library of binding agents, for example by using a technique described in Clackson et al, Nature, 352:624-628 (1991 ) and/or Marks et al, J. Mol Biol, 222:581 -597 (1991 ), or a variation thereof.
  • genes, or portions thereof, that encode a polypeptide of a binding agent may be cloned, subcloned, rearranged or modified for recombinant expression by a suitable cloning procedure and subsequently expressed using a suitable expression system by a method known to those skilled in the art (e.g., see Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, 1982; Antibody Engineering: Methods and Protocols, Vol. 248 of Methods in molecular biology, edited by Benny K. C. Lo, Springer Science & Business Media, 2004; Antibody Engineering, Vol. 1 , Roland E.
  • an antibody can be humanized by exchanging one or more framework regions, or portions thereof (e.g., one or more individual amino acids), with one or more framework regions, or portions thereof (e.g., one or more individual amino acids), from a human antibody.
  • Methods of humanizing an antibody by transferring one or more CDRs e.g., 1 , 2, 3, 4, 5 or all 6 CDRs
  • a donor binding agent e.g., a binding agent comprising framework regions of a mouse monoclonal antibody
  • acceptor binding agent e.g., a binding agent comprising human framework regions
  • Antibody Engineering Methods and Protocols, Vol. 248 of Methods in molecular biology, edited by Benny K. C.
  • a binding agent is modified to include certain amino acid additions, substitutions, or deletions designed to (1 ) reduce susceptibility of a binding agent to proteolysis, (2) reduce susceptibility of a binding agent to oxidation, (3) alter binding affinity to Fc receptors, (4) alter antigen binding affinity of a binding agent, (4) increase serum half-life and/or (5) confer or modify other physicochemical, pharmacokinetic or functional properties of a binding agent.
  • a binding agent can be expressed, isolated from and/or purified from a suitable expression system non-limiting examples of which include a suitable bacteria, insect, plant or mammalian expression system.
  • a nucleic acid encoding a binding agent can be introduced into a suitable mammalian cell line that expresses and secretes the binding agent into the cell culture media.
  • a binding agent comprises a TGFp receptor (e.g., TGFp Receptor 1 , or TGFp Receptor 2), or a TGFp binding portion thereof.
  • TGFp receptor e.g., TGFp Receptor 1 , or TGFp Receptor 2
  • the term "specifically binds” refers to a binding agent that binds to a TGFp polypeptide, or complex thereof, in preference to binding other molecules or other peptides as determined by, for example, a suitable in vitro assay (e.g., an Elisa, Immunoblot, Flow cytometry, and the like).
  • a specific binding interaction discriminates over non-specific binding interactions by about 2-fold or more, often about 10-fold or more, and sometimes about 100-fold or more, 1000-fold or more, 10,000- fold or more, 100,000-fold or more, or 1 ,000,000-fold or more.
  • Non-limiting examples of anti-TNFp antibodies that can be used for a method or device described herein include TW7-28G11 (Biolegend), and clone 7H4 (Biolegend), which bind to LLC.
  • a solid surface comprising a binding agent and the blood or blood product is then separated from the solid surface.
  • a solid surface may comprise an insoluble organic or inorganic solid that may be particulate, crystalline, polymeric, fibrous, porous-hollow fibrous, monolithic, or
  • Non-limiting examples of a solid surface include beads, particles, fibers, porous-membranes, porous-walled hollow fibers, and monolithic structures (a monolith), including combinations of multiple structural types.
  • a solid surface may further comprise or consist of compound constructions, for example in which particles are embedded in a reticular matrix, sandwiched between membranes, or both.
  • a solid surface may comprise or consist of non-porous or porous particles, a porous membrane, a porous filter, or a porous monolith.
  • a solid surface comprises or consist of particles. Particles may be spherical, roughly spherical or non- spherical, and may be of a size (average diameter) ranging from 10 ⁇ to 5 mm, 10 ⁇ to 1 mm, or 100 um to 500 nm.
  • a solid surface comprises a matrix.
  • a solid surface may further comprise or consist of compound constructions, for example in which particles are embedded in a reticular matrix, sandwiched between membranes, or both.
  • a binding agent can be covalently or non-covalently attached to a solid surface.
  • a binding agent is covalently attached to a solid surface.
  • a binding agent is covalently attached to a bead or particle.
  • a binding agent can be attached to a solid surface by a linker. Any suitable method can be used to attach a binding agent to a solid surface.
  • the membranes are in the form of porous-walled hollow fibers.
  • the device contains a porous reticular arrangement of fibers, where such fibers are the substrates to which the first surface-bound ligand and an additional surface-bound ligand are attached.
  • a device described herein is configured for a
  • a device described herein is configured for apheresis or plasma exchange.
  • the portion of a device that contacts the blood or blood product obtained from a subject is often sterile and suitable for medical use.
  • a device comprises a cylinder, cartridge or column that contains a solid surface comprising a binding agent.
  • device consists of a housing that contains the solid surface to which the binding agent is attached.
  • a device contains porous or non-porous particles sandwiched between porous membranes, or frits. In certain such embodiments, the particles are the solid surface to which binding agent is attached. In certain embodiments, a device contains porous or non-porous particles sandwiched between woven or amorphous fibrous filters. In certain such embodiments, the particles are the solid surface to which the binding agent is attached, and the fibrous filters are substantially inert. In certain embodiments, the device contains porous or non-porous particles sandwiched between woven or crystalline frits, and the frit is substantially inert. In certain embodiments, the device contains porous or non-porous particles embedded in a reticular polymer network.
  • particles are the solid surface to which binding agent is bound and the reticular polymer network is substantially inert.
  • the device comprises particles and the particles are confined between membranes, monoliths, a reticular polymer network, woven or amorphous fiber filters, crystalline frits, or a combination thereof.
  • a device contains one or more porous membranes and at least one of such membranes is a solid surface to which the binding agent is attached.
  • the chemical surface of one or more components of a device may be relatively inert or of such a relatively low surface area as to make no significant contribution to the chemical functionality of the device.
  • the chemical surface which is relatively inert or of relatively low surface area is configured so as to create structural integrity, or direct flow of liquids there through, or physically block, entrap, or entrain insoluble materials to prevent them from interfering with the effective use of the device.
  • a method described herein comprises extracorporeal depletion or removal of a transforming growth factor beta (TGFp) polypeptide, or complex thereof, from blood or a blood product obtained from a subject.
  • a method may comprise, in certain embodiments, contacting the blood or blood product with a solid surface comprising a binding agent that specifically binds to a TGFp polypeptide.
  • An antibody that specifically binds to a TGFp polypeptide will, upon contact with blood or a blood product that comprises a TGFp polypeptide, form a bound complex comprising the TGFp polypeptide and the binding agent, where the TGFp polypeptide is retained on the solid surface.
  • the blood or blood product is then, in certain embodiments, separate from the solid surface.
  • a device such as a column, cartridge or cylinder
  • the blood is separated from the solid surface by removing or expelling the blood or blood product from the device.
  • blood or a blood product is obtained directly from a subject, the blood or blood product then enters a device comprising a TGFp specific antibody, bound complexes are formed and retained on the solid surface, and the blood or blood product is returned to the subject, often by way of infusion.
  • a device comprises a plasma exchange system or an apheresis system.
  • Plasma exchange systems are known in the art and are commercially available. Any suitable commercially available plasmapheresis or plasma exchange system that can separate the blood plasma fraction from the cellular fraction can be adapted for use in a method described herein.
  • suitable plasma exchange systems include TERUMO OPTIA and SPECTRA OPTIA system sold by TerumoBCT.
  • a suitable dialysis machine can be retrofitted with device described herein.
  • a device described herein comprises an input port and an output port configured for continuous flow of blood or a blood product obtained from a subject through the device. Any suitable flow rate can be used. In some embodiments a flow rate of blood, or a blood product through a device described herein is 0.1 to 300 ml/min, or 1 to 100 ml/minute. In certain embodiments, blood or a blood product flows from the subject, into the input port where the blood or blood product is contacted with the solid surface comprised within the device, and then exits the device through the output port where the blood or blood product is returned to the subject.
  • the disease or disorder is a cancer, tumor or metastasis.
  • Non-limiting examples include hepatocellular cancer, mesothelioma; solid cancers or tumors, non-limiting examples of which include visceral tumors such as melanomas, breast, pancreatic, uterine and ovarian cancers, testicular cancer, including seminomas, gastric or colon cancer, hepatomas, adrenal, renal and bladder carcinomas, lung, head and neck cancers and brain tumors/cancers; carcinomas, non-limiting examples of which include respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, melanomas, neuroblastoma, squamous cell carcinoma of the head and neck, carcinomas of the uterus, cervix, lung, prostate, breast, head and neck, colon, pancreas, testes, adrenal, kidney, es
  • glioma glioblastoma, meningioma, neuroblastoma, retinoblastoma, astrocytoma and oligodendrocytoma
  • Lymphomas myelomas, and leukemias, non-limiting examples of which include acute and chronic lymphoblastic leukemia, myeloblastic leukemia, multiple myeloma, poorly differentiated acute leukemias (e.g., erythroblastic leukemia and acute megakaryoblastic leukemia), acute promyeloid leukemia (APML), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), which includes B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (C
  • Therapeutic targets can be quantified by measuring the amount of their removal whereas monitoring their inactivation by antibody therapy is difficult to quantify. With apheresis, this can be done by obtaining samples of pre- and post- column plasma during treatment and determination of the target protein concentrations. The total amount of target protein can be determined by elution of the columns that were used. In addition, changes in the blood composition of other potentially important markers can be followed over time post therapy.
  • Example 2 [0067] Included in Example 2 are references to the generation and use of specific TGFpi antigens (26-31 ).
  • PubMed PMID 18.1016/j.cell.2008.07.001. PubMed PMID: 18662538; PMCID: PMC3512574. 2. Shi Y, Massague J. Mechanisms of TGFp signaling from cell membrane to the nucleus. Cell. 2003;1 13(6):685-700. PubMed PMID: 12809600.
  • TGFpeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4.
  • TGFp signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest. 1999;103(2) :197-206. doi:
  • GC1008 a human anti-transforming growth factor-beta (TGFpeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma.
  • TGFpeta human anti-transforming growth factor-beta
  • TGFp3 Human
  • SEQ ID NO:3 SEQ ID NO:3

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Anesthesiology (AREA)
  • Hematology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Des modes de réalisation de l'invention concernent des dispositifs et des procédés pour éliminer, épuiser, réduire ou restreindre le nombre des polypeptides TGFβ issus du sang ou d'un produit sanguin.
PCT/US2017/029930 2016-04-27 2017-04-27 Méthode de traitement du cancer à l'aide d'une aphérèse thérapeutique pour éliminer le tgf-bêta par l'intermédiaire de ses complexes WO2017189899A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662328347P 2016-04-27 2016-04-27
US62/328,347 2016-04-27

Publications (1)

Publication Number Publication Date
WO2017189899A1 true WO2017189899A1 (fr) 2017-11-02

Family

ID=60161172

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/029930 WO2017189899A1 (fr) 2016-04-27 2017-04-27 Méthode de traitement du cancer à l'aide d'une aphérèse thérapeutique pour éliminer le tgf-bêta par l'intermédiaire de ses complexes

Country Status (1)

Country Link
WO (1) WO2017189899A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019053031A1 (fr) * 2017-09-13 2019-03-21 Bavarian Immunology Association GmbH Sang purifié pour utilisation en thérapie anticancéreuse
US11224858B1 (en) 2020-10-01 2022-01-18 Immunicom, Inc. Reduced leaching of a ligand
WO2022071960A1 (fr) * 2020-10-01 2022-04-07 Immunicom, Inc. Lixiviation réduite d'un ligand

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110240560A1 (en) * 2002-05-30 2011-10-06 Kazuo Teramoto Method of adsorbing transforming growth factor ß

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110240560A1 (en) * 2002-05-30 2011-10-06 Kazuo Teramoto Method of adsorbing transforming growth factor ß

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
OIDA ET AL.: "Depletion of TGF-b from fetal bovine serum", J IMMUNOL METHODS, vol. 362, no. 1-2, 2010, pages 195 - 198, XP027509609 *
YAMAMOTO ET AL.: "A novel immunotherapeutic modality with direct hemoperfusion targeting transforming growth factor-beta prolongs the survival of tumor-bearing rats", ONCOL REP., vol. 16, no. 6, 2006, pages 1277 - 1284, XP055437026 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019053031A1 (fr) * 2017-09-13 2019-03-21 Bavarian Immunology Association GmbH Sang purifié pour utilisation en thérapie anticancéreuse
US11224858B1 (en) 2020-10-01 2022-01-18 Immunicom, Inc. Reduced leaching of a ligand
WO2022071960A1 (fr) * 2020-10-01 2022-04-07 Immunicom, Inc. Lixiviation réduite d'un ligand
US11458236B2 (en) 2020-10-01 2022-10-04 Immunicom, Inc. Reduced leaching of a ligand

Similar Documents

Publication Publication Date Title
Lacal et al. Therapeutic implication of vascular endothelial growth factor receptor-1 (VEGFR-1) targeting in cancer cells and tumor microenvironment by competitive and non-competitive inhibitors
JP7437325B2 (ja) Ｉｌ－１１ｒａ抗体
US20190085066A1 (en) Antibodies to hgf and compositions containing
JP5979504B2 (ja) Ｖｅｇｆ結合分子
WO2017189899A1 (fr) Méthode de traitement du cancer à l'aide d'une aphérèse thérapeutique pour éliminer le tgf-bêta par l'intermédiaire de ses complexes
KR20150060686A (ko) 이중 안지오포이에틴-2/Dll4 결합제 및 항-VEGF 제제를 포함하는 약제학적 조합물
AU2018220126B2 (en) Stem cell enhancing therapeutics
CA2691075C (fr) Traitement de tumeurs a l'aide d'un anticorps anti-l1 specifique
EA018260B1 (ru) Антитела к дельта-подобному лиганду 4 человека и их применение
CN102596998A (zh) 血管增殖病症的治疗
JP2021176849A (ja) ヒトカンナビノイド１（ｃｂ１）受容体に結合する抗体
Ronca et al. Antiangiogenic activity of a neutralizing human single-chain antibody fragment against fibroblast growth factor receptor 1
KR20150060687A (ko) 이중 안지오포이에틴-2/Dll4 결합제 및 항-VEGF-R 제제를 포함하는 약제학적 조합물
US20120177651A1 (en) Antigen-binding proteins
TW201438737A (zh) Ｈｇｆ抗體之治療用途
CN102481363B (zh) 含有抗癌特异性膜抗原的抗体的癌治疗剂
CN107488231B (zh) 抗cd56抗体及其用途
CN112236166A (zh) 用于治疗骨疾病的转铁蛋白受体-2的拮抗剂和激动剂
JP2013542720A (ja) 抗エフリン−ｂ２抗体およびその使用
US20160319007A1 (en) Adrenomedullin binder for use in therapy of cancer
Gladh Exploring the Role of PDGF-D in Health and Disease
Polavaram Elucidation of the functions of Neuropilin 2 in osteoclasts in promoting prostate cancer bone metastasis.
US10144772B2 (en) Method for treating melanoma
Laface Migration Stimulating Factor: New Marker for Tumour Progression?
CN117343185A (zh) 一种抗犬pd-1抗体及其用途

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17790462

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17790462

Country of ref document: EP

Kind code of ref document: A1