US20130034861A1 - Early marker of proteinuria in patients treated with an anti-vegf treatment - Google Patents

Early marker of proteinuria in patients treated with an anti-vegf treatment Download PDF

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US20130034861A1
US20130034861A1 US13/518,358 US201013518358A US2013034861A1 US 20130034861 A1 US20130034861 A1 US 20130034861A1 US 201013518358 A US201013518358 A US 201013518358A US 2013034861 A1 US2013034861 A1 US 2013034861A1
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proteinuria
human
therapy
podocytes
vegf
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Vesna D. Garovic
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Mayo Foundation for Medical Education and Research
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • This document relates to methods and materials involved in determining whether or not a human receiving an anti-VEGF therapy has podocyturia (e.g., urinary excretion of podocytes). For example, this document provides methods and materials for detecting the presence or absence of podocytes in a urine sample from a human receiving an anti-VEGF therapy to determine whether or not the human has developed or is at risk for developing proteinuria or kidney injury.
  • podocyturia e.g., urinary excretion of podocytes
  • Angiogenesis has a critical role in the growth, invasion, and metastasis of malignancies.
  • Using angiogenesis inhibitors as an approach to cancer treatment has made significant progress in the field of cancer therapy.
  • Agents that target the vascular endothelial growth factor (VEGF) signaling pathway are advancing in clinical development.
  • VEGF vascular endothelial growth factor
  • a side effect in about 30% of cancer patients receiving anti-VEGF therapy is proteinuria ( ⁇ 300 mg of total protein in a 24-hour urine sample). Proteinuria can be associated with characteristic renal pathologic changes of glomerular endotheliosis, leading to renal toxicity.
  • an anti-VEGF therapy is bevacizumab (Avastin®), a humanized recombinant monoclonal antibody directed against VEGF.
  • This document provides methods and materials related to determining whether or not a human receiving an anti-VEGF therapy (e.g., bevacizumab) has developed or is at risk for developing proteinuria.
  • this document provides methods and materials for detecting urinary podocytes to determine whether or not a human receiving anti-VEGF therapy has or is at risk for developing proteinuria or kidney injury as indicated by podocyturia. Identifying patients who have podocyturia can allow such patients, who have or are at risk for developing toxicity as a result of the clinical use of drugs, to be treated effectively. In addition, identifying patients who do not have podocyturia can avoid unnecessary cessation of anti-VEGF therapy. As described herein, the presence of urinary podocytes can be used to identify humans receiving anti-VEGF therapy as having proteinuria or as being at risk for developing proteinuria as indicated by podocyturia.
  • one aspect of this document features a method for assessing a human receiving an anti-VEGF therapy for a risk of developing proteinuria or renal injury.
  • the method comprises, or consists essentially of, determining whether or not a urine sample from a human receiving anti-VEGF therapy contains urinary podocytes or evidence of urinary podocytes (e.g., podocyte remnants), wherein the presence of such podocytes indicates that the human is at risk for developing proteinuria.
  • this document features a method for assessing a human receiving an anti-VEGF therapy for proteinuria.
  • the method comprises, or consists essentially of, determining whether or not a urine sample from a human receiving anti-VEGF therapy contains urinary podocytes or evidence of urinary podocytes (e.g., podocyte remnants), wherein the presence of such podocytes indicates that the human has proteinuria.
  • this document describes a method for assessing a human receiving an anti-VEGF therapy for proteinuria, wherein the detection of proteinuria demonstrates renal injury.
  • the anti-VEGF therapy can be a bevacizumab therapy, a sunitinib therapy, a sorafenib therapy, or other known or effective therapies.
  • the therapy may be a monoclonal or poloyclonal antibody therapy.
  • a human receiving an anti-epidermal growth factor receptor (EGFR) therapy instead of or in addition to an anti-VEGF therapy, can be assessed for proteinuria or the risk of developing proteinuria or kidney injury as described herein with respect to an anti-VEGF therapy.
  • EGFR anti-epidermal growth factor receptor
  • podocytes can be detected in, for example, a urine sample using an antibody against a protein expressed by podocytes, such as podocin.
  • the antibody can be an antibody directed against a podocalyxin polypeptide, a nephrin polypeptide, or a synaptopodin polypeptide.
  • Podocytes, or their fragments can be detected using any appropriate method including, without limitation, cell staining techniques, immunocytochemistry techniques, and flow cytometry using, for example, anti-podocin antibodies.
  • this document features a method for assessing a human who has received an anti-VEGF therapy for a risk of developing proteinuria.
  • the method comprises, or consists essentially of, determining whether or not a urine sample from a human receiving anti-VEGF therapy contains one or more urinary podocytes or evidence of one or more urinary podocytes, wherein the presence of the one or more urinary podocytes or the evidence indicates that the human is at risk for developing proteinuria.
  • the anti-VEGF therapy can be selected from the group consisting of a bevacizumab therapy, a sunitinib therapy, and a sorafenib therapy.
  • the determining step can comprise using an antibody to detect podocytes.
  • the determining step can comprise using flow cytometry to detect podocytes.
  • the antibody can be an anti-podocin antibody.
  • the method can comprise detecting the presence of the one or more urinary podocytes.
  • the method can comprise classifying the mammal as being at risk of developing proteinuria based at least in part on the presence of the one or more urinary podocytes.
  • the method can comprise detecting the absence of the one or more urinary podocytes.
  • the method can comprise classifying the mammal as not being at risk of developing proteinuria based at least in part on the absence of the one or more urinary podocytes.
  • the human can be a non-pregnant human.
  • the method can comprise determining whether or not the urine sample contains a level of urinary podocytes greater than about three or more urinary podocytes (e.g., greater than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more urinary podocytes) per high power microscope field (400 ⁇ ).
  • a level of urinary podocytes greater than about three or more urinary podocytes (e.g., greater than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more urinary podocytes) per high power microscope field (400 ⁇ ).
  • this document features a method for assessing a human who has received an anti-VEGF or anti-EGFR therapy for proteinuria or a risk of developing proteinuria.
  • the method comprises, or consists essentially of, determining whether or not a urine sample from a human receiving anti-VEGF therapy or an anti-EGFR therapy contains one or more urinary podocytes or evidence of one or more urinary podocytes, classifying the human as having or as being at risk of developing proteinuria if the one or more urinary podocytes or the evidence are present in the urine sample, and classifying the human as not having or as not being at risk of developing proteinuria if the one or more urinary podocytes and the evidence are not present in the urine sample.
  • the human can be a human who received the anti-VEGF therapy.
  • the anti-VEGF therapy can be selected from the group consisting of a bevacizumab therapy, a sunitinib therapy, and a sorafenib therapy.
  • the determining step can comprise using an antibody to detect podocytes.
  • the antibody can be an anti-podocin antibody.
  • the determining step can comprise using flow cytometry to detect podocytes.
  • the method can comprise detecting the presence of the one or more urinary podocytes.
  • the method can comprise detecting the absence of the one or more urinary podocytes.
  • the human can be a non-pregnant human.
  • the method can comprise determining whether or not the urine sample contains a level of urinary podocytes greater than about three or more urinary podocytes (e.g., greater than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more urinary podocytes) per high power microscope field (400 ⁇ ).
  • a level of urinary podocytes greater than about three or more urinary podocytes (e.g., greater than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more urinary podocytes) per high power microscope field (400 ⁇ ).
  • this document features a method for identifying a human who has received an anti-VEGF or anti-EGFR therapy as having proteinuria or a risk of developing proteinuria.
  • the method comprises, or consists essentially of, detecting the presence of one or more podocytes in a urine sample of a human who received anti-VEGF therapy or an anti-EGFR therapy, and classifying the human as having or as being at risk of developing proteinuria based at least in part on the presence.
  • the human can be a human who received the anti-VEGF therapy.
  • the anti-VEGF therapy can be selected from the group consisting of a bevacizumab therapy, a sunitinib therapy, and a sorafenib therapy.
  • the detecting step can comprise using an antibody to detect the one or more podocytes.
  • the antibody can be an anti-podocin antibody.
  • the detecting step can comprise using flow cytometry to detect the one or more podocytes.
  • the human can be a non-pregnant human.
  • the presence of the one or more podocytes in the urine sample can be detected by detecting the presence of remnants of one or more urinary podocytes.
  • the method can comprise determining whether or not the urine sample contains a level of urinary podocytes greater than about three or more urinary podocytes (e.g., greater than 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more urinary podocytes) per high power microscope field (400 ⁇ ).
  • FIG. 1 contains a photograph of urinary cells plated on a collagen-coated slide, cultured for 24 hours, and stained for podocin immunoreactivity.
  • This document provides methods and materials for determining whether or not a human who received or is receiving an anti-VEGF therapy has developed or is at risk for developing proteinuria as indicated by podocyturia. For example, this document provides methods and materials for determining whether or not a human (e.g., a non-pregnant cancer patient) treated with an anti-VEGF therapy has an elevated level of urinary podocytes, thereby indicating that the human has developed or is at risk for developing proteinuria. As disclosed herein, the detection of one or more podocytes or evidence of podocytes (e.g., podocyte remnants) in the urine of a human is indicative that the human developed or is at risk of developing proteinuria. The presence of proteinuria may indicate that the human is experiencing or at risk of developing renal injury. Severe proteinuria may be indicative of nephrotic syndrome.
  • a human e.g., a non-pregnant cancer patient
  • the detection of one or more podocytes or evidence of podocytes e.g.
  • the methods and materials provided herein can be used to assess any type of human who received or is receiving an anti-VEGF therapy, an anti-EGFR therapy, or a combination of an anti-VEGF therapy and an anti-EGFR therapy.
  • the methods and materials provided herein can be used to assess male or female humans for proteinuria or a risk of developing proteinuria.
  • the methods and materials provided herein can be used to assess non-pregnant humans who received or are receiving an anti-VEGF therapy, an anti-EGFR therapy, or a combination of an anti-VEGF therapy and an anti-EGFR therapy for proteinuria or a risk of developing proteinuria.
  • anti-VEGF therapies include, without limitation, bevacizumab therapies, sunitinib therapies, and sorafenib therapies.
  • anti-EGFR therapies include, without limitation, cetuximab therapies, panitumumab therapies, trastuzumab therapies, lapatinib therapies, erlotinib therapies, and geftinib therapies.
  • any appropriate method can be used to determine the level of podocytes in a human's urine.
  • cell staining techniques that include using antibodies that bind to podocytes or polypeptides expressed by podocytes can be used.
  • antibodies include, without limitation, antibodies that have the ability to bind a podocin polypeptide (e.g., GenBank GI No. 7657615; Accession No. NP — 055440.1), a podocalyxin polypeptide (e.g., GenBank GI No. 66277202, Accession No. NP — 001018121.1; GenBank GI No. 33598950, Accession No. NP — 005388.2; GenBank GI No.
  • a podocin polypeptide e.g., GenBank GI No. 7657615; Accession No. NP — 055440.1
  • a podocalyxin polypeptide e.g., GenBank GI No. 6627
  • GenBank GI No. 885926 a GLEPP1 polypeptide (e.g., GenBank GI No. 885926; Accession No.
  • AAA82892.1 a WT1 polypeptide (e.g., GenBank GI No. AAH46461.2; Accession No. 110611793), a CD2AP polypeptide (e.g., GenBank GI No. 11321634; Accession No. NP — 036252.1), an actin polypeptide (e.g., GenBank GI No. 4501881; Accession No. NP — 001091.1), an actinin polypeptide (e.g., GenBank GI No. 3157976; Accession No. AAC17470.1), a cadherin polypeptide (e.g., GenBank GI No. 2281027; Accession No.
  • WT1 polypeptide e.g., GenBank GI No. AAH46461.2; Accession No. 110611793
  • a CD2AP polypeptide e.g., GenBank GI No. 11321634; Accession No. NP — 036252.1
  • BAA21569.1 a catenin polypeptide (e.g., GenBank GI No. 4503131; Accession No. NP — 001895.1), an integrin polypeptide (e.g., GenBank GI No. 47078292; Accession No. NP — 000203.2), a vinculin polypeptide (e.g., GenBank GI No. 340237; Accession No. AAA61283.1), a talin polypeptide (e.g., GenBank GI No. 6682361; Accession No. AAF23322.1), a paxillin polypeptide (e.g., GenBank GI No. 704348; Accession No.
  • a catenin polypeptide e.g., GenBank GI No. 4503131; Accession No. NP — 001895.1
  • an integrin polypeptide e.g., GenBank GI No. 47078292; Accession No. NP — 000203.2
  • a ZO-1 polypeptide e.g., GenBank GI No. 116875767; Accession No. NP — 003248.3
  • flow cytometry techniques can be used to determine the level of podocytes present in a human urine sample.
  • the podocytes detected in a urine sample can be viable podocytes, non-viable podocytes, or a combination thereof.
  • non-viable podocytes can be identifiable podocyte remnants.
  • An antibody can be, without limitation, a polyclonal, monoclonal, human, humanized, chimeric, or single-chain antibody, or an antibody fragment having binding activity, such as a Fab fragment, F(ab′) fragment, Fd fragment, fragment produced by a Fab expression library, fragment comprising a VL or VH domain, or epitope binding fragment of any of the above.
  • An antibody can be of any type (e.g., IgG, IgM, IgD, IgA or IgY), class (e.g., IgG1, IgG4, or IgA2), or subclass.
  • an antibody can be from any animal including, without limitation, birds and mammals.
  • an antibody can be a human, rabbit, sheep, or goat antibody.
  • An antibody can be naturally occurring, recombinant, or synthetic.
  • Antibodies can be generated and purified using any appropriate method.
  • monoclonal antibodies can be prepared using hybridoma, recombinant, or phage display technologies, or a combination of such technologies.
  • antibody fragments can be produced synthetically or recombinantly from a gene encoding a partial antibody sequence.
  • Any antibody that can be used to detect podocytes can have a binding affinity for its antigen of at least 10 4 mol ⁇ 1 (e.g., at least 10 1 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , or 10 12 mol ⁇ 1 ).
  • an anti-podocin antibody that binds to podocin polypeptides at an affinity of at least 10 4 mol ⁇ 1 (e.g., at least 10 1 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , or 10 12 mol ⁇ 1 ) can be used as described herein.
  • the term “elevated level” as used herein with respect to the level of urinary podocytes is any level that is above a median level of podocytes present in urine from a random population of non-pregnant humans known not to have proteinuria (e.g., a random population of 5, 10, 15, 20, 30, 40, 50, 100, 500, or more non-pregnant humans known not to have proteinuria).
  • the random population of non-pregnant humans can be a population of non-pregnant humans receiving an anti-VEGF therapy or a population of non-pregnant humans not receiving an anti-VEGF therapy, provided that the humans do not have proteinuria.
  • the random population of non-pregnant humans can be a population of non-pregnant humans receiving an anti-EGFR therapy or a population of non-pregnant humans not receiving an anti-EGFR therapy, provided that the humans do not have proteinuria.
  • an elevated level of urinary podocytes can be a detectable level of podocytes (e.g., podocin-positive cells) within a urine sample. The presence or absence of such a detectable level of podocytes (e.g., podocin-positive cells) can be determined using an anti-podocin antibody.
  • the level of urinary podocytes of a human is determined, then the level can assessed to determine if the level is an elevated level.
  • the presence of an elevated level of urinary podocytes can indicate that the human has proteinuria or a risk of developing proteinuria.
  • Additional clinical tests can be performed to confirm that a human having an elevated level of urinary podocytes has proteinuria. For example, a total protein determination in a 24-hour urine collection test, a urine dipstick protein analysis test, and/or a protein-creatinine ratio test in a random urine sample can be performed to confirm that a human having an elevated level of urinary podocytes has proteinuria.
  • the level of urinary podocytes present within a human can be assessed using a cutoff value such as 0.85 urinary podocytes present per mg creatinine.
  • a cutoff value such as 0.85 urinary podocytes present per mg creatinine.
  • the level can be compared to a cutoff value (e.g., 0.85 urinary podocytes/mg creatinine).
  • the presence of a level of urinary podocytes greater than or equal to the cutoff value can indicate that the human has proteinuria or a risk of developing proteinuria. Additional clinical tests can be performed to confirm that a human having a level of urinary podocytes greater than or equal to the cutoff value has proteinuria.
  • a total protein determination in a 24-hour urine collection test, a urine dipstick protein analysis test, and/or a protein-creatinine ratio test in a random urine sample can be performed to confirm that a human having a level of urinary podocytes greater than or equal to the cutoff value has proteinuria. If the presence of proteinuria is confirmed by an additional clinical test (e.g., a total protein determination in a 24-hour urine collection test) for a human having a level of urinary podocytes greater than or equal to the cutoff value, then that human can be classified as having proteinuria.
  • an additional clinical test e.g., a total protein determination in a 24-hour urine collection test
  • proteinuria is not confirmed by an additional clinical test (e.g., a total protein determination in a 24-hour urine collection test) for a human having a level of urinary podocytes greater than or equal to the cutoff value, then that human can be classified as being at risk of developing proteinuria.
  • an additional clinical test e.g., a total protein determination in a 24-hour urine collection test
  • a human treated with an anti-VEGF therapy, an anti-EGFR therapy, or both can be classified as having proteinuria or a risk of developing proteinuria if it is determined that the podocyte level in a urine sample from the human treated with the therapy (e.g., the anti-VEGF therapy, anti-EGFR therapy, or both) is greater than the podocyte level in a urine sample obtained from that human at an earlier time point (e.g., at a time prior to any treatments with an anti-VEGF therapy or an anti-EGFR therapy). Additional clinical tests can be performed to confirm that a human experiencing such an increase in urinary podocytes over time has proteinuria.
  • the therapy e.g., the anti-VEGF therapy, anti-EGFR therapy, or both
  • Additional clinical tests can be performed to confirm that a human experiencing such an increase in urinary podocytes over time has proteinuria.
  • a total protein determination in a 24-hour urine collection test, a urine dipstick protein analysis test, and/or a protein-creatinine ratio test in a random urine sample can be performed to confirm that a human experiencing an increase in urinary podocytes over time has proteinuria. If the presence of proteinuria is confirmed by an additional clinical test (e.g., a total protein determination in a 24-hour urine collection test) for a human experiencing an increase in urinary podocytes over time, then that human can be classified as having proteinuria.
  • an additional clinical test e.g., a total protein determination in a 24-hour urine collection test
  • proteinuria is not confirmed by an additional clinical test (e.g., a total protein determination in a 24-hour urine collection test) for a human experiencing an increase in urinary podocytes over time, then that human can be classified as being at risk of developing proteinuria.
  • an additional clinical test e.g., a total protein determination in a 24-hour urine collection test
  • the detection of one or more podocytes in a urine sample can be indicative of podocyturia.
  • a non-pregnant patient receiving an anti-VEGF therapy or anti-EGFR therapy (or both) can be classified as having proteinuria or a risk of developing proteinuria based at least in part on the detection of one or more podocytes in a urine sample. Additional clinical tests can be performed to confirm that a human having one or more detectable urinary podocytes has proteinuria.
  • a total protein determination in a 24-hour urine collection test, a urine dipstick protein analysis test, and/or a protein-creatinine ratio test in a random urine sample can be performed to confirm that a human having one or more detectable urinary podocytes has proteinuria. If the presence of proteinuria is confirmed by an additional clinical test (e.g., a total protein determination in a 24-hour urine collection test) for a human having one or more detectable urinary podocytes, then that human can be classified as having proteinuria.
  • an additional clinical test e.g., a total protein determination in a 24-hour urine collection test
  • proteinuria is not confirmed by an additional clinical test (e.g., a total protein determination in a 24-hour urine collection test) for a human having one or more detectable urinary podocytes, then that human can be classified as being at risk of developing proteinuria.
  • an additional clinical test e.g., a total protein determination in a 24-hour urine collection test
  • a human treated with an anti-VEGF therapy, an anti-EGFR therapy, or both can be monitored using the methods and materials provided herein.
  • Podocytes may appear in a patient's urine before any proteinuria is detected, thus providing an early predictor of a pending adverse event. This early indication may allow health care personnel to alter a patient's anti-VEGF or anti-EGFR treatment plan or to begin treatment for proteinuria. For example, the level of podocytes in a urine sample can be assessed to determine whether or not proteinuria persists in response to decreasing the dose of anti-VEGF therapy or anti-EGFR therapy.
  • This document also provides methods and materials to assist medical or research professionals in determining whether or not a human treated with an anti-VEGF therapy, an anti-EGFR therapy, or both has or is developing proteinuria.
  • Medical professionals can be, for example, doctors, nurses, medical laboratory technologists, and pharmacists.
  • Research professionals can be, for example, principal investigators, research technicians, postdoctoral trainees, and graduate students.
  • a professional can be assisted by (1) determining the level of urinary podocytes in a urine sample, and (2) communicating information about the level to that professional.
  • a professional can be assisted by (1) assessing a urine sample of the presence of urinary podocytes, and (2) communicating information about the presence of urinary podocytes to that professional.
  • Any appropriate method can be used to communicate information to another person (e.g., a professional).
  • information can be given directly or indirectly to a professional.
  • any type of communication can be used to communicate the information.
  • mail, e-mail, telephone, and face-to-face interactions can be used.
  • the information also can be communicated to a professional by making that information electronically available to the professional.
  • the information can be communicated to a professional by placing the information on a computer database such that the professional can access the information.
  • the information can be communicated to a hospital, clinic, or research facility serving as an agent for the professional.
  • This document also provides methods and materials for treating humans with an anti-VEGF therapy such as bevacizumab, an anti-EFGR therapy, or both under conditions that reduce the likelihood of inducing proteinuria.
  • an anti-VEGF therapy such as bevacizumab, an anti-EFGR therapy, or both under conditions that reduce the likelihood of inducing proteinuria.
  • a human needing an anti-VEGF therapy e.g., a human cancer patient needing bevacizumab treatment
  • a standard dose of bevacizumab e.g., 5-15 mg/kg/day
  • a urine sample can be obtained and assessed for urinary podocytes as described herein.
  • the dose of the anti-VEGF therapy can be reduced by at least 30 percent (e.g., 30, 40, 50, 75, 80, 90, or 100 percent) for a period of time.
  • anti-VEGF therapy can be skipped for one or two dosing cycles for a period of time so medication is received every four weeks or every six weeks. After this period of time, a urine sample can be obtained and assessed for urinary podocytes as described herein. If urinary podocytes are not detected or an elevated level of urinary podocytes is not detected, then the dose of the anti-VEGF therapy can be increased (e.g., increased to the original dose or to some degree less than the original dose).
  • the dose or the frequency of the anti-VEGF therapy can be reduced further for an additional period of time (e.g., once every week, every two weeks, every three weeks, or more cycles).
  • the assessment of urine for urinary podocytes or urinary podocyte levels and the adjustment of anti-VEGF therapy dosage can be repeated multiple times until a dose of anti-VEGF therapy is reached that does not induce proteinuria as determined by the presence or level of urinary podocytes detected.
  • a 67 year old female presented with a 7.2 ⁇ 6.1 cm mass involving the central and lower portion of the right kidney. Renal function was normal with a creatinine of 1.0 and no proteinuria. She subsequently underwent a right radical nephrectomy and retroperitoneal lymphadenectomy. Pathology confirmed Grade 2, T2, N0, M1 renal cell carcinoma, clear cell type. Sunitinib therapy was initiated, with good response.
  • a random urine sample (25-50 mL each) was centrifuged for 8 minutes at 700 g at room temperature. The pellets were rinsed twice with human diploid fibroblast (HDF) solution. Next, the pellets were resuspended in Dulbecco's modified eagle's medium (DMEM) F-12 medium with 10% fetal bovine serum that was supplemented with antibiotics for the prevention of bacterial contamination. A one-milliliter aliquot was plated on a collagen-coated tissue culture slide, which was followed by overnight incubation at 37° C. in 5% CO 2 . The next day, the media were removed, followed by two phosphate-buffered saline solution washes.
  • DMEM Dulbecco's modified eagle's medium
  • the slide was fixed with 1 mL of ice cold methanol for 10 minutes at ⁇ 20° C.
  • the slide was incubated with antibodies to podocin (dilution, 1:200). After being washed with phosphate-buffered saline solution, a secondary fluorescein isothiocyanate-labeled antibody was added at a dilution of 1:40 for 30 minutes.
  • the sediment was counterstained with Hoechst nuclear stain to facilitate differentiation of whole cells from cell fragments. Coverslips were mounted with Vectashield (Vector Labs, Burlington, Calif.), and the slides were viewed with a fluorescence microscope (Leica, Germany). Nucleated, positive-staining cells were considered to be podocytes.
  • a renal pathologist who was blinded to the clinical diagnosis and laboratory findings, evaluated each sample to determine the number of cells that were present and the percentage of cells that were stained for podocin.
  • a test is positive for proteinuria if the number of podocytes expressed as a ratio to the creatinine content of the respective urine sample is greater than 0.85 podocytes/mg creatinine.

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US10336822B2 (en) 2009-12-21 2019-07-02 Mayo Foundation For Medical Education And Research Early marker of proteinuria in patients treated with an anti-VEGF treatment

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