WO2014028445A2 - Isoformes de céréblon et leur utilisation en tant que biomarqueurs pour traitement thérapeutique - Google Patents

Isoformes de céréblon et leur utilisation en tant que biomarqueurs pour traitement thérapeutique Download PDF

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WO2014028445A2
WO2014028445A2 PCT/US2013/054663 US2013054663W WO2014028445A2 WO 2014028445 A2 WO2014028445 A2 WO 2014028445A2 US 2013054663 W US2013054663 W US 2013054663W WO 2014028445 A2 WO2014028445 A2 WO 2014028445A2
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Prior art keywords
biomarker
level
subject
isoform
crbn
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PCT/US2013/054663
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English (en)
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WO2014028445A3 (fr
Inventor
Anjan THAKURTA
Anita GANDHI
Michelle F. WALDMAN
Rajesh Chopra
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Celgene Corporation
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Publication of WO2014028445A2 publication Critical patent/WO2014028445A2/fr
Priority to US14/621,298 priority Critical patent/US9587281B2/en
Publication of WO2014028445A3 publication Critical patent/WO2014028445A3/fr
Priority to US15/414,329 priority patent/US20170362660A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • 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

  • cereblon isoforms Provided herein are cereblon isoforms and methods of their use as
  • biomarkers for treating a disease, disorder, or condition with a treatment compound e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4-oxoquinazolin- 3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)benzyl)oxy)- 1 - oxoisoindolin-2-yl)piperidine-2,6-dione.
  • a treatment compound e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4-oxoquinazolin- 3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)benzyl)oxy)- 1 - oxoisoindolin-2-yl)piperidine-2,
  • Cereblon a component of the DDBl-CUL4a-Rocl ubiquitin ligase complex
  • certain immunomodulatory compounds e.g., thalidomide, lenalidomide, and pomalidomide
  • MM myeloma
  • the translated full-length CRBN protein contains 442 amino acid residues. It has been established that the C terminal region of CRBN binds the immunomodulatory compound, thalidomide, and that amino acid residues 374Y and 376W are critical for the binding of thalidomide to CRBN (Ito et al, Science 2010, 327, 1345-1350).
  • CRBN is encoded by a 25 kB gene on chromosome 6, consisting of 11 exons and 10 introns.
  • alternative splicing process can potentially generate multiple functional proteins as well as variants of a protein from a single gene having different structural organization and functional activity.
  • Truncated proteins that have lost interaction domains or critical functional amino acid residues may create non- functional or aberrant CRBN proteins that may interfere with the functions of the full-length CRBN protein and reduce or alter the therapeutic activity of a treatment compound that exerts its activity via its interactions with the full-length CRBN protein.
  • CRBN can thus potentially be used as a biomarker for a treatment with an immunomodulatory agent, such as thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • an immunomodulatory agent such as thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN which has a deletion of amino acid residues 126 to 175 (zf 126-175) or amino acid residues 176 to 228 (zf 176-228) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 3 of CRBN, which has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 4 of CRBN, which has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 5 of CRBN, which has deletions of amino acid residues 176 to 278 (zf 176-278) and amino acid residues 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 6 of CRBN, which has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 7 of CRBN, which has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • Also provided herein is an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 126 to 175 (zi 126-175) or amino acid residues 176 to 228 (zf 176-228) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acid residues 176 to 278 (zf 176-278) and amino acid residues 317 to 382 (A 317-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (A 126-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1 , isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered as compared to the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered as compared to the level of the biomarker in the control sample.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered as compared to the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered as compared to the level of the biomarker in the control sample.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the difference between the level of the biomarker in the biological sample from the subject and the reference level of the biomarker correlates with the responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker;
  • the difference between the level of the biomarker in the biological sample from the subject and the reference level of the biomarker correlates with the responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the difference between the level of the biomarker in the biological sample from the subject and the level of the biomarker in the control sample correlates with the responsiveness of the subject to the treatment.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1 , isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the subject is responsive to the treatment if the level of the biomarker in the second biological sample of the subject is altered as compared to the level of the biomarker in the first biological sample of the subject.
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker with the level of the biomarker in a control sample from the subject;
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is higher than the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is higher than the level of the biomarker in the control sample.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is higher than the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is higher than the level of the biomarker in the control sample.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • an increased level of the biomarker in the biological sample from the subject in comparison with the reference level of the biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • an increased level of the biomarker in the biological sample from the subject in comparison with the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker;
  • an increased level of the biomarker in the biological sample from the subject in comparison with the reference level of the biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • an increased level of the biomarker in the biological sample from the subject in comparison with the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1 , isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • an increased level of the biomarker in the second biological sample in comparison with the level of the biomarker in the first biological sample indicates that the subject is responsive to the treatment.
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker with the level of the biomarker in a control sample from the subject;
  • an increased level of the biomarker in the biological sample in comparison with the level of the biomarker in the control sample indicates the compliance of the subject with the treatment.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is lower than the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is lower than the level of the biomarker in the control sample.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker;
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is lower than the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • a decreased level of the biomarker in the biological sample from the subject in comparison with the reference level of the biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • a decreased level of the biomarker in the biological sample from the subject in comparison with the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker;
  • a decreased level of the biomarker in the biological sample from the subject in comparison with the reference level of the biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • a decreased level of the biomarker in the biological sample from the subject in comparison with the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1 , isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof;
  • a decreased level of the biomarker in the second biological sample in comparison with the level of the biomarker in the first biological sample indicates that the subject is responsive to the treatment.
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising: a) obtaining a biological sample from the subject;
  • biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof; and c) comparing the level of the biomarker with the level of the biomarker in a control sample from the subject;
  • a decreased level of the biomarker in the biological sample in comparison with the level of the biomarker in the control sample indicates the compliance of the subject with the treatment.
  • a probe for determining the level of a biomarker in a sample by hybridizing with a polynucleotide of the biomarker wherein the biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof.
  • the level of the biomarker is used to select a subject for a treatment with a treatment compound, in one embodiment, an immunomodulatory compound; to predict or monitor the responsiveness of a subject to the treatment; or monitoring the compliance of a subject with the treatment.
  • the probe is one that hybridizes with a splice junction of a polynucleotide of the biomarker.
  • the probe is specific for detecting or quantitating an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, or isoform 7.
  • a probe for determining the level of a biomarker in a sample by hybridizing with an mRNA of the biomarker wherein the biomarker is an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof.
  • the level of the biomarker is used to select a subject for a treatment with a treatment compound, in one embodiment, an immunomodulatory compound; to predict or monitor the responsiveness of a subject to the treatment; or monitoring the compliance of a subject with the treatment.
  • the probe is one that hybridizes with a splice junction of an mRNA of the biomarker.
  • the probe is specific for detecting or quantitating an isoform of CRBN, in one embodiment, isoform 1, isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, or isoform 7.
  • an antibody for determining the level of a biomarker in a sample wherein the biomarker is an isoform of CRBN, in one embodiment, isoform 1 , isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof.
  • the level of the biomarker is used to select a subject for a treatment with a treatment compound, in one embodiment, an immunomodulatory compound; to predict or monitor the responsiveness of a subject to the treatment; or monitoring the compliance of a subject with the treatment.
  • the antibody is one that binds to a splice junction of an isoform, in one embodiment, isoform 1 , isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, or isoform 7.
  • the antibody is specific for detecting or quantitating an isoform of CRBN, in one embodiment, isoform 1 , isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, or isoform 7.
  • kits for determining the level of a biomarker in a biological sample from a subject wherein the biomarker is an isoform of CRBN, in one embodiment, isoform 1 , isoform 2, isoform 3, isoform 4, isoform 5, isoform 6, isoform 7, or a combination thereof.
  • the level of the biomarker is used to select a subject for a treatment with a treatment compound, in one embodiment, an immunomodulatory compound; to predict or monitor the responsiveness of a subject to the treatment; or monitoring the compliance of a subject with the treatment.
  • the methods, probes, antibodies, and kits provided herein are based, in part, on the discovery that the change in the level of certain molecules (e.g. , mRNAs, cDNA, or proteins) in a biological sample can be utilized as biomarkers to predict
  • an immunomodulatory compound e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • an immunomodulatory compound e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • the methods provided herein are based on comparison of the level of a biomarker in a biological sample from a subject having or suspected to have a disease, disorder, or condition to a reference level of the biomarker or the level of the biomarker in a control sample.
  • the biomarker level is used to determine or to predict, for example, the likelihood of the responsiveness of the subject to a treatment with a treatment compound, in one embodiment, an immunomodulatory compound, such as thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • an immunomodulatory compound such as thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-
  • FIG. 1 illustrates seven isoforms of CRBN formed via alternative splicing.
  • FIG. 2 illustrates a nucleic acid sequence (SEQ ID No: 1) encoding isoform 1 of CRBN.
  • FIG. 3 illustrates a nucleic acid sequence (SEQ ID No:2) encoding isoform 2 of CRBN.
  • FIG. 4 illustrates a nucleic acid sequence (SEQ ID No:3) encoding isoform 3 of CRBN.
  • FIG. 5 illustrates a nucleic acid sequence (SEQ ID No:4) encoding isoform 4 of CRBN.
  • FIG. 6 illustrates a nucleic acid sequence (SEQ ID No:5) encoding isoform 5 of CRBN.
  • FIG. 7 illustrates a nucleic acid sequence (SEQ ID No: 6) encoding isoform 6 of CRBN.
  • FIG. 8 illustrates a nucleic acid sequence (SEQ ID No: 7) encoding isoform 7 of CRBN.
  • FIG. 9 shows the detection of the seven CRBN isoforms in ⁇ 929 and primary CD 138+ isolated multiple myeloma (MM) cells.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, pig, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • treat refers to alleviating or abrogating a disease, or one or more of the symptoms associated with the disease; or alleviating or eradicating the cause(s) of the disease itself.
  • prevent are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • terapéuticaally effective amount of a compound refers to the amount of the compound that, when administered, is sufficient to prevent the
  • a therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of a disease, disorder, or condition.
  • the term encompasses an amount of the compound that improves overall therapy, reduces, or avoids symptoms or causes of a disease, disorder, or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • level refers to the amount, accumulation, or rate of a biomarker molecule.
  • a level can be represented, for example, by the amount or the rate of synthesis of a massager RNA (mRNA) encoded by a gene, the amount or the rate of synthesis of a polypeptide or protein encoded by a gene, the amount or the rate of synthesis of a biological molecule accumulated in a cell or biological fluid, or the biological activity of a biological molecule in a cell or biological fluid.
  • mRNA massager RNA
  • level refers to an absolute amount of a molecule in a sample or to a relative amount of the molecule, determined under steady-state or non-steady-state conditions.
  • responsiveness refers to the degree of effectiveness of the treatment in lessening or decreasing the symptoms of a disease, disorder, or condition being treated.
  • increased responsiveness when used in reference to a treatment of a cell or a subject refers to an increase in the effectiveness in lessening or decreasing the symptoms of the disease when measured using any methods known in the art.
  • the increase in the effectiveness is at least about 5%, at least about 10%, at least about 20%, at least about 30%>, at least about 40%>, or at least about 50%>.
  • the term "effective patient response" refers to an increase in the therapeutic benefit to a patient in treating a disease, disorder, or condition. In certain embodiments, the increase is at least about 5%, at least about 10%, at least about 20%, at least about 30%), at least about 40%>, or at least about 50%>.
  • An "effective patient tumor response" can be, for example, an about 5%, about 10%>, about 25%, about 50%>, or about 100% decrease in one or more physical symptoms of the disease or the tumor size.
  • the term “likelihood” refers to an increase in the probability of an event.
  • the term “likelihood” when used in reference to the effectiveness of a patient's response to a treatment of a disease, disorder, or condition contemplates an increased probability that the symptoms of the disease, disorder, or condition will be lessened or decreased.
  • predict generally means to determine or tell in advance.
  • the term “predict” can mean that the likelihood of the outcome of the treatment can be determined at the outset, before the treatment has begun, or before the treatment period has progressed substantially.
  • non-naturally occurring refers to materials which are found in nature and that has been structurally modified or synthesized by man.
  • polypeptide, protein, or peptide refers to a polymer of two or more amino acids in a serial array, linked through one or more peptide bond(s).
  • the term encompasses proteins, protein fragments, protein analogues, oligopeptides, and peptides.
  • the amino acids of the polypeptide, protein, or peptide can be naturally occurring amino acids or synthetic amino acids (e.g., mimics of naturally occurring amino acids).
  • the polypeptide, protein, or peptide can be made synthetically or purified from a biological sample.
  • polypeptide, protein, or peptide also encompasses modified polypeptides, proteins, and peptides, e.g., a glycopolypeptide, glycoprotein, or glycopeptide; or a lipopolypeptide, lipoprotein, or lipopeptide.
  • antibody refers to a polypeptide that specifically binds an epitope (e.g., an antigen).
  • the term “antibody” is used herein in the broadest sense and covers fully assembled antibodies, antibody fragments which retain the ability to specifically bind to an antigen (e.g., Fab, F(ab') 2 , Fv, and other fragments), single chain antibodies, diabodies, antibody chimeras, hybrid antibodies, bispecific antibodies, and humanized antibodies.
  • the term “antibody” also covers both polyclonal and monoclonal antibodies.
  • the term “expressed” or “expression” refers to the transcription from a gene to give an R A nucleic acid molecule, e.g. , mRNA, at least complementary in part to a region of one of the two nucleic acid strands of the gene.
  • the term “expressed” or “expression” as used herein also refers to the translation from an RNA molecule to give a protein, a polypeptide, or a portion thereof.
  • An mRNA that is "unregulated” generally refers to an increase in the level of expression of the mRNA in response to a given treatment or condition.
  • An mRNA that is “downregulated” generally refers to a "decrease” in the level of expression of the mRNA in response to a given treatment or condition. In some situations, the mRNA level can remain unchanged upon a given treatment or condition.
  • An mRNA from a patient sample can be "unregulated," i.e., the level of mRNA can be increased, for example, by about 5%, about 10%, about 20%>, about 30%>, about 40%>, about 50%>, about 60%, about 70%, about 90%, about 100%, about 200%, about 300%, about 500%, about 1,000%, about 5,000% or more of the comparative control mRNA level or a reference level.
  • an mRNA can be "downregulated," i.e., the level of mRNA level can be decreased, for example, by about 99%>, about 95%>, about 90%>, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 10%), about 5%>, about 2%>, about 1%> or less of the comparative control mRNA level or a reference level.
  • the level of a polypeptide, protein, or peptide from a patient sample can be increased as compared to a control or a reference level.
  • This increase can be about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 90%, about 100%, about 200%, about 300%, about 500%, about 1,000%, about 5,000% or more of the comparative control protein level or a reference level.
  • the level of a protein biomarker can be decreased. This decrease can be, for example, present at a level of about 99%, about 95%, about 90%>, about 80%>, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 10%, about 5%, about 2%, about 1% or less of the comparative control protein level or a reference level.
  • determining means determining if an element is present or not.
  • the measurement can be quantitative and/or qualitative determinations. "Assessing the presence of can include determining the amount of something present, as well as determining whether it is present or absent.
  • nucleic acid and “polynucleotide” are used interchangeably herein to refer to a polymer of nucleotides, e.g. , deoxyribonucleotides or
  • ribonucleotides or compounds, which can hybridize with a naturally occurring nucleic acid in a sequence specific manner analogous to that of two naturally occurring nucleic acids, e.g., participating in Watson-Crick base pairing interactions.
  • bases or “base”
  • nucleotides or “nucleotide”
  • nucleoside and “nucleotide” are intended to include those moieties that contain not only the known purine and pyrimidine bases, but also other heterocyclic bases.
  • nucleoside and “nucleotide” include those moieties that contain not only conventional ribose and deoxyribose sugars, but other sugars as well. Modified nucleosides or nucleotides also include modifications on the sugar moiety, e.g., wherein one or more of the hydroxyl groups are replaced with halogen atoms or aliphatic groups, or are functionalized as ethers, amines, or the like.
  • analogue of a "nucleic acid” or “polynucleotide” refers to a molecule having a structural feature that is recognized in the literature as being a mimetic, derivative, having an analogous structure, or other like terms, and includes, for example, a polynucleotide incorporating a non-natural nucleotide, a nucleotide mimetic such as a 2'- modified nucleoside, peptide nucleic acid, oligomeric nucleoside phosphonate, and any polynucleotide that has added substituent groups, such as protecting groups or linking moieties.
  • polynucleotides based on the sequences of the polynucleotides.
  • a first polynucleotide and a second polynucleotide are complementary if they bind to each other in a hybridization assay under stringent conditions, e.g., if they produce a given or detectable level of signal in a hybridization assay.
  • Portions of polynucleotides are complementary to each other if they follow conventional base-pairing rules, e.g. , A pairs with T (or U) and G pairs with C, although small regions ⁇ e.g., less than about 3 bases) of mismatch, insertion, or deleted sequence may be present.
  • sequence identity in the context of two nucleic acid sequences refers to the residues in the two sequences which are the same when aligned for maximum correspondence over a specified comparison window, and can take into consideration additions, deletions and substitutions.
  • substantially identical in their various grammatical forms in the context of polynucleotides generally means that a polynucleotide comprises a sequence that has a desired identity, for example, at least 60%, at least 70%>, at least 80%), at least 90%> and at least 95% sequence identity, compared to a reference sequence. Another indication that nucleotide sequences are substantially identical is if two molecules hybridize to each other under stringent conditions.
  • bound can be used herein to indicate direct or indirect attachment.
  • bound (or “bonded") may refer to the existence of a chemical bond directly joining two moieties or indirectly joining two moieties ⁇ e.g., via a linking group or any other intervening portion of the molecule).
  • the chemical bond may be a covalent bond, an ionic bond, a coordination complex, hydrogen bonding, van der Waals interactions, or hydrophobic stacking, or may exhibit characteristics of multiple types of chemical bonds.
  • “bound” includes embodiments where the attachment is direct and also embodiments where the attachment is indirect.
  • isolated and purified refer to isolation of a substance (such as mR A or protein) such that the substance comprises a substantial portion of the sample in which it resides, i.e., greater than the substance is typically found in its natural or un- isolated state.
  • a substantial portion of the sample comprises, e.g., greater than about 1%, greater than about 2%, greater than about 5%, greater than about 10%, greater than about 20%>, greater than about 50%>, or more, usually up to about 90%> to 100%) of the sample.
  • a sample of an isolated mRNA can typically comprise at least about 1% total mRNA.
  • Techniques for purifying polynucleotides are well known in the art and include, for example, gel electrophoresis, ion-exchange chromatography, affinity chromatography, flow sorting, and sedimentation according to density.
  • biological sample refers to a sample obtained from a biological subject, including a sample of biological tissue or fluid origin, obtained, reached, or collected in vivo or in situ.
  • a biological sample also includes samples from a region of a biological subject containing precancerous or cancer cells or tissues. Such samples can be, but are not limited to, organs, tissues, fractions and cells isolated from a mammal.
  • Exemplary biological samples include, but are not limited to, cell lysate, a cell culture, a cell line, a tissue, oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, a skin sample, and the like.
  • biological samples include, but are not limited to, whole blood, partially purified blood, PBMCs, tissue biopsies, and the like.
  • analyte refers to a known or unknown component of a sample.
  • capture agent refers to an agent that binds an mRNA or protein through an interaction that is sufficient to permit the agent to bind and concentrate the mRNA or protein from a homogeneous mixture.
  • probe refers to a capture agent that is directed to a specific target nucleic acid ⁇ e.g., mRNA) biomarker sequence. Accordingly, each probe of a probe set has a respective target nucleic acid ⁇ e.g., mRNA) biomarker.
  • a probe/target nucleic acid duplex is a structure formed by hybridizing a probe to its target nucleic acid biomarker.
  • nucleic acid probe or “oligonucleotide probe” refers to a nucleic acid capable of binding to a target nucleic acid of complementary sequence, such as an mR A biomarker, through one or more types of chemical bonds, usually through complementary base pairing, usually through hydrogen bond formation.
  • a probe may include natural (e.g., A, G, C, or T) or modified bases (7-deazaguanosine, inosine, etc.).
  • the bases in a probe may be joined by a linkage other than a phosphodiester bond, so long as it does not interfere with hybridization.
  • probes may bind target sequences lacking complete complementarity with the probe sequence depending upon the stringency of the hybridization conditions.
  • the probes are directly labeled with an isotope, chromophore, lumiphore, chromogen, or biotin. By assaying for the presence or absence of the probe, one can detect the presence or absence of a target nucleic acid biomarker of interest.
  • stringent assay conditions refers to conditions that are compatible to produce binding pairs of nucleic acids, e.g., probes and target mR As, of sufficient complementarity to provide for the desired level of specificity in the assay while being generally incompatible to the formation of binding pairs between binding members of insufficient complementarity to provide for the desired specificity.
  • stringent assay conditions generally refers to the combination of hybridization and wash conditions.
  • a "label” or a “detectable moiety” in reference to a nucleic acid refers to a composition that, when linked with a nucleic acid, renders the nucleic acid detectable, for example, by spectroscopic, photochemical, biochemical, immunochemical, or chemical means.
  • Exemplary labels include, but are not limited to, radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, enzymes, biotin, digoxigenin, haptens, and the like.
  • a "labeled nucleic acid or oligonucleotide probe” is generally one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic bonds, van der Waals forces, electrostatic attractions, hydrophobic interactions, or hydrogen bonds, to a label such that the presence of the nucleic acid can be detected by detecting the presence of the label bound to the nucleic acid.
  • PCR polymerase chain reaction
  • PCR can be used to amplify specific RNA sequences, specific DNA sequences from total genomic DNA, and cDNA transcribed from total cellular RNA, bacteriophage or plasmid sequences, etc. See generally Mullis et al., Cold Spring Harbor Symp. Quant. Biol, 51 :263 (1987); Erlich, ed., PCR Technology, (Stockton Press, NY, 1989).
  • cycle number refers to the PCR cycle number at which the fluorescence level passes a given set threshold level.
  • the CT measurement can be used, for example, to approximate levels of mRNA in an original sample.
  • the CT measurement is often used in terms of "dCT” or the “difference in the CT” score, when the CT of one nucleic acid is subtracted from the CT of another nucleic acid.
  • the term "about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • CRBN refers to a protein encoded by the CRBN gene in humans, or a variant thereof.
  • CRBN variant is intended to include proteins substantially homologous to a native CRBN, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions ⁇ e.g., CRBN derivatives, homologs, and fragments), as compared to the amino acid sequence of a native CRBN.
  • the amino acid sequence of a CRBN variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 126 to 175 (A 126- 175) or amino acid residues 176 to 228 (A 176-228) in the full-length amino acid sequence of CRBN.
  • the 126-175 and 176-228 amino acid segments are encoded by exons 4 and 5 of the CRBN gene, respectively.
  • the polypeptide is isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the 58-125 and 126-175 amino acid segments are encoded by exons 3 and 4 of the CRBN gene, respectively.
  • the polypeptide is isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (A 126-316) in the full-length amino acid sequence of CRBN.
  • the 126-175, 176-228, 229-249, 250- 278, and 279-316 amino acid segments are encoded by exons 4, 5, 6, 7, and 8 of the CRBN gene, respectively.
  • the polypeptide is isoform 5 of CRBN, wherein the isoform has deletions of amino acid residues 176 to 278 (zi 176-278) and amino acid residues 317 to 382 (A317-382) in the full-length amino acid sequence of CRBN.
  • the 176-228, 229-249, 250-278, 317-338, and 339-382 amino acid segments are encoded by exons 5, 6, 7, 9, and 10 of the CRBN gene, respectively.
  • the polypeptide is isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the 126-175, 176-228, 229-249, 250- 278, 279-316, 317-338, and 339-382 amino acid segments are encoded by exons 4, 5, 6, 7, 8, 9, and 10 of the CRBN gene, respectively.
  • the polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • the 23-57, 56-125, 126-175, 176-228, 229-249, 250-278, 279-316, and 317-338 amino acid segments are encoded by exons 2, 3, 4, 5, 6, 7, 8, and 9 of the CRBN gene, respectively.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 23 to 57 (z/23-57) in the full-length amino acid sequence of CRBN.
  • the 23-57 amino acid segment is encoded by exon 2 of the CRBN gene.
  • the polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • the 58-125 amino acid segment is encoded by exon 3 of the CRBN gene.
  • the polypeptide is isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 126 to 175 (zi 126- 175) in the full-length amino acid sequence of CRBN.
  • the 126-175 amino acid segment is encoded by exon 4 of the CRBN gene.
  • the polypeptide is isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 176 to 228 (zf 176-228) in the full-length amino acid sequence of CRBN.
  • the 176-228 amino acid segment is encoded by exon 5 of the CRBN gene.
  • the polypeptide is isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf317-382) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 229 to 249 (zf229-249) in the full-length amino acid sequence of CRBN.
  • the 229-249 amino acid segment is encoded by exon 6 of the CRBN gene.
  • the polypeptide is isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf317-382) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • provided herein is an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 250 to 278 (z/250-278) in the full-length amino acid sequence of CRBN.
  • the 250-278 amino acid segment is encoded by exon 7 of the CRBN gene.
  • the polypeptide is isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf317-382) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 279 to 316 (zf279-316) in the full-length amino acid sequence of CRBN.
  • the 279-316 amino acid segment is encoded by exon 8 of the CRBN gene.
  • the polypeptide is isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 317 to 338 (zi 317-338) in the full-length amino acid sequence of CRBN.
  • the 317-338 amino acid segment is encoded by exon 9 of the CRBN gene.
  • the polypeptide is isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf317-382) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • polypeptide is isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 339 to 382 (A339-382) in the full-length amino acid sequence of CRBN.
  • the 339-382 amino acid segment is encoded by exon 10 of the CRBN gene.
  • the polypeptide is isoform 2 of CRBN, wherein the isoform has a deletion of amino acids 339 to 382 (z/339-382) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (z/317-382) in the full-length amino acid sequence of CRBN.
  • the polypeptide is isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zi 126-382) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform CRBN comprising from about 100 to about 400 amino acid residues.
  • the polypeptide is isoform 2 of CRBN, which contains about 398 amino acid residues.
  • the polypeptide is isoform 3 of CRBN, which contains about 274 amino acid residues.
  • the polypeptide is isoform 4 of CRBN.
  • the polypeptide isoform 5 of CRBN, which contains about 193 amino acid residues.
  • the polypeptide is isoform 6 of CRBN.
  • the polypeptide isoform 7 of CRBN.
  • an isolated, synthetic, or recombinant polypeptide of an isoform of CRBN comprising from about 100 to about 300 amino acid residues.
  • the polypeptide is isoform 3 of CRBN, which contains about 274 amino acid residues.
  • the polypeptide is isoform 4 of CRBN.
  • the polypeptide isoform 5 of CRBN, which contains about 193 amino acid residues.
  • the polypeptide isoform 6 of CRBN.
  • the polypeptide is isoform 7 of CRBN.
  • provided herein is an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN provided herein.
  • an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 126 to 175 (zi 126-175) or amino acid residues 176 to 228 (zf 176-228) in the full-length amino acid sequence of CRBN.
  • the 126-175 and 176-228 amino acid segments are encoded by exons 4 and 5 of the CRBN gene, respectively.
  • the nucleic acid is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acid residues 176 to 278 (zf 176-278) and amino acid residues 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 23 to 57 (z/23-57) in the full-length amino acid sequence of CRBN.
  • the 23-57 amino acid segment is encoded by exon 2 of the CRBN gene.
  • the nucleic acid is one encoding the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 58 to 125 (z/58-125) in the full-length amino acid sequence of CRBN.
  • the 58-125 amino acid segment is encoded by exon 3 of the CRBN gene.
  • the nucleic acid is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 126 to 175 (zi 126- 175) in the full-length amino acid sequence of CRBN.
  • the 126-175 amino acid segment is encoded by exon 4 of the CRBN gene.
  • the nucleic acid is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • the 176-228 amino acid segment is encoded by exon 5 of the CRBN gene.
  • the nucleic acid is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 ( J317-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 229 to 249 (z/229-249) in the full-length amino acid sequence of CRBN.
  • the 229-249 amino acid segment is encoded by exon 6 of the CRBN gene.
  • the nucleic acid is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 250 to 278 (zf250-278) in the full-length amino acid sequence of CRBN.
  • the 250-278 amino acid segment is encoded by exon 7 of the CRBN gene.
  • the nucleic acid is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 279 to 316(zf279-316) in the full-length amino acid sequence of CRBN.
  • the 279-316 amino acid segment is encoded by exon 8 of the CRBN gene.
  • the nucleic acid is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • provided herein is an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 317 to 338 (zi 317-338) in the full-length amino acid sequence of CRBN.
  • the 317-338 amino acid segment is encoded by exon 9 of the CRBN gene.
  • the nucleic acid is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (z/317-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant nucleic acid encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 339 to 382 (z/339-382) in the full-length amino acid sequence of CRBN.
  • the 339-382 amino acid segment is encoded by exon 10 of the CRBN gene.
  • the nucleic acid is one encoding isoform 2 of CRBN, wherein the isoform has a deletion of amino acids 339 to 382 (z/339-382) in the full- length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (z/317-382) in the full-length amino acid sequence of CRBN.
  • the nucleic acid is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full-length amino acid sequence of CRBN.
  • provided herein is an isolated, synthetic, or recombinant nucleic acid encoding an isoform CRBN, comprising from about 300 to about 1200 base pairs.
  • the nucleic acid is one encoding isoform 2 of CRBN, which contains about 1197 base pairs.
  • the nucleic acid is one encoding isoform 3 of CRBN, which contains about 825 base pairs.
  • the nucleic acid is one encoding isoform 4 of CRBN. In yet another embodiment, the nucleic acid is one encoding isoform 5 of CRBN, which contains about 582 base pairs. In yet another embodiment, the nucleic acid is one encoding isoform 6 of CRBN. In still another embodiment, the nucleic acid is one encoding isoform 7 of CRBN.
  • nucleic acid encoding an isoform of CRBN, comprising from about 300 to about 900 base pairs.
  • the nucleic acid is one encoding isoform 3 of CRBN, which contains about 825 base pairs.
  • nucleic acid is one encoding isoform 4 of CRBN.
  • nucleic acid is one encoding isoform 5 of CRBN, which contains about 582 base pairs.
  • nucleic acid is one encoding isoform 6 of CRBN.
  • nucleic acid is one encoding isoform 7 of CRBN.
  • the nucleic acid is a DNA. In certain embodiments, the nucleic acid is an RNA. In certain embodiments, the nucleic acid is a cDNA. In certain embodiments, the nucleic acid is an mRNA.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 126 to 175 (A 126- 175) or amino acid residues 176 to 228 ( i 176- 228) in the full-length amino acid sequence of CRBN.
  • the 126- 175 and 176-228 amino acid segments are encoded by exons 4 and 5 of the CRBN gene, respectively.
  • the DNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (A 126-316) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acid residues 176 to 278 (A 176-278) and amino acid residues 317 to 382 (A317-382) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (A 126-382) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 23 to 57 ( ⁇ 23-5 ⁇ ) in the full-length amino acid sequence of CRBN.
  • the 23-57 amino acid segment is encoded by exon 2 of the CRBN gene.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 58 to 125 (zf58-125) in the full-length amino acid sequence of CRBN.
  • the 58-125 amino acid segment is encoded by exon 3 of the CRBN gene.
  • the DNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 126 to 175 (zi 126- 175) in the full-length amino acid sequence of CRBN.
  • the 126-175 amino acid segment is encoded by exon 4 of the CRBN gene.
  • the DNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • the 176-228 amino acid segment is encoded by exon 5 of the CRBN gene.
  • the DNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zi 176-278) and amino acids 317 to 382 ( J317-382) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 229 to 249 (z/229-249) in the full-length amino acid sequence of CRBN.
  • the 229-249 amino acid segment is encoded by exon 6 of the CRBN gene.
  • the DNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 250 to 278 (zf250-278) in the full-length amino acid sequence of CRBN.
  • the 250-278 amino acid segment is encoded by exon 7 of the CRBN gene.
  • the DNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 279 to 316(zf279-316) in the full-length amino acid sequence of CRBN.
  • the 279-316 amino acid segment is encoded by exon 8 of the CRBN gene.
  • the DNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • provided herein is an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 317 to 338 (zi 317-338) in the full-length amino acid sequence of CRBN.
  • the 317-338 amino acid segment is encoded by exon 9 of the CRBN gene.
  • the DNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zi 317-382) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 339 to 382 (A339-382) in the full-length amino acid sequence of CRBN.
  • the 339-382 amino acid segment is encoded by exon 10 of the CRBN gene.
  • the DNA is one encoding isoform 2 of CRBN, wherein the isoform has a deletion of amino acids 339 to 382 (z/339-382) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (z/317-382) in the full-length amino acid sequence of CRBN.
  • the DNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform CRBN, comprising from about 300 to about 1200 base pairs.
  • the DNA is one encoding isoform 2 of CRBN, which contains about 1197 base pairs.
  • the DNA is one encoding isoform 3 of CRBN, which contains about 825 base pairs.
  • the DNA is one encoding isoform 4 of CRBN.
  • the DNA is one encoding isoform 5 of CRBN, which contains about 582 base pairs. In yet another embodiment, the DNA is one encoding isoform 6 of CRBN. In still another embodiment, the DNA is one encoding isoform 7 of CRBN.
  • an isolated, synthetic, or recombinant DNA encoding an isoform of CRBN comprising from about 300 to about 900 base pairs.
  • the DNA is one encoding isoform 3 of CRBN, which contains about 825 base pairs.
  • the DNA is one encoding isoform 4 of CRBN.
  • the DNA is one encoding isoform 5 of CRBN, which contains about 582 base pairs.
  • the DNA is one encoding isoform 6 of CRBN.
  • the DNA is one encoding isoform 7 of CRBN.
  • an isolated, synthetic, or recombinant cDNA encoding an isoform of CRBN wherein the isoform has a deletion of amino acid residues 126 to 175 (A 126- 175) or amino acid residues 176 to 228 (A 176-228) in the full-length amino acid sequence of CRBN.
  • the 126-175 and 176-228 amino acid segments are encoded by exons 4 and 5 of the CRBN gene, respectively.
  • the cDNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (A 126-316) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acid residues 176 to 278 (A 176-278) and amino acid residues 317 to 382 (A317-382) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (A 126-382) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • the 23-57 amino acid segment is encoded by exon 2 of the CRBN gene.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • the 58-125 amino acid segment is encoded by exon 3 of the CRBN gene.
  • the cDNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • the 126-175 amino acid segment is encoded by exon 4 of the CRBN gene.
  • the cDNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zi 126-382) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zi23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant cDNA encoding of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 176 to 228 (zi 176-228) in the full-length amino acid sequence of CRBN.
  • the 176-228 amino acid segment is encoded by exon 5 of the CRBN gene.
  • the cDNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zi 176-278) and amino acids 317 to 382 (zJ317-382) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zi 126-382) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • the 229-249 amino acid segment is encoded by exon 6 of the CRBN gene.
  • the cDNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zi 317-382) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • the 250-278 amino acid segment is encoded by exon 7 of the CRBN gene.
  • the cDNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zi 176-278) and amino acids 317 to 382 ( J317-382) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • the 279-316 amino acid segment is encoded by exon 8 of the CRBN gene.
  • the cDNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • the 317-338 amino acid segment is encoded by exon 9 of the CRBN gene.
  • the cDNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf317-382) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • the 339-382 amino acid segment is encoded by exon 10 of the CRBN gene.
  • the cDNA is one encoding isoform 2 of CRBN, wherein the isoform has a deletion of amino acids 339 to 382 (z/339-382) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the cDNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant cDNA encoding an isoform CRBN comprising from about 300 to about 1200 base pairs.
  • the cDNA is one encoding isoform 2 of CRBN, which contains about 1 197 base pairs.
  • the cDNA is one encoding isoform 3 of CRBN, which contains about 825 base pairs.
  • the cDNA is one encoding isoform 4 of CRBN.
  • the cDNA is one encoding isoform 5 of CRBN, which contains about 582 base pairs.
  • the cDNA is one encoding isoform 6 of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN.
  • an isolated, synthetic, or recombinant cDNA encoding an isoform of CRBN comprising from about 300 to about 900 base pairs.
  • the cDNA is one encoding isoform 3 of CRBN, which contains about 825 base pairs.
  • the cDNA is one encoding isoform 4 of CRBN.
  • the cDNA is one encoding isoform 5 of CRBN, which contains about 582 base pairs.
  • the cDNA is one encoding isoform 6 of CRBN.
  • the cDNA is one encoding isoform 7 of CRBN.
  • RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 126 to 175 (A 126- 175) or amino acid residues 176 to 228 (A 176-228) in the full-length amino acid sequence of CRBN.
  • the 126-175 and 176-228 amino acid segments are encoded by exons 4 and 5 of the CRBN gene, respectively.
  • the RNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (A 126-316) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acid residues 176 to 278 (A 176-278) and amino acid residues 317 to 382 (A317-382) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (A 126-382) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 23 to 57 (zf23-57) in the full-length amino acid sequence of CRBN.
  • the 23-57 amino acid segment is encoded by exon 2 of the CRBN gene.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 58 to 125 (zf58-125) in the full-length amino acid sequence of CRBN.
  • the 58-125 amino acid segment is encoded by exon 3 of the CRBN gene.
  • the RNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 126 to 175 (zf 126- 175) in the full-length amino acid sequence of CRBN.
  • the 126-175 amino acid segment is encoded by exon 4 of the CRBN gene.
  • the RNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • RNA encoding of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 176 to 228 (zf 176-228) in the full-length amino acid sequence of CRBN.
  • the 176-228 amino acid segment is encoded by exon 5 of the CRBN gene.
  • the RNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • provided herein is an isolated, synthetic, or recombinant RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 229 to 249 (z/229-249) in the full-length amino acid sequence of CRBN.
  • the 229-249 amino acid segment is encoded by exon 6 of the CRBN gene.
  • the RNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 250 to 278 (zf250-278) in the full-length amino acid sequence of CRBN.
  • the 250-278 amino acid segment is encoded by exon 7 of the CRBN gene.
  • the RNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zi 126-382) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 279 to 316(zf279-316) in the full-length amino acid sequence of CRBN.
  • the 279-316 amino acid segment is encoded by exon 8 of the CRBN gene.
  • the RNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 317 to 338 (A317-338) in the full-length amino acid sequence of CRBN.
  • the 317-338 amino acid segment is encoded by exon 9 of the CRBN gene.
  • the RNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zi 126-382) in the full- length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • RNA encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 339 to 382 (z/339-382) in the full-length amino acid sequence of CRBN.
  • the 339-382 amino acid segment is encoded by exon 10 of the CRBN gene.
  • the RNA is one encoding isoform 2 of CRBN, wherein the isoform has a deletion of amino acids 339 to 382 (z/339-382) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zi 317-382) in the full-length amino acid sequence of CRBN.
  • the RNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • RNA encoding an isoform CRBN, comprising from about 300 to about 1200 bases.
  • the RNA is one encoding isoform 2 of CRBN, which contains about 1194 bases.
  • the RNA is one encoding isoform 3 of CRBN, which contains about 822 bases.
  • the RNA is one encoding isoform 4 of CRBN.
  • the RNA is one encoding isoform 5 of CRBN, which contains about 579 bases.
  • the RNA is one encoding isoform 6 of CRBN.
  • the RNA is one encoding isoform 7 of CRBN.
  • provided herein is an isolated, synthetic, or recombinant RNA encoding an isoform of CRBN, comprising from about 300 to about 900 bases.
  • the RNA is one encoding isoform 3 of CRBN, which contains about 822 bases.
  • the RNA is one encoding isoform 4 of CRBN.
  • the RNA is one encoding isoform 5 of CRBN, which contains about 579 bases.
  • the RNA is one encoding isoform 6 of CRBN.
  • the RNA is one encoding isoform 7 of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding an isoform of CRBN wherein the isoform has a deletion of amino acid residues 126 to 175 (A 126- 175) or amino acid residues 176 to 228 (A 176-228) in the full-length amino acid sequence of CRBN.
  • the 126-175 and 176-228 amino acid segments are encoded by exons 4 and 5 of the CRBN gene, respectively.
  • the mRNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (z/58-175) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (A 126-316) in the full- length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acid residues 176 to 278 (A 176-278) and amino acid residues 317 to 382 (A317-382) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (A 126-382) in the full- length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • provided herein is an isolated, synthetic, or recombinant mR A encoding an isoform of CRBN, wherein the isoform has a deletion of amino acid residues 23 to 57 (zf23-57) in the full-length amino acid sequence of CRBN.
  • the 23-57 amino acid segment is encoded by exon 2 of the CRBN gene.
  • the mRNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • the 58-125 amino acid segment is encoded by exon 3 of the CRBN gene.
  • the mRNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding an isoform of CRBN wherein the isoform has a deletion of amino acid residues 126 to 175 (zi 126- 175) in the full-length amino acid sequence of CRBN.
  • the 126-175 amino acid segment is encoded by exon 4 of the CRBN gene.
  • the mRNA is one encoding isoform 3 of CRBN, wherein the isoform has a deletion of amino acids 58 to 175 (zf58-175) in the full-length amino acid sequence of CRBN.
  • the mR A is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full- length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding of an isoform of CRBN wherein the isoform has a deletion of amino acid residues 176 to 228 (zf 176-228) in the full-length amino acid sequence of CRBN.
  • the 176-228 amino acid segment is encoded by exon 5 of the CRBN gene.
  • the mRNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding an isoform of CRBN wherein the isoform has a deletion of amino acid residues 229 to 249 (zf229-249) in the full-length amino acid sequence of CRBN.
  • the 229-249 amino acid segment is encoded by exon 6 of the CRBN gene.
  • the mRNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • the 250-278 amino acid segment is encoded by exon 7 of the CRBN gene.
  • the mRNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zf 126-316) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zf 317-382) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the mR A is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding an isoform of CRBN wherein the isoform has a deletion of amino acid residues 279 to 316(zi279-316) in the full-length amino acid sequence of CRBN.
  • the 279-316 amino acid segment is encoded by exon 8 of the CRBN gene.
  • the mRNA is one encoding isoform 4 of CRBN, wherein the isoform has a deletion of amino acids 126 to 316 (zi 126-316) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (z/23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding an isoform of CRBN wherein the isoform has a deletion of amino acid residues 317 to 338 (A317-338) in the full-length amino acid sequence of CRBN.
  • the 317-338 amino acid segment is encoded by exon 9 of the CRBN gene.
  • the mRNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zi 317-382) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN, wherein the isoform has a deletion of amino acids 23 to 338 (zf23-338) in the full-length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding an isoform of CRBN wherein the isoform has a deletion of amino acid residues 339 to 382 (zi 339-382) in the full-length amino acid sequence of CRBN.
  • the 339-382 amino acid segment is encoded by exon 10 of the CRBN gene.
  • the mRNA is one encoding isoform 2 of CRBN, wherein the isoform has a deletion of amino acids 339 to 382 (z/339-382) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 5 of CRBN, wherein the isoform has deletions of amino acids 176 to 278 (zf 176-278) and amino acids 317 to 382 (zi 317-382) in the full-length amino acid sequence of CRBN.
  • the mRNA is one encoding isoform 6 of CRBN, wherein the isoform has a deletion of amino acids 126 to 382 (zf 126-382) in the full- length amino acid sequence of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding an isoform CRBN comprising from about 300 to about 1200 bases.
  • the mRNA is one encoding isoform 2 of CRBN, which contains about 1 194 bases.
  • the mRNA is one encoding isoform 3 of CRBN, which contains about 822 bases.
  • the mRNA is one encoding isoform 4 of CRBN.
  • the mRNA is one encoding isoform 5 of CRBN, which contains about 579 bases.
  • the mRNA is one encoding isoform 6 of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN.
  • an isolated, synthetic, or recombinant mRNA encoding an isoform of CRBN comprising from about 300 to about 900 bases.
  • the mRNA is one encoding isoform 3 of CRBN, which contains about 822 bases.
  • the mRNA is one encoding isoform 4 of CRBN.
  • the mRNA is one encoding isoform 5 of CRBN, which contains about 579 bases.
  • the mRNA is one encoding isoform 6 of CRBN.
  • the mRNA is one encoding isoform 7 of CRBN.
  • provided herein is an isolated, synthetic, or recombinant nucleic acid comprising SEQ ID NO: 1 (FIG. 2).
  • an isolated, synthetic, or recombinant nucleic acid comprising SEQ ID NO: 2 (FIG. 3).
  • an isolated, synthetic, or recombinant nucleic acid comprising SEQ ID NO: 3 (FIG. 4).
  • an isolated, synthetic, or recombinant nucleic acid comprising SEQ ID NO: 4 (FIG. 5).
  • an isolated, synthetic, or recombinant nucleic acid comprising SEQ ID NO: 5 (FIG. 6).
  • an isolated, synthetic, or recombinant nucleic acid comprising SEQ ID NO: 6 (FIG. 7).
  • an isolated, synthetic, or recombinant nucleic acid comprising SEQ ID NO: 7 (FIG. 8).
  • a biological marker or "biomarker” is a substance, the change and/or the detection of which indicates a particular biological state, such as, for example, the responsiveness of a disease to a given treatment, e.g., a treatment with a treatment compound, in one embodiment, an immunomodulatory compound, e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)- yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)benzyl)oxy)- 1 - oxoisoindolin-2-yl)piperidine-2,6-dione.
  • an immunomodulatory compound e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)- yl)pipe
  • the biomarker is an isoform of CRBN. In certain embodiments, the biomarker is isoform 1, 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof. In certain embodiments, the biomarker is isoform 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof. In certain embodiments, the biomarker is isoform 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is isoform 1 of CRBN. In certain embodiments, the biomarker is isoform 2 of CRBN. In certain embodiments, the biomarker is isoform 3 of CRBN. In certain embodiments, the biomarker is isoform 4 of CRBN. In certain embodiments, the biomarker is isoform 5 of CRBN. In certain embodiments, the biomarker is isoform 6 of CRBN. In certain embodiments, the biomarker is isoform 7 of CRBN.
  • the biomarker is a nucleic acid encoding an isoform of CRBN. In certain embodiments, the biomarker is a nucleic acid encoding isoform 1, 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof. In certain embodiments, the biomarker is a nucleic acid encoding isoform 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof. In certain embodiments, the biomarker is a nucleic acid encoding isoform 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is a nucleic acid encoding isoform 1 of CRBN. In certain embodiments, the biomarker is a nucleic acid encoding isoform 2 of CRBN. In certain embodiments, the biomarker is a nucleic acid encoding isoform 3 of CRBN. In certain embodiments, the biomarker is a nucleic acid encoding isoform 4 of CRBN. In certain embodiments, the biomarker is a nucleic acid encoding isoform 5 of CRBN. In certain embodiments, the biomarker is a nucleic acid encoding isoform 6 of CRBN. In certain embodiments, the biomarker is a nucleic acid encoding isoform 7 of CRBN.
  • the biomarker is a DNA encoding an isoform of CRBN.
  • the biomarker is a DNA encoding isoform 1, 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is a DNA encoding isoform 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is a DNA encoding isoform 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is a DNA encoding isoform 1 of CRBN. In certain embodiments, the biomarker is a DNA encoding isoform 2 of CRBN. In certain embodiments, the biomarker is a DNA encoding isoform 3 of CRBN. In certain embodiments, the biomarker is a DNA encoding isoform 4 of CRBN. In certain embodiments, the biomarker is a DNA encoding isoform 5 of CRBN. In certain embodiments, the biomarker is a DNA encoding isoform 6 of CRBN. In certain embodiments, the biomarker is a DNA encoding isoform 7 of CRBN.
  • the biomarker is a cDNA encoding an isoform of CRBN.
  • the biomarker is a cDNA encoding isoform 1, 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is a cDNA encoding isoform 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is a cDNA encoding isoform 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is a cDNA encoding isoform 1 of CRBN. In certain embodiments, the biomarker is a cDNA encoding isoform 2 of CRBN. In certain embodiments, the biomarker is a cDNA encoding isoform 3 of CRBN. In certain embodiments, the biomarker is a cDNA encoding isoform 4 of CRBN. In certain embodiments, the biomarker is a cDNA encoding isoform 5 of CRBN. In certain embodiments, the biomarker is a cDNA encoding isoform 6 of CRBN. In certain embodiments, the biomarker is a cDNA encoding isoform 7 of CRBN.
  • the biomarker is an RNA encoding an isoform of CRBN.
  • the biomarker is an RNA encoding isoform 1, 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is an RNA of isoform 2, 3, 4, 5, 6, 7, or 8 encoding CRBN, or a combination thereof.
  • the biomarker is an RNA of isoform 3, 4, 5, 6, 7, or 8 encoding CRBN, or a combination thereof.
  • the biomarker is an RNA encoding isoform 1 of CRBN. In certain embodiments, the biomarker is an RNA encoding isoform 2 of CRBN. In certain embodiments, the biomarker is an RNA encoding isoform 3 of CRBN. In certain embodiments, the biomarker is an RNA encoding isoform 4 of CRBN. In certain embodiments, the biomarker is an RNA encoding isoform 5 of CRBN. In certain embodiments, the biomarker encoding an RNA of isoform 6 of CRBN. In certain embodiments, the biomarker encoding an RNA of isoform 7 of CRBN.
  • the biomarker is an mRNA encoding an isoform of CRBN.
  • the biomarker is an mRNA encoding isoform 1 , 2, 3, 4, 5, 6, 7, or 8 of CRBN, or a combination thereof.
  • the biomarker is an mRNA of isoform 2, 3, 4, 5, 6, 7, or 8 encoding CRBN, or a combination thereof.
  • the biomarker is an mRNA of isoform 3, 4, 5, 6, 7, or 8 encoding CRBN, or a combination thereof.
  • the biomarker is an mRNA encoding isoform 1 of CRBN. In certain embodiments, the biomarker is an mRNA encoding isoform 2 of CRBN. In certain embodiments, the biomarker is an mRNA encoding isoform 3 of CRBN. In certain embodiments, the biomarker is an mRNA encoding isoform 4 of CRBN. In certain embodiments, the biomarker is an mRNA encoding isoform 5 of CRBN. In certain embodiments, the biomarker encoding an mRNA of isoform 6 of CRBN. In certain embodiments, the biomarker encoding an mRNA of isoform 7 of CRBN.
  • the biomarker comprises SEQ ID NO: 1 (FIG. 2). In another embodiment, the biomarker comprises SEQ ID NO: 2 (FIG. 3). In yet another embodiment, the biomarker comprises SEQ ID NO: 3 (FIG. 4). In yet another embodiment, the biomarker comprises SEQ ID NO: 4 (FIG. 5). In yet another embodiment, the biomarker comprises SEQ ID NO: 5 (FIG. 6). In yet another embodiment, the biomarker comprises SEQ ID NO: 6 (FIG. 7). In still another embodiment, provided h the biomarker comprises SEQ ID NO: 7 (FIG. 8).
  • the level of a biomarker provided herein correlates with or is indicative of the responsiveness of a subject having a disease or condition to a treatment with a treatment compound, in one embodiment, an immunomodulatory compound, e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • an immunomodulatory compound e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(
  • the reference level of the biomarker is one that a treatment decision is made based on whether a subject has the level of a biomarker provided here that is altered as compared to the reference level of the biomarker.
  • a subject who has a level of the biomarker that is altered as compared to the reference level of the biomarker has a different probability of responsiveness to the treatment than a subject who has a level of the biomarker the same as the reference level of the biomarker.
  • the reference level of the biomarker is one that a treatment decision is made based on whether a subject has the level of a biomarker provided here above the reference level of the biomarker. In certain embodiments, the reference level of the biomarker is one that a treatment decision is made based on whether a subject has the level of a biomarker provided here below the reference level of the biomarker. A subject who has a level of the biomarker higher than the reference level of the biomarker has a different probability of responsiveness to the treatment than a subject who has a level of the biomarker lower than the reference level of the biomarker.
  • the reference level of the biomarker is measured simultaneously with the level of the biomarker in the biological sample from the subject. In certain embodiments, the reference level of the biomarker is predetermined.
  • the level of the biomarker in a control sample is one that a treatment decision is made based on whether a subject has the level of a biomarker provided here that is altered as compared to the level of the biomarker in the control sample.
  • a subject who has a level of the biomarker that is altered as compared to the level of the biomarker in the control sample has a different probability of responsiveness to the treatment than a subject who has a level of the biomarker the same as the level of the biomarker in the control sample.
  • the level of the biomarker in the control sample is one that a treatment decision is made based on whether a subject has the level of a biomarker provided here above the level of the biomarker in the control sample. In certain embodiments, the level of the biomarker in the control sample is one that a treatment decision is made based on whether a subject has the level of a biomarker provided here below the level of the biomarker in the control sample. A subject who has a level of the biomarker higher than the level of the biomarker in the control sample has a different probability of responsiveness to the treatment than a subject who has a level of the biomarker lower than the level of the biomarker in the control sample.
  • the level of the biomarker in the control sample is measured simultaneously with the level of the biomarker in the biological sample from the subject. In certain embodiments, the level of the biomarker in the control sample is predetermined.
  • the biomarkers provided herein are determined individually. In certain embodiments, two or more of the biomarkers provided herein are determined simultaneously.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered as compared to the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered as compared to the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered as compared to the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is higher than the level of the biomarker in the control sample.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is higher than the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is lower than the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is lower than the level of the biomarker in the control sample.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is lower than the reference level of the biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is lower than the reference level of the biomarker.
  • the biomarker is a polypeptide of a CRBN isoform.
  • the reference level is determined from a disease-free sample from the same subject. In certain embodiments, the reference level is determined from a disease-free sample from a group of subjects.
  • the reference level is determined simultaneously with the level of the biomarker in the biological sample from the subject. In certain embodiments, the reference level is determined independently from the level of the biomarker in the biological sample from the subject.
  • control sample is a disease-free sample from the same subject. In certain embodiments, the control sample is a disease-free sample from a group of subjects.
  • the level of the biomarker in the control sample is determined simultaneously with the level of the biomarker in the biological sample from the subject. In certain embodiments, the level of the biomarker in the control sample is determined independently from the level of the biomarker in the biological sample from the subject.
  • the methods provided herein are coupled with a treatment with a treatment compound, in one embodiment, an immunomodulatory compound, e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • an immunomodulatory compound e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • identifying a subject who is likely to be responsive to the treatment compound comprising: a) obtaining a biological sample from the subject;
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a method of a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • identifying a subject who is likely to be responsive to the treatment compound comprising: a) determining the level of a biomarker in a biological sample from the subject;
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • the biomarkers are used to identify a subject who is likely to be responsive to a treatment with thalidomide, lenalidomide, pomalidomide, 3- (5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4- (morpholinomethyl)benzyl)oxy)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione.
  • the biomarkers are used to identify a subject who is likely to be responsive to treatment by thalidomide.
  • the biomarkers are used to identify a subject who is likely to be responsive to treatment by lenalidomide. In certain embodiments, the biomarkers are used to identify a subject who is likely to be responsive to treatment by pomalidomide. In certain embodiments, the biomarkers are used to identify a subject who is likely to be responsive to treatment by 3-(5-amino-2- methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
  • the biomarkers are used to identify a subject who is likely to be responsive to treatment by (5)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • the difference between the level of the biomarker in the biological sample from the subject and the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • the difference between the level of the biomarker in the biological sample from the subject and the reference level correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • the difference between the level of the biomarker in the biological sample from the subject and the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • an increased level of the biomarker in the biological sample from the subject in comparison with the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • an increased level of the biomarker in the biological sample from the subject in comparison with the reference level of the biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a decreased level of the biomarker in the biological sample from the subject in comparison with the reference level of the biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a decreased level of the biomarker in the biological sample from the subject in comparison with the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a decreased level of the biomarker in the biological sample from the subject in comparison with the reference level of the biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a decreased level of the biomarker in the biological sample from the subject in comparison with the level of the biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • the subject is responsive to the treatment if the level of the biomarker in the second biological sample of the subject is altered as compared to the level of the biomarker in the first biological sample of the subject.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • an increased level of the biomarker in the second biological sample in comparison with the level of the biomarker in the first biological sample indicates that the subject is responsive to the treatment.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • a decreased level of the biomarker in the second biological sample in comparison with the level of the biomarker in the first biological sample indicates that the subject is responsive to the treatment.
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • an increased level of the biomarker in the biological sample in comparison with the level of the biomarker in the control sample indicates the compliance of the subject with the treatment.
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • a decreased level of the biomarker in the biological sample in comparison with the level of the biomarker in the control sample indicates the compliance of the subject with the treatment.
  • the biomarker is a polypeptide of a CRBN isoform.
  • control sample is a disease-free sample from the same subject. In certain embodiments, the control sample is a disease-free sample from a group of subjects.
  • the level of the biomarker in a control sample is determined simultaneously with the level of the biomarker in the biological sample from the subject. In certain embodiments, the level of the biomarker in a control sample is determined independently from the level of the biomarker in the biological sample from the subject.
  • the biomarkers are used to predict the
  • the biomarkers are used to predict the responsiveness of a subject to a treatment with thalidomide. In certain embodiments, the biomarkers are used to predict the responsiveness of a subject to a treatment with lenalidomide. In certain embodiments, the biomarkers are used to predict the responsiveness of a subject to a treatment with pomalidomide.
  • the biomarkers are used to predict the responsiveness of a subject to a treatment 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione. In certain embodiments, the biomarkers are used to predict the responsiveness of a subject to a treatment (5)-3-(4-((4- (morpholinomethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • the level of the biomarker is measured in an in vitro assay to predict the responsiveness of a subject to a treatment with a treatment compound, comprising obtaining a sample of cells from the subject, culturing the cells in the presence or absence of the treatment compound, and determining the level of the biomarker in the cells, wherein the difference between the level of the biomarker in the cells treated with the treatment compound in comparison with the level of the biomarker in the untreated cells indicates the likelihood of responsiveness of the subject to the treatment compound.
  • the level of the biomarker is measured in an in vitro assay to predict the responsiveness of a subject to a treatment with a treatment compound, comprising obtaining a sample of cells from the subject, culturing the cells in the presence or absence of the treatment compound, and determining the level of the biomarker in the cells, wherein an increased level of the biomarker in the cells treated with the treatment compound in comparison with the level of the biomarker in the untreated cells indicates the likelihood of responsiveness of the subject to the treatment compound.
  • the level of the biomarker is measured in an in vitro assay to predict the responsiveness of a subject to a treatment with a treatment compound, comprising obtaining a sample of cells from the subject, culturing the cells in the presence or absence of the treatment compound, and determining the level of the biomarker in the cells, wherein a decreased level of the biomarker in the cells treated with the treatment compound in comparison with the level of the biomarker in the untreated cells indicates the likelihood of responsiveness of the subject to the treatment compound. 5.4.3 Use of mRNAs encoding CRBN iso forms as biomarkers for identifying a subject for a treatment
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is altered as compared to the reference level of the mRNA biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is altered as compared to the level of the mRNA biomarker in the control sample.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is altered as compared to the reference level of the mRNA biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is altered as compared to the reference level of the mRNA biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is higher than the reference level of the mRNA biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is higher than the level of the mRNA biomarker in the control sample.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is higher than the reference level of the mRNA biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is higher than the reference level of the mRNA biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is lower than the level of the mRNA biomarker in the control sample.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is lower than the reference level of the mRNA biomarker.
  • a method of identifying a subject who is likely to be responsive to a treatment with a treatment compound comprising:
  • the subject is likely to be responsive to the treatment if the level of the mRNA biomarker in the biological sample from the subject is lower than the reference level of the mRNA biomarker.
  • the reference level is determined from a disease-free sample from the same subject. In certain embodiments, the reference level is determined from a disease-free sample from a group of subjects.
  • the reference level is determined simultaneously with the level of the mRNA biomarker in the biological sample from the subject. In certain embodiments, the reference level is determined independently from the level of the mRNA biomarker in the biological sample from the subject.
  • control sample is a disease-free sample from the same subject. In certain embodiments, the control sample is a disease-free sample from a group of subjects.
  • the level of the mRNA biomarker in the control sample is determined simultaneously with the level of the mRNA biomarker in the biological sample from the subject. In certain embodiments, the level of the mRNA biomarker in the control sample is determined independently from the level of the mRNA biomarker in the biological sample from the subject.
  • the methods provided herein are coupled with a treatment with a treatment compound, in one embodiment, an immunomodulatory compound, e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • an immunomodulatory compound e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4- oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin
  • a method of a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a method of a treatment with a treatment compound comprising:
  • a treatment with a treatment compound comprising:
  • a method of a treatment with a treatment compound comprising: (i) identifying a subject who is likely to be responsive to the treatment compound, comprising:
  • the mRNA biomarkers are used to identify a subject who is likely to be responsive to a treatment with thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (5)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione.
  • the mRNA biomarkers are used to identify a subject who is likely to be responsive to treatment by thalidomide.
  • the mRNA biomarkers are used to identify a subject who is likely to be responsive to treatment by lenalidomide. In certain embodiments, the mRNA biomarkers are used to identify a subject who is likely to be responsive to treatment by pomalidomide. In certain embodiments, the mRNA biomarkers are used to identify a subject who is likely to be responsive to treatment by 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine- 2,6-dione.
  • the mRNA biomarkers are used to identify a subject who is likely to be responsive to treatment by (5)-3-(4-((4-(morpholinomethyl)- benzyl)oxy)-l-oxoisoindolin-2-yl)piperidine-2,6-dione. 5.4.4 Use of mRNAs encoding CRBN isoforms as biomarkers for predicting the efficacy of a treatment
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • the difference between the level of the mRNA biomarker in the biological sample from the subject and the reference level correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • the difference between the level of the mRNA biomarker in the biological sample from the subject and the level of the mRNA biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • the difference between the level of the mRNA biomarker in the biological sample from the subject and the level of the mRNA biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • an increased level of the mRNA biomarker in the biological sample from the subject in comparison with the reference level of the mRNA biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • an increased level of the mRNA biomarker in the biological sample from the subject in comparison with the level of the mRNA biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising: a) obtaining a biological sample from the subject;
  • an increased level of the mRNA biomarker in the biological sample from the subject in comparison with the reference level of the mRNA biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • an increased level of the mRNA biomarker in the biological sample from the subject in comparison with the level of the mRNA biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a decreased level of the mRNA biomarker in the biological sample from the subject in comparison with the reference level of the mRNA biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a decreased level of the mRNA biomarker in the biological sample from the subject in comparison with the level of the mRNA biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a decreased level of the mRNA biomarker in the biological sample from the subject in comparison with the reference level of the mRNA biomarker correlates with an increased responsiveness of the subject to the treatment.
  • a method of predicting the responsiveness of a subject to a treatment with a treatment compound comprising:
  • a decreased level of the mRNA biomarker in the biological sample from the subject in comparison with the level of the mRNA biomarker in the control sample correlates with an increased responsiveness of the subject to the treatment.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • the subject is responsive to the treatment if the level of the mRNA biomarker in the second biological sample of the subject is altered as compared to the level of the mRNA biomarker in the first biological sample of the subject.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • an increased level of the mRNA biomarker in the second biological sample in comparison with the level of the mRNA biomarker in the first biological sample indicates that the subject is responsive to the treatment.
  • a method of monitoring the efficacy of a treatment of a disease, disorder, or condition in a subject treated with a treatment compound comprising:
  • a decreased level of the mRNA biomarker in the second biological sample in comparison with the level of the mRNA biomarker in the first biological sample indicates that the subject is responsive to the treatment.
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • an increased level of the mRNA biomarker in the biological sample in comparison with the level of the mRNA biomarker in the control sample indicates the compliance of the subject with the treatment.
  • a method of monitoring the compliance of a subject with a treatment of a disease, disorder, or condition with a treatment compound comprising:
  • a decreased level of the mRNA biomarker in the biological sample in comparison with the level of the mRNA biomarker in the control sample indicates the compliance of the subject with the treatment.
  • control sample is a disease-free sample from the same subject. In certain embodiments, the control sample is a disease-free sample from a group of subjects.
  • the level of the mRNA biomarker in a control sample is determined simultaneously with the level of the mRNA biomarker in the biological sample from the subject. In certain embodiments, the level of the mRNA biomarker in a control sample is determined independently from the level of the mRNA biomarker in the biological sample from the subject.
  • the mRNA biomarkers are used to predict the responsiveness of a subject to a treatment with thalidomide, lenalidomide,
  • the mRNA biomarkers are used to predict the mRNA responsiveness of a subject to a treatment with thalidomide. In certain embodiments, the mRNA biomarkers are used to predict the responsiveness of a subject to a treatment with lenalidomide.
  • the mRNA biomarkers are used to predict the responsiveness of a subject to a treatment with pomalidomide. In certain embodiments, the mRNA biomarkers are used to predict the responsiveness of a subject to a treatment with 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione. In certain embodiments, the mRNA biomarkers are used to predict the responsiveness of a subject to a treatment with (5)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-l-oxoisoindolin-2- yl)piperidine-2,6-dione.
  • the level of the mRNA biomarker is measured in an in vitro assay to predict the responsiveness of a subject to a treatment with a treatment compound, comprising obtaining a sample of cells from the subject, culturing the cells in the presence or absence of the treatment compound, and determining the level of the mRNA biomarker in the cells, wherein the difference between the level of the mRNA biomarker in the cells treated with the treatment compound in comparison with the level of the mRNA biomarker in the untreated cells indicates the likelihood of responsiveness of the subject to the treatment compound.
  • the level of the mRNA biomarker is measured in an in vitro assay to predict the responsiveness of a subject to a treatment with a treatment compound, comprising obtaining a sample of cells from the subject, culturing the cells in the presence or absence of the treatment compound, and determining the level of the mRNA biomarker in the cells, wherein an increased level of the mRNA biomarker in the cells treated with the treatment compound in comparison with the level of the mRNA biomarker in the untreated cells indicates the likelihood of responsiveness of the subject to the treatment compound.
  • the level of the mRNA biomarker is measured in an in vitro assay to predict the responsiveness of a subject to a treatment with a treatment compound, comprising obtaining a sample of cells from the subject, culturing the cells in the presence or absence of the treatment compound, and determining the level of the mRNA biomarker in the cells, wherein a decreased level of the mRNA biomarker in the cells treated with the treatment compound in comparison with the level of the mRNA biomarker in the untreated cells indicates the likelihood of responsiveness of the subject to the treatment compound.
  • the levels of mRNAs of the biomarkers can be detected or quantitated by any methods known in the art.
  • Exemplary detecting or quantitating methods include, but are not limited to, northern blots, ribonuclease protection assays, and PCR-based methods.
  • the biomarker is an mRNA molecule
  • the mRNA sequence or a fragment thereof can be used to prepare a probe that is at least partially complementary.
  • the probe can then be used to detect the mRNA sequence in a sample, using any methods known in the art, including, not limited to PCR-based methods, Northern blotting, or a dipstick assay.
  • the detecting or quantitating method is a northern blot, ribonuclease protection assay, or a PCR-based method. In certain embodiments, the detecting or quantitating method is a northern blot. In certain embodiments, the detecting or quantitating method is a ribonuclease protection assay. In certain embodiments, the detecting or quantitating method is a PCR-based method. In certain embodiments, the detecting or quantitating method is qRT-PCR.
  • an assay may be in the form of a dipstick, a membrane, a chip, a disk, a test strip, a filter, a microsphere, a slide, a multiwell plate, or an optical fiber.
  • An assay system may have a solid support on which a nucleic acid corresponding to the mRNA is attached.
  • the solid support may comprise, for example, a plastic, silicon, a metal, a resin, glass, a membrane, a particle, a precipitate, a gel, a polymer, a sheet, a sphere, a polysaccharide, a capillary, a film a plate, or a slide.
  • the assay components can be prepared and packaged together as a kit for detecting an mRNA.
  • the mRNAs can be labeled, if desired, to make a population of labeled mRNAs.
  • a sample can be labeled using methods that are well known in the art (e.g., using an RNA ligase or terminal transferase, or by labeling the RNA
  • the sample is labeled with a fluorescent label.
  • Exemplary fluorescent dyes include, but are not limited to, xanthene dyes, fluorescein dyes, rhodamine dyes, fluorescein isothiocyanate (FITC), 6-carboxyfiuorescein (FAM), 6-carboxy-2',4',7',4,7-hexachlorofiuorescein (HEX), 6- carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE or J), N,N,N',N-tetramethyl-6- carboxyrhodamine (TAMRA or T), 6-carboxy-X-rhodamine (ROX or R), 5- carboxyrhodamine 6G (R6G5 or G5), 6-carboxyrhodamine 6G (R6G6 or G6), rhodamine 110, cyanine dyes ⁇ e.g., Cy3, Cy5, and Cy7 dyes), Alexa dyes ⁇ e.g.
  • nucleic acid probes may be present in specific, addressable locations on a solid support; each corresponding to at least a portion of mRNA sequences of a biomarker.
  • an mRNA assay comprises the steps of 1) obtaining surface-bound probes for one or more biomarkers; 2) hybridizing a population of mRNAs to the surface-bound probes under conditions sufficient to provide for specific binding; (3) removing unbound nucleic acids in the hybridization step; and (4) detecting the hybridized mRNAs.
  • Hybridization can be carried out under suitable hybridization conditions, which may vary in stringency as desired. Typical conditions are sufficient to produce probe/target complexes on a solid surface between complementary binding members, i.e., between surface-bound probes and complementary mRNAs in a sample.
  • stringent hybridization conditions are used.
  • Standard hybridization techniques e.g. , under conditions sufficient to provide for specific binding of target mRNAs in the sample to the probes.
  • Kallioniemi et al. Science 258:818-821 (1992) and WO 93/18186, the disclosure of each which is incorporated herein by reference in its entirety.
  • Several guides to general techniques are available, e.g., Tijssen, Hybridization with Nucleic Acid Probes, Parts I and II (Elsevier, Amsterdam 1993).
  • For descriptions of techniques suitable for in situ hybridizations see Gall et al. Meth. Enzymol., 21 :470-480 (1981); and Angerer et al. in Genetic Engineering: Principles and Methods (Setlow and Hollaender, Eds.) Vol. 7, pages 43-65 (Plenum Press, New York 1985).
  • the mRNA level of a biomarker is determined using a PCR-based method. Examples of PCR assays can be found in U.S. Pat. No.
  • qRT-PCR real-time reverse transcription-PCR
  • mRNAs Bustin et al, Clin. Sci., 2005, 109, 365-379. Quantitative results obtained by qRT-PCR are generally more informative than qualitative data. Examples of qRT-PCR-based methods can be found in U.S. Pat. No. 7,101,663, the disclosure of which is incorporated by reference herein in its entirety.
  • real-time PCR In contrast to regular reverse transcriptase-PCR and analysis by agarose gels, real-time PCR gives quantitative results.
  • An additional advantage of real-time PCR is the relative ease and convenience of use. Instruments for real-time PCR, such as Applied Biosystems 7500, are available commercially. The reagents for real-time PCR, such as TaqMan Sequence Detection chemistry, are also commercially available.
  • the data can be analyzed, for example, using a 7500 Real-Time PCR System Sequence Detection software vl .3, using the comparative CT relative quantification calculation method. Using this method, the output is expressed as a fold-change in expression levels.
  • the threshold level can be selected to be automatically determined by the software. In some embodiments, the threshold level is set to be above the baseline, but sufficiently low to be within the exponential growth region of an amplification curve.
  • the levels of the protein biomarkers provided herein can be detected or quantitated by any methods known in the art.
  • antibody-based methods are used.
  • the detecting or quantitating method is immunoblotting (western blot), an enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, flow cytometry, a cytometric bead array, or mass spectroscopy.
  • the detecting or quantitating method is
  • the detecting or quantitating method is an enzyme-linked immunosorbent assay (ELISA). In certain embodiments, the detecting or quantitating method is a direct ELISA. In certain embodiments, the detecting or quantitating method is an indirect ELISA. In certain embodiments, the detecting or quantitating method is an sandwich ELISA. In certain embodiments, the detecting or quantitating method is immunohistochemistry. In certain embodiments, the detecting or quantitating method is flow cytometry. In certain embodiments, the detecting or quantitating method is a cytometric bead array. In certain embodiments, the detecting or quantitating method is mass spectroscopy.
  • ELISA enzyme-linked immunosorbent assay
  • kits for detecting the mRNA levels of one or more biomarkers comprises one or more probes that bind specifically to the mRNAs of the one or more biomarkers.
  • the kit further comprises a washing solution.
  • the kit further comprises reagents for performing a hybridization assay, mRNA isolation or purification means, detection means, as well as positive and negative controls.
  • the kit further comprises an instruction for using the kit.
  • the kit can be tailored for in-home use, clinical use, or research use.
  • kits for detecting the protein level of one or more biomarkers comprises a dipstick coated with an antibody that recognizes the protein biomarker, washing solutions, reagents for performing the assay, protein isolation or purification means, detection means, as well as positive and negative controls.
  • the kit further comprises an instruction for using the kit.
  • the kit can be tailored for in-home use, clinical use, or research use.
  • Such a kit can employ, for example, a dipstick, a membrane, a chip, a disk, a test strip, a filter, a microsphere, a slide, a multiwell plate, or an optical fiber.
  • the solid support of the kit can be, for example, a plastic, silicon, a metal, a resin, glass, a membrane, a particle, a precipitate, a gel, a polymer, a sheet, a sphere, a polysaccharide, a capillary, a film, a plate, or a slide.
  • the biological sample can be, for example, a cell culture, a cell line, a tissue, an oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, or a skin sample.
  • the treatment compound is an immunomodulatory compound.
  • the term “immunomodulatory compound” refers to a compound that inhibits LPS induced monocyte TNF-a, IL-1B, IL- 12, IL-6, MIP-la, MCP-1, GM-CSF, G-CSF, and/or COX-2 production.
  • the immunomodulatory compound is an IMIDS ® compound.
  • immunomodulatory compounds include, but are not limited to, N- ⁇ [2-(2,6-dioxo(3-piperidyl)-l,3-dioxoisoindolin-4-yl]methyl ⁇ cyclopropylcarboxamide; 3-[2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxo-2,3-dihydro- lH-isoindol-4-ylmethyl]-l , 1 - dimethylurea; (-)-3-(3,4-dimethoxyphenyl)-3-(l-oxo-l,3-dihydroisoindol-2-yl)- propionamide; (+)-3-(3,4-dimethoxyphenyl)-3-(l-oxo-l,3-dihydroisoindol-2-yl)- propionamide; (+)-3-(3,4-dimethoxyphenyl)-3-(l-o
  • immunomodulatory compounds include, but are not limited to, cyano and carboxy derivatives of substituted styrenes, including, but not limited to, those disclosed in U.S. Pat. No. 5,929,117; l-oxo-2-(2,6-dioxo-3-fluoropiperidin-3- yl)isoindolines and 1 ,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl)isoindolines, including, but not limited to, those described in U.S. Pat. Nos.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular immunomodulatory compound may be used in methods provided herein.
  • These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-lnterscience, New York, 1981); Wilen et al., Tetrahedron 1977, 33, 2725-2736; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical
  • the immunomodulatory compound is an 1-oxo- or l,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-isoindoline substituted with amino in the benzo ring, including, but not limited to, those described in U.S. Pat. No. 5,635,517, the disclosure of which is incorporated herein by reference in its entirety.
  • the immunomodulatory compound is a compound of Formula I:
  • R 2 is hydrogen or Ci_ 4 alkyl, in one embodiment, methyl.
  • the immunomodulatory compound is:
  • the immunomodulatory compound is a substituted 2- (2,6-dioxopiperidin-3-yl)phthalimide or substituted 2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindole, including, but not limited to, those described in U.S. Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052; and International Pub. No. WO 98/03502; the disclosure of each of which is incorporated herein by reference in its entirety.
  • the immunomodulatory compound has the formula:
  • each of R 1 , R 2 , R 3 , and R 4 is independently halo, Ci_ 4 alkyl, or Ci_ 4 alkoxy; or
  • R 1 , R 2 , R 3 , and R 4 are -NHR 5 and the remaining of R 1 , R 2 , R 3 , and R 4 are hydrogen;
  • R 5 is hydrogen or Ci_ 8 alkyl
  • R 6 is hydrogen, Ci_g alkyl, benzyl, or halo
  • R 2 , R 3 , and R 4 is fluoro or (ii) one of R 1 , R 2 , R 3 , and R 4 is amino.
  • the immunomodulatory compound has the formula
  • R is hydrogen or methyl
  • the immunomodulatory compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • enantiomerically pure e.g. optically pure (R)- or (5)-enantiomers.
  • the immunomodulatory compound is an isoindole- imide, including, but not limited to, those disclosed in U.S. Pat. No. 7,091 ,353, U.S. Pat. Pub. No. 2003/0045552, and International Pub. No. WO 02/059106, the disclosure of each of which is incorporated herein by reference in its entirety.
  • the immunomodulatory compound is a compound of Formula II:
  • R 1 is H, Ci_8 alkyl, C3-7 cycloalkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, benzyl,
  • Ci_8 alkyl-N(R 6 ) 2 Ci_ 8 alkyl-OR 5 , Ci_ 8 alkyl- C(0)OR 5 , -C(0)NHR 3 , -C(S)NHR 3 , -C(0)NR 3 R 3' , -C(S)NR 3 R 3' , or Ci_ 8 alkyl-0(CO)R 5 ;
  • R 2 is H, F, benzyl, Ci_ 8 alkyl, C 2 _ 8 alkenyl, or C 2 _ 8 alkynyl;
  • R 3 and R 3' are each independently Ci_8 alkyl, C3_ 7 cycloalkyl, C 2 _ 8 alkenyl, C 2 _8 alkynyl, benzyl, C 6-14 aryl, Co-4 alkyl-heterocyclyl, Co-4 alkyl-heteroaryl, Co-8 alkyl-N(R 6 ) 2 , Ci_ 8 alkyl-OR 5 , Ci_ 8 alkyl-C(0)OR 5 , Ci_ 8 alkyl- 0(CO)R 5 , or -C(0)OR 5 ;
  • R 4 is Ci_ 8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, Ci_ 4 alkyl-OR 5 , benzyl, C 6-14 aryl, Co_ 4 alkyl-heterocyclyl, or Co_ 4 alkyl-heteroaryl;
  • R 5 is Ci_ 8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, benzyl, C 6-14 aryl, or heteroaryl;
  • each occurrence of R 6 is independently H, Ci_ 8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, benzyl, C 6-14 aryl, heteroaryl, or Co_ 8 alkyl-C(0)0-R 5 ; or the R 6 groups join to heterocyclyl; and
  • n 0 or 1 ;
  • R 1 is C 3 _ 7 cycloalkyl, C 2 _s alkenyl, C 2 _ 8 alkynyl, benzyl, C 6-14 aryl, Co_ 4 alkyl-heterocyclyl, Co- 4 alkyl-heteroaryl, -C(0)R 3 , -C(0)OR 4 , Ci_8 alkyl-N(R 6 ) 2 , Ci_ 8 alkyl-OR 5 , Ci_ 8 alkyl-C(0)OR 5 ,
  • Ci_ 8 alkyl-0(CO)R 5 R 2 is H or Ci_ 8 alkyl; and R 3 is Ci_ 8 alkyl,
  • C 3 - 7 cycloalkyl C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, benzyl, C 6-14 aryl, Co- 4 alkyl-heterocyclyl, C 0- 4 alkyl-heteroaryl, C 5 _ 8 alkyl-N(R 6 ) 2 ; C 0 _ 8 alkyl-NH-C(0)0-R 5 ; Ci_ 8 alkyl-OR 5 , Ci_ 8 alkyl-C(0)OR 5 , Ci_ 8 alkyl-0(CO)R 5 , or -C(0)OR 5 ; and the other variables are each as defined herein.
  • R 2 is H or Ci_ 4 alkyl.
  • R 1 is Ci_ 8 alkyl or benzyl.
  • R 1 is H, Ci_ 8 alkyl, benzyl, CH 2 OCH 3 ,
  • R 1 is "
  • R 7 is independently H, Ci_8 alkyl, C3-7 cycloalkyl, C 2 _g alkenyl, C 2 _g alkynyl, benzyl, C 6-14 aryl, halogen, C 0 -4 alkyl-heterocyclyl, C 0 -4 alkyl-heteroaryl, Co-s alkyl-N(R 6 ) 2 , Ci_g alkyl-OR 5 , Ci_g alkyl- C(0)OR 5 , Ci_8 alkyl-0(CO)R 5 , or -C(0)OR 5 ; or adjacent occurrences of R 7 can be taken together to form a bicyclic heteroaryl, heterocyclyl, or C 6-14 aryl ring.
  • R 1 is -C(0)R 3 .
  • R 3 is C 0 -4 alkyl-heteroaryl, Ci_8 alkyl, C 6 -i4 aryl, or C0-4 alkyl-OR 5 .
  • the heteroaryl is pyridyl, furyl, or thienyl.
  • R 1 is -C(0)OR 4 .
  • the H of -C(0)NHC(0)- can be replaced with Ci_ 4 alkyl, C 6 _i4 aryl, or benzyl.
  • the immunomodulatory compounds include, but are not limited to, [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- ylmethyl]amide; (2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxo-2,3-dihydro- lH-isoindol-4- ylmethyl)carbamic acid tert-butyl ester; 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))- isoindoline- 1 ,3-dione; N-(2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxo-2,3-dihydro- 1H- isoindol-4-ylmethyl)-acetamide; N- ⁇

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Abstract

La présente invention concerne des isoformes de céréblon et des procédés de leur utilisation en tant que biomarqueurs pour traiter une maladie, un trouble, ou une affection avec un composé de traitement, par exemple, le thalidomide, le lénalidomide, le pomalidomide, la 3-(5-amino-2-méthyl-4-oxoquinazolin-3(4H)-yl)-pipéridine-2,6-dione, ou la (5)-3-(4-((4-(morpholinométhyl)benzyl)oxy)-1-oxoisoindolin-2-yl)pipéridine-2,6-dione.
PCT/US2013/054663 2012-08-14 2013-08-13 Isoformes de céréblon et leur utilisation en tant que biomarqueurs pour traitement thérapeutique WO2014028445A2 (fr)

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US9365640B2 (en) 2011-04-29 2016-06-14 Celgene Corporation Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor
WO2017027672A1 (fr) * 2015-08-12 2017-02-16 Celgene Corporation Méthodes de traitement de tumeurs solides et utilisation de biomarqueurs en tant que facteurs prédictifs de la sensibilité clinique à des traitements immunomodulateurs
US9587281B2 (en) 2012-08-14 2017-03-07 Celgene Corporation Cereblon isoforms and their use as biomarkers for therapeutic treatment
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US10092555B2 (en) 2014-06-27 2018-10-09 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases
US10816544B2 (en) 2017-02-03 2020-10-27 Celgene Corporation Methods for measuring small molecule affinity to cereblon
US10830762B2 (en) 2015-12-28 2020-11-10 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases
US11726080B2 (en) 2018-05-23 2023-08-15 Celgene Corporation Methods for treating multiple myeloma and the use of companion biomarkers for 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile
US11912682B2 (en) 2021-01-13 2024-02-27 Monte Rosa Therapeutics, Inc. Isoindolinone compounds
US11963520B2 (en) 2016-01-19 2024-04-23 Celgene Corporation Transgenic mouse expressing human cereblon

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EP2492686B1 (fr) * 2009-10-20 2018-06-13 Tokyo Institute of Technology Procédé de criblage utilisant le facteur de ciblage de la thalidomide

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US9611465B2 (en) 2009-05-25 2017-04-04 Celgene Corporation Pharmaceutical composition containing core factor involved in proliferation and differentiation of central nervous cell
US9365640B2 (en) 2011-04-29 2016-06-14 Celgene Corporation Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor
US10047151B2 (en) 2011-04-29 2018-08-14 Celgene Corporation Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor
US9857359B2 (en) 2012-06-29 2018-01-02 Celgene Corporation Methods for determining drug efficacy using cereblon-associated proteins
US9587281B2 (en) 2012-08-14 2017-03-07 Celgene Corporation Cereblon isoforms and their use as biomarkers for therapeutic treatment
US10272117B2 (en) 2014-02-24 2019-04-30 Celgene Corporation Methods of using an activator of cereblon for neural cell expansion and the treatment of central nervous system disorders
WO2015127351A1 (fr) * 2014-02-24 2015-08-27 Celgene Corporation Méthodes d'utilisation d'un activateur du céréblon pour l'expansion de cellules neurales et le traitement de troubles du système nerveux central
US10092555B2 (en) 2014-06-27 2018-10-09 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases
US10668057B2 (en) 2014-06-27 2020-06-02 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases
US11419861B2 (en) 2014-06-27 2022-08-23 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases
WO2017027672A1 (fr) * 2015-08-12 2017-02-16 Celgene Corporation Méthodes de traitement de tumeurs solides et utilisation de biomarqueurs en tant que facteurs prédictifs de la sensibilité clinique à des traitements immunomodulateurs
US10830762B2 (en) 2015-12-28 2020-11-10 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases
US11733233B2 (en) 2015-12-28 2023-08-22 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases
US11963520B2 (en) 2016-01-19 2024-04-23 Celgene Corporation Transgenic mouse expressing human cereblon
US10816544B2 (en) 2017-02-03 2020-10-27 Celgene Corporation Methods for measuring small molecule affinity to cereblon
US11644461B2 (en) 2017-02-03 2023-05-09 Celgene Corporation Methods for measuring small molecule affinity to cereblon
US11726080B2 (en) 2018-05-23 2023-08-15 Celgene Corporation Methods for treating multiple myeloma and the use of companion biomarkers for 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile
US11912682B2 (en) 2021-01-13 2024-02-27 Monte Rosa Therapeutics, Inc. Isoindolinone compounds

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