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WO2024168192A1 - Évaluation de bcma dans des échantillons biologiques - Google Patents

Évaluation de bcma dans des échantillons biologiques Download PDF

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Publication number
WO2024168192A1
WO2024168192A1 PCT/US2024/015063 US2024015063W WO2024168192A1 WO 2024168192 A1 WO2024168192 A1 WO 2024168192A1 US 2024015063 W US2024015063 W US 2024015063W WO 2024168192 A1 WO2024168192 A1 WO 2024168192A1
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Prior art keywords
bcma
antibody
sbcma
sample
subject
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English (en)
Inventor
Lizhi YU
Michelle WALDMAN
Yixin Wang
Sarah HERSEY
Shannon CHILEWSKI
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Celgene Corp
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Celgene Corp
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    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57426—Specifically defined cancers leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

  • the present disclosure relates to methods for detection of soluble B-cell maturation antigen (BCMA). Such methods can be used for diagnosing, prognosing, screening, or monitoring a subject suspected to have or having a BCMA-expressing disease or condition, based upon the level of soluble BCMA observed in a patient’s plasma sample, including in connection with treatment methods.
  • BCMA soluble B-cell maturation antigen
  • B-cell maturation antigen is a transmembrane type III protein expressed on mature B lymphocytes.
  • BAFF B cell activator of the TNF family
  • APRIL proliferation inducing ligand
  • MM multiple myeloma
  • CLL chronic lymphocytic leukemia
  • NHL B-cell non-Hodgkin’s lymphoma
  • soluble B cell maturation antigen sBCMA
  • the method can include obtaining the plasma sample from the subject.
  • soluble B cell maturation antigen sBCMA
  • methods of assaying soluble B cell maturation antigen (sBCMA) in a plasma sample including: a) obtaining a plasma sample from a subject; b) contacting the plasma sample from the subject with an anti-BCMA antibody or antigen-binding fragment; and c) detecting sBCMA in the plasma sample from the subject.
  • the method is an immunoassay.
  • the immunoassay in an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • the ELISA is a sandwich ELISA.
  • the method is an electrochemiluminescent assay.
  • the electrochemiluminescent assay is a Meso Scale Discovery (MSD) assay.
  • the contacting is carried out with a first anti-BCMA antibody under conditions to form a complex comprising the anti-BCMA antibody or antigen-binding fragment and sBCMA, and detecting sBCMA comprises detecting the presence or absence of the complex in the sample.
  • the detecting the presence or absence of the complex in the sample is carried out with a second anti-BCMA antibody under conditions to form a complex comprising the first anti-BCMA antibody, the second anti-BCMA antibody, and sBCMA.
  • the second anti-BCMA antibody or antigen-binding fragment thereof is attached to a label capable of producing a detectable signal, and detecting sBCMA comprises assessing the presence or absence of the detectable signal.
  • the second anti-BCMA antibody or antigen-binding fragment binds to an epitope of BCMA that is not the same or does not overlap with an epitope bound by the first anti-BCMA antibody or antigen-binding fragment.
  • soluble B cell maturation antigen sBCMA
  • methods of assaying soluble B cell maturation antigen (sBCMA) in a plasma sample including: a) contacting a plasma sample from a subject with a first anti- BCMA antibody or antigen-binding fragment under conditions to form a complex comprising the anti-BCMA antibody or antigen-binding fragment and sBCMA, optionally washing the sample after the contacting with the first anti-BCMA antibody or antigen-binding fragment; b) contacting the sample produced in step a) with a second anti-BCMA antibody under conditions to form a complex comprising the first anti-BCMA antibody, the second anti-BCMA antibody and sBCMA, wherein the second anti-BCMA antibody is conjugated to a label capable of producing a detectable signal, optionally washing the sample after the contacting with the second anti-BCMA antibody or antigen-binding fragment; and c) detecting sBCMA by assessing the presence or absence of the detectable signal.
  • the method further includes determining the amount of sBCMA present in the sample.
  • the subject has a disease or condition.
  • the disease or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a cancer.
  • the cancer is a leukemia, a lymphoma, or a myeloma.
  • the cancer is a multiple myeloma (MM), optionally a relapsed/refractory MM.
  • the plasma sample is obtained from a blood sample from the subject.
  • the blood sample comprises a single sample.
  • the blood sample comprises multiple samples collected longitudinally from the subject.
  • the subject is a human.
  • the first anti-BCMA antibody or antigen-binding fragment is attached or immobilized to a solid support.
  • the label comprises biotin. In some embodiments, the label comprises horseradish peroxidase. In some embodiments, the label comprises aN- hydroxysuccinimide ester. In some embodiments, the label comprises a polypyridine complex.
  • sBCMA soluble BCMA
  • the disease is myeloma, such as multiple myeloma.
  • treating the subject for the disease includes administering to the subject a therapeutic that treats the disease.
  • the therapeutic targets BCMA.
  • the therapeutic is an anti-BCMA chimeric antigen receptor (CAR) T cell therapy.
  • the anti-BCMA CAR is idecabtagene vicleucel or ciltacabtagene autoleucel.
  • the therapeutic is an anti-BCMA antibody, bispecific antibody, multi-specific antibody, bispecific protein, multi-specific protein or antibody drug product (ADC).
  • the therapeutic targets GPRC5D.
  • the therapeutic is an anti-GPRC5D chimeric antigen receptor (CAR) T cell therapy.
  • the therapeutic is an anti-GPRC5D antibody, bispecific antibody, multi-specific antibody, bispecific protein, multi-specific protein or antibody drug product (ADC).
  • sBCMA soluble BCMA
  • methods of using antibodies and antigen-binding fragments such as in methods for detecting soluble BCMA (sBCMA) in a sample or samples from an individual or methods of diagnosing, prognosing, screening, or monitoring a BCMA-expressing disease or condition.
  • patient serum may not always be available for testing.
  • measuring soluble BCMA (sBCMA) from other types of patient samples such as plasma are needed.
  • the methods include an immunoassay involving contacting a plasma sample with a means for binding soluble BCMA and detecting the soluble BCMA in the sample.
  • BCMA also known as TNR receptor superfamily 17 (TNFRSF17)
  • TNF tumor necrosis factor
  • BCMA is expressed on malignant plasma cells, and regulate B-cell maturation and differentiation into plasma cells.
  • BCMA is a receptor for myeloma survival factors, and is required for survival of long-lived plasma cells in the bone marrow (Seckinger (2017) Cancer Cell 31 (3): 396-421; Tai and Anderson (2015) Immunotherapy 7 (11): 1187-1199).
  • the provided embodiments are for detecting soluble BCMA (sBCMA) in plasma.
  • Soluble BCMA (sBCMA) plasma levels may be a useful adjunctive biomarker for assessing myeloma disease response and progression or as a predictor of response to BCMA-targeting therapies in multiple myeloma patients.
  • BCMA expression is not found on normal cells, except for plasma cells. Still, expression of BCMA is highly upregulated in malignant cells compared to non-malignant cells, making it a specific and robust target antigen for tumors. Specifically, BCMA is upregulated in multiple myeloma, leukemia, and lymphoma cells. The activity of BCMA is correlated with disease activity in patients with chronic lymphocytic leukemia (CLL) (Udd (2015) Blood 126: 2931). In some aspects, it is contemplated that BCMA surface and/or aberrant expression in a variety of cancers, but not in normal tissues and cells, reduces or minimizes off-target activity and/or toxicity.
  • CLL chronic lymphocytic leukemia
  • Human BCMA contains the amino acid sequence of GenBank Accession Number Q02223.2 (SEQ ID NO:1):
  • BCMA can form a soluble (or secreted) form (Rennert et al. , J Exp Med 192:1677-1684 (2000)). It is believed that the extracellular
  • portion of the BCMA receptor is cleaved from the membrane of the plasma cell surface via enzymes such as gamma secretase (y-secretase; Laurent et al., Nature Communications 67333 (2015)). Since it is cleaved, soluble BCMA (sBCMA) can be used as a biomarker for predicting patient outcome, determining prognosis, and optimizing treatment plans for cancer patients (e.g. B-cell cancers such as multiple myeloma and various lymphomas). In some embodiments, if the patient expresses soluble BCMA (sBCMA) or expresses sBCMA at a high level, the patient is determined to have cancer.
  • sBCMA soluble BCMA
  • the methods of assessing sBCMA in a plasma sample as provided herein can be used, for example, for the diagnosis, prognosis, screening or identification, or monitoring of subjects with a BCMA-expressing disease or condition, such as, but not limited to multiple myeloma (e.g., prognosis of survival in patients diagnosed with multiple myeloma (MM)), chronic lymphocytic leukemia (CLL), or B-cell non-Hodgkin’s lymphoma (NHL).
  • the methods as provided herein can also monitor the response of the disease to treatment, based upon the level of soluble BCMA (sBCMA) observed in a patient’s plasma samples collected longitudinally.
  • a longitudinal sample collection involves collecting samples from the same subject at different points in time.
  • a BCMA binding agent such as a BCMA-binding molecule is involved, such as an antibody or an antigen-binding fragment.
  • soluble BCMA soluble BCMA
  • methods of detecting soluble BCMA sBCMA in plasma.
  • the methods can be used in the detection of soluble BCMA (sBCMA) for diagnostic, prognostic, screening, or monitoring methods.
  • soluble BCMA soluble BCMA
  • the methods are performed in vitro.
  • the sample is obtained or isolated from the subject or individual.
  • the subject or individual is a human.
  • the biological sample is a single sample. In some embodiments, the biological sample is a series of samples. In some embodiments, the biological sample includes multiple samples collected at different time points (i.e., longitudinally) from the same subject. In some embodiments, the samples are plasma samples. In some embodiments, the blood sample is collected from a subject. In some embodiments, the blood sample is further processed to result in the plasma sample.
  • plasma samples can be generated immediately after blood collection in evacuated tubes with an anticoagulant additive.
  • the additives may include sodium citrate, ethylenediaminetetraacetic acid (EDTA), or heparin.
  • processing of the sample includes techniques commonly used in the art to purify and/or concentrate a protein sample such as steps involving washing in a buffer, incubation, centrifugation, filtration, immunoprecipitation, adsorption and/or addition of agents that remove contaminants that can interfere with detecting of the binding between soluble BCMA and an antibody.
  • detection of soluble BCMA can be achieved by detection techniques commonly known in the art for detecting the binding between a protein target and binding agent (e.g. an antibody) such as, but not limited to, spectrophotometry, high performance liquid chromatography (HPLC), an aptamer-based assay, a histological or cytological assay, an mRNA expression level assay, immunoassays such as enzyme-linked immunosorbent assay (ELISA), western blot, immunoblotting, immunoprecipitation, radioimmunoassay (RIA), automated imaging, immunohistochemistry (IHC), immunostaining, lateral flow immunoassay, flow cytometry, surface plasmon resonance (SPR), inhibition assay or avidity assay, high-performance liquid chromatography (HPLC), Meso Scale Discovery (MSD) electrochemiluminescence, bead based multiplex immunoassays (MIA), or high- throughput screening of an array such as a microarray or
  • the provided methods involve immunoaffinity-based detection of soluble BCMA (sBCMA) using a specific binding agent or agents.
  • sBCMA soluble BCMA
  • Various methods known in the art for detecting specific antibody-antigen binding can be used.
  • Exemplary immunoassays include fluorescence polarization immunoassay (FPIA), fluorescence immunoassay (FIA), enzyme immunoassay (EIA), nephelometric inhibition immunoassay (NIA), enzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or an electrochemiluminescence assay.
  • the provided methods involve detecting or measuring the amount or concentration of soluble BCMA in the obtained biological sample(s) using an immunoassay.
  • the immunoassay is immunohistochemistry (IHC); flow cytometry; or Western blot.
  • the immunoassay is a colorimetric assay.
  • the immunoassay is a solid-phase immunoassay.
  • the immunoassay is an enzyme linked immunosorbent assay (ELISA), for instance a sandwich ELISA or a competitive ELISA.
  • ELISA enzyme linked immunosorbent assay
  • the immunoassay is a sandwich ELISA.
  • the immunoassay is a lateral flow assay.
  • the immunoassay is a sandwich lateral flow assay.
  • the method comprises the steps of a) contacting a plasma sample from a subject with an anti- BCMA binding agent such as one or more anti-BCMA antibodies, such as a combination or a pair of detection and capture antibodies; and b) detecting soluble BCMA in the sample based on binding between a BCMA protein in the sample with the one or more anti-BCMA binding agents.
  • the anti-BCMA binding agent is an antibody or antigenbinding fragment that binds BCMA.
  • the contacting is carried out under conditions to form a complex comprising the antibody or antigen-binding fragment and its antigen (e.g. BCMA).
  • the contacting is under conditions permissive for binding of the anti-BCMA antibody to BCMA, and detecting whether a complex is formed between the anti-BCMA antibody and BCMA.
  • a method may be an in vitro or in vivo method.
  • the sample is a plasma sample.
  • the plasma sample is diluted or combined with an assay-compatible buffer.
  • the biological sample may be diluted.
  • the dilution can be performed using an assay-compatible buffer.
  • the sample is diluted at least 1.5-fold, such as generally at least 2-fold.
  • the sample is diluted with the same buffer used to dilute the recombinant standards used in the assay. In some embodiments, the sample and the recombinant standards are diluted in the same assay buffer. In some embodiments, the sample is diluted with a different buffer than the one used to dilute the recombinant standards used in the assay. In some embodiments, the sample and the recombinant standards are diluted in different assay buffers.
  • any of a number of available matrix diluents can be used, such as MatrixGuardTM diluent (Cat. No. SM02, Surmodics, MN), MatrixTM Diluent-2 LISS (Cat. No. 102570500, Tulip Diagnostics, India), Plasma Sample diluent (Cat. No. 694, Immunochemistry Technologies, Davis CA) or ELISA General Assay Diluent (Cat. No. BUF037C, Bio-Rad, Hercules, CA).
  • the available matrix diluent can comprise of phosphate-buffered saline (PBS) and/or bovine serum albumin (BSA).
  • the available matrix diluent can comprise tris-buffered saline (TBS) and/or polysorbate 20 (also known as Tween® 20).
  • TBS tris-buffered saline
  • polysorbate 20 also known as Tween® 20
  • the available matrix diluent is PBS.
  • the available matrix diluent is a BSA blocking buffer.
  • the BSA blocking buffer can comprise of TBS, polysorbate 20, and BSA.
  • buffer exchange may be performed on the plasma sample.
  • the buffer is changed out to a matrix diluent.
  • the biological sample may be neutralized to overcome pH related buffer issues.
  • the anti-BCMA antibodies do not need to be attached to a label in order to allow detection of its binding to a target antigen (e.g., BCMA).
  • a target antigen e.g., BCMA
  • detection of binding between an anti-BCMA antibody and a BCMA protein can be achieved through the use of a secondary antibody that is directly or indirectly attached to a label.
  • a system comprising a primary antibody and a secondary antibody may be used to detect the target antigen (e.g., BCMA) bound by the anti-BCMA antibody.
  • BCMA target antigen
  • a primary antibody e.g., a mouse anti- BCMA antibody
  • a sample that may contain the target protein of interest (e.g., human BCMA).
  • a secondary antibody with an appropriate label such as a label described herein, that recognizes the species or isotype of the primary antibody (e.g., an anti-mouse antibody) is then contacted with the sample such that specific detection of the target protein in the sample is achieved.
  • the primary antibody is an anti-BCMA antibody.
  • the primary anti-BCMA antibody is a naked primary anti-BCMA antibody.
  • the primary anti-BCMA antibody is a labeled primary anti-BCMA antibody.
  • Secondary antibodies contemplated herein can be polyclonal or monoclonal.
  • secondary antibodies contemplated herein can be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof.
  • secondary antibody can be reactive against, but not limited to, mouse antibodies, human antibodies, rat antibodies, non-human primate antibodies, horse antibodies, rabbit antibodies, chicken antibodies and goat antibodies.
  • the secondary antibody is an antigenbinding fragment.
  • the one or more antibody is one or more capture antibody that captures soluble BCMA (sBCMA) in the sample.
  • sBCMA soluble BCMA
  • the one or more antibody is one or more detection antibody that binds soluble BCMA (sBCMA) in the sample and is detectable (e.g., is attached to a label).
  • the one or more antibody can be one or more capture antibody (e.g., capture anti -BCMA antibody) and one or more detection antibody (e.g., detection anti-BCMA antibody).
  • the contacting in step a) of the methods herein comprises mixing the sample (e.g., plasma sample obtained from an individual) and one or more an anti- BCMA antibody under conditions to form a complex comprising the antibody or antigenbinding fragment with the BCMA antigen.
  • the plasma sample is mixed with the one or more antibody in the presence of or on or in a solid support or a device comprising a solid support.
  • the sample is mixed with the one or more antibody to produce a mixture and the mixture is subsequently applied to a solid support or a device comprising a solid support.
  • the one or more antibody is directly or indirectly attached to the solid support.
  • the contacting in step a) further comprises one or more incubation of the sample and the one or more antibody.
  • the one or more incubations can be for a time that is suitable to allow the sample to contact the one or more antibody such as for at least or at least about 30 seconds, 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 6 hours, or 12 hours or more but no more than about 24 hours after contacting a sample with the one or more antibody as described herein.
  • the contacting occurs at a temperature of from or from about 0 °C to about 50 °C, such as typically 2 °C to 8 °C or 23 °C to 28 °C or 37 °C to 42 °C.
  • the contacting in step a) further comprises one or more washing under conditions to retain bound BCMA on the solid support and/or to separate the complex away from portions of the sample that are not part of the complex.
  • the detecting in step b) of the methods herein comprises detecting the binding between BCMA with a second substrate specific antibody (e.g. a second anti-BCMA antibody, such as a detection antibody) that is capable of detection of the substrate (e.g. BCMA).
  • a second substrate specific antibody e.g. a second anti-BCMA antibody, such as a detection antibody
  • antibodies e.g., antigen-binding fragments
  • the second antibody is a naked (unlabeled) antibody (e.g., naked anti-BCMA antibody) and detection is indirect by adding a labeled secondary antibody that binds to the naked antibody.
  • the second antibody is a labeled antibody (e.g., labeled anti-BCMA antibody) and the detection is direct.
  • the second antibody is a labeled antibody but is not capable of direct detection.
  • the anti-BCMA antibodies or antigen-binding fragments may be attached directly or indirectly to a label (e.g., can be labeled with a detectable moiety).
  • a label e.g., can be labeled with a detectable moiety
  • the antibody may be conjugated, coupled, or linked to the label.
  • Labels are well known by one of skill in the art.
  • Labels contemplated herein include, but are not limited to, fluorescent dyes, fluorescent proteins, radioisotopes, chromophores, metal ions, gold particles (e.g., colloidal gold particles), silver particles, particles with strong light scattering properties, magnetic particles (e.g., magnetic bead particles such as Dynabeads® magnetic beads), polypeptides (e.g., FLAGTM tag, human influenza hemagglutinin (HA) tag, etc.), enzymes such as peroxidase (e.g., horseradish peroxidase) or a phosphatase (e.g., alkaline phosphatase), streptavidin, biotin, luminescent compounds (e.g., chemiluminescent substrates), oligonucleotides, members of a specific binding pair (e.g., a ligand and its receptor) and other labels well known in the art that are used for visualizing or detecting an antibody when directly or indirectly attached to said antibody.
  • the antibodies or antigen-binding fragments, fluorescent labels, various enzyme-substrate labels, or various N-terminally labeled proteins are known in the art.
  • An indicator moiety, or label group can be attached to the subject antibodies and is selected so as to meet the needs of various uses of the method which are often dictated by the availability of assay equipment and compatible immunoassay procedures.
  • exemplary labels include radionuclides (e.g., 125 I, 131 1, 35 S, 3 H, or 32 P), enzymes (e.g., alkaline phosphatase, horseradish peroxidase, luciferase, or P-galactosidase), fluorescent moieties or proteins (e.g., fluorescein, rhodamine, phycoerythrin, GFP, or BFP), luminescent moieties (e.g., QdotTM nanoparticles supplied by the Quantum Dot Corporation, Palo Alto, Calif), or N- hydroxysuccinimide esters (NHS) moieties, including those comprising polypyridine complexes.
  • radionuclides e.g., 125 I, 131
  • the label is useful for qualitatively and/or quantitatively determining the location of the target antigen (e.g., sBCMA) bound by the antibody (e.g., anti- BCMA antibody). In some embodiments, the label is useful for qualitatively and/or quantitatively determining the amount of target antigen (e.g., sBCMA) bound by the antibody (e.g., anti-BCMA antibody).
  • the target antigen e.g., sBCMA
  • the label is useful for qualitatively and/or quantitatively determining the amount of target antigen (e.g., sBCMA) bound by the antibody (e.g., anti-BCMA antibody).
  • the label is a detectable label (e.g., a fluorescent dye or chemiluminescent label).
  • the label is an affinity label (e.g., a biotin label).
  • the label is compatible for use in a detection assay.
  • the label is compatible for use in a detection or diagnostic assay.
  • an anti-BCMA antibody directly or indirectly attached to a biotin and/or horseradish peroxidase can be used in a detection assay or diagnostic assay provided herein.
  • the biotin and/or horseradish peroxidase labeled anti-BCMA antibody can bind to a BCMA protein (e.g., human BCMA protein) in a sample.
  • Anti-BCMA antibodies that are bound to the BCMA protein can be detected by adding an appropriate substrate that produces a color change in the presence of horseradish peroxidase.
  • an anti-BCMA antibody can be directly or indirectly attached to a polypyridine complex, such as ruthenium (II) tris-bipyridine-(4-methylsulfone).
  • an anti-BCMA antibody can be directly or indirectly attached to a N- hydroxysuccinimide ester (NHS).
  • NHS N- hydroxysuccinimide ester
  • a SULFO-TAGTM NHS-ester can be used in a detection assay or diagnostic assay provided herein. The SULFO-TAGTM NHS-ester labeled anti-BCMA antibody can bind to soluble BCMA (e.g., human sBCMA) in a sample.
  • the label can be an enzyme and detection can be effected by addition of a substrate that produces a signal, e.g. a colorimetric signal.
  • the label can be a polypyridine complex and detection can be effected by applying an electrical current that produces a signal, e.g., a electrochemiluminescence signal.
  • the second antibody (detection antibody) is applied or contacted with the bound BCMA in the complex and allowed to incubate under conditions to allow binding to the bound substrate (e.g. BCMA) in the complex.
  • the incubation can be for a time that is suitable to allow the second antibody (detection antibody) to contact the bound BCMA, such as for at least or at least about 30 seconds, 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 6 hours, or 12 hours or more but no more than about 24 hours after contacting a sample with the second antibody as described herein.
  • the contacting occurs at a temperature of from or from about 0 °C to about 30 °C, such as typically 2 °C to 8 °C or 23 °C to 28 °C.
  • the contacting in step b) further comprises one or more washing steps under conditions to retain binding of the second antibody to the bound substrate or complex and to remove any unbound second antibody.
  • the presence, such as signal, of the second antibody is then detected.
  • Detection methods include, but are not limited to, colorimetric, fluorescent, luminescent, chemiluminescent, or radioactive methods. The choice of the detection method is dependent on the detectable label used.
  • a colorimetric reaction is used in which the antibody is coupled to an enzyme, such as horseradish peroxidase (HRP), alkaline phosphatase or other detectable enzyme.
  • a chemiluminescent reaction is used in which the antibody is coupled to a polypyridine complex, such as ruthenium (II) tris- bipyridine-(4-methylsulfone).
  • an electrical current is applied as part of the detection method.
  • the method can be used to determine the amount of soluble BCMA (sBCMA) in the sample.
  • a method of determining or quantifying the amount of soluble BCMA (sBCMA) in a sample after steps a) and b) above, the method further comprises c) determining or quantifying the amount of soluble BCMA (sBCMA) in the sample by determining or quantifying the amount of BCMA bound by the one or more anti-BCMA antibody.
  • a sample is contacted with the anti-BCMA antibody (e.g., antigen-binding fragment) and binding or formation of a complex between the antibody and the sample (e.g., BCMA in the sample) is determined or detected.
  • the amount of soluble BCMA is determined by a comparison of the detectable signal to a standard curve, such as a standard curve comprising a series of known concentrations of a recombinant or native BCMA.
  • a standard curve such as a standard curve comprising a series of known concentrations of a recombinant or native BCMA.
  • the amount of substrate present in the sample is proportional to the amount of signal, e.g. color or light produced.
  • Methods for quantification of signals are well known in the art such as through use of a luminometer, spectrophotometer, or a digital imaging instrument, such as an instrument with a CCD camera.
  • the digital imaging instrument is MESO SECTOR S 600MM.
  • a substrate standard is generally employed to quantitate or determine the amount of substrate (e.g. BCMA) in the sample.
  • the standard comprises known concentrations (e.g. serial dilutions) of a recombinant or native form of the protein.
  • the concentration of substrate e.g.
  • BCMA BCMA in a sample
  • the amount of soluble BCMA (sBCMA) can be expressed as a concentration of fluid sample.
  • the amount of soluble BCMA (sBCMA) in the test sample can be determine or quantified by comparison to the standard curve.
  • the amount of soluble BCMA detected by the methods is from about 1 to 2000 ng/mL. In some embodiments, the detection range of the assay method is in the range of 1 to 1500 ng/mL. In some embodiments, the detection range of the assay method is in the range of 1 to 1000 ng/mL.
  • soluble BCMA soluble BCMA
  • the method comprises the steps of a) contacting a plasma sample from the subject with one or more anti-BCMA antibody , such as combination or pair of antibodies, under conditions to form one or more complexes comprising the antibody or antigen-binding fragment and BCMA; and b) detecting the presence or absence of soluble BCMA (sBCMA) in the plasma sample based on binding between a BCMA protein in the sample and the one or more anti-BCMA antibody, which, in some cases, can be by detecting the presence or absence of the complex containing bound BCMA.
  • two or more antibodies are contacted with the sample, or a component of the sample, either simultaneously or sequentially.
  • the antibodies can be conjugated directly or indirectly to a moiety that is capable of detection.
  • one or more of the antibodies are modified to permit detection of binding.
  • antibodies can be conjugated to a detectable molecule that permits either direct detection or detection via secondary agents.
  • antibodies are directly labeled as described herein above.
  • the antibodies can be detected using a secondary reagent, such as by a secondary antibody reagent that binds to the primary antibodies and that is coupled to a detectable protein, such as a fluorescent probe or detectable enzyme, such as horseradish peroxidase.
  • the antibodies can be detected using a secondary reagent, such as by a secondary antibody reagent that binds to the primary antibodies such as tris(bipyridine)ruthenium(II) chloride (Ru(bpy)32+) or a tripropylamine (TP A) catalyst.
  • a secondary antibody reagent that binds to the primary antibodies such as tris(bipyridine)ruthenium(II) chloride (Ru(bpy)32+) or a tripropylamine (TP A) catalyst.
  • soluble BCMA is detected using any binding assay or immunoassay known to one of skill in the art including, but not limited to, enzyme linked immunosorbent assay (ELISA) or other similar immunoassay, including a sandwich ELISA or competitive ELISA.
  • ELISA enzyme linked immunosorbent assay
  • the method is a sandwich or competitive immunoassay (e.g. sandwich ELISA or a competitive ELISA assay) and the method comprises a) contacting a plasma sample from the subject with at least one first antibody to capture or bind the soluble BCMA in the sample, such as under conditions to form a complex comprising the antibody or antigen-binding fragment and BCMA; and b) subsequently, such as after one or more optional washing steps, contacting the bound BCMA, such as a complex containing the BCMA, with at least one second antibody to detect the presence or absence of soluble BCMA in the sample or complex.
  • sandwich or competitive immunoassay e.g. sandwich ELISA or a competitive ELISA assay
  • one or more first antibody is used to capture or bind the BCMA.
  • the first antibody is the same as the second antibody and/or competes for binding to BCMA with the second antibody.
  • the first antibody is different than the second antibody, such as binds to a distinct or non-overlapping epitope compared to the second antibody and/or does not compete for binding to BCMA with the second antibody.
  • at least one second antibody is directly or indirectly labeled for detection.
  • the first and second antibody can be part of an antibody pair for use in detecting soluble BCMA as described elsewhere herein.
  • At least one second antibody is directly or indirectly labeled for detection or is capable of detection.
  • the label is biotin.
  • the label is horseradish peroxidase.
  • the biotin and/or horseradish peroxidase label reacts with reagents in the detection buffer.
  • the detection buffer may comprise of TMB (3,3',5,5'-Tetramethylbenzidine).
  • soluble BCMA is detected using any binding assay or immunoassay known to one of skill in the art including, but not limited to, a chemiluminescence immunoassay, including a Meso Scale Discovery (MSD) assay.
  • a chemiluminescence immunoassay including a Meso Scale Discovery (MSD) assay.
  • MSD Meso Scale Discovery
  • a electrochemiluminescent immunoassay uses detection antibodies conjugated to electrochemiluminescent labels to generate light when stimulated by electricity.
  • the electrochemiluminescent immunoassay is a Meso Scale Discovery (MSD) electrochemiluminescence immunoassay.
  • MSD Meso Scale Discovery
  • Meso Scale Discovery is a plate-based assay technique designed for detecting and quantifying substances such as peptides, cytokines, antibodies, and hormones.
  • the soluble factor is immobilized to solid surface, by a first antibody, a capture antibody, and then complexed with a second antibody, a detection antibody that is linked to a N- hydroxysuccinimide ester (NHS) label.
  • the label is a ruthenium (II) tris- bipyridine-(4-methylsulfone) NHS ester.
  • the ruthenium (II) tris- bipyridine-(4-methylsulfone)NHS label is a SULFO-TAGTM label.
  • the SULFO-TAGTM is MSD® Gold SULFO-TAGTM NHS (Catalog number R91AO-1).
  • Detection is accomplished by assessing the emission of light upon electrochemical stimulation.
  • the SULFO-TAGTM label reacts with reagents in the detection buffer.
  • the detection buffer may comprise of tris(bipyridine)ruthenium(II) chloride (Ru(bpy)32+).
  • the detection buffer may also comprise of a tripropylamine (TP A) catalyst.
  • the emission of light is at or at around 620 nm.
  • the MSD assay uses a microplate with a carbon electrode plate surface.
  • the capture antibody is coated on the carbon electrode plate surface.
  • the electrochemical stimulation is provided by electrodes.
  • the electrochemical stimulation can include applying an electrical current across the carbon electrode. Electricity can be applied to the plate electrodes by an instrument, resulting in the light emission of the SULFO-TAGTM labels. Light intensity is measured to quantify the amount of analyte in the sample.
  • the method is a MSD assay and the method comprises a) contacting a plasma sample from the subject with at least one first anti-BCMA antibody to capture or bind soluble BCMA in the sample (e.g., under conditions to form a complex comprising the antibody or antigen- binding fragment and BCMA); and b) detecting the bound BCMA in the sample by adding at least one second anti-BCMA antibody to detect the presence or absence of BCMA in the sample or associated with the complex.
  • at least one second antibody is directly or indirectly labeled for detection or is capable of detection.
  • the label is N-hydroxysuccinimide ester.
  • the N-hydroxysuccinimide ester label is a SULFO-TAGTM label.
  • the provided methods can be carried out by an immunoassay using any means for detecting the soluble BCMA.
  • the provided methods can be carried out using at least one BCMA-targeted antibody or antigen-binding fragment that is able to bind to sBCMA in a plasma sample.
  • a first anti-BCMA antibody e.g. capture antibody
  • a second anti-BCMA antibody e.g. detection antibody
  • the antibodies or antigen-binding fragments thereof specifically bind to BCMA protein.
  • BCMA protein refers to human BCMA.
  • the anti-BCMA antibody can be any of the following known antibody clones: Vicky-1, 19F2, ANC3B1, 1A4, 1D12G9, 3H6, DM16, DM4, MM0108-3D44, BCMA-2366, Vicky-2, 10A9F7, 4D7E5, 8B4, Belantamab (GSK2857914), BAF193, RM0336- 17B1, EPR22457-28 and EPR22457-30, D01P, B01P, 1D12G9, 3H6, or a combination thereof.
  • Antibodies that recognize BCMA can be used in combination for the provided methods.
  • two or more anti-BCMA antibodies e.g. pair of anti-BCMA antibodies
  • exemplary first and second antibody pairs that can be used as the capture and detection antibodies for detecting a sBCMA complex in methods herein include, but are not limited to, clone EPR22457- 28 (Abeam Catalog No. ab267460) and clone EPR22457-30 (Abeam Catalog No. ab259767) or clone D01P (Abnova Catalog No. H00000608-D01P) and clone B01P (Abnova Catalog No.
  • exemplary first and second antibody pairs that can be used as the capture and detection antibodies for detecting a sBCMA complex in methods herein include, but are not limited to, antibody clones from Boster Bio, e.g., Catalog No. EZ0661-CA and Boster Catalog No. EZ0661-DA or from R&D Systems, e.g., Catalog No. MAB1932 (clone 1004024) and Catalog Part No. AF193.
  • two or more anti-BCMA antibodies can be used.
  • exemplary first and second antibody pairs that can be used as the capture and detection antibodies for detecting a sBCMA complex in methods herein include, but are not limited to, antibody clones available from Meso Scale Discovery e.g., MSD Catalog No. B22D8-2 and MSD Catalog No. B22D8-3.
  • the anti-BCMA antibodies may be attached directly or indirectly to a solid support.
  • the antibody may be conjugated, coupled or linked to the solid support.
  • solid supports encompassed herein include, but are not limited to, those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol, nitrocellulose, cellulose, nylon, silicones, and other material well known in the art that is used in a solid support for direct or indirect attachment of an antibody.
  • a solid support examples include, but are not limited to, a bead, column (e.g., chromatography column, etc.), an array (e.g., microarray, nanoarray, etc.), an assay plate, a cartridge, a stick, a filter, or a strip.
  • the solid support can comprise the well of an assay plate.
  • the solid support is a microarray.
  • the solid support can comprise a bead or is a bead.
  • the solid support is a chromatography column (e.g., an affinity chromatography column).
  • a solid support is a discontinuous solid phase of discrete particles, such as those described in U.S. Pat. No. 4,275,149.
  • Methods for directly or indirectly attaching an antibody to a solid support are well known in the art. Methods of attachment generally include non-specific adsorption of the antibody to the solid support or covalent attachment of the antibody, typically through a free amine group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group.
  • Methods of attachment also include indirect attachment of the antibodies to the solid support such as by coating the solid support with a capture reagent, such as streptavidin, and adding affinity labeled antibodies, such as biotin-labeled antibodies, to the solid support so that the interaction between the affinity label (e.g., biotin) and capture reagent (e.g., streptavidin) link the antibodies to the solid support.
  • a capture reagent such as streptavidin
  • affinity labeled antibodies such as biotin-labeled antibodies
  • capture reagent e.g., streptavidin
  • the solid support comprises one or more antibodies that are not anti-BCMA antibodies.
  • the solid support may comprise one or more antibodies that serve as control antibodies.
  • the solid support is part of a device or is compatible or configured for use with a device, such as a diagnostic device.
  • a solid support described herein may be a bead, column, an array, an assay plate, microwell, a cartridge, a stick, a filter, or a strip that is inserted into a device or attached to a device and is used as part of the device in order for the device to be operable.
  • the solid support is the device.
  • the device is a portable device such as a handheld device.
  • the device is a stationary device. The device may be manually operated or automatically operated.
  • the device is an electronic device. Any suitable device for use with the solid supports provided herein or use in the methods provided herein may be used.
  • the solid support is compatible for use in a detection assay. In some embodiments, the solid support is compatible for use in a detection or diagnostic assay. In some embodiments, a sample, e.g. a bodily fluid or other sample as described herein, is contacted with the solid support. In some embodiments, the solid support is useful for qualitatively and/or quantitatively determining the location of the target antigen (e.g., BCMA) bound by the antibody (e.g., anti-BCMA antibody). In some embodiments, the solid support is useful for qualitatively and/or quantitatively determining the amount of target antigen (e.g., BCMA) bound by the antibody (e.g., anti-BCMA antibody).
  • the target antigen e.g., BCMA
  • anti-BCMA antibody e.g., anti-BCMA antibody
  • the device comprises a solid support such as a solid support described herein.
  • a solid support may be or comprise a bead, column, an array, a microwell, an assay plate, a cartridge, a stick, a filter, or a strip.
  • the solid support is inserted into the device, attached to the device and/or held by the device, for example, when the device is operating for detection of one or more protein biomarkers (e.g. BCMA) in a sample.
  • the solid support e.g., one or more microwells, may contain at least an immobilized binding agent, for example a capture reagent, such as an antibody, e.g.
  • the solid support is configured in the device to receive a sample loaded into the device.
  • the sample is added to the solid support prior to its insertion or attachment of the solid support with or into the device.
  • the device is further configured to add solution from a dispenser into the solid support and/or remove solution from the solid support.
  • the solution is or comprises a binding agent, for example a detection reagent, such as an antibody, e.g., a second antibody as described herein for detecting the protein.
  • the solution is or comprises a wash solution.
  • the solution is or comprises a substrate or stop solution.
  • the device is configured to hold one or more of the above solutions and to individually dispense each solution at an appropriate time into the solid support held or inserted in the device.
  • a device provided herein e.g., a device comprising a solid support described herein is useful for qualitatively and/or quantitatively determining the amount of target antigen (e.g., BCMA) bound by the antibody (e.g., anti-BCMA antibody).
  • target antigen e.g., BCMA
  • anti-BCMA antibody e.g., anti-BCMA antibody
  • the device automates or partially automates an assay method that detects a particular biomarker or biomarkers, such as BCMA.
  • actions that may be automated by the instrument include, but are not limited to, mixing or agitation of a sample during an incubation phase, dispensing or adding one or more solutions, washing of a sample, controlling incubation times, optical illumination and/or reading of an assay, and calculation of a biomarker (e.g. BCMA) amount in the sample.
  • the timing of any of the above automated steps can be preset or predetermined, such as to assay specific guidelines.
  • the device is a portable device such as a handheld device.
  • the device is a stationary device.
  • the device may be the size of a desktop printer, or smaller, and may be suitable for use in a physician's office, hospital lab, or residential dwelling.
  • the device may be manually operated or automatically operated.
  • the device is an electronic device.
  • the device comprises a computing system or processor.
  • the computing system comprises one or more computer executable logic (e.g., one or more computer program) that is recorded on a computer readable medium.
  • the computing system or processor is configured to execute some or all of the following functions: (i) processing a signal representative of the detected protein, (ii) comparing data as detected from the sample with a reference standard (iii) calculating an amount or concentration of the protein biomarker in the sample; and/or (iv) displaying or outputting a value representative of the calculated amount or concentration of the protein.
  • the computing system can be configured to perform any one of the methods described herein.
  • the determining the presence or absence or likelihood of having or developing a BCMA-expressing disease or condition comprises comparing the amount or concentration of protein to a threshold or cutoff value as described herein.
  • the comparison to the threshold is performed by a computer.
  • the comparison to a threshold or cutoff is performed by an individual.
  • the computer executable logic can work in any computer that may be any of a variety of types of general-purpose computers such as a personal computer, network server, workstation, handheld device or other computer platform now or later developed.
  • a computing system comprising a computer usable medium having the computer executable logic (computer software program, including program code) stored therein.
  • the computer executable logic can be executed by a processor, causing the processor to perform functions described herein.
  • some functions are implemented primarily in hardware using, for example, a hardware state machine. Implementation of the hardware state machine so as to perform the functions described herein will be apparent to those skilled in the relevant arts.
  • the methods for detecting BCMA as described above can be used in prognostic and/or diagnostic methods in association with a BCMA-expressing disease or condition.
  • the provided methods are used to screen and select subjects eligible for a treatment or therapy e.g., where BCMA is a biomarker for selection of patients.
  • the provided methods are used to monitor subjects who received a treatment or therapy.
  • sBCMA is detected in a sample from the subject in accord with methods described above.
  • diagnosis may be determined from a single sample, from a series of samples, or from changes among the series of samples (e.g., an increase in sBCMA concentration in later time-point samples compared to earlier time-point samples).
  • prognosis may be determined from a single sample, from a series of samples, or from changes among the series of samples (e.g., an increase in sBCMA concentration in later time-point samples compared to earlier time-point samples).
  • a method of screening to identify subjects suitable for a treatment or therapy may be determined from a single sample, from a series of samples, or from changes among the series of samples (e.g., an increase in sBCMA concentration in later time-point samples compared to earlier time-point samples).
  • a method of monitoring subjects who received a treatment or therapy may be determined from a single sample, from a series of samples, or from changes among the series of samples (e.g., an increase in sBCMA concentration in later time-point samples compared to earlier time-point samples).
  • a single sample is collected from a subject.
  • a series of samples are collected from a subject.
  • the series of samples are collected at the same time.
  • the series of samples are collected at any suitable intervals.
  • the series of samples are collected longitudinally from the same subject.
  • the samples are collected from the same subject at different points in time (i.e., longitudinally).
  • the longitudinal samples are collected at any suitable intervals. In some aspects, such intervals may be minutes, hours, days, weeks, months, or years.
  • the sample is obtained in an acute clinical setting.
  • the series of samples may be taken from the same subject at different time points (i. e. , longitudinally) over hours or days.
  • the series of samples may be taken over the course of hours or days.
  • the sample collection between each sample may be separated by a matter of hours.
  • the sample is obtained in a less acute clinical setting.
  • the series of samples may be taken from the same subject at different time points (i.e., longitudinally) over months or years.
  • the series of samples may be taken over the course of months or years.
  • the sample collection between each sample may be separated by a matter of days or months.
  • methods of identifying a subject determined to have, or likely to have or develop, a BCMA-expressing disease or condition which includes methods of detecting soluble (sBCMA) from a plasma sample as described above and further comprises monitoring the subject for diagnostic purposes, including monitoring the subject’s development of a BCMA-expressing disease or disorder.
  • the methods may identify a subject who has, is suspected to have, or is at risk for developing a BCMA-associated disease or disorder.
  • a subject may be diagnosed for the presence of a disease or disorder associated with elevated BCMA expression, such as a BCMA-expressing cancer.
  • the methods include detecting the presence of a BCMA-associated disease, e.g., a tumor.
  • a sample may be obtained from a patient suspected of having a disease or disorder associated with elevated BCMA expression and assayed for the expression level of BCMA.
  • the methods can be used to monitor the size or density of a BCMA-expressing tissue, e.g., tumor, over time, e.g., before, during, or after treatment.
  • methods of diagnosing or determining if a subject has, or is predicted as being likely to have or develop, with a BCMA- expressing disease or condition which includes methods of detecting soluble (sBCMA) from a plasma sample as described above and further comprise, after determining the amount of soluble BCMA (sBCMA) in a sample, comparing the amount of BCMA (sBCMA) to a respective threshold level or value, such as a predetermined threshold level.
  • the subject is diagnosed or determined to have, or is likely to have or develop, a BCMA-expressing disease or condition if the amount of soluble BCMA (sBCMA) in the sample is above the threshold level.
  • a method of diagnosing cancer in a patient comprises: a) obtaining a plasma sample from the subject; and b) testing the sample for the presence of soluble BCMA (sBCMA) expression, wherein the patient is determined to have cancer if the level of sBCMA is above about 5 ng/ml, above about 10 ng/ml, above about 20 ng/ml, above about 30 ng/ml, above about 40 ng/ml, above about 50 ng/ml, above about 60 ng/ml, above about 70 ng/ml, above about 80 ng/ml, above about 90 ng/ml, above about 100 ng/ml, above about 200 ng/ml, above about 300 ng/ml, above about 400 ng/ml, above about 500 ng/ml, above about 600 ng/ml, above about 700 ng/ml, above about 800 ng/ml, or above about 900 ng/ml.
  • sBCMA soluble BCMA
  • the provided methods help monitor a subject with a BCMA- expressing disease or condition for prognostic purposes.
  • a method of determining the prognosis of cancer in a subject comprising a) obtaining a plasma sample from a subject; and b) testing the sample for the level of soluble BCMA (sBCMA) expression.
  • a subject expresses soluble BCMA (sBCMA)
  • the prognosis, or outcome is poor.
  • the patient expresses a high level of soluble BCMA (sBCMA), e.g., greater than above about 5 ng/mL, then the prognosis, or outcome, is poor.
  • the patient's prognosis is poor when the patient expresses a high level of soluble BCMA (sBCMA), wherein a high level of sBCMA is above about 5 ng/ml, above about 10 ng/ml, above about 20 ng/ml, above about 30 ng/ml, above about 40 ng/ml, above about 50 ng/ml, above about 60 ng/ml, above about 70 ng/ml, above about 80 ng/ml, above about 90 ng/ml, above about 100 ng/ml, above about 200 ng/ml, above about 300 ng/ml, above about 400 ng/ml, above about 500 ng/ml, above about 600 ng/ml, above about 700 ng/ml, above about 800 ng/ml, or above about 900 ng/ml.
  • the subjects prognosis is poor when the subject expresses greater than about 10 ng/mL soluble BCMA
  • such methods can further include monitoring the progression of the disease or condition over time.
  • the above methods of determining if a subject has, or is predicted as being likely to have or develop, a BCMA-expressing disease or condition can be repeated periodically after the first test.
  • the provided methods are methods of identifying a subject determined to have, or likely to have or develop, a BCMA-expressing disease or condition, which includes methods of detecting soluble BCMA (sBCMA) from a plasma sample as described above and further comprises identifying the subject as in need of treatment and/or selecting a treatment or therapy for the subject if the determined amount of soluble BCMA (sBCMA) is above a threshold value for the amount of soluble BCMA (sBCMA) in the sample.
  • the provided methods help identify a subject with a BCMA-expressing disease or condition in need of treatment.
  • the provided method help select a treatment or therapy for a subject with a BCMA-expressing disease or condition.
  • the methods may identify a subject with a disease or condition associated with elevated BCMA expression and selecting the subject for a treatment or therapy.
  • the provided methods are used to screen and select subjects eligible for a treatment or therapy, e.g., where BCMA is a biomarker for selection of patients.
  • a subject for a treatment or therapy by predicting a subject’s e.g., subject with BCMA-expressing disease or condition, such as multiple myeloma
  • a subject e.g., subject with BCMA-expressing disease or condition, such as multiple myeloma
  • a BCMA-directed therapy comprising: a) obtaining a plasma sample from a subject; and b) testing the sample for the level of soluble BCMA (sBCMA) expression, wherein if the subject expresses a high level of soluble BCMA (sBCMA), the patient is predicted to not respond to the treatment or therapy.
  • sBCMA level of soluble BCMA
  • the patient is predicted not to respond to the treatment or therapy when the patient expresses a high level of soluble BCMA (sBCMA), wherein a high level of sBCMA is above about 5 ng/ml, above about 10 ng/ml, above about 20 ng/ml, above about 30 ng/ml, above about 40 ng/ml, above about 50 ng/ml, above about 60 ng/ml, above about 70 ng/ml, above about 80 ng/ml, above about 90 ng/ml, above about 100 ng/ml, above about 200 ng/ml, above about 300 ng/ml, above about 400 ng/ml, above about 500 ng/ml, above about 600 ng/ml, above about 700 ng/ml, above about 800 ng/ml, or above about 900 ng/ml.
  • sBCMA soluble BCMA
  • the subject expresses less than about 100 ng/ml, less than about 90 ng/ml, less than about 80 ng/ml, less than about 70 ng/ml, less than about 60 ng/ml, less than about 50 ng/ml, less than about 40 ng/ml, less than about 30 ng/ml, less than about 20 ng/ml, less than about 10 ng/ml, or less than about 5 ng/ml, of soluble BCMA (sBCMA), the patient is identified as a potential subject likely to respond to a treatment or therapy with a BCMA-directed therapy.
  • sBCMA soluble BCMA
  • the subject expresses greater than about 10 ng/ml, greater than about 20 ng/ml, greater than about 30 ng/ml, greater than about 40 ng/ml, greater than about 50 ng/ml, greater than about 60 ng/ml, greater than about 70 ng/ml, greater than about 80 ng/ml, greater than about 90 ng/ml, or greater than about 100 ng/ml of soluble BCMA (sBCMA)
  • sBCMA soluble BCMA
  • the provided methods may help monitoring a subject’s response to a treatment or therapy.
  • a subject e.g. subject with BCMA-expressing disease or condition, such as multiple myeloma
  • a BCMA-directed therapy comprising: a) obtaining a plasma sample from a subject; and b) testing the sample for the level of soluble BCMA (sBCMA) expression, wherein if the concentration of soluble BCMA (sBCMA) in the subject is less than the concentration of soluble BCMA (sBCMA) at pretreatment, then the subject is responding to treatment.
  • sBCMA level of soluble BCMA
  • response is known to those skilled in the art.
  • Guidance documents in particular cancer fields are known to those skilled in the art and provide definitions for “response” for a given cancer type.
  • “response” may include stringent complete remission (sCR), complete remission (CR), near complete remission (nCR), very good partial response (VGPR), partial response (PR), and/or stable disease (SD).
  • response to treatment in multiple myeloma patients is defined as stringent complete remission (sCR), complete remission (CR), near complete remission (nCR), very good partial response (VGPR), or partial response (PR).
  • sCR stringent complete remission
  • CR complete remission
  • nCR near complete remission
  • VGPR very good partial response
  • PR partial response
  • kits for predicting or monitoring a multiple myeloma subject response to treatment with a BCMA-directed therapy comprising: a) obtaining a plasma sample from a subject; and b) testing the sample for the level of soluble BCMA (sBCMA) expression, wherein if the concentration of soluble BCMA (sBCMA) in the subject is less than the concentration of soluble BCMA (sBCMA) at pretreatment, then the subject is predicted to respond or is responding to the BCMA-directed therapy.
  • the subject expresses less than about 100 ng/ml, less than about 90 ng/ml, less than about 80 ng/ml, less than about 70 ng/ml, less than about 60 ng/ml, less than about 50 ng/ml, less than about 40 ng/ml, less than about 30 ng/ml, less than about 20 ng/ml, less than about 10 ng/ml, or less than about 5 ng/ml, of soluble BCMA (sBCMA), the patient is predicted to respond or is responding to treatment with the BCMA-directed therapy.
  • sBCMA soluble BCMA
  • methods of predicting or monitoring a multiple myeloma patient's response to treatment with a BCMA-directed therapy comprise: a) obtaining a sample from a patient; and b) testing the sample for the level of soluble BCMA (sBCMA) expression, wherein if the patient expresses greater than about 10 ng/ml, greater than about 20 ng/ml, greater than about 30 ng/ml, greater than about 40 ng/ml, greater than about 50 ng/ml, greater than about 60 ng/ml, greater than about 70 ng/ml, greater than about 80 ng/ml, greater than about 90 ng/ml, or greater than about 100 ng/ml of soluble BCMA (sBCMA), the patient is predicted to not respond or is not responding to treatment with a BCMA-directed therapy.
  • sBCMA soluble BCMA
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of healthy or normal subjects or in the sample on average in a group of subjects that are not suspected the BCMA-expressing disease or condition.
  • sBCMA soluble BCMA
  • the method is repeated from a sample collected within one week of the first test or previous test, within 2 weeks of the first test or previous test, within 3 weeks of the first test or previous test, within one month of the first test or previous test, within 2 months of the first test or previous test, within 3 months of the first test or previous test, within 4 months of the first test or previous test, within 5 months of the first test or previous test, within 6 months of the first test or previous test or within 1 year of the first test or previous test.
  • the subject is diagnosed or determined to have a BCMA-expressing disease or condition.
  • the subject is selected as in need of treatment.
  • methods of diagnosing or determining if a subject has, or is predicted as being likely to have or develop, with a BCMA- expressing disease or condition which includes methods of detecting soluble BCMA (sBCMA) from a plasma sample as described above and further comprise, after determining the amount of soluble BCMA (sBCMA) in a sample, comparing the amount of soluble BCMA (sBCMA) to a respective threshold level or value, such as a predetermined threshold level.
  • the threshold level is a level that is at or about or above (e.g.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of healthy or normal subjects or in the sample on average in a group of subjects that are not suspected the BCMA-expressing disease or condition.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average based on the subject’s past soluble BCMA (sBCMA) levels.
  • methods of prognosing a subject’s progression of a BCMA-expressing disease or condition which includes methods of detecting soluble BCMA (sBCMA) from a plasma sample as described above and further comprise, after determining the amount of soluble BCMA (sBCMA) in a sample, comparing the amount of BCMA to a respective threshold level or value, such as a predetermined threshold level.
  • the threshold level is a level that is at or about or above (e.g.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5- fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of healthy or normal subjects or in the sample on average in a group of subjects that are not suspected the BCMA-expressing disease or condition.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average based on the subject’s past soluble BCMA (sBCMA) levels.
  • methods of monitoring the progression of a subject’s BCMA-expressing disease or condition which includes methods of detecting soluble BCMA (sBCMA) from a plasma sample as described above and further comprises, after determining the amount of soluble BCMA (sBCMA) in a sample, comparing the amount of soluble BCMA (sBCMA) to a respective threshold level or value, such as a predetermined threshold level.
  • the threshold level is a level that is at or about or above (e.g.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of healthy or normal subjects or subjects that are not suspected the BCMA-expressing disease or condition.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average based on the subject’s past soluble BCMA (sBCMA) levels.
  • methods of screening and/or identifying a subject in need of treatment for a BCMA-expressing disease or condition which includes methods of detecting soluble BCMA (sBCMA) from a plasma sample as described above and further comprises, after determining the amount of soluble BCMA (sBCMA) in a sample, comparing the amount of soluble BCMA (sBCMA) to a respective threshold level or value, such as a predetermined threshold level.
  • the threshold level is a level that is at or about or above (e.g.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of healthy or normal subjects or subjects that are not suspected the BCMA-expressing disease or condition.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of subjects identified to receive a specific treatment or therapy for the BCMA-expressing disease or condition.
  • methods of selecting a treatment or therapy for a subject with a BCMA-expressing disease or condition which includes methods of detecting soluble BCMA (sBCMA) from a plasma sample as described above and further comprises, after determining the amount of soluble BCMA (sBCMA) in a sample, comparing the amount of soluble BCMA (sBCMA) to a respective threshold level or value, such as a predetermined threshold level.
  • the threshold level is a level that is at or about or above (e.g.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of healthy or normal subjects or subjects that are not suspected the BCMA-expressing disease or condition.
  • the threshold level is a level that is at or about or above (e.g. a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of subjects identified to receive a specific treatment or therapy for the BCMA-expressing disease or condition.
  • methods of monitoring the response of subject with a BCMA-expressing disease or condition to a treatment or therapy which includes methods of detecting soluble BCMA (sBCMA) from a plasma sample as described above and further comprises, after determining the amount of soluble BCMA (sBCMA) in a sample, comparing the amount of soluble BCMA (sBCMA) to a respective threshold level or value, such as a predetermined threshold level.
  • sBCMA soluble BCMA
  • the threshold level is a level that is at or about or above (e.g., a level at or about or greater than or greater than about 1.2-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold above) the amount of soluble BCMA (sBCMA), respectively, found in the sample on average in a group of healthy or normal subjects or subjects that are not suspected the BCMA-expressing disease or condition.
  • the threshold level is a level that is at or about or above (e.g.
  • sBCMA soluble BCMA
  • a “subject” or an “individual” is a mammal.
  • a “mammal” includes humans, non-human primates, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, monkeys, etc.
  • the subject is human.
  • BCMA-associated disease or disorder any disease or disorder associated with BCMA or any disease or disorder in which BCMA is specifically expressed and/or in which BCMA has been targeted for treatment (also referred to herein interchangeably as a “BCMA-associated disease or disorder”).
  • Cancers associated with BCMA expression include hematologic malignancies such as multiple myeloma, Waldenstrom macroglobulinemia as well as both Hodgkin’s and non-Hodgkin’s lymphomas. See Coquery et al., Crit Rev Immunol., 2012, 32(4):287-305 for a review of BCMA. Since BCMA has been implicated in mediating tumor cell survival, it is a potential target for cancer therapy.
  • Anti-BCMA antibodies have been previously described such as the inhibitory anti-BCMA antibody SGI which promoted antibodydependent cell-mediated cytotoxicity of BCMA-expressing multiple myeloma cells. See Ryan et al., Mol Cancer Ther.. 2007, 6(ll):3009-3018 and International PCT Pub. No.
  • the disease or disorder associated with BCMA is a B cell- related disorder.
  • the disease or disorder associated with BCMA is one or more diseases or conditions from among glioblastoma, lymphomatoid granulomatosis, posttransplant lymphoproliferative disorder, an immunoregulatory disorder, heavy -chain disease, primary or immunocyte-associated amyloidosis, or monoclonal gammopathy of undetermined significance.
  • the disease or disorder associated with BCMA is an autoimmune disease or disorder.
  • autoimmune diseases or disorder include, but are not limited to, systemic lupus erythematosus (SLE), lupus nephritis, inflammatory bowel disease, rheumatoid arthritis (e.g., juvenile rheumatoid arthritis), ANCA associated vasculitis, idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenia purpura (TTP), autoimmune thrombocytopenia, Chagas’ disease, Grave’s disease, Wegener’s granulomatosis, poly-arteritis nodosa, Sjogren’s syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, vasculitis, diabetes mellitus, Reynau
  • BCMA is expressed on malignant cells and cancers.
  • the cancer e.g., a BCMA-expressing cancer
  • the cancer is a B cell malignancy.
  • the cancer e.g., a BCMA-expressing cancer
  • is a leukemia e.g., B cell leukemia
  • lymphoma e.g., Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, etc.
  • MM multiple myeloma
  • plasma cell malignancy e.g., plasmacytoma
  • Lymphomas contemplated herein include, but are not limited to, Burkitt lymphoma (e.g., endemic Burkitt’s lymphoma or sporadic Burkitt’s lymphoma), non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, small non-cleaved cell lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), marginal zone lymphoma, splenic lymphoma, nodal monocytoid B cell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, pulmonary B cell angiocentric lymphoma, small lymphocytic lymphoma, primary mediastinal B cell lymphoma, lymphoplasmacytic lymphoma (LPL), or mantle cell lymphoma (MCL).
  • Leukemias contemplated here include, but are not limited to, chronic lymphocytic leukemia (CLL), plasma cell leukemia or acute lymphocytic leukemia (ALL).
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphocytic leukemia
  • myelomas e.g., multiple myeloma (MM, e.g., non-secretory multiple myeloma, smoldering multiple myeloma).
  • plasma cell malignancies including, but not limited to, plasmacytoma.
  • a BCMA-expressing cancer include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, myeloma (e.g., multiple myeloma), stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer
  • the subject has persistent or relapsed disease, e.g., following treatment with another BCMA-specific antibody and/or cells expressing a BCMA-targeting chimeric receptor and/or other therapy, including chemotherapy, radiation, and/or hematopoietic stem cell transplantation (HSCT), e.g., allogenic HSCT.
  • HSCT hematopoietic stem cell transplantation
  • the administration effectively treats the subject despite the subject having become resistant to another BCMA-targeted therapy.
  • the subject has not relapsed but is determined to be at risk for relapse, such as at a high risk of relapse, and thus the compound or composition is administered prophylactically, e.g., to reduce the likelihood of or prevent relapse.
  • a subject having a BCMA-expressing cancer comprising administration of a therapeutic, such as a T cell therapy (e.g., CAR T cells or a TCE), wherein the subject has been selected for treatment based on detection of sBCMA by the methods described herein.
  • a therapeutic such as a T cell therapy (e.g., CAR T cells or a TCE)
  • a T cell therapy e.g., CAR T cells or a TCE
  • the T cell therapy is selected from the group consisting of a dose of T cells expressing a recombinant receptor (e.g., a chimeric antigen receptor), a T cell engager (e.g., a bispecific T cell engager), antibody, bispecific antibody, multi-specific antibody, bispecific antigen binding protein, multi-specific antigen binding protein, or antibody drug conjugate, which target, e.g., BCMA or GPRC5D.
  • a recombinant receptor e.g., a chimeric antigen receptor
  • a T cell engager e.g., a bispecific T cell engager
  • antibody bispecific antibody
  • multi-specific antibody e.g., bispecific antigen binding protein
  • multi-specific antigen binding protein e.g., multi-specific antigen binding protein
  • antibody drug conjugate e.g., BCMA or GPRC5D.
  • the T cell therapy is designed to recognize and/or specifically bind to BCMA expressed on cells associated with a B cell malignancy.
  • BCMA cancer in which BCMA is specifically expressed and/or in which BCMA has been targeted for treatment.
  • Cancers associated with BCMA expression include hematologic malignancies such as multiple myeloma, Waldenstrom macroglobulinemia, as well as both Hodgkin’s and non-Hodgkin’s lymphomas. See Coquery et al., Cr it Rev Immunol., 2012, 32(4):287-305 for a review of BCMA. Since BCMA has been implicated in mediating tumor cell survival, it is a potential target for cancer therapy. Chimeric antigen receptors containing mouse anti-human BCMA antibodies and cells expressing such chimeric receptors have been previously described.
  • the disease or disorder associated with BCMA is a B cell-related disorder.
  • the disease or disorder associated with BCMA is one or more diseases or conditions from among glioblastoma, lymphomatoid granulomatosis, post-transplant lymphoproliferative disorder, an immunoregulatory disorder, heavy-chain disease, primary or immunocyte-associated amyloidosis, or monoclonal gammopathy of undetermined significance.
  • the disease or disorder associated with BCMA is an autoimmune disease or disorder.
  • Such autoimmune diseases or disorder include, but are not limited to, systemic lupus erythematosus (SLE), lupus nephritis, inflammatory bowel disease, rheumatoid arthritis (e.g., juvenile rheumatoid arthritis), ANCA associated vasculitis, idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenia purpura (TTP), autoimmune thrombocytopenia, Chagas’ disease, Grave’s disease, Wegener’s granulomatosis, polyarteritis nodosa, Sjogren’s syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, vasculitis, diabetes mellitus, Reynaud’s syndrome, anti-phospholipid syndrome, Goodpasture’s disease, Kawasaki disease, autoimmune
  • BCMA-expressing cancers e.g., a BCMA-expressing cancer
  • Cancers e.g. BCMA-expressing cancers, that can be treated include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, myeloma (e.g., multiple myeloma), stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer and head and neck cancer.
  • BCMA is expressed on malignant cells and cancers.
  • the cancer e.g., a BCMA-expressing cancer
  • the cancer is a B cell malignancy.
  • the cancer e.g., a BCMA-expressing cancer
  • Lymphomas contemplated herein include, but are not limited to, Burkitt lymphoma (e.g., endemic Burkitt lymphoma or sporadic Burkitt lymphoma), non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, small non-cleaved cell lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), marginal zone lymphoma, splenic lymphoma, nodal monocytoid B cell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, pulmonary B cell angiocentric lymphoma, small lymphocytic lymphoma, primary mediastinal B cell lymphoma, lymphoplasmacytic lymphoma (LPL), or mantle cell lymphoma (MCL).
  • Burkitt lymphoma e.
  • Leukemias contemplated here include, but are not limited to, chronic lymphocytic leukemia (CLL), plasma cell leukemia or acute lymphocytic leukemia (ALL). Also contemplated herein are plasma cell malignancies including, but not limited to, multiple myeloma (e.g., non-secretory multiple myeloma, smoldering multiple myeloma) or plasmacytoma.
  • the disease or condition is a plasmacytoma, such as extramedullary plasmacytoma.
  • the subject does not have a plasmacytoma, such as extramedullary plasmacytoma.
  • the disease or condition is multiple myeloma (MM), such as relapsed and/or refractory multiple myeloma (R/R MM).
  • the B cell malignancy is a cancer.
  • the cancer is multiple myeloma.
  • the multiple myeloma is a relapsed or refractory multiple myeloma (R/R MM).
  • the cancer is a lymphoma.
  • the disease or condition associated with BCMA is one that has relapsed in the subject to one or more prior therapies for treating the disease and/or is one in which a subject has not responded to one or more other prior therapies for treating the disease and thus is refractory to treatment with the one or more prior therapies.
  • the disease or condition is multiple myeloma that is a relapsed or refractory disease (hereinafter also called relapsed or refractory multiple myeloma or R/R multiple myeloma).
  • the subject has persistent or relapsed disease, e.g., following treatment with another BCMA-specific antibody and/or cells expressing a BCMA-targeting chimeric receptor and/or other therapy, including chemotherapy, radiation, and/or hematopoietic stem cell transplantation (HSCT), e.g., allogeneic HSCT or autologous HSCT.
  • HSCT hematopoietic stem cell transplantation
  • the subject is resistant to or refractory to treatment, i.e., does not respond following treatment, with another BCMA-specific antibody and/or cells expressing a BCMA- targeting chimeric receptor and/or other therapy.
  • the administration of the T cell therapy e.g., anti-BCMA CAR T cells
  • the subject prior to the initiation of administration of the T cell therapy, the subject has received one or more prior therapies for treating the cancer, e.g., multiple myeloma. In some embodiments, the subject has received at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more prior therapies. In some embodiments, the subject has received at least 3, 4, 5, 6, 7, 8, 9, 10 or more prior therapies. In some embodiments, the subject has relapsed or is refractory to treatment with two or more prior therapies. In some embodiments, the subject has relapsed or is refractory to treatment with three or more prior therapies. In some embodiments, the subject has relapsed or is refractory to treatment with four or more prior therapies.
  • the one more prior therapy may include an autologous stem cell transplant (ASCT), an anti-CD38 antibody, such as daratumumab; an immunomodulatory agent or compounds that as thalidomide, lenalidomide or pomalidomide; a proteasome inhibitor such as bortezomib, carfilzomib or ixazomib; or two or more of any of the above.
  • ASCT autologous stem cell transplant
  • an anti-CD38 antibody such as daratumumab
  • a proteasome inhibitor such as bortezomib, carfilzomib or ixazomib
  • the subject has relapsed or has been refractory to the one or more prior therapies.
  • the subject has R/R multiple myeloma.
  • a subject having been determined to have above or below a threshold level of soluble BCMA is treated with a T cell therapy that includes cells that are genetically modified or engineered with a chimeric antigen receptor (CAR).
  • the CAR generally includes an extracellular antigen (or ligand) binding domain that is directed against an BCMA antigen, linked to one or more intracellular signaling components, in some aspects via linkers and/or transmembrane domain(s).
  • the engineered cells are provided as pharmaceutical compositions and formulations suitable for administration to a subjects, such as for adoptive cell therapy. Also provided are therapeutic methods for administering the cells and compositions to subjects, e.g., patients.
  • the antigen is BCMA.
  • the CAR includes a BCMA-binding portion or portions of the antibody molecule, such as a heavy chain variable (Vn) region and/or light chain variable (VL) region of the antibody, e.g., an scFv antibody fragment.
  • the chimeric receptors, such as CARs generally include an extracellular antigen binding domain, such as a portion of an antibody molecule, generally a variable heavy (VH) chain region and/or variable light (VL) chain region of the antibody, e.g., an scFv antibody fragment.
  • the provided BCMA-binding CARs contain an antibody, such as an anti-BCMA antibody, or an antigen-binding fragment thereof that confers the BCMA- binding properties of the provided CAR.
  • the antibody or antigen-binding domain can be any anti-BCMA antibody described or derived from any anti-BCMA antibody described. See, e.g., Carpenter et al. , Clin. Cancer Res., 2013, 19(8):2048-2060; Feng et al., Scand. J. Immunol. (2020) 92:el2910; U.S. Patent No. 9,034,324; U.S. Patent No. 9,765,342; U.S. Patent Publication No.
  • the anti-BCMA CAR contains one or more single-domain anti-BCMA antibodies.
  • the one or more single-domain anti-BCMA antibodies is derived from an antibody described in W02017025038 or WO2018028647.
  • the anti-BCMA CAR contains two single-domain anti-BCMA antibodies.
  • the two single-domain anti- BCMA antibodies are derived from one or more antibodies described in WO2017025038 or WO2018028647.
  • the BCMA binding domain comprises or consists of A37353-G4S-A37917 (G4S being a linker between the two binding domains), described in W02017025038 or WO2018028647, and provided, e.g., in SEQ ID NOs: 300, 301 and 302 of W02017025038 or WO2018028647 (with or without signal peptide).
  • the anti-BCMA CAR contains an antigen-binding domain that is an scFv containing a variable heavy (Vn) and/or a variable light (VL) region.
  • the scFv containing a variable heavy (Vn) and/or a variable light (VL) region is derived from an antibody described in W02016090320 or W02016090327.
  • the scFv containing a variable heavy (Vn) and/or a variable light (VL) region is derived from an antibody described in WO 2019/090003.
  • the scFv containing a variable heavy (Vn) and/or a variable light (VL) region is derived from an antibody described in W02016094304 or WO2021091978. In some embodiments, the scFv containing a variable heavy (Vn) and/or a variable light (VL) region is derived from an antibody described in WO2018133877. In some embodiments, the scFv containing a variable heavy (Vn) and/or a variable light (VL) region is derived from an antibody described in WO2019149269. In some embodiments, the anti-BCMA CAR is any as described in WO2019173636 or W02020051374A. In some embodiments, the anti-BCMA CAR is any as described in WO2018102752. In some embodiments, the anti-BCMA CAR is any as described in W02020112796 or WO2021173630.
  • the antibody e.g., the anti-BCMA antibody or antigenbinding fragment
  • the anti- BCMA antibody e.g., antigen-binding fragment
  • the anti-BCMA antibody e.g., antigen-binding fragment
  • the anti-BCMA antibody e.g., antigen-binding fragment
  • Also among the antibodies are those having sequences at least at or about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to such a sequence.
  • the antibody is a single domain antibody (sdAb) comprising only a Vn region sequence or a sufficient antigen-binding portion thereof, such as any of the above described Vn sequences (e.g., a CDR-H1, a CDR-H2, a CDR-H3 and/or a CDR-H4).
  • sdAb single domain antibody
  • an antibody provided herein e.g., an anti-BCMA antibody
  • antigen-binding fragment thereof comprising a Vn region further comprises a light chain or a sufficient antigen binding portion thereof.
  • the antibody or antigen-binding fragment thereof contains a Vn region and a VL region, or a sufficient antigenbinding portion of a Vn and VL region.
  • a Vn region sequence can be any of the above described Vn sequence.
  • the antibody is an antigenbinding fragment, such as a Fab or an scFv.
  • the antibody is a full- length antibody that also contains a constant region.
  • the CAR is an anti-BCMA CAR that is specific for BCMA, e.g., human BCMA.
  • Chimeric antigen receptors containing anti-BCMA antibodies including mouse anti-human BCMA antibodies and human anti-human BCMA antibodies, and cells expressing such chimeric receptors have been previously described. See Carpenter et al., Clin Cancer Res., 2013, 19(8):2048-2060; US 9,765,342, WO 2016/090320, W02016090327, W02010104949A2, WO2016/0046724, WO2016/014789, WO2016/094304, WO2017/025038, and WO2017173256.
  • the anti-BCMA CAR contains an antigen-binding domain, such as an scFv, containing a variable heavy (Vn) and/or a variable light (VL) region derived from an antibody described in W02016094304 or WO2021091978.
  • the antigen-binding domain is an antibody fragment containing a variable heavy chain (Vn) and a variable light chain (VL) region.
  • the anti-BCMA CAR contains an antigen-binding domain, such as an scFv, containing a variable heavy (Vn) and/or a variable light (VL) region derived from an antibody described in WO 2016/090320 or W02016090327.
  • Exemplary anti-BCMA CARs include the CARs of idecabtagene vicleucel, ABECMA®, BCMA02, JCARH125, JNJ-68284528 (LCAR-B38M; ciltacabtagene autoleucel; CARVYKTITM) (Janssen/Legend), P-BCMA-101 (Poseida), PBCAR269A (Poseida), P-BCMA- Allol (Poseida), Allo-715 (Pfizer/Allogene), CT053 (Carsgen), Descartes-08 (Cartesian), PHE885 (Novartis), ARI-002 (Hospital Clinic Barcelona, IDIBAPS), and CTX120 (CRISPR Therapeutics).
  • the CAR is the CAR of idecabtagene vicleucel cells.
  • the CAR is the CAR of ABECMA® cells (cells used in ABECMA® immunotherapy).
  • the CAR is the CAR of ciltacabtagene autoleucel cells.
  • the CAR is the CAR of CARVYKTITM cells (cells used in CARVYKTITM immunotherapy).
  • Exemplary CAR-T therapeutics include Bb2121 or Bb2127 (Celgene/Bluebird), JCARH125 or FCARH143 (Celgene/Juno), LCAR-B38M (Nanjing/Janssen/Genscript), MCARH171/ET140 (Celgene/Juno/Eureka), DESCARTES-08 (Cartesian), KITE-585 (Gilead/Kite), and P-BCMA-101 (Poseida).
  • the CAR is the CAR of ABECMA® (idecabtagene vicleucel, see Raje et al., N Engl J Med, 2019, 380:1726-1737; and Munshi et al., N Engl J Med, 2021, 384:705-716).
  • the CAR is the CAR of CARVYKTITM (ciltacabtagene autoleucel, see Berdeja et al., Lancet, 2021, Jul 24;398(10297):314-324; and Martin, Abstract #549 [Oral], presented at 2021 American Society of Hematology (ASH) Annual Meeting & Exposition)).
  • the T cell therapy includes is or comprises a T cell engager (TCE) that is or comprises a binding molecule that binds BCMA and a binding molecule capable of binding to a surface molecule expressed on a T cell.
  • TCE T cell engager
  • the surface molecule is an activating component of a T cell, such as a component of the T cell receptor complex.
  • the surface molecule is CD3 or is CD2.
  • the TCE is or comprises an antibody or antigen-binding fragment.
  • the TCE is selected from among the group consisting of a bispecific T cell engager (BiTE), a checkpoint-inhibitory T cell engager (CiTE), a simultaneous multiple interaction T cell engagers (SMITE), and BiTE-expressing CAR T cells (CART.BiTE cells).
  • a bispecific T cell engager BiTE
  • CiTE checkpoint-inhibitory T cell engager
  • SMITE simultaneous multiple interaction T cell engagers
  • CART.BiTE cells BiTE-expressing CAR T cells
  • the TCE is a bispecific antibody containing at least one antigen-binding domain binding to an activating component of the T cell (e.g., a T cell surface molecule, e.g., CD3 or CD2) and at least one antigen-binding domain binding to BCMA.
  • an activating component of the T cell e.g., a T cell surface molecule, e.g., CD3 or CD2
  • the simultaneous or near simultaneous binding of such an antibody to both of its targets can result in a temporary interaction between the target cell and T cell, thereby resulting in activation, e.g., cytotoxic activity, of the T cell and subsequent lysis of the target cell.
  • the TCE is a bi-specific T cell engager (BiTE).
  • BiTEs are used in connection with the provided methods, uses, articles of manufacture.
  • bi-specific T cell engagers have specificity toward two particular antigens (or markers or ligands).
  • the antigens are expressed on the surface of a particular type of cell.
  • the first antigen is associated with an immune cell or an engineered immune cell
  • the second antigen is associated with a target cell of the particular disease or condition, such as a cancer.
  • bi-specific T cell engagers Numerous methods of producing bi-specific T cell engagers are known, including fusion of two different hybridomas (Milstein and Cuello, Nature 1983;305:537-540), and chemical tethering though heterobifunctional cross linkers (Staerz et al., Nature 1985; 314:628- 631).
  • exemplary bi-specific antibody T cell-engaging molecules are those which contain tandem scFv molecules fused by a flexible linker (see e.g.
  • tandem scFv molecules fused to each other via, e.g., a flexible linker, and that further contain an Fc domain composed of a first and a second subunit capable of stable association (WO2013026837); diabodies and derivatives thereof, including tandem diabodies (Holliger et al., Prot Eng., 9, 299-305 (1996); Kipriyanov et al., J Mol Biol, 1999, 293, 41-66); dual affinity retargeting (DART) molecules that can include the diabody format with a C-terminal disulfide bridge; or triomabs that include whole hybrid mouse/rat IgG molecules (Seimetz et al., Cancer Treat Rev, 2010, 36, 458-467).
  • DART dual affinity retargeting
  • the bi-specific T cell engager is a molecule encoded by a polypeptide construct.
  • the polypeptide construct contains a first component comprising an antigen-binding domain binding to an activating portion of an immune cell or engineered immune cell, and a second component comprising an antigen-binding domain binding to a surface antigen (e.g., target or tumor associated antigen (TAA)) associated with a particular disease or condition (e.g., cancer).
  • TAA tumor associated antigen
  • the first and second components are coupled by a linker.
  • the first component is coupled to a leader sequence encoding a CD33 signal peptide.
  • the polypeptide is a construct containing from N-terminus to C-terminus: a first component comprising an antigen-binding domain binding to an activating portion of the T cell, a peptide linker, and a second component comprising an antigen-binding domain binding to a surface antigen (e.g., target or tumor associated antigen (TAA)) associated with a disease or condition (e.g., cancer).
  • a surface antigen e.g., target or tumor associated antigen (TAA)
  • TAA tumor associated antigen
  • an activating component of the T cell is a T cell surface molecule, such as CD3 or CD2.
  • the surface antigen of the target cell is a tumor associated antigen (TAA, e.g. BCMA).
  • TAA tumor associated antigen
  • the TAA contains one or more epitopes.
  • the peptide linker is or comprises a cleavable peptide linker.
  • the antigen binding domain of the first component of the bispecific T cell engager engages a receptor on an endogenous immune cell in the periphery of the tumor.
  • the endogenous immune cell is a T cell.
  • the engagement of the endogenous T cell receptor redirects the endogenous T cells to the tumor.
  • the engagement of the endogenous T cell receptor recruits tumor infiltrating lymphocytes (TILs) to the tumor.
  • TILs tumor infiltrating lymphocytes
  • the engagement of the endogenous T cell receptor activates the endogenous immune repertoire.
  • the simultaneous or near simultaneous binding of the bispecific T cell engager to both of its targets can result in a temporary interaction between the target cell and T cell, thereby resulting in activation (e.g., cytotoxic activity, cytokine release), of the T cell and subsequent lysis of the target cell.
  • targets e.g., the immune cell and the TAA
  • activation e.g., cytotoxic activity, cytokine release
  • the first component of the bi-specific T cell engager is or comprises an antigen binding domain that binds to an activating component of a T cell.
  • the activating component of the T cell is a surface molecule.
  • the surface molecule is or comprises a T-cell antigen.
  • Exemplary T-cell antigens include but are not limited to CD2, CD3, CD4, CD5, CD6, CD8, CD25, CD28, CD30, CD40, CD44, CD45, CD69, and CD90.
  • the binding of the bispecific T cell engaging molecule with the T cell antigen stimulates and/or activates the T cell.
  • the anti-T cell binding domain includes an antibody or an antigen-binding fragment thereof selected from the group consisting of a Fab fragment, a F(ab')2 fragment, an Fv fragment, an scFv, a scAb, a dAb, a single domain heavy chain antibody, and a single domain light chain antibody.
  • the T cell binding domain on the bi-specific T cell engager is an anti-CD3.
  • the anti-CD3 domain is an scFv.
  • the anti- CD3 domain of the bi-specific T cell engager binds to a subunit of the CD3 complex on a receptor on a T cell.
  • the receptor is on an endogenous T cell.
  • the receptor is on an engineered immune cell further expressing a recombinant receptor.
  • the effects of CD3 engagement of T cells is well known in the art, and include but are not limited to T cell activation and other downstream cell signaling. Any of such bi-specific T cell engagers can be used in the provided disclosure herein.
  • the TCE is a checkpoint-inhibitory T cell engager (CiTE).
  • CiTEs have been generated, including as described in Hermann et al., BloocL 2018 132(Suppl. l):4069 and Zhou et al. , Biomarker Res. 2021, 9:38 (each incorporated herein by reference in its entirety).
  • the CiTE binds to an immune checkpoint protein, such as PD-1 or PD- Ll. In some cases, the CiTE binds to PD-1.
  • the CiTE comprises a PD-1 binding domain with a BiTE targeting a tumor antigen (e.g., BCMA) and a surface molecule expressed by a T cell (e.g., CD3).
  • a tumor antigen e.g., BCMA
  • a surface molecule expressed by a T cell e.g., CD3.
  • the CiTE binds to PD-L1.
  • the CiTE comprises a PD-L1 binding domain with a BiTE targeting a tumor antigen (e.g., BCMA) and a surface molecule expressed by a T cell (e.g., CD3).
  • the TCE is a simultaneous multiple interaction T cell engager (SMITE).
  • SMITES have been generated, including as described in Correnti et al., Leukemia 2018, 32(5): 1239-43 and Zhou et al., Biomarker Res., 2021, 9:38 (each incorporated by reference herein in its entirety).
  • a SMITE comprises two BiTEs.
  • the SMITE binds to a surface molecule expressed by a T cell.
  • the SMITE binds to CD3.
  • the SMITE binds to CD28.
  • the SMITE binds to CD3 and CD28.
  • the SMITE binds to BCMA. In some embodiments, the SMITE binds to an immune checkpoint protein, such as PD-1 or PD-L1. In some embodiments, the SMITE binds to PD-1. In some embodiments, the SMITE binds to PD-L1. In some embodiments, the SMITE binds to CD3, CD28, an immune checkpoint protein, and a TAA.
  • the TCE is or comprises BiTE-expressing CAR T cells (CART.BiTE cells).
  • CART.BiTE cells have been generated as described in Xie and Gu, Nature Rev Cane, 2022, 22:194 and Choi et al. , Nat Biotechnol. , 2019, 37(9): 1049-58.
  • chimeric antigen receptor (CAR)-expressing T cells are engineered to secrete a BiTE.
  • at least one of the CAR or the BiTE binds BCMA.
  • the other of the CAR and the BiTE binds another tumor-associated antigen of the disease or condition, e.g., multiple myeloma.
  • the BiTE binds to the same TAA as the CAR, or a variant thereof.
  • Exemplary monoclonal antibodies, bispecific antibodies, trispecific antibodies, duobodies, or BiTes include CC-93269/EM801 (Celgene/EngMab), AMG 701 or AMG 420 (Amgen), JNJ-64007957 (Janssen), SEA-BCMA (Seattle Genetics), and PF-06863135 (Pfizer).
  • the therapy is a BCMA-directed antibody drug conjugate (ADC) therapy.
  • ADCs include MEDI2228 (Medimmune), AMG 224 (Amgen), and HDP-101 (Heidelberg Max Eder).
  • the methods include one or more screening steps using the methods for detecting soluble BCMA (sBCMA) herein in order to identify subjects for treatment with the T cell therapy and/or continuing the T cell therapy, and/or a step for assessment of treatment outcomes and/or monitoring treatment outcomes.
  • the step for assessment of treatment outcomes can include steps to evaluate and/or to monitor treatment and/or to identify subjects for administration of further or remaining steps of the therapy and/or for repeat therapy.
  • the screening step and/or assessment of treatment outcomes can be used to determine the dose, frequency, duration, timing and/or order of the T cell therapy provided herein.
  • the methods may identify a subject who has, is suspected to have, or is at risk for developing a BCMA-associated disease or disorder.
  • a BCMA-directed T cell therapy e.g., anti -BCMA CAR T cells.
  • a subject may be screened for the level of soluble BCMA (sBCMA), e.g., from a plasma sample from the subject.
  • a subject may be screened for the level of sBCMA prior to treatment with the T cell therapy.
  • the methods include screening for or detecting the level or amount of sBCMA in a subject that has a disease or disorder associated with BCMA expression, e.g., a tumor or a cancer, such as multiple myeloma.
  • a plasma sample may be obtained from a patient suspected of having a disease or disorder associated with BCMA and assayed for the level or amount of sBCMA, for example, using an assay described herein.
  • a subject e.g. human patient or subject
  • methods for treating cancer comprising: a) obtaining a plasma sample from the subject; b) testing the sample for expression of soluble BCMA; and c) if the subject expresses a high level of soluble BCMA, administering to the subject an effective amount of a BCMA-directed therapy, such as any described above.
  • the subject is administered the BCMA-directed therapy if the amount of soluble BCMA (sBCMA) in the plasma sample is above about 5 ng/ml, above about 10 ng/ml, above about 20 ng/ml, above about 30 ng/ml, above about 40 ng/ml, above about 50 ng/ml, above about 60 ng/ml, above about 70 ng/ml, above about 80 ng/ml, above about 90 ng/ml, above about 100 ng/ml, above about 200 ng/ml, above about 300 ng/ml, above about 400 ng/ml, above about 500 ng/ml, above about 600 ng/ml, above about 700 ng/ml, above about 800 ng/ml, or above about 900 ng/ml.
  • sBCMA soluble BCMA
  • the subject is administered the BCMA-directed therapy if the amount of sBCMA in the plasma sample is above about 10 ng/ml.
  • the cancer is selected from multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. In some embodiments, the cancer is multiple myeloma.
  • a method of assaying soluble B cell maturation antigen (sBCMA) in a plasma sample comprising: a) contacting a plasma sample from a subject with an anti -BCMA antibody; and b) detecting sBCMA in the plasma sample from the subject. 2. The method of embodiment 1, further comprising obtaining the plasma sample from the subject.
  • sBCMA soluble B cell maturation antigen
  • a method of assaying soluble B cell maturation antigen (sBCMA) in a plasma sample comprising: a) obtaining a plasma sample from a subject; b) contacting the plasma sample from the subject with an anti-BCMA antibody or antigen-binding fragment; and c) detecting sBCMA in the plasma sample from the subject.
  • sBCMA soluble B cell maturation antigen
  • a method of assaying soluble B cell maturation antigen (sBCMA) in a plasma sample comprising: a) contacting a plasma sample from a subject with a first anti-BCMA antibody or antigen-binding fragment under conditions to form a complex comprising the anti-BCMA antibody or antigen-binding fragment and sBCMA, optionally washing the sample after the contacting with the first anti-BCMA antibody or antigen-binding fragment; b) contacting the sample produced in step a) with a second anti-BCMA antibody under conditions to form a complex comprising the first anti-BCMA antibody, the second anti- BCMA antibody and sBCMA, wherein the second anti-BCMA antibody is conjugated to a label capable of producing a detectable signal, optionally washing the sample after the contacting with the second anti-BCMA antibody or antigen-binding fragment; and c) detecting sBCMA by assessing the presence or absence of the detectable signal.
  • sBCMA soluble B cell maturation antigen
  • the disease or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a cancer.
  • a method of treating a subject having a disease that involves shedding of BCMA comprising determining the amount of soluble BCMA (sBCMA) in the plasma of the subject according to any one of embodiments 1-27 and treating the subject for the disease if the level of soluble BCMA (sBCMA) is above a threshold value.
  • sBCMA soluble BCMA
  • treating the subject for the disease includes administering to the subject a therapeutic that treats the disease.
  • Example 1 Detection of Soluble BCMA (sBCMA) in Plasma Samples with Enzyme Linked Immunosorbent Assay (ELISA)
  • sBCMA soluble B cell maturation antigen
  • a black 96-well plate was coated with 100 pl per well of a human anti-BCMA antibody clone (clone A) in Dulbecco’s phosphate-buffered saline (DPBS) at 7 pg/mL. The plate was incubated at 4 °C, without shaking, overnight. The plate was washed 5 times with wash buffer (0.05% Tween-20 in DPBS), then blocked with 300 pl of bovine serum albumin (BSA) in DPBS per well and incubated at 22 °C, without shaking, for 1 hour. The plate was subsequently washed 1 time with the wash buffer.
  • wash buffer 0.05% Tween-20 in DPBS
  • BSA bovine serum albumin
  • assay buffer 1% BSA in dPBS
  • NAV-HRP Neutravi din-horseradish peroxidase
  • assay buffer 100 ng/mL in assay buffer was added to each well and incubated at 22 °C on a shaker at 300 rpm for 30 minutes. The plate was subsequently washed 5 times with wash buffer, followed by addition of 100 pL per well of Supersignal® West Pico Chemiluminescent substrate (Thermo). Detection of sBCMA was carried out on a Spectramax® M5 ELISA plate reader following manufacturer’s instructions.
  • a Meso Scale Discovery (MSD®) 96-well standard plate was coated with 50 pl per well of human anti-BCMA antibody clone (Clone C) at 5 pg/mL.
  • the plate was washed 4 times with wash buffer (0.05% Tween-20 in Dulbecco’s phosphate-buffered saline), then blocked with 100 pl of Super BlockTM blocking buffer and incubated at 22 °C on a shaker at 500 rpm for 30 minutes.
  • the plates was subsequently washed 4 times with the wash buffer.
  • Plasma and serum samples from 16 multiple myeloma (MM) samples were collected. Plasma and serum samples, as well as recombinant sBCMA samples, were diluted 1: 10 in the blocking buffer.

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Abstract

L'invention concerne des procédés de détection d'un antigène de maturation des lymphocytes B (BCMA) soluble. De tels procédés peuvent être utilisés pour diagnostiquer, pronostiquer, cribler ou surveiller un sujet suspecté d'avoir ou ayant une maladie ou un état exprimant BCMA, sur la base du niveau de BCMA soluble (BCMAs) observé dans un ou plusieurs échantillons de plasma d'un patient, y compris en liaison avec des procédés de traitement.
PCT/US2024/015063 2023-02-10 2024-02-08 Évaluation de bcma dans des échantillons biologiques Ceased WO2024168192A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119470924A (zh) * 2024-01-18 2025-02-18 华中科技大学同济医学院附属同济医院 脑脊液中sBCMA在中枢神经系统自身免疫疾病诊断与监测中的临床应用
CN119470924B (zh) * 2024-01-18 2025-12-12 华中科技大学同济医学院附属同济医院 脑脊液中sBCMA在中枢神经系统自身免疫疾病诊断与监测中的临床应用

Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4275149A (en) 1978-11-24 1981-06-23 Syva Company Macromolecular environment control in specific receptor assays
WO2010104949A2 (fr) 2009-03-10 2010-09-16 Biogen Idec Ma Inc. Anticorps anti-bcma
WO2013026837A1 (fr) 2011-08-23 2013-02-28 Roche Glycart Ag Molécules bispécifiques de liaison à l'antigène activant les lymphocytes t.
WO2016014789A2 (fr) 2014-07-24 2016-01-28 Bluebird Bio, Inc. Récepteurs de l'antigène chimérique bcma
WO2016014565A2 (fr) 2014-07-21 2016-01-28 Novartis Ag Traitement du cancer au moyen d'un récepteur d'antigène chimérique anti-bcma humanisé
WO2016046724A1 (fr) 2014-09-22 2016-03-31 Sacmi Cooperativa Meccanici Imola Societa' Cooperativa Chaîne de fabrication de produits individuels en succession en cycle continu
WO2016090327A2 (fr) 2014-12-05 2016-06-09 Memorial Sloan-Kettering Cancer Center Anticorps ciblant l'antigène de maturation des lymphocytes b et procédés d'utilisation
WO2016090320A1 (fr) 2014-12-05 2016-06-09 Memorial Sloan-Kettering Cancer Center Récepteurs antigéniques chimériques ciblant l'antigène de maturation des cellules b et leurs utilisations
WO2016094304A2 (fr) 2014-12-12 2016-06-16 Bluebird Bio, Inc. Récepteurs de l'antigène chimérique bcma
WO2017025038A1 (fr) 2015-08-11 2017-02-16 Nanjing Legend Biotech Co., Ltd. Récepteurs d'antigènes chimériques basés sur des anticorps à domaine unique et leurs méthodes d'utilisation
US20170183418A1 (en) 2014-04-14 2017-06-29 Cellectis Bcma (cd269) specific chimeric antigen receptors for cancer immunotherapy
US9765342B2 (en) 2012-04-11 2017-09-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric antigen receptors targeting B-cell maturation antigen
WO2017173256A1 (fr) 2016-04-01 2017-10-05 Kite Pharma, Inc. Récepteurs antigéniques chimériques et récepteurs de lymphocytes t et leurs procédés d'utilisation
WO2018085690A1 (fr) 2016-11-04 2018-05-11 Bluebird Bio, Inc. Compositions de lymphocytes t car anti-bcma
WO2018102752A1 (fr) 2016-12-02 2018-06-07 Cartesian Therapeutics, Inc. Immunothérapie anticancéreuse avec des lymphocytes t de récepteur d'antigène chimère cd8+ hautement enrichis
WO2018133877A1 (fr) 2017-01-23 2018-07-26 科济生物医药（上海）有限公司 Anticorps ciblant bcma et son utilisation
WO2019090003A1 (fr) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Récepteurs d'antigènes chimériques spécifiques de l'antigène de maturation des cellules b (bcma)
WO2019149269A1 (fr) 2018-02-01 2019-08-08 信达生物制药(苏州)有限公司 Fragment variable à chaîne unique anti-antigène de maturation des lymphocytes b (bcma) entièrement humain, et application associée
WO2019173636A1 (fr) 2018-03-07 2019-09-12 Poseida Therapeutics, Inc. Compositions de cartyrin et méthodes d'utilisation
WO2020051374A1 (fr) 2018-09-05 2020-03-12 Poseida Therapeutics, Inc. Compositions de cellules allogéniques et méthodes d'utilisation
WO2020069303A1 (fr) * 2018-09-28 2020-04-02 Amgen Inc. Anticorps dirigés contre bcma soluble
WO2020112796A1 (fr) 2018-12-01 2020-06-04 Allogene Therapeutics, Inc. Récepteurs d'antigènes chimériques ciblant l'antigène de maturation des lymphocytes b et leurs méthodes d'utilisation
CN111398600A (zh) * 2020-03-26 2020-07-10 迈杰转化医学研究(苏州)有限公司 一种人源可溶性bcma蛋白的elisa检测试剂盒及其使用方法和应用
WO2021091978A1 (fr) 2019-11-05 2021-05-14 Celgene Corporation Utilisations de récepteurs d'antigènes chimériques anti-bcma
WO2021173630A1 (fr) 2020-02-24 2021-09-02 Allogene Therapeutics, Inc. Cellules car-t de bcma présentant des activités améliorées
US20220267438A1 (en) * 2021-02-16 2022-08-25 Janssen Pharmaceutica Nv Trispecific antibody targeting bcma, gprc5d, and cd3
US20220373550A1 (en) * 2021-05-11 2022-11-24 Janssen Biotech, Inc. Methods and compositions for monitoring the treatment of relapsed and/or refractory multiple myeloma

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4275149A (en) 1978-11-24 1981-06-23 Syva Company Macromolecular environment control in specific receptor assays
WO2010104949A2 (fr) 2009-03-10 2010-09-16 Biogen Idec Ma Inc. Anticorps anti-bcma
US9034324B2 (en) 2009-03-10 2015-05-19 Biogen Idec Ma Inc. Anti-BCMA antibodies
WO2013026837A1 (fr) 2011-08-23 2013-02-28 Roche Glycart Ag Molécules bispécifiques de liaison à l'antigène activant les lymphocytes t.
US9765342B2 (en) 2012-04-11 2017-09-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric antigen receptors targeting B-cell maturation antigen
US20170183418A1 (en) 2014-04-14 2017-06-29 Cellectis Bcma (cd269) specific chimeric antigen receptors for cancer immunotherapy
US20160046724A1 (en) 2014-07-21 2016-02-18 The Trustees Of The University Of Pennsylvania Treatment of cancer using humanized anti-bcma chimeric antigen receptor
WO2016014565A2 (fr) 2014-07-21 2016-01-28 Novartis Ag Traitement du cancer au moyen d'un récepteur d'antigène chimérique anti-bcma humanisé
WO2016014789A2 (fr) 2014-07-24 2016-01-28 Bluebird Bio, Inc. Récepteurs de l'antigène chimérique bcma
WO2016046724A1 (fr) 2014-09-22 2016-03-31 Sacmi Cooperativa Meccanici Imola Societa' Cooperativa Chaîne de fabrication de produits individuels en succession en cycle continu
WO2016090327A2 (fr) 2014-12-05 2016-06-09 Memorial Sloan-Kettering Cancer Center Anticorps ciblant l'antigène de maturation des lymphocytes b et procédés d'utilisation
WO2016090320A1 (fr) 2014-12-05 2016-06-09 Memorial Sloan-Kettering Cancer Center Récepteurs antigéniques chimériques ciblant l'antigène de maturation des cellules b et leurs utilisations
WO2016094304A2 (fr) 2014-12-12 2016-06-16 Bluebird Bio, Inc. Récepteurs de l'antigène chimérique bcma
WO2017025038A1 (fr) 2015-08-11 2017-02-16 Nanjing Legend Biotech Co., Ltd. Récepteurs d'antigènes chimériques basés sur des anticorps à domaine unique et leurs méthodes d'utilisation
WO2018028647A1 (fr) 2015-08-11 2018-02-15 Legend Biotech Usa Inc. Récepteurs d'antigène chimériques ciblant bcma et leurs procédés d'utilisation
WO2017173256A1 (fr) 2016-04-01 2017-10-05 Kite Pharma, Inc. Récepteurs antigéniques chimériques et récepteurs de lymphocytes t et leurs procédés d'utilisation
WO2018085690A1 (fr) 2016-11-04 2018-05-11 Bluebird Bio, Inc. Compositions de lymphocytes t car anti-bcma
WO2018102752A1 (fr) 2016-12-02 2018-06-07 Cartesian Therapeutics, Inc. Immunothérapie anticancéreuse avec des lymphocytes t de récepteur d'antigène chimère cd8+ hautement enrichis
WO2018133877A1 (fr) 2017-01-23 2018-07-26 科济生物医药（上海）有限公司 Anticorps ciblant bcma et son utilisation
WO2019090003A1 (fr) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Récepteurs d'antigènes chimériques spécifiques de l'antigène de maturation des cellules b (bcma)
WO2019149269A1 (fr) 2018-02-01 2019-08-08 信达生物制药(苏州)有限公司 Fragment variable à chaîne unique anti-antigène de maturation des lymphocytes b (bcma) entièrement humain, et application associée
WO2019173636A1 (fr) 2018-03-07 2019-09-12 Poseida Therapeutics, Inc. Compositions de cartyrin et méthodes d'utilisation
WO2020051374A1 (fr) 2018-09-05 2020-03-12 Poseida Therapeutics, Inc. Compositions de cellules allogéniques et méthodes d'utilisation
WO2020069303A1 (fr) * 2018-09-28 2020-04-02 Amgen Inc. Anticorps dirigés contre bcma soluble
WO2020112796A1 (fr) 2018-12-01 2020-06-04 Allogene Therapeutics, Inc. Récepteurs d'antigènes chimériques ciblant l'antigène de maturation des lymphocytes b et leurs méthodes d'utilisation
WO2021091978A1 (fr) 2019-11-05 2021-05-14 Celgene Corporation Utilisations de récepteurs d'antigènes chimériques anti-bcma
WO2021173630A1 (fr) 2020-02-24 2021-09-02 Allogene Therapeutics, Inc. Cellules car-t de bcma présentant des activités améliorées
CN111398600A (zh) * 2020-03-26 2020-07-10 迈杰转化医学研究(苏州)有限公司 一种人源可溶性bcma蛋白的elisa检测试剂盒及其使用方法和应用
US20220267438A1 (en) * 2021-02-16 2022-08-25 Janssen Pharmaceutica Nv Trispecific antibody targeting bcma, gprc5d, and cd3
US20220373550A1 (en) * 2021-05-11 2022-11-24 Janssen Biotech, Inc. Methods and compositions for monitoring the treatment of relapsed and/or refractory multiple myeloma

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
ANGELA STAUFFER: "A Flexible Multiplatform Bioanalytical Strategy for Measurement of Total Circulating Shed Target Receptors: Application to Soluble B Cell Maturation Antigen Levels in the Presence of a Bispecific Antibody Drug", ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES, vol. 19, no. 1, 1 January 2021 (2021-01-01), US, pages 17 - 26, XP093160580, ISSN: 1540-658X, Retrieved from the Internet <URL:https://www.liebertpub.com/doi/pdf/10.1089/adt.2020.1024> DOI: 10.1089/adt.2020.1024 *
BERDEJA ET AL., LANCET, vol. 398, no. 10297, 24 July 2021 (2021-07-24), pages 314 - 324
CARPENTER ET AL., CLIN CANCER RES., vol. 19, no. 8, 2013, pages 2048 - 2060
CARPENTER ET AL., CLIN. CANCER RES., vol. 19, no. 8, 2013, pages 2048 - 2060
CHOI ET AL., NAT BIOTECHNOL., vol. 37, no. 9, 2019, pages 1049 - 58
COQUERY ET AL., CRIT REV IMMUNOL., vol. 32, no. 4, 2012, pages 287 - 305
CORRENTI ET AL., LEUKEMIA, vol. 32, no. 5, 2018, pages 1239 - 43
FENG ET AL., SCAND. J. IMMUNOL., vol. 92, 2020, pages el2910
HERMANN ET AL., BLOOD, vol. 132, no. 1, 2018, pages 4069
HOLLIGER ET AL., PROT ENG., vol. 9, 1996, pages 299 - 305
KIPRIYANOV ET AL., J MOL BIOL, vol. 293, 1999, pages 41 - 66
LAURENT ET AL., NATURE COMMUNICATIONS, 2015, pages 67333
MILSTEINCUELLO, NATURE, vol. 305, 1983, pages 537 - 540
MUNSHI ET AL., N ENGL JMED, vol. 384, 2021, pages 705 - 716
NAGORSENBAUERLE, EXP CELL RES, vol. 317, 2011, pages 1255 - 1260
RAJE ET AL., N ENGLJ MED, vol. 380, 2019, pages 1726 - 1737
RENNERT ET AL., J EXP MED, vol. 192, 2000, pages 1677 - 1684
RYAN ET AL., MOL CANCER THER., vol. 6, no. 11, 2007, pages 3009 - 3018
SECKINGER, CANCER CELL, vol. 31, no. 3, 2017, pages 396 - 421
SEIMETZ ET AL., CANCER TREAT REV, vol. 36, 2010, pages 458 - 467
SHAM MAILANKODY: "GPRC5D-Targeted CAR T Cells for Myeloma", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 387, no. 13, 29 September 2022 (2022-09-29), US, pages 1196 - 1206, XP093160898, ISSN: 0028-4793, Retrieved from the Internet <URL:https://www.nejm.org/doi/pdf/10.1056/NEJMoa2209900?download=true> DOI: 10.1056/NEJMoa2209900 *
STAERZ ET AL., NATURE, vol. 314, 1985, pages 628 - 631
TAIANDERSON, IMMUNOTHERAPY, vol. 7, no. 11, 2015, pages 1187 - 1199
XIEGU, NATURE REV CANC, vol. 22, 2022, pages 194
ZHOU ET AL., BIOMARKER RES, vol. 9, 2021, pages 38
ZHOU ET AL., BIOMARKER RES., vol. 9, 2021, pages 38

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119470924A (zh) * 2024-01-18 2025-02-18 华中科技大学同济医学院附属同济医院 脑脊液中sBCMA在中枢神经系统自身免疫疾病诊断与监测中的临床应用
CN119470924B (zh) * 2024-01-18 2025-12-12 华中科技大学同济医学院附属同济医院 脑脊液中sBCMA在中枢神经系统自身免疫疾病诊断与监测中的临床应用

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