WO2012143498A1 - Bcma-based stratification and therapy for multiple myeloma patients - Google Patents
Bcma-based stratification and therapy for multiple myeloma patients Download PDFInfo
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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- 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
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
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- 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 invention relates to methods for the stratification of a multiple myeloma (MM) patient comprising determining whether or not B-cells, preferably malignant B-cells of said patient express BCMA protein on their surface. Also, methods for selecting an antibody-based multiple myeloma (MM) therapy is based on whether or not BCMA is expressed on the cell surface of B-cells, preferably malignant B-cells of a patient. Furthermore, antibody-based therapies for patients who have BCMA positive malignant B-cells are provided. BACKGROUND OF THE INVENTION
- MM Multiple myeloma
- MM is a heterogenous disease and caused by m o s t l y b y chromosome translocations inter alia t(11 ; 14), t(4;14), t(8;14), del(13), del(17) (Drach et al., (1998) Blood 92(3):802-809;
- MM- affected patients may experience a variety of disease-related symptoms due to bony destruction, bone marrow infiltration, renal failure, immunodeficiency, and the psychosocial burden of a cancer diagnosis.
- new therapies such as chemotherapy and stem cell transplantation approaches are becoming available and have improved survival rates but often bring unwanted side effects, and thus MM remains still incurable (Lee et al., (2004) J Natl Compr Cane Netw 8 (4): 379-383).
- MM is caused by malignancy of the plasma B-cells.
- CD38 was found to express strongly on the surface of myeloma cells (malignant plasma B-cells), i.e. CD38 ++ and therefore to distinguishing plasma B-cells from other hematopoietic cells in the bone marrow.
- BLyS B Lymphocyte stimulator
- BAFF tumor necrosis factors
- TALL-1 TALL-1
- TACI transmembrane activator and calcium modulator cyclophilin ligand interactor
- BCMA and BAFF-R are predominantly expressed on B lymphocytes, while TACI can be found on B cells and activates T cells.
- BCMA and TACI are capable of binding to APRIL (a pjoliferation-inducing ligand) which is the closest structural homologue of BLyS.
- BCMA receptors for BLyS
- BCMA mRNA was up-regulated during the late stages of normal B-cell differentiation and was highly expressed in MM cells (Tarte et al., (2002) Blood 100:1 1 13-1 122; Tarte et al., (2003) Blood 102:592-600; Claudio et al. , (2002) Blood 100:2175-2186).
- BCMA+ B cells Average of BCMA+ B cells are 24% in naive B cells and 20.8% in memory B cells, which is lower than that of plasmoblasts (37.9%). However, it see ms th at BC MA is m ai nly expressed in plasmablasts.
- follicular lymphoma which is defined as a lymphoma of follicle center B cells.
- BCMA protein is expressed on the cell surface of MM cells/cell lines although BCMA protein is originally reported as an integral membrane protein in the Golgi apparatus of human mature B lymphocytes, i.e.
- RNA makes protein and given the fact that BCMA is assigned an important role in MM proliferation, thus implying its presence on the cell surface of MM B-cells, multiple myeloma treatment would automatically have been initiated (Ryan et al . , (2007) Mol Cancer Ther 6: 3009-3018).
- Figure 1 Binding of anti-BCMA antibodies to OPM-2 cells by FACS in OPM-2 cells
- FIG. 1 BCMA Protein (A) and BCMA mRNA (B) expression levels of
- Figure 3 Expression analysis of primary MM cells - exemplary results of positive and negative BCMA expressing patient samples
- the present invention addresses these needs by providing a therapy using anti- BCMA antibodies, preferably in combination with other antibodies or compounds used for the treatment or amelioration of MM, said therapy is based on the present inventors' recognition that the assumption that if BCMA mRNA is detectable BCMA protein is, so to say, automatically present on the surface of MM cells not necessarily correct for each and every patient. I ndeed , the present inventors have found that it is of utmost importance to screen MM patient for the presence or absence, respectively, of the expression of BCMA on the protein level, i.e., for its presence or absence, respectively, on the cell surface of MM cells.
- the present invention provides a method for the stratification of a multiple myeloma (MM) patient disposed to respond favorably to an anti-BCMA antibody therapy, comprising determining whether B-cells of said patient, preferably malignant B-cells (MM cells or MM B-cells) expresses BCMA protein on the surface of said B-cells, wherein said patient is disposed to respond favorably to said anti-BCMA antibody therapy, if said B-cells express BCMA protein on their surface.
- MM multiple myeloma
- the present invention provides a method for diagnosing a BCMA negative multiple myeloma (MM) patient, comprising determining whether B-cells, preferably malignant B-cells, of said patient express BCMA protein on their surface, wherein said patient suffers from BCMA negative MM, if no BCMA protein is detectable on the surface of said B-cells.
- MM multiple myeloma
- the present invention provides a method for selecting an antibody-based multiple myeloma (MM) therapy, comprising determining whether B-cells of a patient, preferably malignant B-cells, express BCMA protein on the surface of said B-cells, wherein, if said B-cells are BCMA positive, the patient may be subject to an anti-CD20 antibody therapy and/or an anti-CD38 antibody therapy and/or an anti-BCMA antibody therapy and/or an anti-CS1 antibody therapy, or, if said B-cells are BCMA-negative, the patient is subject to an anti-CD20 antibody therapy and/or an anti-CD38 antibody therapy and/or an anti-CS1 antibody therapy.
- MM multiple myeloma
- an anti-BCMA antibody therapy for use in the treatment or amelioration of a multiple myeloma (MM) patient whose B-cells are disposed to be BCMA positive,
- an anti-BCMA antibody for use in the treatment or amelioration of a multiple myeloma (MM) patient diagnosed in accordance with the method(s) of the present invention
- an anti-CD20 antibody and/or an anti-CD38 antibody and/or an anti-CS1 antibody therapy for use in the treatment or amelioration of a multiple myeloma (MM) patient whose B-cells are BCMA negative.
- an expression cassette includes one or more of the expression cassettes disclosed herein and reference to “the method” includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein.
- the conjunctive term "and/or" between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by "and/or", a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or” as used herein.
- An object of the present invention is to the provide a method for stratification of MM patients based on BMCA expression on the surface of the patients' B-cells, preferably malignant B-cells and new therapy for MM patients using an anti-BCMA antibody, preferably combined with other antibodies such as anti-CD38, anti-CD20 and/or anti-CS1 antibodies based on the correlation of expression of BCMA gene, i.e. BCMA mRNA and BCMA protein on the surface of B-cells, preferably malignant B-cells of MM patients.
- an anti-BCMA antibody therapy may be superior in comparison to, for example, an anti-CD20 antibody therapy, since CD20 is believed to be expressed on each and every B-cell. Accordingly, all B-cells would be depleted, while, without being bound by theory, an anti-BCMA antibody therapy may not necessarily deplete all healthy B-cells of a patient, since BCMA is not or essentially not expressed on each and every healthy B-cell during development and/or homeostasis.
- the preset invention provides a method for the stratification of a multiple myeloma (MM) patient disposed to respond favorably to an anti-BCMA antibody therapy, comprising determining whether B-cells, preferably malignant B-cells of said patient expresses BCMA protein on the surface of said B-cells, wherein said patient is disposed to respond favorably to said anti-BCMA antibody therapy, if said B-cells express BCMA protein on their surface.
- MM multiple myeloma
- the present invention provides a method for diagnosing a BCMA negative multiple myeloma (MM) patient, comprising determining whether B-cells, preferably malignant B-cells of said patient express BCMA protein on their surface, wherein said patient suffers from BCMA negative MM, if no BCMA protein is detectable on the surface of said B-cells.
- the term "stratification" as used herein includes the statistic division of a population of MM patients into subpopulation of MM patients with BCMA on the basis of expression of transcripts of BCMA gene, i.e. mRNA as well as of detection of said translated gene product, i.e.
- BCMA protein localized on the cell surface for example, by an anti-BCMA antibody in order to consider whether or not a therapy using an anti- BCMA antibody for MM patients may be beneficial.
- Detection of BCMA on the cell surface of B-cells preferably malignant B-cells is preferred.
- BCMA expression on mRNA level can be additionally tested/determined.
- said term refers to sorting patients into those who may or may not benefit from an anti-BCMA antibody based therapy for treating or ameliorating multiple myeloma.
- stratifying patients involves determining as to whether not BCMA is expressed on the surface of B-cells, preferably malignant B-cells of patients suffering from MM.
- B-cells means lymphocytes that play an important role in the humoral immune response (as opposed to the cell-mediated immune response, which is governed by T cells).
- B cells The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells (APCs) and eventually develop into memory B cells after activation by antigen interaction.
- APCs antigen-presenting cells
- B-cells include "plasma cells", sometimes also called herein "plasma B-cells". These plasma cells or plasma B-cells are also encompassed by the term "B cells” when used herein.
- B cells also precursor B-cells as well as B-cells in all stages of their development and/or lineage commitment are encompassed by the term "B cells”.
- B cells are an essential component of the adaptive immune system. While the term "B-cells" also includes normal (i.e., healthy) B-cells, it preferably includes malignant B-cells, in particular malignant B-cells associated with MM (i.e., MM B-cells).
- B cells include both normal and malignant B-cells; with malignant B-cells being preferred (i.e., MM B-cells).
- Malignant describes lymphocytes (in particular B cells) that contribute to a progressively worsening disease, in particular MM as described herein. The term is most familiar as a description of cancer, here MM.
- Malignant BCMA positive B cells are not self-limited in their growth, are capable of invading into adjacent tissues, and may be capable of spreading to distant tissues (metastasizing). Malignant when used herein is synonymous with cancerous.
- malignant B-cells are of main interest in the context of the present invention, since they should be targeted by antibodies, in particular by anti-BCMA antibodies, for which purpose these B-cells are analyzed for the expression of BCMA on their cell surface as described herein.
- MM patients that are subject to the methods and/or antibody-based therapies of the present invention have preferably malignant B- cells; said malignant B-cells are preferably Multiple myeloma cells. Of course, said patients also (or still have) have normal B-cells.
- Malignant B-cells can preferably be determined, detected and/or isolated by the means and methods described herein below.
- malignant B-cells of a patient can be determined, detected and/or isolated by one or more of the specific (i.e., characteristic) B-cell surface marker(s) as described herein and, in particular as embodied in the claims (CD38 positive, CD56 positive or negative, CD 45 positive and/or CD19 positive).
- MM Multiple Myeloma
- Kahler's disease (after Otto Kahler)
- MM is an incurable clonal B-cell neoplasia characterized by the accumulation of malignant plasma B-cells within the bone marrow, in close contact with stromal cells.
- MM is a progressive disease inter alia, for example, caused by multiple genetic insults, i.e.
- chromosomal translocations mainly caused by translocations such as t(1 1 ; 14), t(4; 14), t(8;14), or deletions such as del(13), and del(17) to the precursor plasma B-cell that tumor cells proliferate drastically and become apoptosis resistance.
- B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surface. When they are activated to secrete antibodies, they are known as plasma cells. Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node known as the germinal center.
- the immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome where it stimulates an antibody gene to overproduction. [0037] As mentioned above, a chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and an oncogene (often 1 1 q13, 4p16.3, 6p21 , 16q23 and 20q1 1 [10]) is frequently observed in patients with multiple myeloma.
- This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma.
- the result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations.
- the chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) the thirteenth chromosome is also observed in about 50% of cases.
- MM patients that are subject to the methods and/or antibody-based therapies of the present invention have preferably any of the herein mentioned chromosomal translocation(s) and/or deletion(s).
- cytokines especially IL-6
- Angiogenesis the attraction of new blood vessels
- the produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms.
- MM is preferably staged in accordance with the International Staging System (Greipp et al. (2005), J. Clin. Oncol. 23 (15): 3412-3420 and/or in accordance with the Durie-Salmon Staging System (Durie et al. (1975), Cancer
- stage III one or more of
- Serum paraprotein > 7g/dl_ if IgG, > 5 g/dL if IgA
- Stages I, II, and III of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:
- ⁇ A serum creatinine ⁇ 2 mg/dL ( ⁇ 177 umol/L)
- MM patients that are subject to the methods and/or antibody-based therapies of the present invention are preferably staged in accordance with the International Staging System and/or in accordance with the Durie-Salmon Staging System.
- MM patients that are subject to the methods and/or antibody-based therapies of the present invention may have stage I, II or III MM in accordance with the International Staging System and/or in accordance with the Durie-Salmon Staging System.
- MM patients may experience a variety of disease-related symptoms because of bony destruction, bone marrow infiltration, renal failure, immunodeficiency, and the psychosocial burden of a cancer diagnosis. Exciting new therapies and treatment approaches are becoming available but often bring unwanted side effects.
- myeloma Most cases of myeloma also feature the production of a paraprotein, an abnormal antibody that can cause kidney problems and interferes with the production of normal antibodies leading to immunodeficiency. Hypercalcemia (high calcium levels) are often encountered. Myeloma is diagnosed with blood tests (such as protein electrophoresis, peripheral blood smear), microscopic examination of the bone marrow (bone marrow biopsy), and X-rays of commonly involved bones
- BCMA Breast Cancer ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
- the BCMA may be isolated from a variety of sources, such as from murine or human tissue types or from another source, or prepared by recombinant or synthetic methods. "BCMA” is the abbreviation of B cell maturation antigen. BCMA was isolated as a receptor for BLyS (B Lymphocyte stimulator; trademark of Human Genome Science Rockville, MD), also referred to as BAFF, THANK, TALL-1 , TNFSF13, zTNF4.
- BLyS B Lymphocyte stimulator; trademark of Human Genome Science Rockville, MD
- BCMA is type I single transmembrane receptors and belongs to the TNF family receptors, and is predominantly expressed on B lymphocytes.
- BCMA used herein also encompasses native sequence BCMA and BCMA variants (which are further defined herein), and may be isolated from a variety of sources, such as from murine or human tissue types or from another source, or prepared by recombinant or synthetic method.
- a "native sequence BCMA comprises a polypeptide having the same amino acid sequence as BCMA derived from nature.
- Such native sequence BCMA can be isolated from nature or can be produce by recombinant or synthetic means.
- the naturally- occurring truncated or secreted forms of the BCMA e.g. soluble forms containing for instance, an extracellular domain sequence
- naturally-occurring variant forms e.g., alternatively spliced forms
- naturally occurring allelic variants of the BCMA e.g., allelic variants of the BCMA.
- the native sequence BCMA is a mature or full-length native sequence BCMA polypeptide comprising amino acids 1 to 184 of SEQ ID NO:1 or fragment thereof. Such fragments are preferably biologically active.
- Biologically active as used herein, means having an in vivo or in vitro activity which may be performed directly or indirectly.
- Biologically active fragments of BCMA may have, for example, 70% amino acid homology with the active site of the receptor, more preferably at least 80%, and most preferably, at least 90% homology. Identity or homology with respect to the receptor is defined herein as the percentage of amino acid residues in the candidate sequence which are identical to the BCMA residues in SEQ ID NO: 1 , or which are identical to a defined portion of the amino acid residues in SEQ ID NO: 1.
- Biological activity can be tested by way of interaction with APRIL and/or BAFF.
- BCMA extracellular domain refers to a form of BCMA which is essentially free of transmembrane and cytoplasmic domains of BCMA. Ordinarily, BCMA extracellular domain will have less than 1 % of such transmembrane and cytoplasmic domains and will preferably have less than 0.5% of such domains.
- BCMA ECD will comprise amino acid residues 8 to 41 of SEQ ID NO:1 , or amino acid residues 4 to 51 of SEQ ID NO: 1 , or amino acid residues 1 to 53 of SEQ ID NO: 1.
- the BCMA ECD comprises amino acid residues 1 to 51 of SEQ ID NO:1.
- transmembrane domain identified for the BCMA polypeptide of the present invention is identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain.
- the exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain specifically mentioned herein.
- the BCMA ECD may optionally comprise amino acids 8-41 (SEQ ID NO: 1 ).
- BCMA- variant means an active BCMA as defined below having at least about 80% amino acid sequence identity with the BCMA having the deduced amino acid sequence shown in SEQ ID NO:1 for a full-length native sequence BCMA or with a BCMA sequence.
- BCMA variants include, for instance, BCMA polypeptides wherein one or more amino acid residues are added, or deleted, at the end or C-terminus of the sequence of SEQ ID NO:1 .
- a BCMA variant will have at least about 80% or 85% amino acid sequence identity, more preferably at least about 90% amino acid sequence identity, and even more preferably at least about 95% amino acid sequence identity with the amino acid sequence of SEQ ID NO:1.
- Percent (%) amino acid sequence identity is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the BCMA sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publically available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximum alignment over the full length of the sequences being compared.
- the term "disposed to respond favorably" when used in the context of the present invention means that MM B-cells from a patient who is administered an antibody-based therapy, in particular an anti-BCMA antibody therapy are more likely to be susceptible to said antibody.
- the likelihood that MM B-cell (preferably obtained from a patient) may respond favorably is dependent on the expression of BCMA on the cell surface of a MM B-cell as described herein. More specifically, the MM B-cell may respond favorably to said antibody if expression level of BCMA on the cell surface of a MM B-cell is higher than that of (a) reference cell(s) as described herein.
- the expression level of BCMA on the cell surface of a MM B-cell is determined as described herein.
- BCMA Surface expression of BCMA can, for example, be done by Fluorescence Activated Cell Sorting (FACS) using an appropriate anti-BCMA antibody.
- FACS Fluorescence Activated Cell Sorting
- Anti-BCMA antibody can either be generated by means and methods commonly known in the art or are commercially available.
- the invention also includes antibodies specifically reactive with BCMA.
- Antiprotein/anti-peptide antisera or monoclonal antibodies can be made by standard protocols (See, for example, Antibodies: A Laboratory Manual ed. by Harlow and Lane (Cold Spring Harbor Press: 1988)).
- a mammal such as a mouse, a hamster or rabbit can be immunized with an immunogenic form of the peptide.
- Techniques for conferring immunogenicity on a protein or peptide include conjugation to carriers, or other techniques, well known in the art.
- An immunogenic portion of BCMA can be administered in the presence of an adjuvant. The progress of immunization can be monitored by detection of antibody titers in plasma or serum. Standard ELISA or other immunoassays can be used with the immunogen as antigen to assess the levels of antibodies.
- the antibodies are immunospecific for antigenic determinants of BCMA or its co-receptors, e.g. antigenic determinants of a polypeptide of SEQ ID NO: 1 , or a closely related human or non-human mammalian homolog (e.g. 70, 80 or 90 percent homologous, more preferably at least 95 percent homologous).
- the anti-BCMA antibodies do not substantially cross react (i.e.
- BCMA contains an extracellular domain. Said extracellular domain is preferably targeted by an antibody applied in the methods and antibody-based therapies of the present invention.
- a preferred anti-BCMA antibody is an anti-human BCMA antibody such as a rat anti-human BCMA antibody, a mouse anti-human BCMA antibody, a camelid anti-human BCMA antibody, a sheep anti-human BCMA antibody.
- an antibody from a species other than that to be diagnosed is applied.
- the patient is a dog or cat
- a mouse, rat, sheep, camelid anti-dog or anti-cat BCMA antibody is applied.
- an anticalin i.e., a lipocalin mutein such as a tear lipocalin mutein, bacterial lipocalin mutein or an hNGAL lipocalin mutein directed against BCMA, preferably human BCMA
- a lipocalin mutein such as a tear lipocalin mutein, bacterial lipocalin mutein or an hNGAL lipocalin mutein directed against BCMA, preferably human BCMA
- a particularly preferred antibody applied in the methods of the present invention is the anti-human antibody Vicky- 1 and/or MAB 193 (clone 335004).
- Vicky-1 is a rat lgG1 isotype and is available from GeneTex, Catalogue number #GTX17323.
- MAB193 is a rat lgG2a isotye and is available from R&D Systems, catalogue number #MAB 193.
- BCMA preferably BCMA expressed on the surface of MM B-cells is detectable with Vicky-1 or MAB 193.
- patients as described herein that may suffer from MM or are suspected to suffer therefrom have MM B-cells that are detectable with Vicky-1 or MAB 193.
- said patient more specifically B-cells, in particular, MM B-cells of said patients
- said patient are, so to say, Vicky-1 and/or MAB193 positive.
- a MM B-cell is deemed to express BCMA on its surface (i.e., it is BCMA positive or has a certain BCMA expression level), if it shows a detectable signal that is above (or exceeds that of) a reference cell, preferably a BCMA negative cell, more preferably a BCMA negative B-cell, even more preferably a BCMA negative MM B-cell.
- a preferred BCMA negative MM B-cell is U266B1 , JJN-3 or LP-1 , with U266B1 and JJN-3 being preferred.
- such a BCMA negative cell line may nevertheless have detectable BCMA mRNA.
- a detectable signal due to expression of BCMA on a B-cell of interest is above the detectable signal of a reference cell.
- "Above" in the context of a detectable signal means the detectable signal due to expression of BCMA on the surface of a B-cell of interest such as one or more B-cells from a patient, is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or higher than the signal from a BCMA negative reference cell.
- the MAB193 or Vicky-1 antibody is preferably used for detecting/isolating/determining BCMA expression on the surface of B-cells, preferably malignant B-cells of a patient, preferably MM patient.
- a “signal” or “detectable signal” reflects the result of an antibody-antigen reaction.
- the antibody-antigen reaction is preferably the reaction of an anti-BCMA antibody with BCMA.
- a signal can be determined by way of the signal provided by the signal generating group of an antibody, in particular an antibody against BCMA which is described herein.
- the signal can be any signal which is detectable by, for example, spectroscopic, photochemical, biochemical, immunochemical, or chemical means as described herein below.
- a signal can also be determined by way of the signal provided by the signal generating group of an antigen-specific receptor which is described herein below.
- a signal generating group refers to a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means.
- useful labels include radiolabels such as 32 P, 35 S, or 25 l; fluorescent dyes (for example, Cy-3, Cy-5); chromophores, electron-dense reagents; enzymes that generate a detectable signal (e.g., as commonly used in an ELISA); or spin labels.
- the label or detectable moiety has or generates a measurable signal, such as a radioactive, chromogenic, or fluorescent signal, that can be used to quantify the amount of bound detectable moiety in a sample.
- the detectable moiety can be incorporated in or attached to signal generating group either covalently, or through ionic, van der Waals or hydrogen bonds, e.g., incorporation of radioactive nucleotides, or biotinylated nucleotides that are recognized by streptavidin.
- the label or detectable moiety may be directly or indirectly detectable. Indirect detection can involve the binding of a second directly or indirectly detectable moiety to the detectable moiety.
- the detectable moiety can be the ligand of a binding partner, such as biotin, which is a binding partner for streptavidin, or a nucleotide sequence, which is the binding partner for a complementary sequence, to which it can specifically hybridize.
- the binding partner may itself be directly detectable, for example, an antibody may be itself labelled with a fluorescent molecule.
- the binding partner also may be indirectly detectable.
- the antibody-specific receptor When the antibody-specific receptor is "capable of binding to a signal generating group" this means that it can bind to a signal generating group.
- the antibody-specific receptor may carry a functional group which is able to bind to a signal generating group.
- a functional group can be streptavidin/avidin which binds to biotin, an antigen such as a tag, for example, GST or histidine residues which binds to an antibody, a sugar which binds a lectin or the known Dig/Anti-Dig system.
- the moiety that binds to the functional group carries the signal generating group.
- any immunoassay known in the art can be used for immunologically detecting the binding of an antibody to an antigen or the binding of an antigen to an antibody.
- Immunoassays are well known to the skilled artisan. Methods for carrying out such assays as well as practical applications and procedures are summarized in related textbooks. Examples of related textbooks are Tijssen, P., In: Practice and theory of enzyme immunoassays, Burdon, R.H. and v. Knippenberg, P. H. (eds.), Elsevier, Amsterdam (1990), pp. 221 -278, and various volumes of Colowick, S. P. and Caplan, N.O. (eds.), Methods in Enzymology, Academic Press, dealing with immunological detection methods, especially volumes 70, 73, 74, 84, 92 and 121.
- Immunoassays include precipitation (particularly immunoprecipitation), electrochemiluminescence (electro-generated chemiluminescence), RIA (radioimmunoassay), ELISA (enzyme-linked immunosorbent assay), sandwich enzyme immune tests, electrochemiluminescence sandwich immunoassays (ECLIA), dissociation-enhanced lanthanide fluoro immuno assay (DELFIA), scintillation proximity assay (SPA), turbidimetry, nephelometry, latex- enhanced turbidimetry or nephelometry, solid phase immune tests, and mass spectrometry such as SELDI-TOF, MALDI-TOF, or capillary electrophoresis-mass spectrometry (CE-MS).
- ELIA electrochemiluminescence sandwich immunoassays
- DELFIA dissociation-enhanced lanthanide fluoro immuno assay
- SPA scintillation
- suitable immunoassays include microplate ELISA-based methods, fully- automated or robotic immunoassays and latex agglutination assays.
- an immunoassay is an assay in which an antibody specifically binds an antigen to provide for the detection and/or quantification of an antibody or an assay in which an antigen binds to an antibody to provide for the detection and/or quantification of said antigen.
- the antigen is preferably BCMA or a fragment thereof, said fragment being preferably immunologically detectable, and the antibody is preferably an anti-BCMA antibody.
- Immunologically detectable when used herein preferably includes that a signal generated by the binding of an antibody to an antigen or by the binding of an antigen to an antibody as described herein is detectable by means and methods commonly known and applied in the art.
- "immunologically detectable” preferably means that a signal generated by the reaction of an anti-BCMA antibody and BCMA or fragment thereof is above (or exceeds that of) a reference cell as described herein, i.e., a MM B-cell of interest is then BCMA positive.
- immunologically detectable when used herein preferably includes that a signal generated by the binding of an antibody to an antigen or by the binding of an antigen to an antibody as described herein is not detectable by means and methods com m only known and appl ied i n the art. I n the context of the present, "not immunologically detectable” preferably means that a signal generated by the reaction of an anti-BCMA antibody and BCMA or fragment thereof is equal to or below that of a reference cell as described herein, i.e., a MM B-cell of interest is then BCMA negative.
- MM B-cell of interest means B-cells, preferably malignant B-cells obtained from a patient suffering from MM or who is suspected to suffer from MM. Prior to analyzing said MM B-cell of interest in accordance with the methods of the present invention, it cannot be said as to whether or not said B-cells are BCMA positive or negative, respectively. [0071] In addition or as an the alternative to a comparison of the expression level of BCMA on the cell surface of a MM B-cell with a BCMA negative cell, also a BCMA positive cell line can serve as a reference cell.
- Suitable BCMA positive cell lines in the sense of the present invention are NCI-H929, MOLP-2, OPM-2, MOLP-8, RPMI8226, KMS-12-BM or L-363.
- a MM B-cell of interest is deemed to be BCMA-positive if it has at least the equal expression level of BCMA as a reference cell line.
- the expression is preferably determined as described herein (i.e., by way of the signal generated by a cell).
- a MM B-cell is deemed to not express BCMA on its surface (i.e., it is BCMA negative), if it does essentially not show a detectable signal that is above a reference cell, preferably a BCMA negative cell, more preferably a BCMA negative B-cell, even more preferably a BCMA negative MM B-cell.
- a preferred BCMA negative MM B-cell is U266B1 , JJN-3 or LP-1 , with U266B1 and JJN-3 being preferred.
- such a BCMA negative cell line may nevertheless have detectable BCMA mRNA.
- the skilled person is readily in a position to determine whether a detectable signal due to expression of BCMA on a B-cell of interest is not above (i.e., equal to or below) the signal of a reference cell.
- detectable signal in the context of a detectable signal means the detectable signal due to expression of BCMA on the surface of a B-cell of interest such as one or more B-cells from a patient is the same as the signal of a BCMA negative reference cell.
- Below in the context of a detectable signal means that the B-cell of interest such as one or more B-cells from a patient shows a signal that is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or even 100% lower than the signal from a BCMA negative reference cell.
- the findings of the present inventors also provide the skilled person with a method for selecting an antibody-based multiple myeloma (MM) therapy, comprising determining whether B-cells of a patient express BCMA protein on the surface of said plasma B-cells, wherein, if said plasma B-cells are BCMA positive, the patient may be subject to an anti-CD20 antibody therapy and/or an anti-CD38 antibody therapy and/or an anti-BCMA antibody therapy, or, if said B-cells are BCMA-negative, the patient is subject to an anti-CD20 antibody therapy and/or an anti-CD38 antibody therapy.
- MM multiple myeloma
- the present invention provides methods and means for selecting one or more appropriate antibody-based therapies for the treatment or prevention of MM.
- the term "potentially" when used in the context of a therapeutic effect means that an anti-BCMA antibody- though such an antibody is deemed to have a therapeutic effect based on the outcome of the methods of the present invention - does not necessarily have to be therapeutically effective. This is so because - self-explanatory as it is - the methods of the present invention cannot provide a 100% safe prediction whether or not a patient may be susceptible to such an antibody, since, apart from the expression of BCMA on the surface of a MM B-cell, individual factors such as age, body weight, general health, sex, diet, drug interaction and the like may have an influence as to whether or not a patient will be susceptible to such an antibody.
- the likelihood that an anti-BCMA antibody has a therapeutic effect is more than 50% in comparison to a patient, whose MM B-cells does not show cell surface expression of BCMA.
- the likelihood is more that 60%, 70%, 80% or 90%, more preferably more than 95%.
- BCMA-negative MM patient may be CD20 and/or CD38-positive and/or CS1-positive before making him/her subject to an anti-CD20 and/or anti-CD38 and/or CS1 antibody-based therapy.
- Further antibody-based therapies i.e., one or more antibody-based therapies in addition (i.e., as combination) to an anti-BCMA antibody-based therapy (if a patient is BCMA positive) or as an alternative to an anti-BCMA antibody-based therapy (if a patient is BCMA negative), that are encompassed by the present invention, may be based on the target indicated in the outer left column of the table that follows below. If the antibody directed against the target as indicated in the outer left column is conjugated to a toxin, then such a conjugate is also encompassed by said further antibody-based therapy. the maytansinoid
- MoAb may target in patients with systemic AL-
- the inhibitory anti-FGFR3 antibody, PRO-001 is cytotoxic to
- TACI Atacicept (TACI-Ig) fusion protein preclincial Yaccoby Leukemia 2008 22, 406-413
- NRI engineered NRI gene introduction combined with adenovirus
- Tocilizumab gene delivery inhibited the in vivo S6B45 cell growth human immunoglobulin
- DOX is as potent as free doxorubicin to inhibit the immunoconjugate with growth of MM cells. But target delivery of matriptase M24-DOX preclincial
- doxorubicin doxorubicin by the matriptase antibody significantly reduced the toxicity toward cardiomyocytes that lack matriptase expression
- NCT00505895 High-dose cyclophosphamide in chimeric with a human II combination with rituximab in patients with primary
- IgGl Fc (ongoing) refractory, high-risk, or relapsed myeloma, also being studied for the treatment of peripheral neuropathy in patients with MGUS
- NCT00477815 Zevalin radioimmunotherapy with
- NCT00664898 safety and pharmacology of SGN-40 administered in combination with Bortezomib
- CD40 SGN-40 (Dacetuzumab) humanized IgGl (Velcade, PS-341) in patients with relapsed or
- NCT00525447 is the study of SGN40, lenalidomide, and dex in MM patients
- CD40 human IgGl patients that is relapsed or has not responded to
- radioactive iodine 131 NCT00135200 to see whether the treatment with
- muIgG2a (131) myeloma cells resistant to chemotherapy
- NCT00346255 given as an intravenous infusion weekly for two consecutive weeks every three humanized (maytansine I
- CD56 BB-10901 (IMGN901) weeks to relapsed and relapsed refractory CD56- DM1 conjugation) (ongoing)
- NCT00259740 to determine if denosumab is
- NCT00104650 to determine the effectiveness of AMG 162 in reducing urinary N-
- NCT00428545 in combination with bortezomib
- VEGF Avastin beuacizumab humanized NCT00410605 (added with lenalidomide and
- NCT00625144 studying the side effects of giving fludarabine and busulfan together with
- NCT00401843 in combination with bortezomib
- I/II NCT00911859 added with Velcade-Melphalan-
- IL-6R MRA humanized II
- NCT00421525 in patients with recurrent or refractory multiple myeloma who have failed at least humanized IgGl or two prior standard systemic treatments. Its isotope,
- CD74 variant milatuzumab (hLLl, I/II
- doxorubicin conjugate activity in non-Hodgkin's lymphoma and multiple myeloma in vitro and in tumor xenograft models Stein et al. 2007 & 2009
- Alpha-4 I/II NCT00675428 patients with relapsed or refractory natalizumab (Tysabri) humanized IgG4
- IGF-1R human IgG2 751,871 is well tolerated and may constitute a novel
- B-cells can be selected and/or identified by way of a B-cell surface marker.
- a "B cell surface marker” or “B cell surface antigen” herein is an antigen expressed on the surface of a B cell which can be targeted with an antagonist which binds thereto.
- Exemplary B cell surface markers include, but are not limited to CD19, CD20, CD21 , CD22, CD23, CD24, CD37, CD40, CD52, D53, CD72, CD73, CD74, CDw75, CDw76, CD77, CDw78, CD79a, CD79b, CD80, CD81 , CD82, CD83, CDw84, CD85, CD86, CDI 80 (RP105), FcRH2 (IRTA4), CD79A, C79B, CR2, CCR6, CD72, P2X5, HLA-DOB, CXCR5 (BLRI), FCER2, BR3 (aka BAFF-R), TACI, BTLA, NAG 14 (aka LRRC4), SLGC16270 (aka LOC283663), FcRHI (IRTA5), FcRH5 (IRTA2), ATWD578 (aka MGC15619), FcRH3 (IRTA3), FcRH4 (IRTAI), FcRH6 (aka LOC
- MM B-cells may be detected, selected and/or identified by way of a B-cell surface marker as described above. However, preferably MM B-cells are selected and/or identified by way of the following markers: CD19, CD56, CD1 17, CD20, CD28, CD27, CD81 and/or CD200 (see also Table 2 of Rawston et al. (2008), Haematologica 93(3):431 -438.
- MM B-cells of the present invention are preferably characterized to be at least CD38 positive, CD56 positive or negative, CD45 positive, and CD19 positive.
- B-cells preferably malignant B-cells that are subject to the methods of the present invention are preferably obtained from a patient.
- a patient according to this invention is a mammal, preferably said patient or mammal suffers from MM or is suspected to suffer from MM.
- "Mammal" for purposes of treatment refers to any animal classified as a mammal, including human, domestic and farm animals, nonhuman primates, and any other animal that has mammary tissue.
- a mammal includes human, rodents such as mouse, rat or rabbit, dog, cat, chimpanzee, horse, pig, etc., with human being preferred.
- a patient also includes human and veterinary patients, with human patients being preferred. In each one of the above methods, the mammal may be one that suffers from multiple myeloma.
- a mammal "in need” of treatment can include, but are not limited to, mammals that have multiple myeloma or are suspected to have multiple myeloma.
- a "subject" when used herein includes mammalian and non-mammalian subjects.
- B-cells obtained from a patient are preferably contained in a sample.
- sample any biological sample obtained from a subject, cell line, tissue culture, or other source containing at least B-cells.
- Biological samples include body fluids (such as blood, serum, plasma, urine, saliva, synovial fluid and spinal fluid) and tissue sources found to contain B-cells. Methods for obtaining tissue biopsies and body fluids from subjects are well known in the art.
- PBMCs peripheral blood mononuclear cells
- B cells and T cells is preferred as a source.
- a sample which includes peripheral blood mononuclear cells (PBMCs), in particular B cells and T cells is preferably taken from peripheral blood of a human patient.
- PBMCs peripheral blood mononuclear cells
- Other preferred samples are whole blood, serum, plasma or synovial fluid , with plasma or serum being most preferred.
- a sample from peripheral blood of a human patient is particularly preferred
- a patient is to be treated with an anti-BCMA antibody.
- the antibody applied for the treatment of a patient as well as the antibody applied in the methods for stratification, diagnosis or selecting an antibody-based MM therapy is preferably a monoclonal antibody, polyclonal antibody, chimeric antibody, humanized antibody, bispecific antibody, domain antibody (dAb) or nanobody.
- antibody also includes but is not limited to polyclonal, monoclonal, monospecific, polyspecific such as bispecific, non-specific, humanized, human, single- chain, chimeric, synthetic, recombinant, hybrid, mutated, grafted, domain (VHH) and in vitro generated antibodies as well as nanobodies including camelid antibodies and humanized camelid antibodies. Accordingly, the term “antibody” also relates to a purified serum, i.e. , a purified polyclonal serum. Accordingly, said term preferably relates to a serum, more preferably a polyclonal serum and most preferably to a purified (polyclonal) serum.
- antibody as employed in the invention also relates to derivatives or variants of the antibodies described herein which display the same specificity as the described antibodies.
- antibody variants include humanized variants of non- human antibodies, "affinity matured” antibodies (see, e.g. Hawkins et al. J. Mol. Biol. 254, 889-896 (1992) and Lowman et al. , Biochemistry 30, 10832- 10837 (1991 )) and antibody mutants with altered effector function (s) (see, e.g., US Patent 5, 648, 260).
- an antigen-binding domain refers to a part of an antibody molecule that comprises amino acids responsible for the specific binding between antibody and antigen.
- the part of the antigen that is specifically recognized and bound by the antibody is referred to as the "epitope" as described herein above.
- an antigen-binding domain may typically comprise an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH); however, it does not have to com prise both .
- Fd fragments for example, have two VH regions and often retain some antigen-binding function of the intact antigen-binding domain.
- antigen-binding fragments of an antibody examples include (1 ) a Fab fragment, a monovalent fragment having the VL, VH, CL and CH1 domains; (2) a F(ab')2 fragment, a bivalent fragment having two Fab fragments linked by a disulfide bridge at the hinge region; (3) a Fd fragment having the two VH and CH1 domains; (4) a Fv fragment having the VL and VH domains of a single arm of an antibody, (5) a dAb fragment (Ward et al., (1989) Nature 341 :544-546), which has a VH or VL domain; (6) an isolated complementarity determining region (CDR), and (7) a single chain Fv (scFv).
- a Fab fragment a monovalent fragment having the VL, VH, CL and CH1 domains
- F(ab')2 fragment a bivalent fragment having two Fab fragments linked by a disulfide bridge at the hinge region
- the two domains of the Fv fragment, VL and VH> are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci USA 85:5879-5883).
- scFv single chain Fv
- immunoglobulin (Ig) is used interchangeably with “antibody” herein.
- a further aspect of the present invention is an anti-BCMA antibody therapy for use in the treatment of a multiple myeloma (MM) patient whose plasma B-cells are disposed to be BCMA positive.
- a still further aspect of the present invention is an anti-BCMA antibody for use in the treatment of a multiple myeloma (MM) patient diagnosed with a method of the present invention.
- an anti-CD20 antibody and/or an anti-CD38 antibody for use in the treatment of a multiple myeloma (MM) patient whose B-cells are BCMA negative.
- an anti-BCMA antibody is conjugated to a toxin including chemotherapeutic agent that is toxic against malignant plasma B-cells in MM patients.
- chemotherapeutic agents are disclosed in WO 2010/121093 such as Bortezomib (Velcade), Thalidomide (Thalomid), Lenalidomide (Revlimid).
- beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i. e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
- Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
- Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
- the anti-BCMA antibody, anti-CD20 antibody, anti-CD38 antibody and/or anti- CS1 antibody is preferably administered in an "effective amount".
- An “effective amount” is an amount sufficient to carry out a specifically stated purpose.
- An “effective amount” can be determined empirically and by known methods relating to the stated purpose.
- the term “therapeutically effective amount” refers to an amount of a therapeutic agent of this invention effective to "treat” or "ameliorate” MM in a mammal (aka patient).
- the therapeutically effective amount may be a growth inhibitory amount or a cytotoxic amount
- the therapeutically effective amount of the drug active for any one of the following: reducing the number of cancer cells; reducing the number of malignant MM B-cells, tumor size; inhibiting (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibiting (i.e., slow to some extent and preferably stop) tumor metastasis; inhibiting, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
- the drug can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic.
- a "treatment" or a "therapeutically effective amount” refers to a course of administration of the therapeutic agent, which course may include several dosings spread over a period of time to achieve a desired effect.
- the B cell depleting agents i.e., the anti-BCMA antibody, anti-CD20 antibody, anti-CD38 antibody or any other antibody directed against a target expressed on the surface of a B cell such as CS1
- the B cell depleting agents can be administered to a patient by a variety of methods, such as by intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by subcutaneous, intramuscular, intraperitoneal, intracerobrospinal, intra-articular, intrasynovial, intrathecal, or inhalation routes.
- These antibodies are preferably administered in the form of a pharmaceutical compositions.
- the dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
- the pharmaceutical composition of the invention may comprise further agents such as additional anti-tumor agents as exemplified herein elsewhere.
- kits comprising an anti-BCMA antibody and instructions for use, in particular instructions as how to perform the methods of the present invention.
- the kit comprises at least one container and a label or package insert on or associated with the container.
- Suitable containers include, for example, bottles, vials, syringes, etc.
- the containers may be formed from a variety of materials such as glass or plastic.
- the container can have a sterile access port for extracting a therapeutic agent (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
- the label or package insert can indicate that the composition is used for treating MM.
- the kit may further comprise a second container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes
- a pharmaceutically-acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
- BWFI bacteriostatic water for injection
- phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
- BWFI bacteriostatic water for injection
- phosphate-buffered saline such as phosphate-buffered saline, Ringer's solution and de
- Anti-BCMA IgGs and appropriate isotype control IgGs were labeled with ALEXA Fluor® 488 using ALEXA Fluor® 488 Monoclonal Antibody Labeling Kit (Invitrogen, #A20181 ). Labeling and calculation of the degree of labeling was performed according to manufacturers' instructions.
- Bone marrow aspirates from MM patients were filtered through a 70 ⁇ cell strainer (BD, 352350). Plasma cell numbers have previously been determined and based on that, aspirate volumes for staining were calculated:
- CD38-APC (BD, clone: HIT2, #555462)
- CD56-PE-Cy-7 (BD, clone: NCAM16.2, #335791 )
- CD45-APC-Cy7 (BD, clone: 2D1 ; #557833)
- 6 ⁇ of CD19- PerCP-Cy5.5 (BD, clone: HIB19, #561295).
- Plasma cells were identified by gating on the CD45 low, CD38 high, CD19 low population and, in case the patients expressed CD56 on their plasma cells, on CD56 high. As reference non plasma cells were gated on for CD45 high, CD38 low, CD56 low.
- the fluorescence intensities of the Alexa488 were measured for both populations, e.g. for Vicky-1 and rat lgG1. Histogrammes derived from specific antibody and isotype control fluorescent signals were overlaid and the difference noted.
- Patients are considered BCMA positive if their non-plasma cells show no difference in fluorescence intensity for Vicky-1 and Mab193 and isotype controls as well as a clear increase in fluorescence on plasma cells for Vicky-1 and MAB193 as compared to the fluorescence measured for rat lgG1 or lgG2a respectively.
- RNA expression levels were analyzed in RT-PCR using Primers described in Li et al (Med Oncol (2010) 27:439-445).
- total cellular RNA was isolated from MM cell as is commonly done in the art. The isolated RNA was applied as a template for the first strand cDNA synthesis by reverse transcription (RT), and cDNA used as a template for polymerase chain reaction (PCR).
- Fig. 2(A) shows the result of BCMA protein level by FACS using Vicky-1 in 10 MM cell lines.
- BCMA protein level on the cell surface was varied in each cell line.
- NCI-H929 very strong indicated as +++ in Table 3
- MOLP-2 very strong indicated as +++ in Table 3
- OPM-2 as well as KMS-12-BM
- KMS-12-BM strong indicated as ++ in Table 3
- U226B1 , JJN-3 and LP-1 showed no BCMA protein expression on the cell surface of said cell lines.
- Fig 2(B) indicates BCMA mRNA level of 10 different MM cell lines. The relative expression levels were resulted from the normalization by GAPDH mRNA level.
- BCMA mRNA level was very high for example, in NCI-H929 cell line as it also showed high protein level. Although it was found that no expression of BCMA protein on the cell surface of U266B1 , JJN-3 as well as LP-1 was detectable, BCMA mRNA in said cell lines were detectable, and it is noted that BCMA mRNA level of JJN-3 and LP-1 cell lines rather showed higher. Thus, the inventor concluded that there is no solid correlation between BCMA protein in the cell surface and BCMA mRNA in MM cell lines.
- Table 3 Summary of protein and mRNA expression levels in 10 different MM cell lines [0098] BCMA protein expression on bone marrow plasma cells of MM patients
- MM cells malignant plasma B-cells
- Vicky-1 or MAB193 Bone marrow aspirates of 23 patients were analyzed for BCMA expression in FACS.
- FACS Fluorescence Activated Cell Sorting
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SG2013076930A SG194500A1 (en) | 2011-04-21 | 2012-04-20 | Bcma-based stratification and therapy for multiple myeloma patients |
MA36351A MA35056B1 (en) | 2011-04-21 | 2012-04-20 | BCMA-BASED STRATIFICATION AND TREATMENT FOR PATIENTS WITH MULTIPLE MYELOMA |
JP2014505643A JP2014520248A (en) | 2011-04-21 | 2012-04-20 | BCMA-based stratification and treatment of patients with multiple myeloma |
CA2832510A CA2832510A1 (en) | 2011-04-21 | 2012-04-20 | Bcma-based stratification and therapy for multiple myeloma patients |
MX2013012167A MX2013012167A (en) | 2011-04-21 | 2012-04-20 | Bcma-based stratification and therapy for multiple myeloma patients. |
CN201280029972.2A CN103608039A (en) | 2011-04-21 | 2012-04-20 | BCMA-based stratification and therapy for multiple myeloma patients |
EA201301180A EA201301180A1 (en) | 2011-04-21 | 2012-04-20 | BCMA-BASED STRATIFICATION AND THERAPY OF PATIENTS SUFFERING WITH MULTIPLE MYELOMA |
KR1020137030684A KR20140031905A (en) | 2011-04-21 | 2012-04-20 | Bcma-based stratification and therapy for multiple myeloma patients |
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TNP2013000412A TN2013000412A1 (en) | 2011-04-21 | 2013-10-11 | Bcma-based stratification and therapy for multiple myeloma patients |
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KR20140031905A (en) | 2014-03-13 |
EP2699259A1 (en) | 2014-02-26 |
US20140193433A1 (en) | 2014-07-10 |
SG194500A1 (en) | 2013-12-30 |
PE20140612A1 (en) | 2014-06-07 |
TN2013000412A1 (en) | 2015-03-30 |
AP2013007178A0 (en) | 2013-10-31 |
IL228701A0 (en) | 2013-12-31 |
JP2014520248A (en) | 2014-08-21 |
CN103608039A (en) | 2014-02-26 |
MX2013012167A (en) | 2013-12-10 |
US20130101599A1 (en) | 2013-04-25 |
CO6801644A2 (en) | 2013-11-29 |
EP2699259B1 (en) | 2016-07-27 |
CL2013003031A1 (en) | 2014-08-18 |
MA35056B1 (en) | 2014-04-03 |
EA201301180A1 (en) | 2014-03-31 |
US20160131655A1 (en) | 2016-05-12 |
AU2012244676A1 (en) | 2013-10-24 |
CA2832510A1 (en) | 2012-10-26 |
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