Compositions and methods for treatment of drug resistant multiple myeloma

Abstract

This invention relates to a novel target for production of immune and non-immune based therapeutics and for disease diagnosis. More particularly, the invention provides therapeutic antibodies against TMEM154 antigens, which are differentially expressed in cancer, and diagnostic and therapeutic usages, wherein the cancer is relates to multiple myeloma, including multiple myeloma precursor diseases. This invention further relates to extracellular domains of TMEM154 proteins and variants, and therapeutic usages thereof.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a polyclonal or monoclonal antibody, or antibody binding fragment, that specifically binds to a TMEM154 polypeptide comprising at least one of SEQ ID NOS: 10, 5, 62 or 63, or a fragment thereof, in a pharmaceutically acceptable carrier, and a second medicament, wherein said second medicament is suitable for treatment of multiple myeloma, wherein said antibody and said second medicament are provided in a single dosage form or separately, and wherein said second medicament is selected for a synergistic effect between said antibody and said second medicament. 
     
     
         2 . Use of the composition of  claim 1  for treatment of multiple myeloma. 
     
     
         3 . Use of  claim 2 , wherein said multiple myeloma is selected from the group consisting of a precursor to myeloma, multiple myeloma cancers which produce light chains of kappa-type and/or light chains of lambda-type; aggressive multiple myeloma; refractory multiple myeloma, and drug resistant multiple myeloma. 
     
     
         4 . Use of a polyclonal or monoclonal antibody, or antibody binding fragment, that specifically binds to a TMEM154 polypeptide comprising at least one of SEQ ID NOS: 10, 5, 62 or 63, or a fragment thereof, for treatment of a disease selected from the group consisting of a precursor to myeloma, multiple myeloma cancers which produce light chains of kappa-type and/or light chains of lambda-type; aggressive multiple myeloma; refractory multiple myeloma, and drug resistant multiple myeloma. 
     
     
         5 . The use of  claim 3  or  4 , wherein said aggressive multiple myeloma comprises primary plasma cell leukemia (PCL). 
     
     
         6 . Use of  claim 4  or  5 , further comprising use of another medicament for treatment of multiple myeloma, wherein said antibody and said other medicament are provided in a single dosage form or separately. 
     
     
         7 . Use of any of  claims 4 - 6 , further comprising use of another therapy in combination with said antibody. 
     
     
         8 . The composition or use of any of  claims 1 - 7 , wherein said polyclonal or monoclonal antibody, or antibody binding fragment specifically binds to a TMEM154 polypeptide comprising SEQ ID NO: 10 or a fragment thereof. 
     
     
         9 . The composition or use of  claim 8 , wherein said polyclonal or monoclonal antibody, or antibody binding fragment specifically binds to a TMEM154 polypeptide consisting essentially of SEQ ID NO: 10. 
     
     
         10 . The composition or use of any of  claims 1 - 9  wherein the antibody or fragment specifically binds to a polypeptide consisting essentially of an amino acid sequence of SEQ ID NO:5. 
     
     
         11 . The composition or use of any of  claims 1 - 10 , wherein the antibody or fragment specifically binds to a peptide consisting essentially of at least one SEQ ID NOS: 62 or 63. 
     
     
         12 . The composition or use of any of  claims 1 - 11 , wherein the antibody or fragment is selected from the group consisting of: a fully human antibody, a humanized or primatized antibody, a chimeric antibody, Fab, Fab′, F(ab′)2, F(ab′), F(ab), Fv or scFv fragment and minimal recognition unit. 
     
     
         13 . The composition or use according to any one of  claims 1 - 12 , wherein the antibody or fragment is coupled to a detectable marker, or to an effector moiety. 
     
     
         14 . The composition or use of  claim 13 , wherein:
 the effector moiety is one or more of a radionuclide, fluorophore, an enzyme, a toxin, a therapeutic agent, a chemotherapeutic agent, a cytokine antibody, a cytokine receptor, or an immunomodulatory agent; or   the detectable marker is one or more of a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound or a chemiluminescent compound.   
     
     
         15 . Use of an antibody or a fragment that specifically binds to a TMEM154 polypeptide comprising SEQ ID NO 10 for diagnosing a disease selected from the group consisting of a precursor to myeloma, multiple myeloma cancers which produce light chains of kappa-type and/or light chains of lambda-type; aggressive multiple myeloma; refractory multiple myeloma, and drug resistant multiple myeloma, the use comprising detecting in a sample obtained from a subject the presence of a polypeptide and/or an over expressed level of said polypeptide having an amino acid sequence comprising SEQ ID NO: 10 or a fragment thereof; wherein said over expressed level is determined with regard to a normal level of said polypeptide in a corresponding normal tissue. 
     
     
         16 . The use of  claim 15 , wherein said aggressive multiple myeloma comprises primary plasma cell leukemia (PCL). 
     
     
         17 . The use of  claim 15  or  16 , wherein the detection is conducted by immunoassay. 
     
     
         18 . An assay for detecting the presence of a polypeptide having an amino acid sequence consisting essentially of SEQ ID NO: 10 or a fragment thereof in a biological sample, comprising contacting an isolated sample from a subject with an antibody or a fragment that specifically binds to a TMEM154 polypeptide comprising SEQ ID NO: 10, wherein a presence of said polypeptide having said amino acid sequence consisting essentially of SEQ ID NO:10 is indicative of a presence of a disease selected from the group consisting of a precursor to myeloma, multiple myeloma cancers which produce light chains of kappa-type and/or light chains of lambda-type; aggressive multiple myeloma; refractory multiple myeloma, and drug resistant multiple myeloma. 
     
     
         19 . A method for diagnosing a disease selected from the group consisting of a precursor to myeloma, multiple myeloma cancers which produce light chains of kappa-type and/or light chains of lambda-type; aggressive multiple myeloma, refractory multiple myeloma, and drug resistant multiple myeloma, in a subject, comprising detecting in the subject or in a sample obtained from said subject a polynucleotide and/or an overexpressed level of said polynucleotide having a sequence at least 85% homologous to the nucleic acid sequence as set forth in at least one of SEQ ID NOs:57, 1-4, or 41; wherein said overexpressed level is determined with regard to a normal level of said polynucleotide in a corresponding normal tissue. 
     
     
         20 . The method of  claim 19 , wherein diagnosing comprises screening for multiple myeloma in a subject, detecting a presence or a severity of multiple myeloma in a subject, distinguishing multiple myeloma from other diseases, providing prognosis of multiple myeloma, monitoring progression or relapse of multiple myeloma, in a subject, assessment of treatment efficacy or relapse of multiple myeloma, in a subject, selecting a therapy and a treatment for multiple myeloma, in a subject, optimization of a given therapy for multiple myeloma, in a subject, monitoring the treatment of multiple myeloma, in a subject, predicting the suitability of a therapy for specific patients or subpopulations, determining the appropriate dosing of a therapeutic product in patients or subpopulations. 
     
     
         21 . The method or assay of  claims 18 - 20 , wherein said aggressive multiple myeloma comprises primary plasma cell leukemia (PCL). 
     
     
         22 . An siRNA, antisense RNA, or ribozyme that binds the transcript according to any of SEQ ID NOs:57, 1-4, 41, and inhibits its expression, adapted for treatment or diagnosis of multiple myeloma. 
     
     
         23 . The use, method, composition, siRNA, antisense RNA, or ribozyme of any of the above claims, wherein said precursor form of the disease is selected from the group consisting of MGUS (monoclonal gammopathy of undetermined significance), Waldenstrom's macroglobulinemia (WM, also known as lymphoplasmacytic lymphoma) which may proceed to multiple myeloma; smoldering multiple myeloma (SMM), indolent multiple myeloma, and premalignant forms of multiple myeloma which may also proceed to multiple myeloma.