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(12) Patent Application Publication (10) Pub. No.: US 2012/0009177 A1 Platt Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0009177 A1 Platt Et Al US 20120009177A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0009177 A1 Platt et al. (43) Pub. Date: Jan. 12, 2012 (54) GENE EXPRESSION MARKERS FOR Publication Classification PREDICTING RESPONSE TO INTERLEUKIN-6 RECEPTOR-INHIBITING (51) Int. Cl. MONOCLONAL ANTIBODY DRUG A 6LX 39/395 (2006.01) TREATMENT A6IP37/02 (2006.01) C40B 40/06 (2006.01) (75) Inventors: Adam Platt, Congleton (GB); CI2O I/68 (2006.01) Jianmei Wang, Welwyn Garden C40B 30/04 (2006.01) City (GB); Guiyuan Lei, Welwyn Garden City (GB); Laurent Essioux, Attenschwiller (FR): (52) U.S. Cl. .................... 424/130.1; 435/6.12: 435/6.11: Wei-min Liu, Dublin, CA (US); P. 506/9; 506/16 Mickey Williams, Great Falls, VA (US) (73) Assignee: Roche Molecular Systems, Inc., (57) ABSTRACT Pleasanton, CA (US) This invention provides methods, compositions, and kits relating to gene product biomarkers where gene expression (21) Appl. No.: 13/154,158 levels are correlated with therapeutic response of rheumatoid (22) Filed: Jun. 6, 2011 arthritis patients to treatment with an IL-6 receptor antago nist, Such as an IL6-R antibody. The methods, compositions, Related U.S. Application Data and kits of the invention can be used to identify rheumatoid (60) Provisional application No. 61/352.285, filed on Jun. arthritis patients who are likely, or not likely, to respond to 7, 2010. IL-6 receptor antagonist treatments. US 2012/00091 77 A1 Jan. 12, 2012 GENE EXPRESSION MARKERS FOR in some embodiments any one of from 2 to 20, 30, 40, 50, 60. PREDICTING RESPONSE TO 70, 80, or all of the genes set forth in Table 3. INTERLEUKIN-6 RECEPTOR-INHIBITING 0009. In some embodiments, the step of determining the MONOCLONAL ANTIBODY DRUG level of expression of the biomarker gene comprises measure TREATMENT the level of RNA expressed by the marker gene. The amount of RNA expressed may be determined, e.g., using an ampli CROSS-REFERENCE TO RELATED fication area reaction Such as qPCR, or by using a probe array. APPLICATIONS For example, a nucleic acid array forming a probe set may be used to detect RNA expressed of the biomarker gene. RNA 0001. This application claims benefit of U.S. provisional expression levels are typically determined by measuring the application No. 61/352.285, filed Jun. 7, 2010, which is level of cDNA transcribed from the RNA isolated from the herein incorporated by reference for all purposes. patient. RNA expression levels can be determined using known probesets to quantify expression level. As known in BACKGROUND OF THE INVENTION the art, Such probes sets may comprises multiple probes that 0002 Tocilizumab is the first humanized interleukin-6 hybridize to the target sequence of interest. Alternatively, receptor (IL-6R)-inhibiting monoclonal antibody that has expression of a marker gene can be determined by measuring been developed to treat rheumatoid arthritis. As with other the level of expression of a protein encoded by the gene. treatments, the antibody exhibits a range of therapeutic effi 0010. The levels of expression are compared to standard cacy in patients. Thus, there is a need to determine those control data, e.g., the expression data set generated in patients that are more likely to respond positively to treatment Example 1 and 2. An increased level of expression of the with tocilizumab and/or patients that are likely to not respond marker gene or decreased level of expression of the biomarker to treatment. The present invention addresses this need. gene may be determined by using statistical models for deter mining whether expression of the biomarker gene is indica BRIEF SUMMARY OF THE INVENTION tive of therapeutic response of a patient to treatment with an IL-6R antibody such as tocilizumab. In some the invention 0003. The invention is based, in part, on the discovery of provides an electronic device or computer Software that changes in gene expression that are associated with a positive employs the use of a statistical model to determine likelihood therapeutic response to treatment with an agent that modulate of therapeutic responses. IL-6-mediated signal transduction, Such as an anti-IL-6 anti body that inhibits transduction or an IL-6R-inhibiting mono 0011. In some embodiments, the levels of expression of clonal antibody Such as tocilizumab. genes set forth in Table 5 are evaluated to identify rheumatoid 0004 Thus, in one aspect, the invention provides a method arthritis patients that are likely to be responsive, or unrespon of identifying a rheumatoid arthritis patient that is likely to sive, to treatment with an IL-6R antagonist Such as tocili respond to treatment with tocilizumab; or of identifying a Zumab. In typical embodiments, anywhere from 2 to 10, 20, patient that is likely not to respond to treatment with tocili 30, 40, 50, 60, 70, 80, or 90, or all of the genes in column C, Zumab; wherein the method comprises identifying the levels column D, column E. column F. column G, column H. column of expression of a gene set forth in Table 1, Table 2, or Table I, or column J are analyzed to determined likelihood of a 3. Such genes can be identified using a variety of techniques, therapeutic response. including array probe sets and amplification techniques. The level of expression of the marker gene is then compared to the DETAILED DESCRIPTION OF THE INVENTION expression level shown in the data set used to establish a 0012. As used herein, a “positive therapeutic response' or correlation. “therapeutic benefit” refers to an improvement in, and/or 0005. In a further aspect, the invention provides, a kit for delay in the onset of any symptom of rheumatoid arthritis. predicting the therapeutic response of a rheumatoid arthritis 0013 As used herein “negative therapeutic response' patient to a treatment regimen that comprises administration refers to a lack of improvement of one or more symptoms of of an IL-6R antibody such as tocilizumab. In some embodi rheumatoid arthritis. ments, the kit also includes an electronic device or computer 0014. An “interleukin-6 receptor (IL-6R) inhibiting anti Software to compare the marker gene expression level of a body” refers to an antibody to IL-6 receptor where the anti biomarker gene set forth in Table 1, Table 2, or Table 3 from body binds to IL-6 receptor and antagonizes (i.e., inhibits) the patient to a dataset. The endpoint for evaluating therapeu IL-6 receptor activity. An example of Such an antibody is tic response can be any symptom of rheumatoid arthritis, e.g., tocilizumab, a humanized IL-6R monoclonal antibody (see, the endpoints evaluated in Example 1. e.g., Sato et al., Cancer Res 1993:53: 851-6; and U.S. Pat. No. 0006. In some embodiments, the marker gene is any one of 7,479.543) that is used for the treatment of rheumatoid arthri the genes set forth in Table 1. In some embodiments, the tis. marker genes are at least two genes set forth in Table 1. Thus, 0015. In the current invention, a “gene set forth in Table 1 in some embodiments any one of from 2 to 20, 30, 40, 50, 60. refers to the gene that corresponds to the probesets annotated 70, 80, or all of the genes set forth in Table 1. in Table 1. Similarly, a “gene set forth in Tables 2, 3, or 5 0007. In some embodiments, the marker gene is any one of refers to the gene that corresponds to the probesets annotated the genes set forth in Table 2. In some embodiments, the in the respective Table. For Tables 1-3, the “Representative marker genes are at least two genes set forth in Table 2. Thus, Public ID' is listed as the accession number Table 1. The in some embodiments any one of from 2 to 20, 30, 40, 50, 60. “Representative Public ID is the accession number of a 70, 80, or all of the genes set forth in Table 2. representative sequence. For consensus-based probe sets, the 0008. In some embodiments, the marker gene is any one of representative sequence is only one of several sequences (se the genes set forth in Table 3. In some embodiments, the quence Sub-clusters) used to build the consensus sequence in marker genes are at least two genes set forth in Table 3. Thus, the probe set used in the Examples and it is not directly used US 2012/00091 77 A1 Jan. 12, 2012 to derive the probe sequences. The representative sequence is 0021. The expression levels of any gene expression prod chosen during array design as a sequence that is best associ uct of one of the genes set forth in Table 1, Table 2, or Table ated with the transcribed region being interrogated by the 3 may be measured, however, typically expression of multiple probe set. As understood in the art, there are naturally occur genes is assessed. Gene expression levels may be measured ring polymorphisms for many gene sequences. Genes that are using any number of methods known in the art. In typical naturally occurring allelic variations for the purposes of this embodiments, the method involves measuring the level of invention are those genes encoded by the same genetic locus. RNA. RNA expression can be quantified using any method, The proteins encoded by allelic variations of a gene set forth e.g., employing a quantitative amplification method Such as in Table 1, Table 2, or Table 3 typically have at least 95% qPCR. In other embodiments, the methods employ array amino acid sequence identity to one another, i.e., an allelic based assays.
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