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(19) TZZ¥__T (11) EP 3 178 848 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 14.06.2017 Bulletin 2017/24 C07K 16/28 (2006.01) A61K 39/395 (2006.01) C07K 16/30 (2006.01) (21) Application number: 15198715.3 (22) Date of filing: 09.12.2015 (84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AL AT BE BG CH CY CZ DE DK EE ES FI FR GB yet been filed GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Cueni, Leah Noëmi et al Designated Extension States: F. Hoffmann-La Roche AG BA ME Patent Department Designated Validation States: Grenzacherstrasse 124 MA MD 4070 Basel (CH) (71) Applicant: F. Hoffmann-La Roche AG 4070 Basel (CH) (54) TYPE II ANTI-CD20 ANTIBODY FOR REDUCING FORMATION OF ANTI-DRUG ANTIBODIES (57) The present invention relates to methods of treating a disease, and methods for reduction of the formation of anti-drug antibodies (ADAs) in response to the administration of a therapeutic agent comprising administration of a Type II anti-CD20 antibody, e.g. obinutuzumab, to the subject prior to administration of the therapeutic agent. EP 3 178 848 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 178 848 A1 Description Field of the Invention 5 [0001] The present invention relates to methods of treating a disease, and methods for reduction of the formation of anti-drug antibodies (ADAs) in response to the administration of a therapeutic agent. Background 10 [0002] The number of biotechnology-derived therapeutic agents available for use in clinical settings has dramatically increased in recent years, and includes recombinant human cytokines (e.g. α and β interferon, interleukin-2), cellular growth factors (e.g. GM-CSF), hormones (e.g. glucagon), neuromuscular antagonists (e.g. botulinum toxin), blood prod- ucts (e.g. clotting factor VIII), recombinant receptors (e.g. etanercept) and monoclonal antibodies. Although therapeutic proteins are generally considered safe and non-toxic, antibodies against these therapeutic agents, known as anti-drug 15 antibodies (ADAs), can develop during treatment. [0003] ADAs have been observed in connection with various therapeutic agents, such as erythropoietin, factor VIII , insulin, immunotoxins and monoclonal antibodies (Schellekens and Casadevall, J Neurol (2004), 251 [Suppl 2]:II/4-II/9; Mossoba et al., Clin Cancer Res (2011) 17(11): 3697-3705; Hsu et al., British Journal of Dermatology (2014) 170, 261-273). ADA formation is frequent for example in autoimmune patients treated with TNF blockers and impacts clinical 20 outcome (Schaeverbecke et al., Rheumatology (2015) doi: 10.1093/rheumatology/kev277). [0004] The developmentof ADAs may influence serum concentrations and functionof therapeuticagents. The presence of ADAs may increase clearance of the therapeutic agent through formation of immune complexes between therapeutic agent and antibody (neutralizing, non-neutralizing or both), thus reducing the therapeutic agent’s half-life. Furthermore, the activity and effectiveness of the therapeutic agent may be decreased through binding of antibody to the therapeutic 25 agent. ADAs can also be associated with allergic or hypersensitivity reactions and other adverse events. [0005] Since these adverse events associated with immune responses can influence the safety and efficacy profile of therapeutics, identification and development of strategies to overcome or inhibit ADAs is of great interest. [0006] Several protein engineering approaches have been investigated to reduce the immunogenicity of protein ther- apeutics, including for example masking or alteration of protein B cell epitopes or modification of protein T cell epitopes. 30 However, clinical safety and success of these approaches has not been tested and will require a significant degree of time to evaluate. Therefore, there exists an immediate need to develop new interventions using FDA-approved reagents to prevent ADA responses. [0007] Chemotherapy-based approaches aimed at host immune suppression have been reported (Mossoba et al., Clin Cancer Res (2011) 17(11): 3697-3705). 35 [0008] The anti-CD20 antibody rituximab has been used in combination with methotrexate and intravenous immune globulin to achieve tolerance to enzyme replacement therapy in a Morbus Pompe patient (Mendelsohn et al., NEJM (2009) 360:2, 194-195). However, in a clinical trial, host pretreatment with rituximab did not inhibit the human immune response against the immunotoxin LMB-1 (Hassan et al., Clin Cancer Res (2004) 10, 16-18). 40 Summary of the Invention [0009] The present invention is based on the surprising finding that the formation of ADAs in response to administration of an immunogenic therapeutic agent to a subject can effectively and sustainably be prevented by pre-treatment of said subject with a Type II anti-CD20 antibody, such as obinutuzumab. 45 [0010] Accordingly, in a first aspect the present invention provides a method for reducing the formation of anti-drug antibodies (ADAs) against a therapeutic agent in a subject, comprising administration of an anti-CD20 antibody to the subject prior to administration of the therapeutic agent. In one embodiment the period of time between the administration of the anti-CD20 antibody and administration of the therapeutic agent is sufficient for reduction of the number of B-cells in the subject in response to the administration of the CD20 antibody. 50 [0011] In a further aspect, the invention provides a method of treating a disease in a subject, the method comprising a treatment regimen comprising (i) administration to the subject of a Type II anti-CD20 antibody, and consecutively after a period of time 55 (ii) administration to the subject of a therapeutic agent, wherein the period of time between the administration of the anti-CD20 antibody and the administration of the therapeutic agent is sufficient for reduction of the number of B-cells in the subject in response to the administration of the CD20 2 EP 3 178 848 A1 antibody. In one embodiment, the treatment regimen effectively reduces the formation of anti-drug antibodies (ADAs) in the subject in response to the administration of the therapeutic agent as compared to a corresponding treatment regimen without the administration of the anti-CD20 antibody. 5 [0012] In a further aspect, the invention provides a Type II anti-CD20 antibody for use in a method for reducing the formation of anti-drug antibodies (ADAs) against a therapeutic agent in a subject, comprising administration of the anti- CD20 antibody to the subject prior to administration of the therapeutic agent. In one embodiment, the period of time between the administration of the anti-CD20 antibody and administration of the therapeutic agent is sufficient for reduction of the number of B-cells in the subject in response to the administration of 10 the CD20 antibody. [0013] In a further aspect, the invention provides a Type II anti-CD20 antibody for use in a method of treating a disease in a subject, the method comprising a treatment regimen comprising (i) administration to the subject of the anti-CD20 antibody, 15 and consecutively after a period of time (ii) administration to the subject of a therapeutic agent, wherein the period of time between the administration of the anti-CD20 antibody and the administration of the therapeutic agent is sufficient for reduction of the number of B-cells in the subject in response to the administration of the CD20 20 antibody. In one embodiment, the treatment regimen effectively reduces the formation of anti-drug antibodies (ADAs) against the therapeutic agent in the subject (in response to the administration of the therapeutic agent) as compared to a corre- sponding treatment regimen without the administration of the anti-CD20 antibody. [0014] In a further aspect, the invention provides the use of a Type II anti-CD20 antibody in the manufacture of a 25 medicament for reduction of the formation of anti-drug antibodies (ADAs) against a therapeutic agent in a subject, wherein the medicament is to be used in a treatment regimen comprising (i) administration to the subject of the anti-CD20 antibody, and consecutively after a period of time 30 (ii) administration to the subject of a therapeutic agent, wherein the period of time between the administration of the anti-CD20 antibody and the administration of the therapeutic agent is sufficient for reduction of the number of B-cells in the subject in response to the administration of the CD20 antibody. 35 In one embodiment, the treatment regimen effectively reduces the formation of anti-drug antibodies (ADAs) against the therapeutic agent in the subject as compared to a corresponding treatment regimen without the administration of the anti-CD20 antibody. [0015] In still a further aspect, the invention provides a kit for the reduction of the formation of anti-drug antibodies (ADAs) against a therapeutic agent in a subject, comprising a package comprising a Type II anti-CD20 antibody com- 40 position and instructions for using the anti-CD20 antibody composition in a treatment regimen comprising (i) administration to the subject of the anti-CD20 antibody composition, and consecutively after a period of time (ii) administration to the subject of a therapeutic agent, 45 wherein the period of time between the administration of the anti-CD20 antibody composition and the administration of the therapeutic agent is sufficient for reduction of the number of B-cells in the subject in response to the administration of the CD20 antibody.
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