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THETWO TONTTI USTUDIUL 20170267753A1 LUI HI HA UNIT ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017 /0267753 A1 Ehrenpreis (43 ) Pub . Date : Sep . 21 , 2017 ( 54 ) COMBINATION THERAPY FOR (52 ) U .S . CI. CO - ADMINISTRATION OF MONOCLONAL CPC .. .. CO7K 16 / 241 ( 2013 .01 ) ; A61K 39 / 3955 ANTIBODIES ( 2013 .01 ) ; A61K 31 /4706 ( 2013 .01 ) ; A61K 31 / 165 ( 2013 .01 ) ; CO7K 2317 /21 (2013 . 01 ) ; (71 ) Applicant: Eli D Ehrenpreis , Skokie , IL (US ) CO7K 2317/ 24 ( 2013. 01 ) ; A61K 2039/ 505 ( 2013 .01 ) (72 ) Inventor : Eli D Ehrenpreis, Skokie , IL (US ) (57 ) ABSTRACT Disclosed are methods for enhancing the efficacy of mono (21 ) Appl. No. : 15 /605 ,212 clonal antibody therapy , which entails co - administering a therapeutic monoclonal antibody , or a functional fragment (22 ) Filed : May 25 , 2017 thereof, and an effective amount of colchicine or hydroxy chloroquine , or a combination thereof, to a patient in need Related U . S . Application Data thereof . Also disclosed are methods of prolonging or increasing the time a monoclonal antibody remains in the (63 ) Continuation - in - part of application No . 14 / 947 , 193 , circulation of a patient, which entails co - administering a filed on Nov. 20 , 2015 . therapeutic monoclonal antibody , or a functional fragment ( 60 ) Provisional application No . 62/ 082, 682 , filed on Nov . of the monoclonal antibody , and an effective amount of 21 , 2014 . colchicine or hydroxychloroquine , or a combination thereof, to a patient in need thereof, wherein the time themonoclonal antibody remains in the circulation ( e . g . , blood serum ) of the Publication Classification patient is increased relative to the same regimen of admin (51 ) Int . Cl. istration of the monoclonal antibody but without the co COOK 16 / 24 ( 2006 .01 ) administration of the effective amount of colchicine and /or A61K 31 /4706 ( 2006 .01 ) hydroxychloroquine. Further disclosed are therapeutic com A61K 31 / 165 ( 2006 . 01 ) binations, and kits containing the monoclonal antibodies and A61K 39 /395 ( 2006 .01 ) hydroxychloroquine and / or colchicine . US 2017 /0267753 A1 Sep . 21, 2017 COMBINATION THERAPY FOR [ 0004 ] It is therefore of high importance to develop meth CO -ADMINISTRATION OF MONOCLONAL ods to prevent ADA development in patients receiving ANTIBODIES biologic therapy that are safer than those that are currently in practice . CROSS -REFERENCE TO RELATED APPLICATIONS SUMMARY [0005 ] Broadly , the present invention is based on the [0001 ] This application is a continuation - in - part of U . S . unexpected discovery that colchicine and hydroxychloro patent application Ser . No . 14 / 947, 193 , filed Nov . 20 , 2015 , quine increase the time that a monoclonal antibody remains which claims the benefit of U . S . Provisional Application No . in the circulation or circulatory system ( e . g . , blood serum ) of 62 /082 ,692 , filed Nov. 21 , 2014 . The disclosures of each of a patient by reducing the clearance of the monoclonal these are incorporated herein by reference in their entireties antibody from the body . The co - administration of colchicine for all purposes. and hydroxychloroquine and a monoclonal antibody thus increase the clearance time ofmonoclonal antibody from the BACKGROUND body . Unlike known and conventional attempts to increase the effectiveness of monoclonal antibody therapies by pre 10002 ] Monoclonal antibodies have been developed for venting the formation of HACAs and other anti -drug anti the treatment of a variety of conditions including autoim bodies ( such as immunosuppression ) , the present invention mune disorders , cancer , asthma, hypercholesterolemia and may mitigate or even eliminate one of more of these sepsis . The development of therapeutic monoclonal antibod drawbacks . ies in these areas of medicine has progressed at a rapid pace . [0006 ] Accordingly , a first aspect of the present invention The number of new biologic agents that have been approved is directed to a method for enhancing the efficacy of mono by the Food and Drug Administration (FDA ) each year has clonal antibody therapy , which entails co -administering a quadrupled between 2004 and 2008 . This relatively new therapeutic monoclonal antibody , or a functional fragment class of medications has resulted in marked improvement in thereof, and an effective amount of colchicine or hydroxy a number of patients with complex and potentially life chloroquine , or a combination thereof, to a patient in need threatening conditions , and in some cases , they have thereof. replaced traditional small molecule pharmaceuticals as treat 10007 ] A related aspect of the present invention is directed ments of choice . These medications also accounted for to a method of prolonging or increasing the time a thera approximately 17 % of total global spending on medicines in peutic monoclonal antibody remains in the circulation or 2016 with an overall market value of $ 200 billion . circulatory system of a patient, which entails co -adminis [ 0003 ] An important influence on the utility of biologic tering an effective amount of a therapeutic monoclonal therapy in an individual patient is the development of antibody, or a functional fragment thereof, and an effective anti - drug antibodies ( ADA ) . ADAs have been documented amount of colchicine, hydroxychloroquine , or a combina in patients receiving multiple doses of a variety monoclonal tion thereof, to a patient in need thereof. Clearance time of antibodies , including infliximab ( IFX ) , a treatment for the monoclonal antibody from the circulation ( e . g . , blood inflammatory bowel disease , rheumatoid arthritis , psoriatic serum ) of the patient is increased relative to the same arthritis and other autoimmune diseases . The development regimen of administration of the monoclonal antibody but of ADAs to IFX , as well as other monoclonal antibodies, is without the co -administration of the effective amount of associated with systemic reactions that can occur during or colchicine and /or hydroxychloroquine . within a few days of drug infusion . When severe , they can [0008 ] Another aspect of the present invention is directed require discontinuation of biologic therapies . In addition , a to a therapeutic combination , which includes a therapeuti number of studies have shown that ADAs reduce the efficacy cally effective amount of a monoclonal antibody, and an of biologic therapy. From a pharmacokinetic standpoint, effective amount of colchicine or hydroxychloroquine , or a ADAs have been shown to enhance the clearance of biologic combination thereof. medications . Strategies that have been developed to prevent [0009 ] A further aspect of the present invention is directed ADA formation and their negative effect on the efficacy of to a kit , which includes a therapeutic combination , which biologic therapies include adherence to consistent timing of includes a therapeutically effective amount of a monoclonal drug infusions or subcutaneous injection regimens, and the antibody , and an effective amount of colchicine or hydroxy co - administration of oral immunomodulating medications chloroquine , or a combination thereof. The kit may include such as thiopurines (azathioprine or its precursor agent both agents in a single dosage form or in separate dosage 6 -mercaptopurine ) , and methotrexate . Although studies have forms, in which case the respective dosage forms may be shown that this strategy of co -administration of the afore disposed in separate containers in the kit . The kit may further mentioned immunomodulating agents reduces ADA produc include printed instructions for using the therapeutic com tion , rapid clearance of biologic agents and infusion reac bination to practice the methods described herein . tions, patients on both classes of drugs may become further [0010 ] In some embodiments of these aspects of the immunosuppressed , placing them at increased risk for present invention , the monoclonal antibody is chronically opportunistic infections, tuberculosis , overwhelming fungal administered ( over a prolonged period of time) such as in the infections and a variety of cancers . In fact, hepatosplenic case of treatment of auto - immune diseases , e . g . , monoclonal T - cell lymphoma, a rare , deadly cancer seen primarily in antibodies that target ( and thus inhibit ) TNF - a , such as young males with Crohn ' s disease , has only been described adalimumab , certolizumab pegol, golimumab , and inflix in patients receiving monoclonal antibodies (MAD ) against imab . tumor necrosis factor alpha ( TNF - a ) in combination with 0011 ] Hydroxychloroquine has a long history of use as an thiopurine drugs . anti -malarial drug . Clinical studies have shown that US 2017 /0267753 A1 Sep . 21, 2017 hydroxychloroquine is not effective as a treatment for IBD , decreasing the removal of the monoclonal antibody from the cancer, Clostridium infection , sepsis ( except due to malaria ), circulation . It is also believed that hydroxychloroquine asthma or hyperchloresterolemia . Hydroxychloroquine is raises lysosomal pH , which causes disruption of lysososmal used as a disease -modifying anti - rheumatic drug in the function such as processing of antigens ( such as monoclonal treatment of rheumatoid arthritis and is commonly employed proteins ) and antigen presentation to mononuclear cells . as treatment for systemic lupus erythematosis . Thus , hydroxychloroquine is effective treatment for several disor ders . However, its specific
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  • WO 2010/142752 Al

    WO 2010/142752 Al

    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 16 December 2010 (16.12.2010) WO 2010/142752 Al (51) International Patent Classification: nia 94568 (US). ROBARGE, Kirk D. [US/US]; 1679 C07D 213/75 (2006.01) Λ61K 31/4439 (2006.01) 27th Avenue, San Francisco, California 94122 (US). C07D 401/12 (2006.01) A61K 31/444 (2006.01) STANLEY, Mark S. [US/US]; 284 Lauren Avenue, A61K 31/506 (2006.01) A61P 37/04 (2006.01) Pacifica, California 94044 (US). TSUI, Vickie Hsiao- A61K 31/495 (2006.01) Wei [US/US]; 2626 Martinez Avenue, Burlingame, Cali fornia 94010 (US). WILLIAMS, Karen [GB/GB]; 8/9 (21) International Application Number: Spire Green Centre, Flex Meadow, Harlow, Essex CM 19 PCT/EP2010/058128 5TR (GB). ZHANG, Birong [US/US]; 3060 San Andreas (22) International Filing Date: Drive, Union City, California 94587 (US). ZHOU, Aihe 10 June 2010 (10.06.2010) [US/US]; 1361 Stephen Way, San Jose, California 95129 (US). (25) Filing Language: English (74) Agent: KLOSTERMEYER-RAUBER, Doerte; Gren- (26) Publication Language: English zacherstrasse 124, CH-4070 Basel (CH). (30) Priority Data: (81) Designated States (unless otherwise indicated, for every 61/186,322 11 June 2009 ( 11.06.2009) US kind of national protection available): AE, AG, AL, AM, (71) Applicant (for all designated States except US): F. AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, HOFFMANN-LA ROCHE AG [CWCH]; Grenzacher- CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, strasse 124, CH-4070 Basel (CH).