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