10 장. 항체의약품 바이오의약품의실제 단클론항체의약품 미생물면역학전공 (youhee@cha.ac.kr)
2 공부할내용 중요의약품명상품명타겟항원적응증 Adalimumab Humira TNF α 관절염, 척추염, 크론병 Infliximab Remicade TNF α 관절염, 척추염, 크론병 Rituximab Rituxan CD20 비호지킨성림프종 Bevacizumab Avastin VEGF A 전이성대장암 / 직장암, 폐암 Ranibizumab Lucentis VEGF A (Bevacizumab 의 Fab) 습성노인황반변성 (AMD) Trastuzumab Herceptin HER 2/Errb2 (EGFR) 전이성유방암 Cetuximab Erbitux EGFR 전이성직결장암, 편평세포암 Natalizumab Tysabri α4 인테그린다발성경화증 (MS) Omalizumab Xolair IgE 알러지 Palivizumab Synagis RSV 의 F 단백질 RSV 감염 Basiliximab Simulect CD25 (IL 2R) 면역억제 Daclizumab Zenapax CD25 (IL 2R) 면역억제 Alemtuzumab CamPath CD52 면역억제 Muromonab CD3 Orthoclone OKT3 CD3 면역억제? Eculizumab Soliris C5 ( 보체 ) 발작성야간헤모글로빈뇨증 암기자료
3 Monoclonal Antibody Technology hybridomas overcome some of limitations of antisera as a source of antibodies used to produce monoclonal antibodies (mab) recognize one epitope potential for numerous biomedical applications most of current applications involve in vitro diagnostic testing ti and research mab production 미생물학 2. 면역반응의조절 : 단클론항체 (mab)
4 Optimization and humanization of mab 항원결합부위최적화 고도의친화성과선택성을갖는인간유래가변부위 Human scfv phage display library 인간유래가변부위 (Fv) 를 PCR 로증폭 15 aa linker 로두가변부위를연결 (single chain Fv) scfv 를 M13 piii 에융합하여 M13 합성특정항원과결합하는 M13 클론을선별선별된 scfv 두부분을각각인간항체유전자에삽입 항체의약품의최적화기술 (PDL)
5 Induction Theory: Antibodies The most intense therapy, when alloimmune response is greatest Induce tolerance Provide background immunosuppression during immediate post op period, while renal function stabilizes Use antibodies against cell surface receptors Anti thymocyte IgG = ATG (eatg/atgam, ratg/thymoglobulin) Basiliximab (CD25), Daclizumab (CD25), Alemtuzumab (CD52) cf. These are also used for leukemia Antibody mediated signal blockage leads to hyper activation of immune signalings, eventually resulting in immune tolerance cf. Antibodies from mouse contain Muro in their names. Humanized/chimeric antibodies contain ZU/XI in their names less antigenicity, longer half life T 세포의과활성화를통한면역관용유도
6 Humanized/Chimeric Antibodies Why humanization? 안정성증가 부작용감소 HAMA reaction (human anti mouse IgG antibody): 관절부종, 발진, 신부전등 75% >90% 83% 100% 항체의약품의특징
7 Humanized/Chimeric Antibodies Absolute difference (95% CI) Half life Ref. Daclizumab (90% human) 16% ( 24% to 8%) 30 days NEJM. 1998 Transpl.1999 Basiliximab 14% 7 days Lancet. 1997 (75% human) ( 20% to 9%) Transpl.1999 Transpl. 2001 Biopsy confirmed acute rejection 항체의약품의특징
8 Humanized/Chimeric Antibodies Advantages High efficacy reduce renal rejection rates by approx 30% in classic triple therapy Short courses IV, in hospital only Compliance guaranteed Few adverse effects Severe re exposure hypersensitivity observed Disadvantages Cost But cost effective to add basiliximab to ciclosporin regimens (NICE TA 99) Same report states that should not be added to tacrolimus regimens. Discomfort Daclizumab is a 5 dose, fortnightly regimen & requires infusion 항체의약품의특징
9 Basiliximab and Daclizumab Simulect and Zenapax mab against the α chain (CD25) of the IL 2R 적응증 : 신장이식환자에서의급성거부반응예방 (20 mg every 4 days) : Cyclosporine 대체및병용요법 cf. Zenapax has been discontinued completely (January 2009) 면역억제제
10 Alemtuzumab Campath, MabCampath or Campath 1H A new mab binding to CD52, present on the mature lymphocytes, but not on the stem cells. (even on monocytes and DCs) used for chronic lymphocytic leukemia (CLL), cutaneous T cell lymphoma (CTCL) and T cell lymphoma. Also used for transplantation (BM, kideny etc) Also used for treatment of MS. A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus (CMV). 면역억제제
11 Muromonab-CD3 Orthoclone OKT3 the first monoclonal antibody (mab) FDA approved for human use (1986). Indications : 신장, 심장및간이식환자에서의급성거부반응의치료 : 투여후수시간내 CD3 림프구 (thymocytes) 수가급격히감소 ( 치료중지후 48 시간후에정상으로돌아옴 ) Unlike basiliximab and daclizumab, it is not approved for prophylaxis of transplant rejection, although h a 1996 review has found it to be safe for that. It has also been investigated for use in treating T cell acute lymphoblastic leukemia (ALL). 면역억제제
12 Rituximab Rituxan and MabThera A new mab against CD20 primarily found on B cells (a new horizon!) Used to treat diseases characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells. cf. Various mabs targeting CD20 have been being tested. 면역억제제, 골수암치료제
Rituximab 면역억제제, 골수암치료제
Rituximab 최초로승인된암치료용단클론항체 B 세포표면의 CD20 항원과결합하는카이메릭단클론항체 (Chimeric mab) 적응증 : B 세포비호지킨성림프육종 CD20? B 세포비호지킨성림프육종세포에서 90% 이상발현조혈줄기세포, pro B 세포, 정상혈장세포, 기타정상세포에는존재하지않음 (pre B, mature B 세포에일부발현 ) 작용기작 항체의존성세포독성 (ADCC) 보체의존성세포독성 (CDC) Direct lysis/apoptosis? 면역억제제, 골수암치료제
15 Adalimumab Humira "human mab in rheumatoid arthritis PDL 기술로탄생한최초의 umab b (100% human) mab against the TNF α (inflammation especially in autoimmune diseases) 적응증 : 활성류마티스성관절염, 건성관절염, 크론병 (Crohn s disease) : MTX에비해탁월 may increase the risk of infections. Monthly cost is ~$1,662, similar to that of Enbrel. cf. $13~85 (MTX) 염증억제 (RA, 척추염, 크론병 )
16 Infliximab Remicade mab against the TNF α 적응증 : 활성류마티스성관절염, 건성관절염, 크론병 (Crohn s disease) Yearly cost is ~$19,000~22,000, similar to that of Humira or Enbrel. 염증억제 (RA, 척추염, 크론병 )
17 Bevacizumab Avastin mab against VEGF A involved in the growth of new blood vessels the first clinically available, angiogenesis inhibitor in the US 적응증 : 전이성대장암, 직장암, 폐암 FDA approved in 2004, for combination use with standard chemotherapy for metastatic colon cancer. 전이성대장암치료제
18 Ranibizumab Lucentis mab Fab fragment from Bevacizumab against the α chain (CD25) of the IL 2R 적응증 : 습성노인성망막변성 (AMD), a common form of age related vision loss. Ranibizumab typically costs $2,000 a dose, while the equivalent dose of bevacizumab typically costs $100. http://www.youtube.com/watch?v=hegkpe9mteg 습성노인황반변성 (AMD) 치료제
19 Trastuzumab http://www.herceptin.com 전이성유방암치료제
20 Trastuzumab Herceptin mab against the outside of the HER 2/neu, receptor kinase that binds to EGF etc cf. HER 2 = human EGF receptor 2 적응증 : 전이성 (late stage) 유방암및난소암 ( 유방암및난소암세포는약 25~30% 가 HER 2/neu를과발현 ) : 항체의존성세포매개세포독성 (ADCC) 로작용 being studied for the treatment of other cancers that overexpress HER 2/neu. 전이성유방암치료제
21 Cetuximab Erbitux mab against the EGFR 적응증 : 전이성직결장암 (Ras 는정상 ), 머리및목의세포종 : 통상적으로 combination therapy 를시행 ($30,000 for 8 week program) 전이성직결장암, 편평세포암치료제
22 Natalizumab Tysabri mab against the cell adhesion molecule α4 integrin believed to work by reducing the ability of inflammatory immune cells to attach to and pass through hthe cell layers lining i the intestines ti and dblood brain b barrier 적응증 : 다발성경화증 (monotherapy), 크론병 approved in the US (2004) withdrawn due to 3 cases of progressive multifocal leukoencephalopathy (PML) when administered in combination with IFN β returned to the US market (2006) under a special prescription program. under DR for cancer treatment 다발성경화증 (MS) 치료제
23 Omalizumab Xolair mab against both the IgE (free) and the mige (membrane bound) It does not bound to IgE already bound by the high affinity IgE receptor (FcεRI) 적응증 : 대기앨러지원 (aeroallergen) 에대한알러지 : especially for moderate to severe allergic asthma, which does not respond to high doses of corticosteroids. its first of such approval in Australia (2002), EU and USA (2014). 알러지치료제
24 Palivizumab http://www.synagis.com
25 Palivizumab Synagis mab against the A epitope of the RSV (respiratory syncytial virus) F protein, which is required for the entry into the cells. 적응증 : 조산, 선천성심장질환, 폐기관지이형증등의이유로 RSV 감염위험이높은소아에게사용 RSV 감염예방제
26 Bianca s Battle http://biancasbattle.com/ PNH/aHUS 치료제
27 PNH, an ahus Paroxysmal nocturnal hemoglobinuria aka. Marchiafava Micheli syndrome a rare, acquired, life threatening disease as an atypical hemolytic uremic syndromes (ahus) characterized by RBC destruction ti by the complement system. due to a defect in the formation of surface proteins via glycophosphatidylinositol (GPI) on the RBC, which normally function to inhibit such immune reactions. PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (i.e. deficiency of GPI etc.). Allogeneic bone marrow transplantation is the only curative therapy, but has significant rates of both mortality and ongoing morbidity. PNH( 야간발작성헤모글로빈뇨증 )/ahus( 비정형용혈요독증후군 ) 치료제
28 Eculizumab Soliris mab against C5, inhibiting C5 cleavage developed by Alexion Pharmaceuticals to treat PNH and ahus as well approved for PNH (2007) and ahus (2011) in EU and US (the only and an orphan drug) effective at reducing the need for blood transfusions and improving quality of life. considered to be the most expensive drug in the world (~ 430,000 or $440,000/year) currently being investigated as a potential treatment for other rare disorders associated with the complement system. PNH( 야간발작성헤모글로빈뇨증 )/ahus( 비정형용혈요독증후군 ) 치료제