医学免疫学课件：AntibodyDrugConjugateApplication

1、The Application of Antibody-Drug Conjugatesin Cancer TherapyHistory of cancer therapyComponents of ADCApplication of ADC OverallAdcetris, Brentuximab vedotinKadcyla, Adotrastuzumab emtansine1234Future and ChallengeCONTENTSHistory of cancer therapyComponents of ADCApplication of ADC OverallAdcetris,

2、Brentuximab vedotinKadcyla, Adotrastuzumab emtansine1234Future and ChallengeCONTENTSHistory孙燕. 肿瘤药物治疗百年回顾与展望J. 中华肿瘤杂志, 2005, 26(11):701-703.HistoryPerez H L, Cardarelli P M, Deshpande S, et al. Antibody-drug conjugates: current status and future directions.J. Drug Discovery Today, 2014, 19(7):869881

3、.History of cancer therapyThe component of ADCThe application of ADC OverallAdcetris, Brentuximab vedotinKadcyla, Adotrastuzumab emtansine1234The future and challengeCONTENTSComponent Question: How to design a ADC?Component-Antibody Tumor specificMaintains binding, stability, internalization, PKMini

4、mal nonspecific bindingComponent-linker 1. Cleavable Linkers：bystander killing2. Non-cleavable Linkers：stable，modified- Stable in circulation- Rapidly intracellular release of drugComponent-drug MechanismCommon Used DrugMicrotubule disruptionDM1,DM4,MMAE,MMAFDNA damageCalicheamicin,duocarmicin,SN-38

5、,D6.5,PDB dimersTranscriptional inhibitorAmnitinConjunction strategiesRandom conjugation：heterogeneousSite-specific Conjugation：homogeneousAnswer: How to design a ADC?History of cancer therapyThe component of ADCThe application of ADC OverallAdcetris, Brentuximab vedotinKadcyla, Adotrastuzumab emtan

6、sine1234The future and challengeCONTENTSApplicationPolakis P. Antibody Drug Conjugates for Cancer Therapy .J. Pharmacol Rev. 2016 Jan;68(1):3-19ApplicationPhase I : 24Phase I/II : 10Phase III : 1Approved: 2Discontinued: 18Reason of discontinued: Lack of antitumor response Unacceptable toxicity Chang

7、e in company strategyJackson D, Stover D. Using the Lessons Learned From the Clinic to Improve the Preclinical Development of Antibody Drug Conjugates.J. Pharmaceutical Research, 2014:1-12Brentuximab vedotin(Adcetris)CD30-Positive Hodgkins lymphoma and anaplastic large-cell lymphomaCD30-specific mon

8、oclonal antibody enzyme-cleavable linkerantitubulin agent monomethyl auristatin E (MMAE) producing the antibodydrug conjugate brentuximab vedotin(SGN-35)In August 2011, got FDA approval Anas Y, Bartlett N L, Leonard J P, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas.J. New

9、 England Journal of Medicine, 2010, 363(19):1812-1821Current status of Hodgkins lymphoma Autologous hematopoietic stem-cell transplantation (ASCT) is only effective in approximately 50% of such patientsApproximately 15 to 30% of patientswith Hodgkins lymphoma do not have along-term remission with co

10、nventional therapyAmong those who have a relapse after ASCT, overall survival is 55% at 2 years and 32% at 5 years.Anas Y, Bartlett N L, Leonard J P, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas.J. New England Journal of Medicine, 2010, 363(19):1812-1821The mechanismSente

11、r P D, Sievers E L. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma.J. Nature Biotechnology, 2012, 30(7):631-637Ashley M. Newland Pharm.D, Jenny X L P D, Lindsey E W P D, et al. Brentuximab vedotin: a CD30-directed

12、 antibody-cytotoxic drug conjugate.J. Pharmacotherapy, 2013, 33(1):93-104Adverse eventsfatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheralneuropathyThe result of phase 2 trialTumor reductions were observed in 94% of the 102 enrolled Hodgkin lymphoma patients and the ORR was 75%.The resul

13、t of another phase 2 trialA reduction from baseline in tumor size was found in 56 patients (97%)The result of phase 3 trial (published in lancet on March, 2015)Consolidation therapy with brentuximab vedotin might increase the possibility of cure or potentially avoid exposure to subsequent toxic ther

14、apies, and seems to be effective in this young cancer population with high unmet need.Clinical trial 1,000 times selectiveAdo-trastuzumab emtansine (Kadcyla)HER2-Positive Advanced Breast Cancerthe humanized monoclonal antibody trastuzumab Cytotoxic maytansinoid DM1 the stable thioether linker 4-N-ma

15、leimidomethyl-cyclohexane-1-carbonyl (MCC)In 2013, got FDA approvalSunil V, David M, Luca G, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer.J. New England Journal of Medicine, 2012, 367(19):1783-1791.The second leading cause of cancer-related death 232 670 new cases in women w

16、ith 40 000 breast-cancer-related deaths in 2014. up to 5% with metastatic disease.20% to 30% of with relapse.Current status of Breast cancer Various biological markers estrogen and progesterone receptors human epidermal growth factor receptor 2 HER2The mechanism（Similar to Adcetris）Step1. Guide:Rast

17、uzumab component guides the ADC to HER2-overexpressing cancer cellsStep2. EndocytosisStimulation of cellular endocytosis of the receptor-ADC complexStep3. DegradationBe internalized and undergoes lysosomal proteolytic degradationStep4. Drug releaseYield the active metabolite lysine-MCC-DM1Step5. Act

18、ionDisrupts the cell cycle during the G2-M phase Causes apoptosisMoreoverdemonstrating in vitro activity against trastuzumab-resistant tumorsClinical trial T-DM1 significantly prolonged progression-free and overall survival in patients with HER2-positive advanced breast cancer previously treated wit

19、h trastuzumab(曲妥单抗)and a taxane.Less toxicity than lapatinib plus capecitabine Determination of its use in combination with pertuzumab(帕妥珠单抗) is on the wayHistory of cancer therapyThe component of ADCThe application of ADC OverallAdcetris, Brentuximab vedotinKadcyla, Adotrastuzumab emtansine1234The

20、future and challengeCONTENTSFuture and challengeAntibodymore specific to tumor cellConjugationsite-specific conjugation modalitiesLinkeroptimization of linkers with balanced stability Agentsidentification of novel, potent cytotoxic agentsReferencePerez H L, Cardarelli P M, Deshpande S, et al. Antibo

21、dy-drug conjugates: current status and future directions.J. Drug Discovery Today, 2014, 19(7):869881.Senter P D, Sievers E L. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma.J. Nature Biotechnology, 2012, 30(7):631

22、-637.Ashley M. Newland Pharm.D, Jenny X L P D, Lindsey E W P D, et al. Brentuximab vedotin: a CD30-directed antibody-cytotoxic drug conjugate.J. Pharmacotherapy, 2013, 33(1):93-104.Moskowitz C H, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell tr

23、ansplantation in patients with Hodgkins lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial.J. Lancet, 2015, 385(9980):1853-1862.Anas Y, Bartlett N L, Leonard J P, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas

24、.J. New England Journal of Medicine, 2010, 363(19):1812-1821.ReferenceBradley A M, Devine M, Deremer D. Brentuximab vedotin: An anti-CD30 antibody-drug conjugateJ. American Journal of Health-System Pharmacy, 2013, 70(7):589-597.Jackson D, Stover D. Using the Lessons Learned From the Clinic to Improve the Preclinical Development of Antibody Drug Conjugates.J. Pharmaceutical Research, 2014:1-12.Polakis P. Antibody Drug Conjugates for Cancer Therapy .J. Pharmacol Rev. 2016 Jan;68(1):3-19 Beverly A. Teicher, Ph.D., and James H. Doroshow. The Promise of AntibodyDrug Conjugates .J. N