高福2017长沙计算生物学会议

1、精准医疗与肿瘤免疫治疗 高 福 院士 团队 谭曙光 2017-4-22 长沙，湖南 Herman Eisen(19182014) 美国科学院院士 1. Thebalancebetweenspecificityanddegeneracyofantigen recognitiondeterminestheoutcomeofimmuneresponse 2. Bindingaffinityversusepitopedensity 中医“阴阳”对免疫学基础理论的重新认识 3 Yin and yang in immune systembalance is the key ImmunotherapyCan

2、cers Achilles Heel 2011 Cell. Douglas Hanahan et al. Cancer immunotherapy has got a boost in clinical science 2014 Mechanisms involved in tumor microenvironment (TEM) -driven immune suppression 1. Blockade of T cell recruitment to TEM by abnormal expression of chemokines or tumor vasculature ; 2. Up

3、-regulated PD-L1 expression on cancer cells and up-regulated PD-1 on T cells caused the exhaustion of anti- cancer T cell activity; 3. Exhaustion of T cell function through the aberrant production of Metabolites. 5. Cancer- associated fibroblasts mediated Tcell trapping and CXCL12-regulated T cell e

4、xclusion. 4. B cells autoantibody production and suppression of CD8 cells. 2015 Science. Johanna A. Joyce,et al. Modulating anti-tumor immunity 2016 Cell. A. Karolina Palucka et al. Tumor immunotherapy uImmune checkpoint antibody (PD-1, PD-L1, CTLA-4.) uCAR-T uT-cell receptor (NY-ESO-1) 8 History of

5、 immune checkpoint therapy Simple engagement of pMHC and TCR is insufficient for T cell activation. 1980s Costimulatory signals were essential for T cell activation but most tumors do not express costimulatory molecules Clinical success: 1.Anti-CTLA-4: phase III clinical trials with anti- CTLA-4 in

6、melanoma: improved overall survival and 20% patients living 4 years; 2.Anti-PD-1/PD-L1: A phase III trail showed response rate of 30-40% and overall survival rate was 72.9% for nivolumab. T cell priming elicits a parallel program that will eventually stop the response, the CTLA-4 (1994,1995) and PD-

7、1/PD- L1 (2000), etc. Mid-1990s FDA approval: 2011: ipilimumab, anti-CTLA-4; 2014: nivolumab, pembroluzimab, anti-PD-1. 2016: atezolizumab, anti-PD-L1 Late-1990s 2000s-2010s Activation of T cells requires two signals 2015 Science. Padmanee Sharma et al. Mechanisms of PD-1/PD-L1 immune checkpoint blo

8、ckade and tumor immunotherapy PD-1- and PD-L1-blocking antibodies under clinical development Shuguang Tan, et. al. Protein Cell. 2016 Rapid Eradication of a Bulky Melanoma Mass with One Dose of Immune checkpoint therapy A, B: before treatment; C,D: 3 weeks after one dose treatment with ipilimumab (a

9、ntiCTLA-4) and nivolumab (anti-PD-1) 2015 N Engl J Med, Paul B. Chapman, et al. T细胞与APC细胞表面的抗原识别与免疫抑制 How do the antibody drugs work? How to develop more efficient therapeutics targeting immune checkpoint? Structural basis of monoclonal antibody based immunocheckpoint blockade 2. Anti-PD-1 MAbs作用机制

10、3. Anti-CTLA-4抗体药物作用机制 1. Anti-PD-L1 MAbs 作用机制 Recent reports of four representative PD-1/PD-L1 antibody complex structures nivolumab pembrolizuma b avelumabBMS-936559durvalumab TargetPD-1PD-1PD-L1PD-L1PD-L1 MAb class Human IgG4 Humanized IgG4 Human IgG1Human IgG4Human IgG1 Develope r StageFDA appro

11、ved (melanoma, NSCLC) FDA approved (melanoma, NSCLC, HNSCC) phase III (Gastric cancer, urothelial cancer, ovarian cancer, NSCLC, etc.) phase III (melanoma, NSCLC, etc.) phase III (melanoma, NSCLC, etc.) Ref 2016 Nat Commun- a/b 2016 Cell Res- a 2016 Cell Res-b2016 Nat Commun-b 2017 Protein Cell A di

12、meric structure of hPD-L1 2010 Protein Cell. Yong Chen, et al. Avalumab 阻断PD-1/PD-L1作用机制 Kefang Liu, et. al. Cell Res. 2016 Durvalumab 阻断PD-1/PD-L1作用机制 Tan S, et. al. Protein Cell 2017 (accepted) 三种PD-L1抗体药物作用模式 Tan S, et. al. Protein Cell 2017 (accepted) 三种PD-L1抗体药物结合区域各不相同 Tan S, et. al. Protein C

13、ell 2017 (accepted) PD-L1抗体药物的结合分析 MAbsKa (104/ms)Kd (10-4/s)KD (nM) atezolizumab8.931.561.75 durvalumab42.82.850.667 avelumab1610.7530.0467 BMS-9365591058.680.83 Tan S, et. al. Protein Cell 2017 (accepted) Durvalumab VH 结合热点区域与小分子药物开发 Tan S, et. al. Protein Cell 2017 (accepted) Anti-PD-L1抗体药物作用机制小结

14、 I.PD-L1各抗体药物结合PD-L1作用模式差异显著，且结 合动力学具有较大差异，导致各抗体药物药代动力学各 不相同； II.这些抗体与PD-L1相互作用热点区域可能成为小分子药 物开发的重要靶点。 Structural basis of monoclonal antibody based immunocheckpoint blockade 2. Anti-PD-1 MAbs作用机制 3. Anti-CTLA-4抗体药物作用机制 1. Anti-PD-L1 Mabs 作用机制 1. Overall structure of nivolumab/PD-1 Tan S, et. al. Nat

15、 Commun 2017 2. N-Loop dominated interaction with nivolumab Tan S, et. al. Nat Commun 2017 Dysregulation of glycan modification and tumor development and progression Whether tumor induced disordered glycosylation of PD-1 would affect the binding to nivolumab or not? 1. Glycan modification could be o

16、bserved in PD-1 Tan S, et. al. Nat Commun 2017 2. However, N-glycosylation of PD-1 is no related to nivolumab binding Tan S, et. al. Nat Commun 2017 3. Glycosylation independent recognition to nivolumab and N-loop dominated binding (1). Glycosylation did not affect binding affinity to nivolumab. (2)

17、. N-loop of PD-1 d o m i n a t e s t h e binding to nivolumab. Tan S, et. al. Nat Commun 2017 How does the binding of nivolumab interrupt the interaction of PD-1/PD-L1? 4. PD-1/PD-L1 blockade Stereo clash to PD-L1 binding Tan S, et. al. Nat Commun 2017 What is the difference between nivolumab and pe

18、mbrolizumab when binding to PD-1? 6. Distinct blockade binding mode compared with pembrolizumab CD loop Tan S, et. al. Nat Commun 2017 Co-addministration of nivolumab and pembrolizumab might less likely affect each other Better than single treatment? Need more efforts 肿瘤抑制性PD-1抗体筛选 Unpublished data

19、PD-1抗体作用位点 Unpublished data Summary 2 I.unexpected N-terminal loop outside the IgV domain of PD-1 dominats the binding to nivolumab II.N-glycosylation is not involved in recognition to nivolumab III. Nivolumab shows a completely different binding area on PD-1 from that of pembrolizumab Structural ba

20、sis of monoclonal antibody based immunocheckpoint blockade 2. Anti-PD-1 MAbs作用机制 3. Anti-CTLA-4抗体药物作用机制 1. Anti-PD-L1 Mabs 作用机制 Recent reports of CTLA-4/MAb complex structures ipilimumabtremelimumab TargetCTLA-4CTLA-4 MAb classHuman IgG1Humanized IgG2 Developer StageFDA approved (melanoma) Phase III trials (melanoma, NSCLC, HNSCC) Ref 2017 Oncotarget (accepted) 2016 Nat Commun-a What is the reason for different clinical performances between these two MAbs? Binding epitope? Fc