治疗性降压疫苗研究进展

Therapeutic vaccines for hypertension 治疗性降压疫苗研究进展治疗性降压疫苗研究进展 Liao Yu-Hua, MD. Institute of Cardiology, Union hospital Huazhong University of Science 344:1660-1663 Luther HP, et al. Hypertension. 1997;29:678-682 Fu ML, et al. J Hypertens. 2000;18:945-953 Liao YH, et al. Hypertens Res. 2002;25:641646. Homuth V, et al. Hypertonie 2003 (online article ) Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Arterial remodeling was generated after 1 year immunized by EC2 peptide of AT1-receptor in Wistar rats Bin Wang, Yu-Hua Liao, et al. Heart and Vessel, 2005;20(4):153-8. Before immune A year after immune * *p0.01 EC2 of rat AT1- receptor with tetanus-toxoid and CFA Antibody against AT1 receptor UIC Union Institute of Cardiology Why research vaccine for hypertension? Primary hypertension isnt recognized an autoimmune desease, because of without autoimmune damage in target organs But there is autoimmune response in hypertension, because we found the autoantibodies against AT1 receptor in patients with hypertension Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology A story： from autoantibodies of hypertension to vaccines of hypertension(HT) Autoantibodies of HT ? HT vaccines ? Autoimmune damage? Dangerous warningPathogenesis of HT prevention and treatment of HT Safety signal Foshan, 2008 World Congress of Vaccine Whether vaccine might be used to treat hypertension? UIC Union Institute of Cardiology Our exploration: AT1 receptor vaccine We hypothesize that different antibodies against different extracellular parts of the AT1 receptor displayed different effects (stimulating or blocking or neutralizing effect?) If a peptide corresponding to extracellular region of receptor could produce the blocking antibodies by active immunization, the peptide may be used to construct a vaccine against the AT1 receptor Li LD, Liao YH et al. Circulation. 2005;112supplement:II176-177 Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology SBP lowered after immunization in our previous work (32 weeks) SHR Wistar BP of SHR could be reduced by immunization with ATR12181 with tetanus-toxoid and CFA BP of Wistar rats could not be reduced by immunization with ATR12181 with tetanus-toxoid and CFA Li LD, Liao YH et al. Circulation. 2005;112supplement:II176-177 Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Effect of vaccines on SBP and Ab titre in SHR (64th week) Left plot showed the platform of antibody titre at 8th week and repeated subcutaneous injections every 4, 8 or 12 weeks. Right plot showed there was a significant decrease in SBP level at 8th week in the ATR12181 group, compared with SHR control（ -17 mmHg） . SHR Control SHR ATR12181 subcutaneous injections of vaccine-ATR12181 Zhu F, Liao YH, Li LD et al: Cell Mol Immunol (2006) 3(2)107-114 UIC Union Institute of Cardiology ATR12181 Abs bind specifically to AT1A receptor Ab against ATR12181 control antibody Western blot VSMC incubated with IgG from ATR12181 could produce green staining， but it is negative in control. Western blot bands at 41 kDa was produced by affinity columnpurified ATR12181. Zhu F, Liao YH, Li LD et al: Cell Mol Immunol (2006) 3(2)107-114 Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Effects of vaccine-ATR12181 on cardiac pathological changes (64th week) Control group ATR12181 group LVH is evident in control group, but LVH is improved in ATR12181 group. Zhu F, Liao YH, Li LD et al: Cell Mol Immunol (2006) 3(2)107-114 UIC Union Institute of Cardiology Cardiac Parameters significantly improved in vaccinated SHR (64th week) Control group ATR12181 group SBP (mmHg) 1974 1806* HR (beats/min) 38823 39222 Body weight (g) 38318 53836* Heart Weight (g) 1.590.06 1.330.11* HW/BW (mg/g) 4.20.2 2.50.1* IVSd (cm) 0.270.01 0.220.02* LVIDd(cm) 0.680.03 0.580.04* LVPWd(cm) 0.280.02 0.230.02* EF(%) 79.43.0 81.53.1n=6 per group, *P0.01 Feng Zhu， Yu-Hua Liao, et al. Circulation, 2006, 114(Supplement):II-575. Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Effects of vaccine-ATR12181 on pathological changes of 3rd grade mesenteric arteries (64th week) SHR-Control SHR-ATR12181 N=6 per group, *P0.01 Wall-to-lumen ratio of mesenteric arteries is significantly decreased in SHR-ATR12181 group, comparing with SHR-control group. Feng Zhu， Yu-Hua Liao, et al. Circulation, 2006, 114(Supplement):II-575. Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Effects of vaccine-ATR12181 on cardiac pathological changes (64th week) Control group ATR12181 group Cardiac fibrosis is reduced in the ATR12181 group， compared with the control. Feng Zhu， Yu-Hua Liao, et al. Circulation, 2006, 114(Supplement):II-575. Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Effects of vaccine-ATR12181 on renal pathological changes (64th week) Control group ATR12181 group Glomerular damages, interstitial fibrosis and protein cast in kidney are evident in control group, but pathological changes are improved in ATR12181 group Feng Zhu， Yu-Hua Liao, et al. Circulation, 2006, 114(Supplement):II-575. Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology A story： from autoantibodies of hypertension to vaccines of hypertension(HT) Autoantibodies of HT ? HT vaccines ? Autoimmune damage? Dangerous warningPathogenesis of HT prevention and treatment of HT Safety signal Autoimmune damage? Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Safety of the ATR12181 Vaccine (64weeks) We didnt find any signs of autoimmune damages in the sections of heart， Kidney, brain, aorta, liver, lung and spleen of Wistar rats in ATR12181 group. Feng Zhu， Yu-Hua Liao,et al. Circulation, 2006, 114(Supplement):II-575. UIC Union Institute of Cardiology Electron photomicrographs of renal cortex in ATR12181 group (64weeks) There were no signs of depositions in basement membrane or other places of glomcruluses in vaccinated group. Feng Zhu， Yu-Hua Liao,et al. Circulation, 2006, 114(Supplement):II-575. SHR-ATR12181 vaccine SHR-control Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Summary The interruption of the RAS pathway by ATR12181 vaccine offers the potential to prevent the development of hypertension and its associated pathophysiological alterations with infrequent administration Preliminary evaluation found that the vaccine- ATR12181 was efficacy and safety for observation of long term on 64 weeks Feng Zhu， Yu-Hua Liao,et al. Circulation, 2006, 114(Supplement):II-575. Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: double-blind, randomised, placebo-controlled phase IIa study Alain C Tissot, Patrik Maurer, Juerg Nussberger, Robert Sabat, Thomas Pfi ster, Stanislav Ignatenko, Hans-Dieter Volk, Hans Stocker, Philipp Mller, Gary T Jennings, Frank Wagner, Martin F Bachmann* Cytos Biotechnology AG, Wagistrasse 25, 8952 Schlieren, Switzerland Alain C Tissot .Lancet 2008; 371: 82127 Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Phase IIa of Clinical trial of CYT006-AngQb shows reduction in day-time blood pressure Mean (SEM) change from baseline of the ambulatory day-time blood pressure is shown. SEM=standard error of the mean; N=number of participants per group The antibody response was long- lived with a half-life of 3-4 months. Alain C Tissot .Lancet 2008; 371: 82127Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Phase IIa of Clinical trial of CYT006- AngQb shows Safety Immune markers didnt note any changes in mean levels of C1, C3, and C3a Immune cells didnt find changes from baseline in mean number of HLA-DR+ T- cells and CD69+ T-cells The study didnt observe treatment-related or clinically significant increases in the proportion of the large subsets of immune cells tested, and in particular of activated T cells Alain C Tissot .Lancet 2008; 371: 82127 Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Construction of ATRQ-001 vaccine Recently, in order to translate for human vaccine, we improved the ATR- 12181 vaccine for ATRQ-001. The ATRQ-001 vaccine is a peptide from the extracellular component of the human AT1A receptor conjugated to the Q virus-like particle. Foshan, 2008 World Congress of Vaccine UIC Union Institute of Cardiology Rationale of efficacy and safety for blocking vaccine A design of self B-cell epitope peptides combined with foreign T-cell epitope carrier 1. The self B-cell epitope peptide is coupled with a foreign carrier protein. 2. Self B-cell epitopes are segregated from the cytotoxic T-cell (Tc) epitopes in self-antigen. 3. As there is no Th cell tolerance to the foreign carrier protein, a regular antibody response against the self molecule is mounted. 4. B-cell produce Abs blocking self antigens 5. Furthermore, there will not be any self T-cell epitope specific T-cell clones to cause autoimmune damage Feng Zhu， Yu-Hua Liao*. Current Opinion in Investigational Drugs,2008,9(3):286-294 Foshan, 2008 World Congress of Vaccine History of Renin-Angiotensin System Vaccines Angiotensinogen Angiotensin I Angiotensin II ATR1 Vasoconstruction Volume retension ACE Renin Chemical Drugs Renin inhibitor ACEI ARB Hypertension Vaccines Renin Vaccine Ang I Vaccine Ang II Vaccine ATR1 Vaccine 1987,Michel JB 2000,Michel JB 2006, Bachmann MF 2005,Liao YH Liudong