Slide 1: Novel Targetable Pathways in Costimulation Pathway Blockade
Novel Targetable Pathways in Costimulation Pathway Blockade Richard N. Pierson III, MD Professor of Surgery, Harvard Medical School Cardiac Surgeon, Massachusetts General Hospital, Boston, Massachusetts, USA rpierson@mgh.harvard.edu No significant financial conflicts to declare Consultant, Moderna (
Slide 2: Costimulation Pathways: Novel Reagents Approaching the Clinic
Costimulation Pathways: Novel Regents Approaching the Clinic Richard N. Pierson III, MD Professor of Surgery, Harvard Medical School Cardiac Surgeon, Massachusetts General Hospital, Boston, Massachusetts, USA rpierson@mgh.harvard.edu None of the reagents discussed are approved for any clinical indic
Slide 3: Emerging Costimulation Blockade Approaches
CD154 TNX - 1500 (Tonix) BMS - 986004 (BMS), AT - 1501 (Eledon); HZN 4920 (dazodalibep, Horizon) CD28 FR104 (OSE, Veloxis) lulizumab (NCT04066114, BMS); Acazicolcept (Alpine, ICOSL vIgD - Fc) CD2 Primatized Rh - loCD2bR1 (NHP Reagent Resource Center) Siplizumab (ITBMed) Emerging Costimulation Blocka
Slide 4: Anti-CD154 IgG1 antibodies and prothrombotic safety signal
Emerging Costimulation Blockade: CD154 γ IgG1 antibodies against CD154 form immune complexes with soluble CD154, activate platelets via Fc RIIa hu5c8: Ruplizumab (Biogen) IDEC - 131: (Biogen/IDEC) Clinical trials halted due to prothrombotic safety signal
Slide 5: Fc-modified anti-CD154 IgG4 with reduced FcγRIIa binding
Emerging Costimulation Blockade: CD154 • Aglycosyl IgG 1 CD 154 Ab exhibits reduced efficacy in allo islet model (Ferrant et al 2004 ) • Fc R silenced CD154 domain Ab exhibits reduced efficacy in allo kidney model (Kim et al 2016) • TNX - 1500 is an Fc - modified IgG4 CD154 with reduced bi
Slide 6: Heart allotransplant study design in NHPs
Emerging Costimulation Blockade: CD154 Low - dose TNX - 1500 monoRx (loTNX - 1500) Low - dose TNX - 1500 + MMF (loTNX - 1500 +MMF) Protocol biopsies : POD ~45 and 90 Heterotopic abdominal heart allotransplant model EOS : POD 180 Group - 1 : n=4 Group - 2 : n=4 Group - 3 : n=5 Historical: n=5 Prima
Slide 7: Heart allograft survival in NHPs prolonged with standard dose
Emerging Costimulation Blockade: CD154 Treatment Group MST (range) hu5c8 (Rx off d90) 133 days (90 - 173) loTNX 99 days (35 - 183) loTNX + MMF 88 days (58 - 146) stTNX >265 days (116 - 305) Results - Heart Allograft Survival in NHPs is significantly prolonged with standard dose TNX - 1500 (stTNX)
Slide 8: Suppression of anti-donor alloantibody elaboration
Emerging Costimulation Blockade: CD154 Results - TNX - 1500 suppresses anti - donor - alloantibody elaboration loTNX - 1500 (n=4) loTNX - 1500 + MMF (n=4) stTNX - 1500 (n=5)
Slide 9: Immune injury: CAV severity scores
Emerging Costimulation Blockade: CD154 Results - Immune Injury CAV significantly more severe with loTNX - 1500+MMF ISHLT scores * P<0.05 ** P<0.01 *** P<0.005 **** p<0.001 CAV severity scores
Slide 10: Platelet counts stable, no thromboembolic complications
Emerging Costimulation Blockade: CD154 Results - Platelet counts stable No thromboembolic complications were observed Miura S et al ATC 2022, #582
Slide 11: Cynomolgus kidney allotransplant study design
Emerging Costimulation Blockade: CD154 0 6w 12w 18w 24w 30w 20mg/kg q wk 20mg/kg q wk MMF Tacrolimus Group A (n=6) Group B (n=6) Conventional IS (n=20) 6 Standard Dose TNX - 1500 (Group A) 6 Reduced - Dose TNX - 1500+MMF (Group B) Compared with Historical Results Steroids MMF No IS (n=4) 20mg/kg q
Slide 12: Kidney results: no thromboembolic complications
Emerging Costimulation Blockade: CD154 Lassiter G, Kawai T et al ATC 2022, Abstract #172 TNX - 1500 > loTNX - 1500 + MMF No thromboembolic complications were observed ~stTNX ~loTNX+MMF
Slide 13: Conclusions
Emerging Costimulation Blockade: CD154 Conclusions • Standard - dose TNX - 1500 inhibits pathologic alloimmunity in NHPs • Consistently prolonged NHP cardiac and renal allograft survival • Relative expansion of Tregs in peripheral blood • No CMV activation (no prophylaxis) • No clinical thrombotic
Slide 14: Emerging Costimulation Blockade: CD28
CD28 Emerging Costimulation Blockade : CD28 References: Poirier et al. Immunotherapy 2010; Transpl Int 2011; Am J Transplant 2012 T cell APC Selective CD28 blockade APC CD80/CD86 blockade FR104: domain - associated antibody, PEGylated LEA29Y: CTLA4 - Ig
Slide 15: Emerging Costimulation Blockade: CD28
CD28 Emerging Costimulation Blockade : CD28 References: Poirier et al. Immunotherapy 2010; Transpl Int 2011; Am J Transplant 2012 T cell APC Selective CD28 blockade APC CD80/CD86 blockade FR104: domain - associated antibody, PEGylated LEA29Y: CTLA4 - Ig
Slide 16: CD28
Emerging Costimulation Blockade: CD28
Slide 17: FR104 monotherapy promotes baboon kidney allograft survival
Emerging Costimulation Blockade: CD28 17 FR104 monoRx promotes baboon kidney allo - Tx survival Superior control of graft rejection vs Belatacept (steroid - resistant) FR104 Belatacept Days post - transplantation Tac for only 1 month Steroids if BPAR Tacrolimus 30 day Rx Expanded intragraft Tregs
Slide 18: FR104 promotes monkey heart allograft survival
Emerging Costimulation Blockade: CD28 FR104 Rx promotes monkey heart allo - Tx survival Possibly synergistic when combined with CD40 or CD154 N=5 - 7 per group Rx stopped after d84 No viral illness (no Rx) Azimzadeh, Pierson, unpublished
Slide 19: CD2: loCD2 to replace anti-CD8 for tolerance induction in NHP
CD2: - loCD2 to replace CD8 for tolerance induction in NHP Emerging Costimulation Blockade: CD2 A D C B A. Engineered for NHP studies B. Suppressive in MLR C. Prolonged depletion of CD8 TEM, Relative sparing of CD4 N, CM D. Predominance of T regs
Slide 20: Emerging Costimulation Blockade Approaches: status
CD154 Tonix emphasizing transplantation (allo, xeno) for TNX - 1500 Phase 1 targeted for 2022 pending IND approval CD28 OSE/Veloxis in Phase 2 for kidney transplantation with FR104 “Encouraging so far…” CD2 Primatized loCD2 effective in kidney tolerance model Siplizumab for human kidney tolerance:
Slide 21: Thank you for your attention!
Thank you for your attention! Emerging Costimulation Blockade Approaches