Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Anti-CD2 producing pig xenografts effect localized depletion of human T cells in a huSCID model (#145)

Jamie L Brady 1 , Robyn M Sutherland 1 , Wayne J Hawthorne 2 , Philip J O'Connell 2 , Peter J Cowan 3 , Andrew M Lew 1
  1. WEHI, Parkville, VIC, Australia
  2. Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead, NSW, Australia
  3. Immunology Research Centre, St Vincent's Hospital, Fitzroy, Vic, Australia

We genetically engineered anti-CD2 mAb to produce a more clinically relevant chimeric Ab by fusing the variable regions to human IgG3. The chimeric anti-human CD2 retained its ability to deplete T cells in a humanized mouse model (hu-SCID). Pig neonatal islet cell clusters (NICCs) transduced with adenovirus encoding this Ab secreted anti-human CD2. Transplantation of transduced NICCs in hu-SCIDs showed local deletion of T cells at the graft site but the peripheral immune system was left intact.

We previously reported that in vitro our anti-CD2 Ab is a non-activating Ab. However in the light of the devastating effects of the CD28 superagonist TGN1412 trial we have revisited our previous results. We have utilized the hu-SCID model to test for cytokine release in vivo after administration of our chimeric anti-CD2 Ab. OKT3, an antibody known to initiate cytokine release syndrome, was used as a positive control.Whereas treatment with OKT3 led to the elevation of pro-inflammatory cytokines in the plasma of hu-SCIDs, no such evidence of a “cytokine storm” was observed after administration of anti-CD2. No upregulation of the T cell activation markers CD69 and CD25 were detected after administration of anti-human CD2 whereas OKT3 treatment induced expression of both these markers on T cells in this system.

We have demonstrated that xenografts expressing a clinically relevant anti-CD2 can exert local immunosuppression. We have further utilized the hu-SCID model to assess safety of the anti-CD2 Ab prior to first-in-human clinical trials.