LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation

Rousse, J.; Royer, P.-J.; Evanno, G.; Lheriteau, E.; Ciron, C.; Salama, A.; Shneiker, F.; Duchi, R.; Perota, A.; Galli, C.; Cozzi, E.; Blancho, G.; Duvaux, O.; Brouard, S.; Soulillou, J.-P.; Bach, J.-M.; Vanhove, B.

doi:10.1101/2022.09.08.507114

bioRxiv · 10.1101/2022.09.08.507114

LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation

Rousse, J.·Royer, P.-J.·Evanno, G.·Lheriteau, E.·Ciron, C.·Salama, A.·Shneiker, F.·Duchi, R.·Perota, A.·Galli, C.·Cozzi, E.·Blancho, G.·Duvaux, O.·Brouard, S.·Soulillou, J.-P.·Bach, J.-M.·Vanhove, B.

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Abstract

Anti-thymocyte/lymphocyte globulins (ATGs/ALGs) are immunosuppressive drugs used in induction therapies to prevent acute rejection in solid organ transplantation. Because of animal origin, ATGs/ALGs contain highly immunogenic carbohydrate xenoantigens eliciting antibodies that are associated with subclinical inflammatory events possibly impacting long-term graft survival. Their strong and long-lasting lymphodepleting activity also increases the risk for infections. To circumvent these drawbacks, LIS1 has been engineered as a glyco-humanized polyclonal antibody obtained by immunizing genetically modified pigs knocked out for major xeno-antigens Gal and Neu5Gc. It is Fc-silenced in humans and differs from other ATGs/ALGs by its mechanism of action excluding antibody-dependent cell-mediated cytotoxicity and being restricted to complement and phagocyte-mediated cytotoxicity, apoptosis and antigen masking, resulting in profound inhibition of T-cell alloreactivity in mixed-leucocyte-reactions. Preclinical evaluation in macaques showed that LIS1 impacted CD4+, CD8+ effector T cells but not T-reg, B cells or myeloid cells. Compared with rabbit ATG, LIS1 induced transient depletion of target T cells in the peripheral blood but was equivalent in preventing allograft rejection in a skin allograft model. The novel therapeutic modality of LIS1 might present advantages in induction treatment after organ transplantation by shortening the T-cell depletion period while maintaining adequate immunosuppression and reducing immunogenicity.

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Rousse, J., Royer, P.-J., Evanno, G., Lheriteau, E., Ciron, C., Salama, A., Shneiker, F., Duchi, R., Perota, A., Galli, C., Cozzi, E., Blancho, G., Duvaux, O., Brouard, S., Soulillou, J.-P., Bach, J.-M., Vanhove, B.. 2022-09-11. LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation. https://doi.org/10.1101/2022.09.08.507114

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