Date: Saturday, May 30, 2020
Session Name: Poster Session C: Immunosuppression Preclinical Studies
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Anti-thymocyte globulin (ATGs) are polyclonal antibody products that target and deplete T cells for immunosuppression in transplantation (prophylaxis of rejection). Since ATGs are derived from the plasma of animals immunized with T cells or thymocytes, there are limitations in production speed, lot to lot variability, adverse reactions to animal-specific antigens, short half-life, and anti-drug antibody responses in the recipients. Making a fully human recombinant ATG (rhATG) would combine efficiency advantages of a polyclonal with the safety advantages of a fully human recombinant antibody.
*Methods: Trianni humanized mice were immunized with a single donor of human thymocytes or T cells and high titer antibody responses were confirmed by flow cytometry. B cells were harvested from blood, spleen and bone marrow and run through a microfluidics platform to capture individual B cells in droplets, linking the native antibody heavy and light chain, and subsequently cloned as full-length IgK-IgG1 into Chinese hamster ovary (CHO) cells for antibody production. Antibodies were characterized for function and antigen-specificity. Immune deficient (NSG; Jackson Labs) animals engrafted with human PBMCs were used as a model of graft-versus-host disease (GVHD). Mice were treated with a single dose of 6mg/kg rhATG or rabbit ATG and a vehicle negative control with 6 animals per group monitored for immune modulation, clinical severity and death over 35 days.
*Results: Immune cell targeting antibodies in the rhATG product were measured by ELISA and found to efficiently bind to immune cell-expressed proteins including CD45, CD4, CD3 and CD5, similar to rabbit ATG. Antibodies were also found to bind to PBMCs, were able to deplete cells in vitro, and bind to Fcγ receptor to induce ADCC. Immune deficient animals that were well engrafted and treated were found to have >95% depletion of PMBC immune cells 2 days after treatment; however, PBMC immune cells rebounded 7 days after treatment in all groups. Survival analysis shows delays to GVHD in both rabbit ATG and rhATG compared to the vehicle control.
*Conclusions: rhATG provides many advantages over animal-derived ATG including scalability and consistent manufacturing, a longer half-life in vivo, and the potential for repeated lower doses with a more potent product without anti-animal immune-mediated reactions. Pre-clinical and clinical studies will be done to evaluate rhATG for toxicity, pharmacokinetics, and function for inducing immunosuppression to prevent acute transplant rejection and reduce other inflammatory auto-immune reactions.
To cite this abstract in AMA style:Keating SM, Adler AS, Mizrahi RA, Leong J, Asensio MA, Lim YW, Niedecken AR, Chiang Y, Leong R, Johnson DS. A Recombinant, Fully Human ATG Polyclonal Antibody Drug Drives Immune Cell Depletion in a Model of Graft-versus-Host Disease [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/a-recombinant-fully-human-atg-polyclonal-antibody-drug-drives-immune-cell-depletion-in-a-model-of-graft-versus-host-disease/. Accessed August 14, 2020.
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