Anti-Inducible Costimulator Monoclonal Antibody Treatment of Canine Chronic Graft- versus-Host Disease Scott S. Graves, Maura H. Parker, Diane Stone,

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Anti-Inducible Costimulator Monoclonal Antibody Treatment of Canine Chronic Graft- versus-Host Disease Scott S. Graves, Maura H. Parker, Diane Stone, George E. Sale, Smitha P.S. Pillai, Melissa M. Johnson, Rainer Storb Biology of Blood and Marrow Transplantation Volume 24, Issue 1, Pages 50-54 (January 2018) DOI: 10.1016/j.bbmt.2017.09.010 Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Schema for induction and treatment of chronic GVHD in DLA-mismatched unrelated HCT dogs. On day 0 recipients received 9.2 Gy total body irradiation and donor marrow. On day 1 recipient dogs were given apheresed donor buffy coat cells obtained from their respective donors. Immunosuppression (arrows) consisted of .4 mg/kg methotrexate injected i.v. on days 1, 3, 6, and 11 and oral CSP given on days –1 to 78 at dosing designed to maintain serum levels at 100 to 300 ng/mL. Oral ursodiol was given on days –1 to 80 to reduce the incidence of liver GVHD. Clinical signs of GVHD occurred from days 47 to 112 (tick marks). Biology of Blood and Marrow Transplantation 2018 24, 50-54DOI: (10.1016/j.bbmt.2017.09.010) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Histopathology of abdominal skin biopsies demonstrating the effect of anti-ICOS on chronic GVHD of the skin. (A) Skin biopsies from dog H799 collected 4 days after the third injection of anti-ICOS injection show dense lymphocytic infiltration surrounding the pilo-sebaceous structure and follicular epithelium (arrows). Lymphocytes are present in the superficial and deep dermis and exocytosis of the epidermis is multifocal. (B) The biopsy collected 7 days after the third injection of anti-ICOS reveals minimal numbers of lymphocytes surrounding the pilo-sebaceous structures, few lymphocytes in the superficial dermis, and no epidermal exocytosis is present. Magnification is 100×. Biology of Blood and Marrow Transplantation 2018 24, 50-54DOI: (10.1016/j.bbmt.2017.09.010) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Serum levels of α-ICOS. Blood was collected from dogs within 2 minutes and at .5, 1, 6, 24, 48, and 72 hours after injection of anti-ICOS mAb (4 mg/kg, i.v.) for the first 2 doses. For the third dose the 72-hour time point was replaced by a day 9 draw. One dog provided blood at days 10 through 17 after the third injection of anti-ICOS. Serum from the blood samples was tested for levels of anti-ICOS by ELISA. Anti-ICOS levels were zero for blood samples from all 5 dogs collected before injection of ICOS. Data are presented as mean levels of antibody ± standard deviation for 5 dogs. Biology of Blood and Marrow Transplantation 2018 24, 50-54DOI: (10.1016/j.bbmt.2017.09.010) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Anti-ICOS extends survival of dogs with GVHD. Two groups of dogs were studied from the initial diagnosis of chronic GVHD to euthanasia. In the control group, dogs H642, H634, H678, H694, H708, H720, H709, and H698 were untreated during this period aside from antibiotic and fluid support. The anti-ICOS mAb-treated group, dogs H789, H799, H800, H803, and H805, received either 1 or 2 courses of anti-ICOS mAb. The difference in the survival periods of the 2 groups was significant (log-rank test). Biology of Blood and Marrow Transplantation 2018 24, 50-54DOI: (10.1016/j.bbmt.2017.09.010) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions