FR255734, a Humanized, Fc-Silent, Anti-CD28 Antibody, Improves Psoriasis in the SCID Mouse-Psoriasis Xenograft Model Siba P. Raychaudhuri, Smriti Kundu-Raychaudhuri,

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FR255734, a Humanized, Fc-Silent, Anti-CD28 Antibody, Improves Psoriasis in the SCID Mouse-Psoriasis Xenograft Model Siba P. Raychaudhuri, Smriti Kundu-Raychaudhuri, Kouichi Tamura, Taro Masunaga, Kaori Kubo, Kaori Hanaoka, Wen-Yue Jiang, Leonore A. Herzenberg, Leonard A. Herzenberg Journal of Investigative Dermatology Volume 128, Issue 8, Pages 1969-1976 (August 2008) DOI: 10.1038/jid.2008.38 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 FR255734 inhibits T-cell proliferation and cytokine production. (a) Humanized, Fc-silent anti-CD28 antibody inhibited T-cell proliferation in a dose-dependent manner. T cells were cultured with antihuman CD3 and CD28 antibody and human CD80/P815. Several doses of FR255734 (3–10,000ngml−1) were added to the culture to determine the inhibitory effect. Maximum inhibitory effect was seen at 300ngml−1 dose where this effect reached a plateau. Results were expressed as mean±SD of triplicate wells of six individuals. Mouse IgG2 isotype control did not inhibit T-cell proliferation. Each experiment was performed in triplicate. (b) FR255734 at 300ngml−1 significantly inhibited IFN-γ production by anti-human CD3CD28 antibody stimulation. CTLA4-Ig, a positive control, showed similar inhibitory effect. Unstimulated PBMCs produced very small amount of IFN-γ ≤30pgml−1 compared with CD3CD28 stimulated PBMCs. Human IgG2 and mouse IgG2 isotype controls did not inhibit IFN-γ production. (c) FR255734 at 300ngml−1 dose inhibited IFN-γ production significantly after tetanus toxoid stimulation. CTLA4-Ig had shown similar inhibition. Unstimulated PBMCs produced very small amount was ≤30pgml−1 of IFN-γ compared with tetanus toxoid stimulated PBMCs. Each experiment was performed in triplicate. Human IgG2 and mouse IgG2 isotype controls did not inhibit IFN-γ production. (d) FR255734 antibody at 300ngml−1 dose inhibited IL-2 production significantly after CD3CD28 antibody stimulation. CTLA4-Ig showed similar effect. Unstimulated PBMCs produced very small amount, ≤20pgml−1, of IL-2 compared with CD3CD28 antibody-stimulated PBMCs. Human IgG2 and mouse IgG2 isotype controls did not inhibit IL-2 production. (e) FR255734 antibody at 300ngml−1 inhibited IL-2 production significantly after tetanus toxoid stimulation. CTLA4-Ig also significantly inhibited IL-2 production. Unstimulated PBMCs produced very small amount, ≤20pgml−1, of IL-2 compared with tetanus toxoid-stimulated PBMCs. Results are expressed as mean±SD of results from six individual experiments. Each experiment was performed in triplicate. Human IgG2 and mouse IgG2 isotype controls did not inhibit IL-2 production. Journal of Investigative Dermatology 2008 128, 1969-1976DOI: (10.1038/jid.2008.38) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Histopathological and immunohistochemical studies in pre- and post-treated biopsies of transplanted psoriasis plaques. Transplanted psoriasis graft on a SCID mouse was treated with FR255734 at 10ngml−1 per week for 4 weeks. Pretreatment (a) and post-treated (b) tissues were stained for expression of CD3 and counterstained with hematoxylin. Histopathological studies of the post-treated (b) graft demonstrated significant thinning of the epidermis and marked reduction of CD3-positive infiltrates. Dark brown positive cells marked by arrows indicate CD3+ lymphocytes. Original magnification × 200. Journal of Investigative Dermatology 2008 128, 1969-1976DOI: (10.1038/jid.2008.38) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Immunohistochemical studies for CD3+ lymphocytes in pre (a) and post (b) treated biopsies from a psoriasis graft treated with human IgG2. Compared with Figure 2 there is no histopathological improvement in the post-treated (b) section. In both pre- (a) and post-treated (b) biopsies, the same degree of epidermal thickening typical for psoriasis along with marked CD3+ lymphocyte infiltrates is seen within dermis and epidermis. Black arrows indicate brown-colored CD3+ lymphocytes. Journal of Investigative Dermatology 2008 128, 1969-1976DOI: (10.1038/jid.2008.38) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 TNF-α-positive dermal infiltrates in pre- and post-treated biopsies following treatment with FR255734, 10mgkg−1 per week for 4 weeks. Pretreatment (a) and post-treated (b) tissues were stained for TNF-α with a rabbit anti-human polyclonal antibody and counterstained with hematoxylin. Post-treated (b) graft demonstrated significant thinning of the epidermis and marked reduction of TNF-α-positive dermal infiltrates. Brown positive cells marked by arrows indicate intracellular expression of TNF-α. Original magnification × 400. Journal of Investigative Dermatology 2008 128, 1969-1976DOI: (10.1038/jid.2008.38) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 ICAM-1 expression in pre- and post-treated biopsies following treatment with FR255734, 10mgkg−1 per week for 4 weeks. Pretreatment (a) and post-treated (b) tissues were stained for ICAM-1 with a rabbit anti-human polyclonal antibody and counterstained with hematoxylin. Post-treated (b) graft demonstrated significant thinning of the epidermis and marked reduction of ICAM-1 in the blood vessels. Brown positive cells marked by black arrows indicate expression of ICAM-1 on the luminal endothelial cells on both sides of a blood vessel extending from deep dermis to the papillary dermis. Original magnification × 200. Journal of Investigative Dermatology 2008 128, 1969-1976DOI: (10.1038/jid.2008.38) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions