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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-08-2480.
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Blood, 15 July 2003, Vol. 102, No. 2, pp. 564-570
IMMUNOBIOLOGY
Selective blockade of CD28 and not CTLA-4 with a single-chain Fv– 1-antitrypsin fusion antibody
Bernard Vanhove,
Geneviève Laflamme,
Flora Coulon,
Marie Mougin,
Patricia Vusio,
Fabienne Haspot,
Jérôme Tiollier, and
Jean-Paul Soulillou
From the Institut de Transplantation et de Recherche en Transplantation, Institut National de la Santé et de la Recherche Médicale (INSERM) U437, Centre Hospitalier Universitaire (CHU) Hotel Dieu, Nantes, France; INSERM U463, Institut de Biologie, Nantes, France; and Sangstat Europe, Lyon, France
B7-1 and B7-2 are costimulatory molecules expressed on antigen-presenting cells. The CD28/B7 costimulation pathway is critical for T-cell activation, proliferation, and Th polarization. Blocking both cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and CD28 interactions with a CTLA-4/Ig fusion protein inhibits various immune-mediated processes in vivo, such as allograft rejection and autoimmunity. However, selective blockade of CD28 may represent a better strategy for immunosuppression than B7 blockade, because CTLA-4/B7 interactions have been shown to participate in the extinction of the T-cell receptor–mediated activation signal and to be required for the induction of immunologic tolerance. In addition, selective CD28 inhibition specifically decreases the activation of alloreactive and autoreactive T cells, but not the activation of T cells stimulated by exogenous antigens presented in the context of self major histocompatibility complex (MHC) molecules. CD28 blockade cannot be obtained with anti-CD28 dimeric antibodies, which cluster their target and promote T-cell costimulation, whereas monovalent Fab fragments can block CD28 and reduce alloreactivity. In this study, we report the construction of a monovalent single-chain Fv antibody fragment from a high-affinity antihuman CD28 antibody (CD28.3) that blocked adhesion of T cells to cells expressing the CD28 receptor CD80. Genetic fusion with the long-lived serum protein  1-antitrypsin led to an extended half-life without altering its binding characteristics. The anti-CD28 fusion molecule showed biologic activity as an immuno-suppressant by inhibiting T-cell activation and proliferation in a mixed lymphocyte reaction.
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