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Construction and Characterization of Bispecific Costimulatory Molecules Containing a Minimized CD86 (B7-2) Domain and Single-Chain Antibody Fragments for Tumor Targeting

Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, D-60596 Frankfurt am Main [F. R., M. B., W. W.], and MEMOREC Stoffel GmbH, D-50829 Köln [B. G.], Germany

ABSTRACT

Efficient T-cell activation requires two signals. The first signal, which confers specificity, is provided by interaction of the T-cell receptor with peptides presented by MHC molecules. One of the second costimulatory signals is induced by binding of B7 proteins on the surface of antigen-presenting cells to CD28 on the T-cell surface. Expression of B7 molecules on tumor cells can result in the activation of tumor specific T lymphocytes and induce protective antitumor immunity. However, at present such gene-therapeutic approaches are limited by the inability to selectively target B7 gene expression to cancer cells. As an alternative approach we exploited recombinant antibody fragments to localize a costimulatory B7 molecule to the surface of tumor cells. We constructed chimeric proteins that contain in a single polypeptide chain a portion of human B7-2 (CD86) genetically fused to single-chain (sc) Fv antibody domains specific for the tumor-associated antigens epidermal growth factor receptor and the closely related ErbB2 receptor tyrosine kinase. A small recombinant fragment of human CD86 was characterized that corresponds to amino acid residues 1–111 (CD86₁₁₁) of the mature protein. CD86₁₁₁ produced in the yeast Pichia pastoris and CD86₁₁₁ expressed in bacteria was functionally active and displayed specific binding to B7 counter receptors. Bacterially expressed CD86₁₁₁-scFv fusion proteins specifically localized to the respective target antigens on the surface of tumor cells and markedly enhanced the proliferation of primary T cells when bound to immobilized tumor antigen.

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