Heuser Claudia, Diehl Volker, Abken Hinrich, Hombach Andreas
Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Köln, Germany.
Zentrum für Molekulare Medizin Köln (ZMMK), Universität zu Köln, Köln, Germany.
Int J Cancer. 2003 Sep 10;106(4):545-552. doi: 10.1002/ijc.11279.
Interleukin-12 (IL-12) is a disulfide-linked p40-p35 heterodimeric cytokine and plays a key role in linking innate cellular immunity to an adaptive Th1 response against pathogens and tumor cells and in counteracting a Th2 immune response. The pathogenesis of Hodgkin's disease (HD) is partially attributed to a Th2 dominance associated with functional anergy of T cells that accumulate in the near vicinity to the malignant Hodgkin/Reed-Sternberg (H/RS) cells. To revert Th2 polarization in the tumor lesion, we generated an anti-CD30-IL-12 antibody-cytokine fusion protein that binds to CD30 on H/RS cells and is composed of a CD30 binding domain (HRS3-scFv) linked to p40-p35 murine single chain IL-12. The HRS3-scFv-hi-IL-12 fusion protein is expressed as a 110 kD polypeptide, can be purified by affinity chromatography, and has binding specificities to both the CD30 antigen and the IL-12 receptor. After binding to CD30(+) H/RS cells, the fusion protein stimulates T cells to secrete IFN-gamma, a predominant Th1 cytokine, and induces NK cells to lyse CD30(+) cells with high efficiency. These properties make the HRS3-scFv-hi-IL-12 fusion protein suitable for the specific immunotherapy of Hodgkin's lymphoma.
白细胞介素-12（IL-12）是一种通过二硫键连接的p40-p35异源二聚体细胞因子，在将先天性细胞免疫与针对病原体和肿瘤细胞的适应性Th1反应相联系以及对抗Th2免疫反应中发挥关键作用。霍奇金淋巴瘤（HD）的发病机制部分归因于Th2优势，这与积聚在恶性霍奇金/里德-斯腾伯格（H/RS）细胞附近的T细胞功能无能有关。为了逆转肿瘤病灶中的Th2极化，我们构建了一种抗CD30-IL-12抗体-细胞因子融合蛋白，它能与H/RS细胞上的CD30结合，由与p40-p35小鼠单链IL-12相连的CD30结合域（HRS3-scFv）组成。HRS3-scFv-hi-IL-12融合蛋白以110 kD多肽形式表达，可通过亲和层析纯化，对CD30抗原和IL-12受体均具有结合特异性。与CD30(+) H/RS细胞结合后，该融合蛋白刺激T细胞分泌主要的Th1细胞因子γ干扰素，并诱导NK细胞高效裂解CD30(+)细胞。这些特性使得HRS3-scFv-hi-IL-12融合蛋白适用于霍奇金淋巴瘤的特异性免疫治疗。
