Ciapponi L, Maione D, Scoumanne A, Costa P, Hansen M B, Svenson M, Bendtzen K, Alonzi T, Paonessa G, Cortese R, Ciliberto G, Savino R
I.R.B.M. P.Angeletti, Pomezia, Rome, Italy.
Nat Biotechnol. 1997 Oct;15(10):997-1001. doi: 10.1038/nbt1097-997.
Neutralization of cytokine activity by monoclonal antibodies or receptor antagonists is beneficial in the treatment of immune and neoplastic diseases, but the necessity for continuous parenteral delivery of these anticytokine agents poses considerable practical limitations. A viable alternative is to induce a neutralizing antibody response. Using transgenic mice with high circulating levels of human interleukin-6 (hIL-6), we show that injection of the hIL-6 receptor antagonist Sant1 (an IL-6 variant with seven amino-acid substitutions) induces a strong anti-hIL-6 antibody response. The elicited antibodies bind circulating hIL-6 with very high affinity, totally masking it, and neutralize hIL-6 bioactivity both in vitro and in vivo.
单克隆抗体或受体拮抗剂对细胞因子活性的中和作用在免疫和肿瘤疾病治疗中具有益处，但这些抗细胞因子药物需要持续胃肠外给药，这带来了相当大的实际限制。一个可行的替代方法是诱导产生中和抗体反应。利用人白细胞介素6（hIL-6）循环水平高的转基因小鼠，我们发现注射hIL-6受体拮抗剂Sant1（一种有七个氨基酸替换的IL-6变体）可诱导强烈的抗hIL-6抗体反应。所引发的抗体以非常高的亲和力结合循环中的hIL-6，将其完全掩盖，并在体外和体内中和hIL-6的生物活性。
