Terenzi A, Bolognesi A, Pasqualucci L, Flenghi L, Pileri S, Stein H, Kadin M, Bigerna B, Polito L, Tazzari P L, Martelli M F, Stirpe F, Falini B
Institute of Haematology, University of Perugia, Italy.
Br J Haematol. 1996 Mar;92(4):872-9. doi: 10.1046/j.1365-2141.1995.404942.x.
The anti-CD30 immunotoxin (IT) Ber-H2/saporin is effective in patients with refractory Hodgkin's disease. However, responses are short and partial, one of the main reasons being the inability to repeat IT doses because of formation of human antibodies against the murine antibody and/or the toxin. To overcome this problem, we constructed two new anti-CD30 ITs by covalently linking the mouse monoclonal antibody Ber-H2 to the type 1 ribosome-inactivating proteins (RIPs) momordin (MOM) and pokeweed antiviral protein from seeds (PAP-S), which do not cross-react with each other or with saporin. Both ITs inhibited protein synthesis by Hodgkin's disease and anaplastic large-cell lymphoma (ALCL)-derived CD30+ target cell lines with a very high efficiency (IC50 ranging from < 5 x 10(-13) M to 2.75 x 10(-11) M, as RIP). In a SCID mouse model of xenografted CD30+ human ALCL, a 3d treatment with non-toxin doses of Ber-H2/MOM (50%LD50), started 24 h after transplantation, prevented tumour development in about 40% of the animals and significantly delayed tumour growth rate in the others. Main toxicity signs in mice and rabbits were dose-related increase of serum transaminases (AST and ALT) and creatine phosphokinase (CPK). LD50 (as RIP) in Swiss mice was 7 mg/kg for Ber-H2/MOM and 0.45 mg/kg for Ber-H2/PAP-S. Sequential administration of two anti-CD30 ITs (Ber-H2/MOM and Ber-H2/saporin) was well tolerated and did not result in formation of antibodies cross-reacting and with the two plant toxins. The results presented in this paper suggest that in the future, sequential administration of anti-CD30 humanized antibodies linked to antigenically distinct type 1 RIPs (saporin, MOM, PAP-S) should be feasible.
抗CD30免疫毒素（IT）Ber-H2/皂草素对难治性霍奇金病患者有效。然而，反应短暂且不完全，主要原因之一是由于针对鼠抗体和/或毒素产生人抗体，无法重复给予IT剂量。为克服这一问题，我们通过将小鼠单克隆抗体Ber-H2与1型核糖体失活蛋白（RIP）苦瓜素（MOM）和种子商陆抗病毒蛋白（PAP-S）共价连接，构建了两种新的抗CD30 IT，它们彼此之间以及与皂草素均无交叉反应。两种IT均能高效抑制霍奇金病和间变性大细胞淋巴瘤（ALCL）来源的CD30+靶细胞系的蛋白质合成（作为RIP，IC50范围为<5×10⁻¹³M至2.75×10⁻¹¹M）。在异种移植CD30+人ALCL的SCID小鼠模型中，移植后24小时开始用无毒剂量的Ber-H2/MOM（50%LD50）进行3天治疗，约40%的动物肿瘤发育得到预防，其他动物肿瘤生长速度显著延迟。小鼠和兔子的主要毒性体征是血清转氨酶（AST和ALT）和肌酸磷酸激酶（CPK）与剂量相关的升高。瑞士小鼠中Ber-H2/MOM的LD50（作为RIP）为7mg/kg，Ber-H2/PAP-S为0.45mg/kg。序贯给予两种抗CD30 IT（Ber-H2/MOM和Ber-H2/皂草素）耐受性良好，未导致产生与两种植物毒素交叉反应的抗体。本文给出的结果表明，未来序贯给予与抗原性不同的1型RIP（皂草素、MOM、PAP-S）连接的抗CD30人源化抗体应该是可行的。
