Caron P C, Schwartz M A, Co M S, Queen C, Finn R D, Graham M C, Divgi C R, Larson S M, Scheinberg D A
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Cancer. 1994 Feb 1;73(3 Suppl):1049-56. doi: 10.1002/1097-0142(19940201)73:3+<1049::aid-cncr2820731344>3.0.co;2-1.
Long-term survival rates of patients with acute myelogenous leukemia treated with intensive chemotherapy are 15-20%, despite efforts to develop new treatment strategies. Murine M195 (131I-M195), an anti-CD33, immunoglobulin (Ig) G2a monoclonal antibody has reactivity restricted to early myeloid cells and myeloid leukemic blasts but not hematopoietic progenitors. Previous trials in patients with relapsed or refractory myeloid leukemia showed that 131I-M195 rapidly targeted to the bone marrow and internalized into target cells. This article describes a therapeutic dose escalation study in which 24 patients received from 50 mCi/m2 to 210 mCi/m2 of 131I-M195 in divided doses. Cytoreduction of peripheral cell counts and bone marrow blasts occurred without nonhematopoietic toxicity. Doses of 131I-M195 greater than 135 mCi/m2 were associated with marrow cytoreduction sufficient to necessitate bone marrow transplant. However, 37% of the patients developed human anti-mouse antibody, preventing retreatment. To decrease immunogenicity and improve effector function, chimeric IgG1 and IgG3, and complementarity-determining region-grafted, humanized IgG1 and IgG3 versions of mouse M195 were developed by genetic engineering techniques. The new versions maintained specificity and biologic function, and they were superior to the mouse M195 in their ability to perform antibody-dependent cellular cytotoxicity against leukemia cells. Humanized M195, but not chimeric M195, showed a 4-8.6 times higher avidity than its mouse counterpart. Because effector function of IgG depends to a large extent on Fc clustering, a homodimeric HuG1 also was developed. Homodimeric HuG1 showed an ability to cause additional dramatic improvements in effector functions, as well as an ability to internalize and retain radioisotope in target leukemia cells. Monomeric and dimeric forms of humanized M195 may be advantageous in the therapy of acute myelogenous leukemia.
尽管一直在努力开发新的治疗策略，但接受强化化疗的急性髓性白血病患者的长期生存率仅为15%至20%。鼠源M195（131I-M195）是一种抗CD33免疫球蛋白（Ig）G2a单克隆抗体，其反应性仅限于早期髓样细胞和髓性白血病母细胞，而不作用于造血祖细胞。先前针对复发或难治性髓性白血病患者的试验表明，131I-M195能迅速靶向骨髓并内化进入靶细胞。本文描述了一项治疗剂量递增研究，24例患者接受了分剂量的131I-M195，剂量范围为50 mCi/m2至210 mCi/m2。外周血细胞计数和骨髓母细胞减少，且未出现非造血毒性。131I-M195剂量大于135 mCi/m2时，骨髓细胞减少足以需要进行骨髓移植。然而，37%的患者产生了人抗鼠抗体，无法再次治疗。为了降低免疫原性并改善效应功能，通过基因工程技术开发了嵌合IgG1和IgG3以及互补决定区移植的人源化IgG1和IgG3版本的鼠源M195。新版本保持了特异性和生物学功能，并且在对白血病细胞进行抗体依赖性细胞毒性作用方面优于鼠源M195。人源化M195而非嵌合M195的亲和力比其鼠源对应物高4至8.6倍。由于IgG的效应功能在很大程度上取决于Fc聚集，因此还开发了一种同二聚体HuG1。同二聚体HuG1显示出能够进一步显著改善效应功能，以及在靶白血病细胞中内化和保留放射性同位素的能力。人源化M195的单体和二聚体形式在急性髓性白血病的治疗中可能具有优势。
