Sharkey R M, Blumenthal R D, Hansen H J, Goldenberg D M
Center for Molecular Medicine and Immunology, University of Medicine and Dentistry of New Jersey, Newark 07103.
Cancer Res. 1990 Feb 1;50(3 Suppl):964s-969s.
We have examined three methods that may be useful for improving the therapeutic efficacy of antibody-targeted radionuclides. The principal limitation of radioimmunotherapy is myelotoxicity and thrombocytopenia. These are due mainly to the length of time the radioantibody remains in the blood. The clearance time of a radiolabeled immunoglobulin G (IgG) may be decreased by using fragments prepared from the IgG. Using murine monoclonal antibodies against human colonic cancer in an animal model with a transplantable human colonic tumor, we have shown that fractionated doses of 131I-labeled F(ab')2 fragments can provide similar tumoricidal activity as a single injection of IgG, but toxicity to the normal tissues is reduced significantly at this tumoricidal level. Thus, it is expected that improved tumoricidal activity may be achieved by further escalating the dose of F(ab')2 that is administered at each injection. An anti-antibody (second antibody) may also be used to remove an anti-tumor antibody rapidly from the blood. By allowing intact IgG to be used instead of fragments, a higher percentage of the radiolabeled anti-tumor antibodies may be concentrated in the tumor to provide higher tumor doses, yet toxicity to the normal tissues may be controlled by the removal of the radiolabeled antibody from the blood. We have shown that the injection of a second antibody 48 h after 131I-labeled anti-carcinoembryonic antigen antibody is given can reduce toxicity at least 2-fold without affecting the tumoricidal activity of the radioantibody. A third method for reducing the myelotoxicity of radioantibody treatment involves the use of cytokines to increase the production of white blood cells. For example, interleukin 1 may be given prior to, or sometime after, radioantibody treatment to increase the number of circulating white blood cells and thereby reduce myelotoxicity. Thus, modification of some of the biological factors limiting radioimmunotherapy may provide for improvements in cancer treatment with radiolabeled antibodies.
我们研究了三种可能有助于提高抗体靶向放射性核素治疗效果的方法。放射免疫疗法的主要局限性是骨髓毒性和血小板减少症。这些主要是由于放射性抗体在血液中停留的时间长短所致。通过使用从免疫球蛋白G（IgG）制备的片段，可以缩短放射性标记的IgG的清除时间。在具有可移植人结肠肿瘤的动物模型中，使用抗人结肠癌的鼠单克隆抗体，我们已经表明，分次给予131I标记的F(ab')2片段可提供与单次注射IgG相似的杀肿瘤活性，但在这种杀肿瘤水平下，对正常组织的毒性显著降低。因此，预计通过进一步提高每次注射时给予的F(ab')2剂量，可以实现更高的杀肿瘤活性。抗抗体（第二抗体）也可用于快速从血液中清除抗肿瘤抗体。通过允许使用完整的IgG而不是片段，更高比例的放射性标记抗肿瘤抗体可集中在肿瘤中以提供更高的肿瘤剂量，同时通过从血液中清除放射性标记抗体来控制对正常组织的毒性。我们已经表明，在给予131I标记的抗癌胚抗原抗体48小时后注射第二抗体，可以将毒性降低至少2倍，而不影响放射性抗体的杀肿瘤活性。降低放射性抗体治疗骨髓毒性的第三种方法涉及使用细胞因子来增加白细胞的产生。例如，白细胞介素1可以在放射性抗体治疗之前或之后的某个时间给予，以增加循环白细胞的数量，从而降低骨髓毒性。因此，对一些限制放射免疫疗法的生物学因素进行修饰可能会改善放射性标记抗体在癌症治疗中的效果。
