Oldham R K
Biological Therapy Institute, Franklin, Tennessee 37065-1700.
Mol Biother. 1991 Sep;3(3):148-62.
Forty-three patients with disseminated refractory malignancies each received an individually specified combination of either Adriamycin (n = 24) or mitomycin-C (n = 19) conjugated to a cocktail of murine monoclonal antibodies (mAb). Cancers were typed with both immunohistochemistry and flow cytometry using a panel of antibodies. Cocktails of up to six antibodies were selected based on total binding of greater than 80% of the malignant cells in the biopsy specimen. These mAb cocktails were then drug conjugated, safety tested, and administered intravenously. The Adriamycin immunoconjugates were well tolerated in 22/24 patients, with 17/24 having significant side effects. Fever, chills, pruritus, and skin rash were by far the most common transitory reactions. All were well controlled with premedication. A total of up to 1 g Adriamycin and 5 g mAb were administered to each patient. The limiting factor appeared to be a variable dissociation of active Adriamycin from the antibody that unpredictably caused hemopoietic depression. Similar findings were noted among 19 patients treated with mitomycin-C conjugates. Thrombocytopenia at a 60-mg dose of mitomycin-C in this schedule was dose limiting. Serological evidence suggested that the development of an immunoglobulin M antibody specific against the mouse mAb had the specificity and sensitivity to predict clinical reactions. These antibodies were quantitatively less in mitomycin-C-treated patients. Selected patients were retreated. One patient with chronic lymphocytic leukemia was treated on three occasions with regression of peripheral lymph nodes. Two patients with breast carcinoma had definite improvement in ulcerating skin lesions, and two patients with tongue carcinoma had shrinkage of their lesions. No responses were seen with mitomycin-C conjugates but binding was noted to tumors. Drug-induced colitis was seen at higher doses with some binding of these conjugates to normal colon epithelium. This study demonstrated the feasibility of preparing individually specified drug immunoconjugate cocktails for patients with refractory malignancies. Cocktail formulation and antibody delivery to the tumor in vivo was accomplished. There was limited antigenic drift among various biopsies within the same patient over time. The major technical hurdle continues to be the selection of effective drug conjugation methods to optimally bind drugs to mAbs for targeted cancer therapy.
43例播散性难治性恶性肿瘤患者每人接受了阿霉素（n = 24）或丝裂霉素-C（n = 19）与一组鼠单克隆抗体（mAb）偶联的个体化指定组合。使用一组抗体通过免疫组织化学和流式细胞术对癌症进行分型。根据活检标本中超过80%的恶性细胞的总结合情况，选择多达六种抗体的组合。然后将这些单克隆抗体组合进行药物偶联、安全性测试并静脉给药。阿霉素免疫偶联物在22/24例患者中耐受性良好，24例中有17例有明显副作用。发热、寒战、瘙痒和皮疹是迄今为止最常见的短暂反应。所有这些反应通过预处理都得到了很好的控制。每位患者总共给予了高达1 g的阿霉素和5 g的单克隆抗体。限制因素似乎是活性阿霉素与抗体的可变解离，这不可预测地导致了造血抑制。在用丝裂霉素-C偶联物治疗的19例患者中也观察到了类似的结果。在此方案中，60 mg剂量的丝裂霉素-C导致的血小板减少是剂量限制性的。血清学证据表明，针对小鼠单克隆抗体的免疫球蛋白M抗体的产生具有预测临床反应的特异性和敏感性。在丝裂霉素-C治疗的患者中，这些抗体的数量较少。对选定的患者进行了再次治疗。1例慢性淋巴细胞白血病患者接受了三次治疗，外周淋巴结消退。2例乳腺癌患者溃疡皮肤病变有明显改善，2例舌癌患者病变缩小。丝裂霉素-C偶联物未见反应，但观察到与肿瘤有结合。在较高剂量时出现了药物性结肠炎，这些偶联物与正常结肠上皮有一些结合。本研究证明了为难治性恶性肿瘤患者制备个体化指定药物免疫偶联物组合的可行性。完成了组合制剂和抗体在体内向肿瘤的递送。同一患者不同活检样本随时间推移的抗原漂移有限。主要技术障碍仍然是选择有效的药物偶联方法，以使药物最佳地与单克隆抗体结合用于靶向癌症治疗。
