Oldham R K, Lewis M, Orr D W, Avner B, Liao S K, Ogden J R, Avner B, Birch R
Williamson Medical Center, Biological Therapy Institute, Franklin, TN 37065-1676.
Mol Biother. 1988;1(2):103-13.
Twenty-three patients with disseminated refractory malignancies each received a tailored combination of adriamycin-conjugated murine monoclonal antibodies. Tumors were typed using a panel of antibodies. Cocktails of up to six antibodies were selected based on binding greater than 80% of the malignant cells as tested by immunoperoxidase and flow cytometry. These monoclonal antibodies were then conjugated to Adriamycin and administered intravenously. Seventeen of 23 patients had reactions to the administration of immunoconjugates, but these were tolerable in all but two patients. Fever, chills, pruritus, and skin rash were by far the most common transitory reactions. All were well controlled with premedication. In several patients there was limited antigenic drift among various biopsies within the same patient over time. This observation confirms the necessity for the use of a cocktail of antibodies if one wishes to cover all tumor cells. Preliminary serologic evidence suggests that the development of an IgM antibody, which is specific against the mouse monoclonal antibody, has the specificity and sensitivity to predict clinical reactions. Selected patients were re-treated. One patient with chronic lymphocytic leukemia had re-treatment on three occasions and demonstrated 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. In the course of the study free Adriamycin released from the monoclonal antibodies was discovered to be a limiting factor in the amount of antibody that could be administered. Up to 1 g of Adriamycin and up to 5 g of monoclonal antibody were administered. The limiting factor appeared to be a variable dissociation of active Adriamycin from the antibody that unpredictably caused hemopoietic depression. This study demonstrates the feasibility and reviews technical considerations in preparing immunoconjugate cocktails for patients with refractory malignancies. The major technical hurdle appears to be the selection of an effective conjugation method that can be used to optimally bind Adriamycin to monoclonal antibodies for targeted cancer therapy.
23例播散性难治性恶性肿瘤患者每人接受了阿霉素偶联鼠单克隆抗体的个体化联合治疗。使用一组抗体对肿瘤进行分型。根据免疫过氧化物酶和流式细胞术检测，选择结合率大于80%恶性细胞的多达六种抗体的组合。然后将这些单克隆抗体与阿霉素偶联并静脉给药。23例患者中有17例对免疫偶联物给药有反应，但除2例患者外，其他患者均可耐受。发热、寒战、瘙痒和皮疹是迄今为止最常见的短暂反应。所有反应通过预处理均得到良好控制。在一些患者中，同一患者不同活检组织随时间推移存在有限的抗原漂移。这一观察结果证实，如果希望覆盖所有肿瘤细胞，使用抗体组合的必要性。初步血清学证据表明，针对小鼠单克隆抗体的IgM抗体的产生具有预测临床反应的特异性和敏感性。选择的患者接受了再次治疗。1例慢性淋巴细胞白血病患者接受了三次再次治疗，外周淋巴结出现消退。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。在研究过程中，发现从单克隆抗体中释放的游离阿霉素是可给药抗体量的限制因素。阿霉素给药量高达1g，单克隆抗体给药量高达5g。限制因素似乎是活性阿霉素与抗体的可变解离，这不可预测地导致造血抑制。本研究证明了为难治性恶性肿瘤患者制备免疫偶联物组合的可行性，并回顾了技术方面的考虑因素。主要技术障碍似乎是选择一种有效的偶联方法，可用于将阿霉素最佳地结合到单克隆抗体上以进行靶向癌症治疗。
