Pietersz G A, Cunningham Z, McKenzie I F
Department of Pathology, University of Melbourne, Parkville, Vic., Australia.
Immunol Cell Biol. 1988 Feb;66 ( Pt 1):43-9. doi: 10.1038/icb.1988.5.
Methotrexate (MTX) is a folic acid antagonist widely used in the treatment of cancer but, like other such agents, has non-specific toxic side effects. With the aim of reducing these toxic effects, MTX was coupled to monoclonal antibodies (MoAb) in one of two ways; either (a) directly using an active ester derivative or (b) via human serum albumin (HSA), to act as an intermediary and so increase the amount of MTX bound. The MTX coupled directly to anti-Ly-2.1 antibody had approximately 10 molecules of MTX per antibody molecule, whereas the HSA coupled material had 24 molecules of MTX per antibody molecule. After coupling MTX directly to antibody there was a loss of potency of the MTX, and MTX-MoAb conjugates were 30-fold less potent than free MTX, although the antibody-coupled material was more specific than free MTX and bound only to the antibody-reactive target cells. By contrast, the MTX-HSA-MoAb conjugates were 3.5 times less potent than free MTX and were 8.5 times more potent than MTX-MoAb conjugates. Thus, by increasing the amount of drug bound to antibody, more toxic conjugates were made--an important principle for the use of such conjugates for the treatment of cancer in man.
甲氨蝶呤（MTX）是一种广泛用于癌症治疗的叶酸拮抗剂，但与其他此类药物一样，具有非特异性毒性副作用。为了降低这些毒性作用，MTX通过以下两种方式之一与单克隆抗体（MoAb）偶联：（a）直接使用活性酯衍生物，或（b）通过人血清白蛋白（HSA）作为中间体，从而增加结合的MTX量。直接与抗Ly-2.1抗体偶联的MTX每个抗体分子约有10个MTX分子，而与HSA偶联的材料每个抗体分子有24个MTX分子。将MTX直接与抗体偶联后，MTX的效力有所损失，MTX-MoAb缀合物的效力比游离MTX低30倍，尽管抗体偶联材料比游离MTX更具特异性，且仅与抗体反应性靶细胞结合。相比之下，MTX-HSA-MoAb缀合物的效力比游离MTX低3.5倍，比MTX-MoAb缀合物高8.5倍。因此，通过增加与抗体结合的药物量，制备出了毒性更强的缀合物——这是此类缀合物用于人类癌症治疗的一个重要原则。
