Mechanisms of growth inhibition by anti-transferrin receptor monoclonal antibodies.
Mechanisms of growth inhibition by anti-transferrin receptor monoclonal antibodies.
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发表时间：
1986-04
期刊：
影响因子：
11.2
通讯作者：
R. Taetle;J. Castagnola;J. Mendelsohn
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文献类型：
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作者：
R. Taetle;J. Castagnola;J. Mendelsohn
在之前的研究中，免疫球蛋白A、抗转铁蛋白受体抗体(42/6)抑制多种正常和恶性人类造血细胞的生长。为了确定其生长抑制机制，我们比较了 42/6 和 B3/25（一种免疫球蛋白 G 抗转铁蛋白受体抗体，不抑制淋巴细胞生长）对转铁蛋白 (TF) 结合和摄取的影响。与之前的研究一样，TF 和抗 TF 受体抗体在 4℃ 下对人 TF 受体的亲和力常数相似，但计算出的抗体结合位点数量更高。抗体B3/25在4℃或37℃下均不抑制TF结合。在4℃下，抗体42/6抑制TF与正常的有丝分裂原刺激的单核细胞的结合。然而，TF 并不抑制 42/6 结合，表明 42/6 通过非竞争性（可能是空间位阻）机制抑制 TF 结合。当细胞在 37 摄氏度下同时暴露于标记的 TF 和未标记的抗 TF 受体抗体时，42/6 仅轻微抑制 TF 结合。在 37°C 下，抗体和 TF 的初始吸收很快，但当单核细胞或 HL60 细胞与 42/6 或 B3/25 一起培养 2 天时，TF 结合和免疫反应性 TF 受体位点减少。然而，与 B3/25 培养的细胞结合的 TF 继续进入细胞，而用 42/6 培养的细胞将不再吸收结合的 TF。使用可溶性铁代替 TF 培养的 HL60 细胞进行的研究表明，TF 结合位点和 TF 摄取的变化并非继发于生长抑制。我们得出的结论是，与抑制性 (42/6) 和非抑制性 (B3/25) 抗 TF 受体抗体一起孵育会导致 TF 结合位点减少。然而，接触 42/6 也会抑制 TF 吸收，并因缺铁而导致生长抑制。针对转运关键营养分子（例如铁）的受体的单克隆抗体可以通过阻止配体进入细胞内部来抑制细胞生长。
In previous studies, an immunoglobulin A, anti-transferrin receptor antibody (42/6) inhibited growth of a variety of normal and malignant human hemopoietic cells. To determine its mechanism of growth inhibition, we compared effects of 42/6 and B3/25, an immunoglobulin G anti-transferrin receptor antibody which does not inhibit lymphocyte growth, on transferrin (TF) binding and uptake. As in previous studies, affinity constants of TF and anti-TF receptor antibodies for human TF receptors at 4 degrees C were similar, but the number of calculated binding sites was higher for the antibodies. Antibody B3/25 did not inhibit TF binding at either 4 degrees C or 37 degrees C. At 4 degrees C, antibody 42/6 inhibited TF binding to normal, mitogen-stimulated mononuclear cells. However, TF did not inhibit 42/6 binding, suggesting 42/6 inhibited TF binding by noncompetitive, possibly steric, mechanisms. When cells were simultaneously exposed to labeled TF and unlabeled anti-TF receptor antibodies at 37 degrees C, 42/6 inhibited TF binding only slightly. Initial uptake of antibodies and TF at 37 degrees C was rapid, but when mononuclear cells or HL60 cells were cultured with either 42/6 or B3/25 for 2 days, TF binding and immunoreactive TF receptor sites decreased. However, TF bound to cells cultured with B3/25 continued to enter the cell, whereas cells cultured with 42/6 would no longer take up bound TF. Studies using HL60 cells grown with soluble iron in lieu of TF showed that changes in TF binding sites and TF uptake were not secondary to growth inhibition. We conclude that incubation with both inhibitory (42/6) and noninhibitory (B3/25) anti-TF receptor antibodies results in decreased TF binding sites. However, exposure to 42/6 also inhibits TF uptake and causes growth inhibition by iron deprivation. Monoclonal antibodies to receptors transporting critical nutrient molecules, such as iron, may inhibit cell growth by blocking ligand access to the cell's interior.