Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with cytotoxic payloads. However, the present strategies for the synthesis of ADCs either yield unstable or heterogeneous products or involve complex processes. Here, we report a computational approach that leverages molecular docking and molecular dynamics simulations to design ADCs that self-assemble through the non-covalent binding of the antibody to a payload that we designed to act as an affinity ligand for specific conserved amino acid residues in the antibody. This method does not require modifications to the antibody structure and yields homogenous ADCs that form in less than 8 min. We show that two conjugates, which consist of hydrophilic and hydrophobic payloads conjugated to two different antibodies, retain the structure and binding properties of the antibody and its biological specificity, are stable in plasma and improve anti-tumour efficacy in mice with non-small cell lung tumour xenografts. The relative simplicity of the approach may facilitate the production of ADCs for the targeted delivery of cytotoxic payloads.

中文翻译：

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计算设计的抗体-药物偶联物通过亲和配体自组装。

抗体-药物偶联物（ADC）将抗体的高特异性与细胞毒性有效载荷结合在一起。但是，目前用于ADC合成的策略要么产生不稳定的或异质的产物，要么涉及复杂的过程。在这里，我们报告了一种计算方法，该方法利用分子对接和分子动力学模拟来设计ADC，这些ADC通过抗体与有效载荷的非共价结合而自组装，我们设计该有效载荷充当特定保守氨基酸残基的亲和配体。抗体。该方法不需要修饰抗体结构，并且可以在不到8分钟的时间内形成均质的ADC。我们显示了两种偶联物，它们由与两种不同抗体偶联的亲水性和疏水性有效载荷组成，保留抗体的结构和结合特性及其生物学特异性，在血浆中稳定并提高非小细胞肺癌异种移植小鼠的抗肿瘤功效。该方法的相对简单性可以促进针对细胞毒性有效载荷的靶向递送的ADC的生产。