抗体偶联药物的内吞和细胞内转运机理研究

Antibody-drug conjugate (ADC) is a hybrid molecule that connects a monoclonal antibody with cytotoxic agents through chemical bonds. As new format of cancer therapeutics, ADCs have achieved great success in clinical treatment due to the low side-effects and high potency. It is suggested that the ADC molecules must be internalized and transported to lysosome where the toxic payloads are released and thus kill the tumor cells. Internalization is a key step for ADCs to function. However, multiple mechanisms, including endocytosis, intracellular trafficking, release of conjugated drugs, are little explored. The objective of this proposal is to identify the signals of ADC endocytosis, the pathways of internalization through investigating on clathrin-mediated endocytosis, macropinocytosis and lipid-rafts involved process, the sorting signals from endosome to lysosome, and the degradation pathways involved in proteosome or lysosome which lead to the dissociation of the cytotoxic drugs. The mechanism study is significant for design of new ADCs and improving their clinical efficacy.

抗体偶联药物（antibody-drug conjugate, ADC）是单抗与细胞毒素的化学连接产物，是一类新颖的肿瘤靶向治疗药物。通过与细胞膜特定抗原结合，ADC被肿瘤细胞内吞，并经过胞内转运，最终释放出细胞毒素而将肿瘤细胞杀死。一般认为ADC的内化是决定其疗效的关键，但是决定ADC的内吞信号、内吞途径以及在细胞内的转运机理至今尚未搞清。本研究选择FDA已经批准的ADC产品和本实验室自制的ADC药物作为模式分子，首先研究ADC分子的内吞过程并确定ADC的内吞信号；阐明网格蛋白依赖的内吞、巨胞饮和脂筏介导途径在ADC内吞中的意义；研究ADC分子分选到内体和溶酶体的信号和转运机理，阐明ADC在胞内的降解和毒素释放途经，明确蛋白酶体和溶酶体途径在ADC降解中的作用。这些ADC内化过程的详细机理研究，可以指导新型ADC的设计，提高其临床治疗效果。

抗体偶联药物（ADC）是一类新型的抗体药物，ADC药物的内吞是其成功发挥疗效的关键，迄今ADC药物的内吞机理还未搞清。我们以两种经典的ADC产品（Adcetris和Kadcyla）出发，用分子与细胞生物学方法，研究了这些ADC分子的内吞过程。我们的研究发现脂筏（lipid rafts）介导的穴样内吞途径是ADC药物内吞的主要途径。ADC分子结合细胞膜上的受体分子，然后通过小窝蛋白（caveolin-1, CAV-1）穴样内陷（caveolae）进入内体，再转运至溶酶体，在溶酶体中抗体部分可以被降解，并释放出携带的毒素分子，最终导致肿瘤细胞的死亡。 调节脂筏形成、运输和促进其溶酶体降解的药物，可以影响ADC的疗效。这一ADC的内吞和胞内转运规律的详细机理研究，为设计高效ADC新药奠定了基础，并对单抗和ADC药物的临床正确应用提供指引。

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