Mesothelin (MSLN) is a lineage restricted cell surface protein expressed in about 30% of human cancers and high MSLN expression is associated with poor survival in several different cancers. The restricted expression of MSLN in normal tissue and its frequent expression in cancers make MSLN an excellent target for antibody-based therapies. Many clinical trials with agents targeting MSLN have been carried out but to date none of these agents have produced enough responses to obtain FDA approval. MSLN shedding is an important factor that may contribute to the failure of these therapies, because shed MSLN acts as a decoy receptor and allows release of antibodies bound to cell-surface MSLN. We have investigated the mechanism of shedding and show here that members of the ADAM, MMP and BACE families of proteases all participate in shedding, that more than one protease can produce shedding in the same cell, and that inhibition of shedding greatly enhances killing of cells by an immunotoxin targeting MSLN. Our data indicates that controlling MSLN shedding could greatly increase the activity of therapies that target MSLN.

间皮素（MSLN）是一种受谱系限制的细胞表面蛋白，在约30％的人类癌症中表达，MSLN的高表达与几种不同癌症中的不良存活率相关。MSLN在正常组织中的限制性表达及其在癌症中的频繁表达使MSLN成为基于抗体的疗法的极佳靶标。已经针对靶向MSLN的药物进行了许多临床试验，但是迄今为止，这些药物均未产生足够的反应以获得FDA批准。MSLN脱落是可能导致这些疗法失败的重要因素，因为脱落的MSLN充当诱饵受体并允许释放与细胞表面MSLN结合的抗体。我们已经研究了脱落的机理，并在这里表明ADAM，MMP和BACE蛋白酶家族的成员都参与了脱落，一个以上的蛋白酶可以在同一细胞中产生脱落，并且抑制脱落可以大大增强针对MSLN的免疫毒素对细胞的杀伤力。我们的数据表明，控制MSLN脱落可以大大提高针对MSLN的疗法的活性。