BicycleTx Limited, B900 Babraham Research Campus, Cambridge CB22 3AT, U.K.
Bicycle Therapeutics, Inc., 4 Hartwell Place, Lexington 02421-3122, Massachusetts, United States.
J Med Chem. 2022 Nov 10;65(21):14337-14347. doi: 10.1021/acs.jmedchem.2c00065. Epub 2022 Oct 6.
Bicycle toxin conjugates (BTCs) are a promising new class of molecules for targeted delivery of toxin payloads into tumors. Herein we describe the discovery of BT8009, a Nectin-4 targeting BTC currently under clinical evaluation. Nectin-4 is overexpressed in multiple tumor types and is a clinically validated target for selective delivery of cytotoxic payloads. A Nectin-4 targeting bicyclic peptide was identified by phage display, which showed highly selective binding for Nectin-4 but suffered from low plasma stability and poor physicochemical properties. Multiparameter chemical optimization involving introduction of non-natural amino acids resulted in a lead Bicycle that demonstrated high affinity for Nectin-4, good stability in biological matrices, and a much-improved physicochemical profile. The optimized Bicycle was conjugated to the cytotoxin Monomethyl auristatin E via a cleavable linker to give the targeted drug conjugate BT8009, which demonstrates potent anticancer activity in in vivo rodent models.
标题：用于肿瘤靶向递送毒素有效载荷的新型双环毒素偶联物
摘要：双环毒素偶联物（BTCs）是一类很有前途的新型分子，用于将毒素有效载荷靶向递送至肿瘤中。本文描述了一种新型的 Nectin-4 靶向 BTC（BT8009）的发现，目前正在进行临床评估。Nectin-4 在多种肿瘤类型中过表达，是一种经过临床验证的用于选择性递送细胞毒性有效载荷的靶标。通过噬菌体展示技术鉴定了一种 Nectin-4 靶向双环肽，该双环肽对 Nectin-4 表现出高度选择性结合，但存在血浆稳定性差和理化性质差的问题。通过涉及引入非天然氨基酸的多参数化学优化，得到了一种先导双环物，该双环物对 Nectin-4 具有高亲和力、在生物基质中稳定性良好，并且理化性质得到了很大改善。优化后的双环物通过可裂解接头与细胞毒素单甲基奥瑞他汀 E 偶联，得到了靶向药物偶联物 BT8009，该偶联物在体内啮齿动物模型中表现出很强的抗肿瘤活性。
